Ms. X., aged 55 years, has been complaining of severe fatigue and “indigestion.” Her son is quite concerned and decides to take her to the emergency department. On arrival she appears very anxious, and her facial skin is cool and clammy; her blood pressure is 90/60, and the pulse is around 90, weak, and irregular. She is given oxygen, an intravenous line is opened, and leads for ECG are attached. Blood is taken for determination of serum enzymes and electrolytes. Tentative diagnosis is myocardial infarction involving the left ventricle. Her son provides information that indicates Ms. X is a long-time smoker, has a stressful job as a high school teacher, is recently separated after 20 years of marriage, and is fearful of losing the family home. She has also seemed to be more fatigued and stopped going to the gym about 18 months ago. She has begun to rely on “fast foods” like pizza and fried chicken and cooks infrequently. Her father had died of a heart attack at age 50. She had also noticed more fatigue and intermittent leg pain when walking or climbing stairs at work. Generalized atherosclerosis is suspected.

1. List the high-risk factors for atherosclerosis in this patient’s history.
2. Describe how atherosclerosis causes myocardial infarction.
3. It is suspected that the indigestion reported in the history was really angina. Explain how this pain may have occurred.
4. Explain each of the admitting signs.
5. What is “atypical” in Ms. X’s symptoms? How does this affect treatment and prognosis?
6. What information do serum enzyme and electrolyte levels provide?
7. What purpose does the ECG serve? It is determined that Ms. X. has a large infarct in the anterior left ventricle.
8. Ms. X. is showing increasing PVCs on the ECG. State the cause and describe the effect if these continue to increase in frequency.
9. On day 6 after admission Ms. X is preparing to go home with her son and they receive instructions on lifestyle modifications that are desirable if Ms. X is to avoid another MI. What measures should be included in such a discussion?
10. Discuss how stress could have played a factor in Ms. X’s MI and her future post discharge.
11. Ms. X’s condition becomes less stable and she remains in the hospital. On the seventh day following admission, she is found unconscious on the floor of her bathroom. Her pulse is weak and elevated, and her skin is moist with pallor evident. Her BP is 50 systolic. A diagnosis of cardiogenic shock is made, and resuscitation efforts are started.
12. Explain why Ms. X. has experienced cardiogenic shock at this time.
13. Describe the effects of cardiogenic shock on the organs of the body.
14. What problems will occur if decompensated shock occurs? How is compensation limited in this situation?
15. Ms. X dies shortly later. What is the cause of death in this case?

Have you ever sent a text message that revealed your most intimate of thoughts and emotions?  Text messages are often raw, unvarnished, and immediate, not to mention can be taken completely out of context. However, we send them to those who are expected to guard them from publication.

The status of text messages in criminal investigations remains unsettled in the US. Is it reasonable for people to expect the contents of their electronic text messages to remain private, especially from law enforcement? Do we have a right to privacy for text message conversations? Even the United States Supreme Court has struggled with the legal challenges raised by emerging technology, most especially in the realm of cellular phones and their contents.

Situation 1

David Leon Riley was arrested on August 22, 2009, after a traffic stop resulted in the discovery of loaded firearms in his car. The officers took Riley's phone, and searched through his messages, contacts, videos, and photographs. Based in part on the data stored on Riley's phone, the officers charged him with an unrelated shooting that had taken place several weeks prior to his arrest.

Situation 2

Gregory Diaz, was arrested for the sale of the illicit drug ecstasy and his cell phone, containing incriminating evidence, was seized and searched without a warrant. In trial court proceedings, Diaz motioned to suppress the information obtained from his cell phone, which was denied   on the grounds that the search of his cell phone was incident to a lawful arrest.

Situation 3

At 6:08am, on October 4, 2009, Trisha Oliver frantically called 911 from her apartment in Cranston, Rhode Island when her six-year-old son, Marco Nieves, stopped breathing. The Fire Department took Marco to Hasbro Children's Hospital, where he was found to be in full cardiac arrest. He died 11 hours later.

By 6:20am, Sgt. Michael Kite of the Cranston Police Department had arrived at the apartment, where he found Oliver, her boyfriend Michael Patino, and their 14-month-old daughter, Jazlyn Oliver. Kite observed a couple of stripped beds  and linens on the floor, a trash can with vomit inside it, dark brown vomit in a toilet, and, crucially, a cell phone on the kitchen. Kite picked up the cell phone.

Kite viewed a text message on the phone, which was owned by Trisha Oliver, reading "Wat if I got 2 take him 2 da hospital wat do I say and dos marks on his neck omg." The message was sent from Oliver to Patino, although the sending of the message apparently failed. There were other messages on the phone "with profane language and references to punching Marco—three times—the hardest of which was in the stomach," according to court records. Patino was then arrested and charged with murder. He later confessed to the death of Marco Nieves.

Sgt. Kite claims he picked up the phone because it was "beeping," and that he thought it might help get in touch with the boy's birth father.

Patino's attorney argues to exclude the State‘s core evidence from being used at trial, which is the text messages. He wants any other evidence steaming from it such as all cell phones and their contents, all cell phone records, and critical portions of the Defendant‘s videotaped statement and his written statement given to the police suppressed as well. The attorney claims, the cell phone searches were "illegal as warrantless or in excess of the warrants obtained," and "As such, all of these searches and seizures, therefore, were unreasonable in violation of the Fourth Amendment,"

I realized the information I presented is limited...What do you think about the cases in general? Do you think that Riley or Diaz had an expectation of privacy? Do you think that Patino and Oliver had an expectation of privacy, since the phone was on the kitchen counter in their apartment? Would it make a difference if the phone was found outside in the grass? Do you think the police violated their fourth amendment rights? Should the police have secured a search warrant before looking in the phone in any of these situations? How should the judge handle these cases? Keep in mind that these ruling are used for the basis of future decisions by the courts. Should digital contents of a cell phone be categorized as a warrantless search? Do you think these situations are different from each other or should they all be handled the same?

Write a Python 3 program called “parse.py” using the template for a Python program that we covered in this module. Note: Use this mod7.txt input file.

Name your output file “output.txt”.

Build your program using a main function and at least one other function.

Give your input and output file names as command line arguments.

Your program will read the input file, and will output the following information to the output file as well as printing it to the screen:

1. Output the full text of the file
2. Output the number of words in the file
3. Output the number of sentences in the file
4. Output the first sentence in the file
5. Output the last sentence in the file
6. Output the length of the first sentence
7. Output the length of the last sentence

This is mod7.txt

I do not come here as an advocate, because whatever position the suffrage movement may occupy in the United States of America, in England it has passed beyond the realm of advocacy and it has entered into the sphere of practical politics. It has become the subject of revolution and civil war, and so tonight I am not here to advocate woman suffrage. American suffragists can do that very well for themselves. I am here as a soldier who has temporarily left the field of battle in order to explain - it seems strange it should have to be explained, what civil war is like when civil war is waged by women. I am not only here as a soldier temporarily absent from the field at battle; I am here, and that, I think, is the strangest part of my coming, I am here as a person who, according to the law courts of my country, it has been decided, is of no value to the community at all; and I am adjudged because of my life to be a dangerous person, under sentence of penal servitude in a convict prison. It is not at all difficult if revolutionaries come to you from Russia, if they come to you from China, or from any other part of the world, if they are men. But since I am a woman it is necessary to explain why women have adopted revolutionary methods in order to win the rights of citizenship. We women, in trying to make our case clear, always have to make as part of our argument, and urge upon men in our audience the fact, a very simple fact, that women are human beings. Suppose the men of Hartford had a grievance, and they laid that grievance before their legislature, and the legislature obstinately refused to listen to them, or to remove their grievance, what would be the proper and the constitutional and the practical way of getting their grievance removed? Well, it is perfectly obvious at the next general election the men of Hartford would turn out that legislature and elect a new one. But let the men of Hartford imagine that they were not in the position of being voters at all, that they were governed without their consent being obtained, that the legislature turned an absolutely deaf ear to their demands, what would the men of Hartford do then? They couldn't vote the legislature out. They would have to choose; they would have to make a choice of two evils: they would either have to submit indefinitely to an unjust state of affairs, or they would have to rise up and adopt some of the antiquated means by which men in the past got their grievances remedied. Your forefathers decided that they must have representation for taxation, many, many years ago. When they felt they couldn't wait any longer, when they laid all the arguments before an obstinate British government that they could think of, and when their arguments were absolutely disregarded, when every other means had failed, they began by the tea party at Boston, and they went on until they had won the independence of the United States of America. It is about eight years since the word militant was first used to describe what we were doing. It was not militant at all, except that it provoked militancy on the part of those who were opposed to it. When women asked questions in political meetings and failed to get answers, they were not doing anything militant. In Great Britain it is a custom, a time-honoured one, to ask questions of candidates for parliament and ask questions of members of the government. No man was ever put out of a public meeting for asking a question. The first people who were put out of a political meeting for asking questions, were women; they were brutally ill-used; they found themselves in jail before 24 hours had expired. We were called militant, and we were quite willing to accept the name. We were determined to press this question of the enfranchisement of women to the point where we were no longer to be ignored by the politicians. You have two babies very hungry and wanting to be fed. One baby is a patient baby, and waits indefinitely until its mother is ready to feed it. The other baby is an impatient baby and cries lustily, screams and kicks and makes everybody unpleasant until it is fed. Well, we know perfectly well which baby is attended to first. That is the whole history of politics. You have to make more noise than anybody else, you have to make yourself more obtrusive than anybody else, you have to fill all the papers more than anybody else, in fact you have to be there all the time and see that they do not snow you under. When you have warfare things happen; people suffer; the noncombatants suffer as well as the combatants. And so it happens in civil war. When your forefathers threw the tea into Boston Harbour, a good many women had to go without their tea. It has always seemed to me an extraordinary thing that you did not follow it up by throwing the whiskey overboard; you sacrificed the women; and there is a good deal of warfare for which men take a great deal of glorification which has involved more practical sacrifice on women than it has on any man. It always has been so. The grievances of those who have got power, the influence of those who have got power commands a great deal of attention; but the wrongs and the grievances of those people who have no power at all are apt to be absolutely ignored. That is the history of humanity right from the beginning. Well, in our civil war people have suffered, but you cannot make omelettes without breaking eggs; you cannot have civil war without damage to something. The great thing is to see that no more damage is done than is absolutely necessary, that you do just as much as will arouse enough feeling to bring about peace, to bring about an honourable peace for the combatants; and that is what we have been doing. We entirely prevented stockbrokers in London from telegraphing to stockbrokers in Glasgow and vice versa: for one whole day telegraphic communication was entirely stopped. I am not going to tell you how it was done. I am not going to tell you how the women got to the mains and cut the wires; but it was done. It was done, and it was proved to the authorities that weak women, suffrage women, as we are supposed to be, had enough ingenuity to create a situation of that kind. Now, I ask you, if women can do that, is there any limit to what we can do except the limit we put upon ourselves? If you are dealing with an industrial revolution, if you get the men and women of one class rising up against the men and women of another class, you can locate the difficulty; if there is a great industrial strike, you know exactly where the violence is and how the warfare is going to be waged; but in our war against the government you can't locate it. We wear no mark; we belong to every class; we permeate every class of the community from the highest to the lowest; and so you see in the woman's civil war the dear men of my country are discovering it is absolutely impossible to deal with it: you cannot locate it, and you cannot stop it. "Put them in prison," they said, "that will stop it." But it didn't stop it at all: instead of the women giving it up, more women did it, and more and more and more women did it until there were 300 women at a time, who had not broken a single law, only "made a nuisance of themselves" as the politicians say. Then they began to legislate. The British government has passed more stringent laws to deal with this agitation than it ever found necessary during all the history of political agitation in my country. They were able to deal with the revolutionaries of the Chartists' time; they were able to deal with the trades union agitation; they were able to deal with the revolutionaries later on when the Reform Acts were passed: but the ordinary law has not sufficed to curb insurgent women. They had to dip back into the middle ages to find a means of repressing the women in revolt. They have said to us, government rests upon force, the women haven't force, so they must submit. Well, we are showing them that government does not rest upon force at all: it rests upon consent. As long as women consent to be unjustly governed, they can be, but directly women say: "We withhold our consent, we will not be governed any longer so long as that government is unjust." Not by the forces of civil war can you govern the very weakest woman. You can kill that woman, but she escapes you then; you cannot govern her. No power on earth can govern a human being, however feeble, who withholds his or her consent. When they put us in prison at first, simply for taking petitions, we submitted; we allowed them to dress us in prison clothes; we allowed them to put us in solitary confinement; we allowed them to put us amongst the most degraded of criminals; we learned of some of the appalling evils of our so-called civilisation that we could not have learned in any other way. It was valuable experience, and we were glad to get it. I have seen men smile when they heard the words "hunger strike", and yet I think there are very few men today who would be prepared to adopt a "hunger strike" for any cause. It is only people who feel an intolerable sense of oppression who would adopt a means of that kind. It means you refuse food until you are at death's door, and then the authorities have to choose between letting you die, and letting you go; and then they let the women go. Now, that went on so long that the government felt that they were unable to cope. It was [then] that, to the shame of the British government, they set the example to authorities all over the world of feeding sane, resisting human beings by force. There may be doctors in this meeting: if so, they know it is one thing to feed by force an insane person; but it is quite another thing to feed a sane, resisting human being who resists with every nerve and with every fibre of her body the indignity and the outrage of forcible feeding. Now, that was done in England, and the government thought they had crushed us. But they found that it did not quell the agitation, that more and more women came in and even passed that terrible ordeal, and they were obliged to let them go. Then came the legislation - the "Cat and Mouse Act". The home secretary said: "Give me the power to let these women go when they are at death's door, and leave them at liberty under license until they have recovered their health again and then bring them back." It was passed to repress the agitation, to make the women yield - because that is what it has really come to, ladies and gentlemen. It has come to a battle between the women and the government as to who shall yield first, whether they will yield and give us the vote, or whether we will give up our agitation. Well, they little know what women are. Women are very slow to rouse, but once they are aroused, once they are determined, nothing on earth and nothing in heaven will make women give way; it is impossible. And so this "Cat and Mouse Act" which is being used against women today has failed. There are women lying at death's door, recovering enough strength to undergo operations who have not given in and won't give in, and who will be prepared, as soon as they get up from their sick beds, to go on as before. There are women who are being carried from their sick beds on stretchers into meetings. They are too weak to speak, but they go amongst their fellow workers just to show that their spirits are unquenched, and that their spirit is alive, and they mean to go on as long as life lasts. Now, I want to say to you who think women cannot succeed, we have brought the government of England to this position, that it has to face this alternative: either women are to be killed or women are to have the vote. I ask American men in this meeting, what would you say if in your state you were faced with that alternative, that you must either kill them or give them their citizenship? Well, there is only one answer to that alternative, there is only one way out - you must give those women the vote. You won your freedom in America when you had the revolution, by bloodshed, by sacrificing human life. You won the civil war by the sacrifice of human life when you decided to emancipate the negro. You have left it to women in your land, the men of all civilised countries have left it to women, to work out their own salvation. That is the way in which we women of England are doing. Human life for us is sacred, but we say if any life is to be sacrificed it shall be ours; we won't do it ourselves, but we will put the enemy in the position where they will have to choose between giving us freedom or giving us death. So here am I. I come in the intervals of prison appearance. I come after having been four times imprisoned under the "Cat and Mouse Act", probably going back to be rearrested as soon as I set my foot on British soil. I come to ask you to help to win this fight. If we win it, this hardest of all fights, then, to be sure, in the future it is going to be made easier for women all over the world to win their fight when their time comes.

Question: From the Article Below, write a review of the current status of development of antibiotics." I do not have the figures!"

Article: Antibiotic discovery in the twenty-first century: current trends and future perspectives

New antibiotics are necessary to treat microbial pathogens that are becoming increasingly resistant to available treatment.

Despite the medical need, the number of newly approved drugs continues to decline. We offer an overview of the pipeline for

new antibiotics at different stages, from compounds in clinical development to newly discovered chemical classes. Consistent

with historical data, the majority of antibiotics under clinical development are natural products or derivatives thereof. However,

many of them also represent improved variants of marketed compounds, with the consequent risk of being only partially

effective against the prevailing resistance mechanisms. In the discovery arena, instead, compounds with promising activities

have been obtained from microbial sources and from chemical modification of antibiotic classes other than those in clinical use.

Furthermore, new natural product scaffolds have also been discovered by ingenious screening programs. After providing selected

examples, we offer our view on the future of antibiotic discovery.

The Journal of Antibiotics advance online publication, 16 June 2010; doi:10.1038/ja.2010.62

Keywords: antibiotics; natural products; pipeline

Medical progress in the prevention and treatment of many diseases,

which have resulted in significantly increasing life expectancy, may be

put at risk without the introduction into clinical practice of new

antibiotics effective against multidrug-resistant (MDR) pathogens.

Although most stakeholders agree that new antibiotics could tackle

this unmet medical need, opinions vary on how new antibiotics could

be discovered and brought into the market in a cost-effective manner.

1–3 Two considerations would probably meet with unanimous

consensus: the golden era of antibiotic discovery is gone and it will not

be repeated; and genomics, combinatorial chemistry and highthroughput

screening do not represent the magic bullet to fill the

pipeline with new developmental drug candidates. In this respect, it is

important to underline the contribution that natural products,

especially those of microbial origin, can provide to antibiotic discovery,

as advocated by Demain4,5 on several occasions. The decreasing

number of drugs approved for clinical use, year after year, suggests

that the ‘ailing pharmaceutical industry’ is not yet following the

‘prescription’ of Demain,6 as spelled out in 2002.

The purpose of this review is to highlight some of today’s features of

antibiotic discovery in the context of the current medical needs and

the existing pipeline of antibacterial agents in clinical development.

Our main focus will be on chemical classes that, if developed into

drugs, would be new to the clinic. However, these classes would not

necessarily be new to science. For example, a ‘look-back’ strategy was

applied to antibiotics discovered during the golden era, which were

then reexamined using contemporary tools in the light of current

medical needs.7 Although some important breakthroughs have also

been made in identifying new promising drug candidates from

synthetic origin, for reason of space, and in the spirit of the important

contributions to the field by Demain, we would limit ourselves

to antibiotics of microbial origin and their derivatives reported

since 2005.

CURRENT ANTIBIOTIC PIPELINE

Infections due to methicillin-resistant Staphylococcus aureus (MRSA),

vancomycin-resistant Enterococcus faecium (VRE) and fluoroquinolone-

resistant Pseudomonas aeruginosa are rapidly increasing in US

hospitals, and even more frightening is the recent occurrence of

panantibiotic-resistant infections, involving Acinetobacter species,

MDR P. aeruginosa and carbapenem-resistant Klebsiella species.8,9

Although antibiotic resistance continues to grow in hospitals and in

the community, involving both Gram-positive and Gram-negative

pathogens, the number of newly approved agents has been decreasing,

with only six new antibiotics approved since 2003.

In the late 90s, following the global concern regarding the rapid

increase in MRSA, many companies redirected their attention to target

Gram-positive pathogens, particularly MRSA, VRE and penicillinresistant

Streptococcus pneumoniae, as evidenced by the commercial

and clinical success of linezolid and daptomycin, the only antibiotics

belonging to new classes introduced in clinical practice since the early

1960s. However, most antibiotics currently under development for

Gram-positive infections are improved derivatives of existing drugs

(see Table 1). As vancomycin has been increasingly used for the

treatment of a wide range of infections, second-generation glycopep-

tides with improved profile over vancomycin were developed. Among

them, telavancin, a once-a-day derivative of vancomycin, was

approved by the US Food and Drug Administration (FDA) in 2009.

Oritavancin, derived from the vancomycin-related glycopeptide chloroeremomycin,

is highly active against VRE strains and shows a long

plasma half-life. However, in 2008, the FDA did not authorize its

commercialization. The long-acting glycopeptide dalbavancin, a derivative

of the teicoplanin-related glycopeptide A40926, was also not

approved by FDA, because of insufficient clinical evidence of efficacy.

If approved, dalbavancin would be the first antibiotic to be administered

once weekly.10

Resistance to methicillin in S. aureus is mediated by the production

of a penicillin-binding protein with reduced affinity for b-lactams. The

most recent cephalosporins, ceftobiprole and ceftaroline (Table 1),

have been specifically designed to enhance activity against MRSA and,

thanks to their oral availability, are particularly attractive for the

community setting. Ceftobiprole is quickly bactericidal against a wide

range of Gram-positive pathogens, including MRSA and VRE and has

been approved in Canada and Switzerland.11 However, early in 2010,

the FDA did not grant market authorization to ceftobiprole, and later

the European authority issued a negative opinion on this compound.

Ceftaroline, which is active against most Gram-positive pathogens

with the exclusion of enterococci, has completed phase III studies and

may be submitted for FDA approval.12 Both cephalosporins, however,

lose potency against MRSA compared with methicillin-susceptible

S. aureus strains. The injectable carbapenem PZ-601 has shown potent

activity against drug-resistant Gram-positive pathogens, including

MRSA, and is currently undergoing phase II studies.13

After the success of linezolid, many new oxazolidinones are being

developed for Gram-positive infections. Radezolid14 and torezolid15

are currently in phase II trials, whereas RWJ-416457 has completed the

phase I trial. Despite the fact that the use of fluoroquinolones has been

associated with increased incidence of MRSA,16 several new members

of this class are under development: delafloxacin, nemonoxacin,

zabofloxacin and WCK-771 (Table 1) are the most advanced.

The extensive use of fluoroquinolones and other wide-spectrum

antibiotics such as cephalosporins, by affecting the normal gut flora,

has led to the rapid diffusion of Clostridium difficile-associated

diarrhea, particularly in elderly and immunocompromised patients.

Difimicin, currently in phase III, and ramoplanin, with phase II

completed, are microbial products under development for prevention

and treatment of C. difficile-associated diarrhea, acting locally by

decolonizing the gut (Table 1).

Other compounds which have completed phase I clinical trials

include the oral and injectable pleuromutilin BC-3205,17 the FabI

inhibitor AFN-1252 targeting staphylococcal infections18 and the

lipopeptide friulimicin (Table 1).19

The scenario is even more disappointing for compounds targeting

Gram-negative pathogens, in which old drugs have been revamped for

new uses, and none of them has reached phase III yet (Table 1).

Ceftazidime is a marketed cephalosporin being developed in combination

with NXL104, a representative of a new class of b-lactamase

inhibitors,20 which renders cephalosporin effective against most

b-lactamase-producing enterobacteria. If approved, this combination

would be the first alternative to piperacillin/tazobactam. NXL104 is

also under investigation in combination with ceftaroline.21 CXA-101 is

a ceftazidime-like compound with improved stability against the

AmpC b-lactamase, but it shows no improvements against MDR

P. aeruginosa,22 unless administered in combination with tazobactam.

The new aminoglycoside ACHN-490, effective against pathogens

resistant to this class, has recently completed phase I.23 The new

monobactam BAL-30072, stable against metalloenzymes, is ready to

start clinical development against difficult-to-treat Gram negatives,

including Pseudomonas and Acinetobacter.24

The increasing spread of MDR Gram-negative pathogens, particularly

P. aeruginosa, Acinetobacter spp. and some Enterobacteriaceae has

renewed the interest toward narrow-spectrum compounds, to avoid

other clinical conditions associated with the use of broad-spectrum

antibiotics. However, because of a long history of success in the

empirical treatment of infections, many hospitals lack rapid and

effective tools for identifying etiological agents. This limitation poses

significant hurdles for the clinical development of narrow-spectrum

compounds.

APPROACHES LEADING TO NEW ANTIBIOTIC CLASSES

It is generally agreed that the best way to overcome the decreasing

efficacy of existing antibacterial agents is to introduce into practice

compounds belonging to classes that are new to the clinic. Microbial

sources can provide a rich reservoir of such compounds, and the

different approaches used usually aim at discovering either a novel

class or an improved variant of a poorly explored class. However,

this must be carried out in a high background of many known

compounds, some of which are encountered in random screening

programs at a relatively high frequency. Thus, the discovery of an

antibacterial agent belonging to a new chemical class or an improved

variant of an existing class is a rare event, and the approaches

described below reflect strategies designed and implemented to

capture this rare event. Appropriate strategies include retrieving

microbial strains from underexplored environments, screening new

microbial taxa, mining microbial genomes and using innovative

assays. These strategies have led to some novel chemical classes, as

illustrated in Figure 1.

As an example of the first strategy, investigation of deep-sea

sediment samples led to the discovery of abyssomicins (Figure 1),

which are polycyclic antibiotics from the new marine actinomycete

taxon Verrucosispora.25 The compounds were discovered using a simple

agar diffusion assay, which involved pursuing antibiotics the action of

which could be reverted upon addition of p-aminobenzoic acid.

Abyssomicins represent a new chemical class, and preliminary studies

indicate that they act as substrate mimics of chorismate. Interestingly,

only abyssomicin C and its atrop stereoisomer show antibiotic activity

against Gram-positive bacteria, including MDR S. aureus.26

An additional example of a new chemical class discovered by

screening new taxa is represented by thuggacins (Figure 1), which

are thiazole-containing macrolides produced by the myxobacteria

Sorangium cellulosum and Chondromyces crocatus.27 These compounds

show activity against Mycobacterium tuberculosis and their target

appears to be the electron transport chain.

Another successful approach has been exploring microbial genomes

for the presence of secondary metabolite pathways. As the corresponding

genes are organized in clusters and bioinformatic tools allow

a reasonable prediction of the pathway product, this bioactivityindependent

approach can directly target structural novelty. On a

pioneering work of this type, scientists at Ecopia Biosciences (now

Thallion Pharmaceuticals, Montreal, QC, Canada) identified ECO-

02301, a linear polyene from Streptomyces aizunensis with antifungal

activity28 and ECO-0501, a glycosidic polyketide from Amycolatopsis

orientalis with activity against Gram-positive pathogens, including

MDR isolates (Figure 1).29 In a similar approach, a novel cyclic

lipopeptide, designated orfamide (Figure 1), was identified from the

Pseudomonas fluorescens genome.30 In this case, the bioinformatic

prediction that the peptide contained four leucine residues suggested

feeding with 15N-Leu, which facilitated compound purification and

characterization. Orfamide shows a moderate antifungal activity

against amphotericin-resistant strains of Candida albicans and may

prove beneficial in agriculture and crop protection.

Another important strategy for discovering new classes of antibiotics

has been the implementation of increased-sensitivity assays in

screening programs. One such approach relied on the antisense

technology. When the level of a desired bacterial target is depleted

by overexpression of the cognate antisense mRNA, the strain becomes

hypersensitive to compounds acting on that target. By using a target

against which few compounds are known to act, the increased

sensitivity of the assay should allow the identification of compounds

routinely missed with growth inhibition assays on the wild-type

strain.31 One assay involved the FabH/FabF enzyme, required for

fatty acid biosynthesis in bacteria. Antimicrobial activities were

detected by agar diffusion in a two-plate assay, in which one plate

was inoculated with S. aureus carrying the antisense construct and the

other plate with an S. aureus control. Different inhibition halos in the

two plates indicated an increased sensitivity of the ‘antisense strain.’

After screening 4250 000 microbial product extracts, the assay led to

the identification of a new chemical class that includes platensimycin

(Figure 1), produced by Streptomyces platensis, and related compounds.

Platensimycin shows antibacterial activity against Grampositive

pathogens, including MDR strains, and was also effective in

an experimental model of infection.32

In another increased-sensitivity assay, a high-throughput screening

program was implemented to identify inhibitors of a cell-free translational

system affecting steps other than elongation. The assay made

use of a model ‘universal’ mRNA that could be translated with similar

efficiency by cell-free extracts from bacterial, yeast or mammalian cells.

The rationale behind the approach was to use a sensitive assay and to

discard frequently encountered compounds using a polyU-based assay.

This program led to the identification of GE81112 (Figure 1), a novel

tetrapeptide produced by a Streptomyces sp., which targets specifically

the 30S ribosomal subunit by interfering with fMet-tRNA binding to

the P-site.33 The compound was highly effective against a few Grampositive

and Gram-negative strains, if grown in minimal or chemically

defined medium, suggesting active uptake by the cells.34

The above examples illustrate how different approaches can lead to

novel antibiotic classes. Usually, when unexploited microbial diversity

is accessed, there is no need for specific, high-sensitivity assays.

Whichever the approach chosen, there is no guarantee of success.

The reader is referred to a recent review for suggestions on how to

increase the probabilities of success.35

IMPROVED VARIANTS FROM MICROBIAL SOURCES

New variants of known classes can be found by screening microbial

strains, by varying cultivation procedures or by manipulating the

biosynthetic pathway. There is an increasing amount of literature

related to pathway manipulation and this trend is likely to continue as

methodological advancements result in increased success rates. In

some cases, the desired variant might not be a more active compound,

but a molecule carrying functional groups suitable for further chemical

modifications. As the antibiotics in clinical use belong to a few

classes, which have been extensively explored by screening and

chemical modification, there is probably little space for finding

improved variants within those classes. We provide selected examples

of microbial strains producing improved variants of chemical classes

not yet in clinical use.

Lantibiotics, which are ribosomally synthesized peptides that

undergo posttranslational modifications to yield the active structures

containing the typical thioether-linked (methyl)lanthionines, are produced

mostly from strains belonging to the Firmicutes and, to a lesser

extent, to the Actinobacteria. Their antimicrobial activity is limited to

Gram-positive bacteria. The prototype molecule is nisin, discovered in

the 1920s and used as a food preservative for440 years.36 Lantibiotics

with antibacterial activity are divided into two classes according to

their biogenesis: lanthionine formation in class I compounds requires

two separate enzymes, a dehydratase and a cyclase, whereas a single

enzyme carries both activities for class II lantibiotics. Until recently,

the occurrence of class I compounds was limited to the Firmicutes (see

below). Although compounds from both classes exert their antimicrobial

activity by binding to Lipid II, they do so by binding to

different portions of this key peptidoglycan intermediate.

As lantibiotics bind Lipid II at a site different from that affected by

vancomycin and related glycopeptides, they are active against MDR

Gram-positive pathogens and have attracted attention as potential

drug candidates. The compound NVB302, a derivative of deoxyactagardine

B (Figure 2a) produced by a strain of Actinoplanes liguriae, is

currently a developmental candidate for the treatment of C. difficileassociated

diarrhea.37 Independently, a screening program, designed to

detect cell-wall-inhibiting compounds turned out to be very effective

in identifying lantibiotics from actinomycetes.38 It consisted of identifying

extracts active against S. aureus but inactive against isogenic

L-forms, discarding extracts the activity of which was abolished by

b-lactamases or by excess N-caproyl-D-alanyl-D-alanine. Among the

new lantibiotics identified, the most active compound was NAI-107

(Figure 2a), produced by Microbispora sp.39 This compound represents

the first example of a class I lantibiotic produced by actinomycetes. It

is currently a developmental candidate for the treatment of nosocomial

infections by Gram-positive pathogens.40 The same screening

program led to the identification of additional class I lantibiotics from

actinomycetes. Among them, the compound 97518 (Figure 2a),

structurally related to NAI-107,41 afforded improved derivatives by

chemical modification.42 Another interesting advancement in the

lantibiotic field has been the discovery of two-component lantibiotics

produced by members of the class Bacilli. The best characterized

compound is haloduracin43,44 (Figure 2a), whereas lichenicidin has

been proposed from genomic studies but has not yet confirmed by

structural elucidation.45 Although their antimicrobial activities have

not been described in detail, recent work suggests similar activities for

haloduracin and nisin.44

Thiazolylpeptides are highly modified, ribosomally synthesized

peptides that inhibit bacterial protein synthesis by affecting either

one of two targets: elongation factor Tu, as for GE2270 and related

compounds; or the loops defined by 23S rRNA and the L11 protein,

exemplified by thiostrepton. Most thiazolylpeptides show potent

activity against Gram-positive pathogens, yet their poor solubility

has limited clinical progress, and only a derivative of GE2270 has

entered clinical trials for the topical treatment of acne.46 Novel

members of this class have been described (Figure 2b): thiomuracins47

belong to the subgroup targeting EF-Tu, with an antibacterial profile

similar to GE2270; thiazomycin48 and philipimycin,49 which target the

50S subunit, show high activity against Gram-positive strains, and a

similar profile to thiostrepton.

For ribosomally synthesized peptides, such as lantibiotics and

thiopeptides, new representatives can be generated by site-directed

mutagenesis of the corresponding structural genes. Libraries of new

molecules have been obtained, many of which, as in the examples of

actagardine50 and thiocillin,51 retained antibiotic activities comparable

with those of the parent molecule.

CHEMICAL DERIVATIVES

Many papers have been published in the past 5 years reporting

chemical programs aimed at overcoming the prevailing resistance

mechanisms and/or to improve the drug profile of known microbial

products. Novel approaches included the use of new tools, such as

click chemistry and total synthesis. For the classical approach of semisynthesis,

we will limit the examples to selected compounds not yet in

clinical use.

Click chemistry is a new synthetic approach that can accelerate drug

discovery by using a few practical and reliable reactions. A ‘click’

reaction must be of wide scope, giving consistently high yields with

various starting materials; it must be easy to perform, insensitive to

oxygen or water and use only readily available reagents; finally,

reaction work-up and product isolation must be simple, without

chromatographic purification.52 As an example, this approach was

used to produce new lipophilic teicoplanin and ristocetin aglycons

with improved activity against Gram-positive bacteria, including

VRE.53 For aminoglycosides, which usually require multiple protection–

deprotection steps to selectively manipulate the desired amino

and hydroxyl groups, click chemistry allowed the transformation

of neomycin B into several novel building blocks that were used for

the specific modification of the ring systems, thus generating new

neomycin analogs the biological activity of which is currently under

investigation.54

For some low-molecular-weight compounds, total synthesis has

become available and will be useful to design preliminary SAR for new

classes of antibiotics (such as platensimycin) or to access new

derivatives for already known classes (such as tetracyclines). Indeed,

the novel scaffold and intriguing biological property of platensimycin

captured the interest of several research groups, which reported

different elegant total syntheses.55 In addition, medicinal chemistry

studies have been conducted, and the design, synthesis and biological

evaluation of several platensimycin analogs incorporating varying

degrees of molecular complexity have been reported.56–58 Preliminary

data indicate that certain modifications of the intricate cage region can

be made without detrimental effects on potency, whereas even small

modifications of the benzoic acid region result in a drastic loss of

activity (Figure 1). Another remarkable chemical improvement in the

synthesis of natural product analogs was a short and enantioselective

synthetic route to a diverse range of 6-deoxytetracycline antibiotics

(Figure 3a). This new approach targeted not a single compound but a

group of structures with the D ring as a site of structural variability.

A late-stage, diastereoselective C-ring construction was used to couple

structurally varied D-ring precursors with an AB precursor containing

much of the essential functionality for binding to the bacterial

ribosome. Results of antibacterial assays and preliminary data

obtained from a murine septicemia model show that many of the

novel tetracyclines synthesized have potent antibiotic activities. This

synthetic platform gives access to a broad range of tetracyclines that

would be inaccessible by semi-synthesis and provides a powerful

engine for the discovery of new tetracyclines.59,60

Even on larger molecules, semi-synthetic and synthetic chemistry

has been successfully applied to study and optimize lead compounds.

The lipoglycodepsipeptide ramoplanin (Figure 3b) is 2–10 times more

active than vancomycin against Gram-positive bacteria and maintains

full activity against VRE and all MRSA strains. However, its systemic

use has been prevented by its low tolerability at the injection site,

apparently related to the length of the fatty acid side chain.

To overcome this problem, the fatty acid side chain was selectively

removed and replaced with different carboxylic acids. Many derivatives

showed an antimicrobial activity similar to that of the precursor,

and a significantly improved local tolerability.61 The recently

described, fully synthetic lactam analog of ramoplanin showed the

same biological activity as the natural product. Moreover, a set of

alanine analogs, obtained by total synthesis, has provided insights into

the importance of individual amino-acid residues on ramoplanin

activity. The MICs of each alanine-containing analog parallels its

ability to bind Lipid II. Apart from positions 5, 6 and 9, which can

tolerate alanine substitutions, MICs increased 415-fold upon alanine

replacement, with dramatic effects observed for positions 4, 8, 10 and

12. The new data thus confirm the importance of the ornithine

residues at positions 4 and 10, with the latter directly involved in

target binding, most likely by ion pairing with the diphosphate of

Lipid II.62,63

The mannopeptimycins, which were originally isolated in the late

1950s from Streptomyces hygroscopicus, have been recently revived

because of their promising activity against clinically important Grampositive

pathogens, including S. pneumoniae, MRSA and VRE. They

also bind to Lipid II, but in a manner different from ramoplanin,

mersacidin and vancomycin. Multiple approaches have been used to

optimize the mannopeptimycin activity profile, including selective

chemical derivatization, precursor-directed biosynthesis and pathway

engineering. The SAR data have shown that substitution of a hydrophobic

ester group on the N-linked mannose or serine moieties

suppressed antibacterial activity, whereas hydrophobic acylation on

either of the two O-mannoses, particularly the terminal mannose,

significantly enhanced activity. AC98-6446 (Figure 3b) represents an

optimized lead obtained by adamantyl ketalization of a cyclohexyl

analog prepared by cyclohexylalanine-directed biosynthesis. AC98-

6446 showed superior antimicrobial potency and properties, both

in vitro and in vivo.7,64

Laspartomycin is active against VRE and MRSA strains. Recently,

enzymatic cleavage of its lipophilic moiety allowed the synthesis of

various acylated derivatives (Figure 3b), even if none was more potent

than the parent antibiotic.65 The cyclic heptapeptide GE23077 is a

potent and selective inhibitor of bacterial RNA polymerase

that, probably because of its hydrophilicity, is unable to cross

bacterial membranes. New derivatives obtained by modifying different

moieties were reported. Although many of them retained activity

on the enzyme, none showed a significant antibacterial activity

apart from marginal inhibition of Moraxella catarrhalis growth

(Figure 3b).66

FUTURE PERSPECTIVES

This brief and nonexhaustive excursus on the present and future

pipeline of antibacterial agents for treating human diseases provides

opportunities for additional considerations. The first is that, of the

antibiotics under clinical development (Table 1), 67% are natural

products themselves, or natural product-derived compounds, a percentage

perfectly in line with that found with exisiting drugs.67

The second consideration is that the major players in antibacterial

development are small companies, which are not deterred by the small

market size for these drugs. However, it should be noted that a

significant number of the compounds listed in Table 1 were not

discovered by small companies, but actually represent projects abandoned

by large pharmaceuticals companies. Thus, it remains to be

seen whether small biotechs will dedicate sufficient resources and be

successful in discovering and developing novel antibacterial agents.

In this relatively grim scenario, microbial products continue to

provide new chemical classes or unexpectedly active variants of

chemical classes already known to science. New technologies can

now provide access to unexplored microbial diversity or to hypersensitive

assays to detect bioactive compounds. Furthermore, the information

derived from rapidly accessing the genome of many microbial

strains can provide new routes to natural product discovery, as well as

making more effective traditional, bioassay-based screening efforts.

In our opinion, no single technology will represent the magic bullet

for antibiotic discovery, but only the painstaking integration of a

multidiscplinary team with profound knowledge of microbiology,

chemistry and bioinformatics will ultimately lead to new antibacterial

agents of medical relevance and commercial success.

EXCEL FILE:

ID   labor   capital   output  
1   161   186   22808  
2   230   440   68492  
3   482   552   93173  
4   167   367   48392  
5   484   356   96154  
6   457   488   115872  
7   260   345   62347  
8   144   413   92449  
9   453   167   81814  
10   171   385   34737  
11   333   446   100980  
12   433   397   68220  
13   134   282   46412  
14   446   495   177014  
15   341   471   162274  
16   361   170   63177  
17   244   347   97495  
18   114   473   23889  
19   425   240   46083  
20   386   414   135926  
21   339   262   177840  
22   296   492   70235  
23   515   242   68256  
24   388   178   45140  
25   112   298   23231  
26   110   299   30685  
27   248   571   89655  
28   391   298   120213  
29   518   510   58543  
30   342   328   52362  
31   325   390   110437  
32   246   416   87904  
33   94   318   45364  
34   79   444   32203  
35   267   110   17871  
36   449   446   126027  
37   289   405   103114  
38   323   383   75941  
39   320   239   67650  
40   191   500   56794  
41   215   275   21314  
42   317   399   95994  
43   510   396   106012  
44   365   222   55234  
45   464   325   158961  
46   136   454   58819  
47   54   446   34480  
48   38   536   25786  
49   437   283   58534  
50   474   271   84758  
51   442   445   90695  
52   324   209   106071  
53   93   451   47288  
54   191   275   22402  
55   233   292   60231  
56   354   365   83070  
57   468   414   81712  
58   323   399   147514  
59   481   314   57580  
60   108   285   18021  
61   300   332   56500  
62   233   355   121812  
63   97   435   24275  
64   255   406   99659  
65   312   326   90840  
66   469   406   94408  
67   85   290   25020  
68   82   472   26000  
69   123   486   19131  
70   372   251   71159  
71   144   201   19419  
72   282   404   60460  
73   451   174   41478  
74   386   426   88251  
75   265   208   44219  
76   381   409   92240  
77   161   268   49087  
78   63   293   15873  
79   184   187   15424  
80   253   400   87290  
81   440   278   87504  
82   374   334   83354  
83   128   293   25694  
84   272   205   59109  
85   237   449   72875  
86   501   431   86604  
87   264   278   62480  
88   128   322   39636  
89   104   326   14311  
90   224   153   24681  
91   50   520   9444  
92   203   244   28348  
93   215   505   40185  
94   39   270   14495  
95   262   594   119577  
96   28   398   62506  
97   97   431   12520  
98   315   194   34005  
99   484   263   132414  
100   87   277   30639  

QUESTIONS:

1. Create the relevant variables for the estimation of a Cobb-Douglass Production function:

lnQ = ln(Output)

lnL = ln(Employment)

lnK = ln(Capital)

2. Construct the sample mean, sample standard deviation, median for Output, Employment, and Capital. WRITE DOWN THESE STATISTICS

3. Run a linear regression of ln(Output) (dependent variable) on ln(Employment) and ln(Capital) as independent variables. For this part of the analysis you have to:

A. Is this coefficient significant? YES or NO, EXPLAIN

B. What effect does Employment have on Output? EXPLAIN

C. What coefficient indicates the effect of Capital on Output? WRITE THE VALUE HERE

D. Is this coefficient significant? YES or NO, EXPLAIN

E. What effect does Capital have on Output? EXPLAIN

F. What does the sum of the coefficients for Labor and Capital suggest about the type of returns to scale displayed by this production function?

G. Construct individual firms’ productivity. Which firm is the most productive? Which firm is the least productive?

6. The American Red Cross created a series of advertisements encouraging viewers to donate blood. After viewing the advertisement, Amanda went to the local Red Cross office and donated a pint of blood. Afterwards, Amanda returned home feeling satisfied that she had performed a good deed. Was this a marketing exchange?
A. No, because the Red Cross is non-profit organization.
B. Yes, because the Red Cross ran an advertisement.
C. Yes, because the donated blood was exchanged for a feeling of satisfaction.
D. No, because no money was exchanged.
E. No, because the Red Cross did not provide Amanda with a product.

7. The __________ department of an organization works closely with a network of other departments and employees to help provide the customer-satisfying products required for the organization to survive and prosper.
A. purchasing
B. marketing
C. human resources
D. accounting
E. information systems

8. The text explains that the two central concerns of marketing are
A. market share and customer satisfaction.
B. discovering and satisfying needs.
C. promotion and sales.
D. maximizing an organization's sales and products.
E. needs and wants.

9. Cara has had her current cell phone for 1 year. She saw the iPhone and decided it was perfect for her. The ads she read in magazines and saw on TV pointed out the terrific advantages of the iPhone over her current phone. Based on this information Cara most likely has a __________ for the iPhone.
A. requirement
B. value
C. idea
D. use
E. want

10. The term market is best defined as
A. people with a need and a want for a product.
B. organizations with the need and desire for a product.
C. organizations with products that satisfy people's needs and wants.
D. people with the desire and ability to buy a specific product.
E. people with the desire and the need for a product.

Part-1
Government insists the society to stop consuming the cigarettes and to protect their health.
Smoking is injurious to health is a slogan used by all the countries throughout the world in which
creating awareness among this cigarettes smokers. Cigarette causes cancer and other diseases to
the human body. Government wants to reduce the cigarette consumption, hence imposing higher
amount of tax by which increasing the price to cut the cigarette smoking. There are two methods:
attempted to achieve this objective.

First Method:
Creating awareness through advertisements in theaters, newspapers, television and other
channels, printing health warnings on cigarette pockets, and posters fixed in shops are the
various measures taken by the government to reduce the demand of the cigarettes. Based on the
government initiatives, personal healthcare issues and the taste and preferences of the smokers
are not favor for the product when the prices are constant and leads to shift the demand curve.

Questions:
3- Explain the effect of government initiatives on supply of the product with tabulated
numerical illustrations as examples.

4 Explain the effect of government measures on Demand of the product with
tabulated numerical illustrations as examples. And also draw the diagrams.
(Drawing: Search the appropriate image from Google and paste in your answer
sheet). (5 Marks

Part-II
Second Method:
Government has been trying to increase the price of cigarettes by which imposing maximum tax
on the product. Higher price discourages smokers to reduce the numbers of cigarettes smoking in
a day. The demand of the product meets changes in terms of production and consumption, thus
the demand curve is to be changed.

6. Because of the increase in the price of the product will it be shift in the supply and
demand curve? What are the factors which will affect the shifting in supply and
demand: Illustrate the answer with a table and a graph.

7- How the initiative taken by the government will affect the cost and revenue of the
supplier. Also explain how the profitability of the company?

1. Suppose that a person stops on the roadway and assists a stranded motorist. How would Kant explain his behavior?

He was an impartial spectator and sympathized with the person in trouble.

He stopped and helped because he didn’t want to think of himself as someone who wouldn't pay attention to the needs of others.

He would make sure that there wasn’t anyone else who could assist the motorist.

He would consider the consequences of not assisting the motorist.

He would assist the motorist because God commanded him to help.

2. According to Kant, a morally good person does the right thing because ____.

it's the right thing to do, not primarily for anything he antecedently wants to accomplish

his conscience would bother him otherwise

it’s something that an impartial spectator would do

the person being helped might reciprocate the favor at a future time

the consequences would be beneficial in the long run

3. With which statement would Kant agree?

Morality consists of truths that we discover using our powers of theoretical reason. These truths are rooted in the necessary and fundamental nature of things.

Morality consists of principles of action that we construct using our powers of practical reason.

Morality consists of attitudes that we feel from an impartial perspective. These attitudes are rooted in contingent features of human nature.

All of the above.

A and C only.

4. With which statement about the will would Kant agree?

A good will acts in accordance with duty, out of respect for the moral law.

A good will acts in accordance with duty, out of inclination.

The only thing good without qualification is a good will.

All of the above.

A and C only.

5. In contrast to all forms of consequentialism, including utilitarianism, Kant's theory is ___ in nature.

deontological

teleological

divine

intuitive

mystical

Hyaluronic acid (HA): (P.S This is a biology related course, but theres also some chemistry..)

The premise for adding HA to moisturisers is that aging skin is associated with loss of skin moisture. The key molecule involved in skin moisture is hyaluronic acid. 1g of HA can attach to and hold approximately 6L of water. HA is composed of repeating disaccharides (two sugar molecules), D-glucuronic acid and N-acetyl-D-glucosamine. Depending on the length of the repeating disaccharides, the molecule can be low molecular weight (short chains) or high molecular weight (long chains). Within the human body, HA has a half-life of only 3-5 minutes in the blood, less than a day in the skin and 1 to 3 weeks in cartilage

I need some experts to help answer these questions. Any help is welcome! Thank you :)

• How do the sex hormones affect skin aging?
• In humans where is HA found?

• What are the functions of HA?
• HA is synthesized by specific enzymes called HA Synthases primarily in mesenchymal cells. HA is transported across the cell plasma membrane to the ECM through pore-like structures. The HA receptor on the cell surface (which imports HA into the cell) is CD44 which is found on virtually all cells. This tells us that that HA requires transport to move across the cell plasma membrane, would you expect that this would affect delivery of the topical creams? In answering this question think about whether HA is required to be extra or intracellular to be effective.
• Where is endogenously (synthesised within the body) made HA located in the integument?
• Does endogenous HA penetrate past the lipid-rich stratum granulosum? If not, why not? With respect to what you have been taught regarding the epidermis, what might this mean for exogenous (external) hydrophilic topical treatments reaching the lower levels of the epidermis?