Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
tuberculosis ( tb ) is a contagious , infectious disease , due to mycobacterium tuberculosis ( mt ) , which usually lasts throughout the life course and determines the formation of tubercles in different parts of the body .
mt has very ancient origins : it has survived over 70,000 years and it currently infects nearly 2 billion people worldwide ; with around 10.4 million new cases of tb each year , almost one third of the world 's population are carriers of the tb bacillus and are at risk for developing active disease .
tb has always been associated with a high mortality rate over the centuries , and also nowadays , it is estimated to be responsible for 1.4 million tb deaths , among infectious diseases after human immunodeficiency virus ( hiv ) .
due to its infectious nature , complex immunological response , chronic progression and the need for long - term treatment , tb has always been a major health burden ; in more recent years , the appearance of multi - drug resistant forms and the current tb - hiv epidemic , associated with its severe social implications , treating and preventing tb have represented a permanent challenge over the course of human history [ 4 , 5 ] .
it has been hypothesized that the genus mycobacterium originated more than 150 million years ago .
mycobacterium ulcerans , causing infections since ancient times , requires specific environmental conditions as reflected nowadays in its distribution worldwide .
three million years ago , an early progenitor of mt might have infected early hominids in east africa   and 20.000 - 15.000 years ago , for the first time , the common ancestor of modern strains of mt might have appeared [ 8 , 9 ] .
egyptian mummies , dating back to 2400 bc , reveal skeletal deformities typical of tuberculosis ; characteristic pott 's lesions are reported and similar abnormalities are clearly illustrated in early egyptian art [ 10 , 11 ] .
the first written documents describing tb , dating back to 3300 and 2300 years ago , were found in india and in china respectively [ 12 , 13 ] .
the ancient hebrew word schachepheth is used in the biblical books of deuteronomy and leviticus in order to describe tb ; in the same period , in the andean region , archeological evidence of early tb , including pott 's deformities , was provided by peruvian mummies , suggesting that the disease was present even before the colonization of the first european pioneers in south america [ 15 - 18 ] . in the ancient greece tb
hippocrates described phtisis as a fatal disease especially for young adults , accurately defining its symptoms and the characteristic tubercular lung lesions .
excellent discoveries of the early scientists who studied tb were made in the same period : in greece , isocrates was the first author supposing that tb was an infectious disease , while aristotle suggested the contagious nature of " king 's evil " in pigs and oxes . in roman times ,
tb is mentioned by celso , aretaeus of cappadocia and caelius aurelianus , but it is not recognized as sharing the same etiology of extrapulmonary manifestations such as scrofula , pott 's disease and tb lupus . according to the greek clarissimus galen , who became personal physician of the roman emperor marcus aurelius in 174 ad , the symptoms of tb include fever , sweating , coughing and blood stained sputum ; he recommended fresh air , milk and sea voyages as successful treatments for the disease [ 20 - 22 ] .
after the decline of the roman empire , tb was widespread in europe in the viii and xix centuries , as witnessed by several archaeological findings .
the byzantine doctors aetius of amida , alexander of tralles and paul of aegina described the pulmonary and glandular forms of tb , while in the arabic empire , avicenna supposed the contagious nature of tb .
in the middle ages , scrofula , a disease affecting cervical lymph nodes , was described as a new clinical form of tb .
the illness was known in england and france as " king 's evil " , and it was widely believed that persons affected could heal after a royal touch . in the 12 century , william of malmesbury reported complementary treatments including visits at royal tombs , the kings ' touch or the use of a coin - talisman .
the practice of the king 's touch established by english and french kings continued for several years .
queen anne was the last english monarch to use this practice ( 1712 ) , george i put an end to it in 1714 , while in france it continued up to 1825 . in the middle ages , moreover , the french surgeon guy de
chauliac ( 1363 ) for the first time proposed a healing intervention for the cure of the " king 's evil " .
guy de chauliac was also strongly in favour of the removal of scrofulous gland with an engraving , as recommended by paul of aegina , who advised the surgical removal of the diseased gland , taking care not to harm vessels or nerves of which the neck region is rich .
as far as concerns the contagious nature of tb , a clear definition was first given by girolamo fracastoro in the sixteenth century .
the exact pathological and anatomical description of the disease was illustrated in 1679 by francis sylvius , in his work opera medica , in which he describes tubercles , their progression to abscesses , cavities and empyema in the lungs and in other sites of consumptive patients .
short afterwards , in italian health law , in particular in an edict issued by the republic of lucca in 1699 , there is the first official reference to the infectious nature of the disease . in 1735
the health board of the republic ordered the compulsory notification and isolation of consumptives , forbidding their admission in public hospitals , and establishing specific places for their treatment .
in 1720 , for the first time , the infectious origin of tb was conjectured by the english physician benjamin marten , in his publication " a new theory of consumption " . for the early eighteenth century
both terms consumption and phthisis were used in the 17 and 18 centuries , until in the mid-19 century johann lukas schnlein coined the term " tuberculosis " . in the 18 century in western europe , tb had become epidemic with a mortality rate as high as 900 deaths per 100,000 inhabitants per year , more elevated among young people . for this reason ,
tb was also called " the robber of youth " . during the industrial revolution , the diffusion of particularly problematic social conditions , such as extremely deprived work settings , poorly ventilated and overcrowded housing , primitive sanitation , malnutrition and other risk factors ,
up to a third of english tradesmen and employees died of tb , whereas the same proportion decreased to a sixth in the upper class .
the extreme anemic pallor of people affected by tb was at the origin of the new term " white plague " , coined during the 18 century [ 20 , 35 ] .
one hundred years later , tb was defined as " captain of all these men of death " because of its epidemic proportions in europe and north america , determining one in four deaths . at the beginning of the 19 century
, there was a large scientific debate about different theories concerning the etiopathological origin of phthisis , arguing whether it might be considered : an infectious disease  as generally considered in southern europe  an hereditary one  as stated in northern europe  or a form of cancer .
on the other hand , the discussion was about scrofula , tubercles , and phthisis as separate disease entities or manifestations of the same illness . in 1793 , the caseous necrosis , " cheese - like " , phthisic abscesses were named " tubercles " by the scottish pathologist matthew baille . in 1810 , the french physician gaspard - laurent bayle of vernet described the disseminated " miliary " tb in his work recerches sur la phthisie pulmonaire , recognizing tb not only as a disease affecting the lung , but a generalized one , clinically defined by coughing , difficulty in breathing , fever and purulent expectoration [ 37 , 38 ] . in 1819 ,
the french theophile laennac identified the presence of consolidation , pleurisy and pulmonary cavitation as pathognomonic signs of pulmonary or extrapulmonary tb .
tuberculosis most commonly affects the respiratory tract , but it could also infect gastrointestinal , bones , joints , nervous systems , lymph nodes , genitourinary tract and skin with inflammatory infiltration , caseation , necrosis , abscesses , fibrosis , formation of tubercles and calcification [ 39 , 40 ] .
he described their first appearance in the lungs , in their " miliary " ( " millet seed - like " ) form , their progressing to larger tubercles containing " cheese - like " ( " caseous " ) material , their breakdown into pus , and eventually forming cavities and empyema .
extra - pulmonary phthisic tubercles were recognized in the intestines , liver , meninges and other organs , as also described by sir percivall pott , a british surgeon that in 1779 defined as " pott 's disease " the vertebral collapse and spinal cord paralysis caused by tb infection [ 33 , 36 , 37 , 41 , 42 ] . in 1843 , the german physician philipp friedrich hermann klencke succeeded in the experimental reproduction of human and bovine forms of tb , causing generalized tb in rabbits , through a successful inoculation of material from a miliary tubercle into their liver and lungs . in 1849 lebert , publishing his work traite pratique des maladies scrofuleuses et tuberculeuses , suggested that the " king 's evil " was a childhood disease that might cause suppuration and ulceration of different body 's sites such as skin , ears , eyes , joints , bones , with a different pathogenesis from tb .
the first successful remedy against tb was the introduction of the sanatorium cure , described for the first time in 1854 in the doctoral dissertation " tuberculosis is a curable disease " by hermann brehmer , a botany student suffering himself from tb , who reported his healing after a travel to the himalayan mountains .
afterwards brehmer founded an institution in gorbersdorf , a mountain town situated in a fir forest , in order to cure patients with continuous fresh air and good nutrition .
the subsequent sanatoria were built with the same setup and permitted to cure a lot of tb patients in the next decades .
the infectious nature of tb was demonstrated in 1865 by jean - antoine villemin , a french military surgeon at the army medical school .
he formulated his hypothesis observing that tb was more frequent among soldiers who stationed for long times in barracks than among those in the field .
he also highlighted how healthy army recruits coming from the countryside often became consumptive some months after the beginning of their service .
villemin 's experiments consisted in inoculating a rabbit with " a small amount of purulent liquid from a tuberculous cavity " removed at autopsy from an individual died of tb .
as described in villemin 's work cause et nature de la tuberculose : son inoculation de l'homme au lapin , the inoculated animal remained alive and no disease signs were discovered , but at autopsy , three months later , extensive tb was evident .
villemin suggested that phthisis could be similar to glanders , an infectious disease in horses [ 20 , 34 , 36 , 37 , 47 ] .
preuves rationelles et exprimentales de sa spcificit et de son inoculabilit , dated 1868 , in which he stated the presence of tblike illnesses in different animals .
the author also noticed that more crowded urban areas had a higher prevalence of tb and that some parts of the world , like new zealand and australia , seemed to have not known tb until the arrival of pioneers .
some years later , in 1867 , theodor albrecht edwin klebs was one of the early scientists to try to isolate the tb bacillus , sowing tuberculous material on egg white , stored in sterile flasks . in his experiments , the culture was quickly muddy and it was possible to recognize mobile bacilli , which , after inoculation into the peritoneal cavity , caused the disease in guinea pigs .
using the methylene blue staining recommended by paul ehrlich , he identified , isolated and cultivated the bacillus in animal serum .
robert koch presented this extraordinary result to the society of physiology in berlin on 24 march 1882 , determining a milestone in the fight against tb . in the decades following this discovery , the pirquet and mantoux tuberculin skin tests ,
albert calmette and camille gurin ( bcg ) vaccine , selman waksman streptomycin and other anti - tuberculous drugs were developed .
koch contributed also to the elucidation of the infectious etiology of tb and for his scientific results , he was awarded the nobel prize in medicine in 1905 [ 33 , 51 ] .
nowadays tb is still a major public health problem , for this reason a combined strategy , based on improving drug treatment , diagnostic instruments , and prevention strategy , is necessary , in order to eradicate m. tuberculosis by the year 2050 , as committed by the world health organization ( who ) .

Answer:
summarytuberculosis ( tb ) is a contagious , infectious disease , due to mycobacterium tuberculosis ( mt ) that has always been a permanent challenge over the course of human history , because of its severe social implications .
 it has been hypothesized that the genus mycobacterium originated more than 150 million years ago . in the middle ages , scrofula ,
 a disease affecting cervical lymph nodes , was described as a new clinical form of tb .
 the illness was known in england and france as " king 's evil " , and it was widely believed that persons affected could heal after a royal touch . in 1720 , for the first time , the infectious origin of tb was conjectured by the english physician benjamin marten , while the first successful remedy against tb was the introduction of the sanatorium cure .
 the famous scientist robert koch was able to isolate the tubercle bacillus and presented this extraordinary result to the society of physiology in berlin on 24 march 1882 . in the decades following this discovery , the pirquet and mantoux tuberculin skin tests , albert calmette and camille gurin bcg vaccine ,
 selman waksman streptomycin and other anti - tuberculous drugs were developed .


Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
charging of grains of identical insulating
 materials during collisions
 has been of considerable interest recently , both for its intrinsic
 physics and for its applications to situations ranging from volcanic
 dust plumes and desert sandstorms to industrial powder processing .
however , work up to now has not explained why in some instances
 charging grows , rather than diminishes as one might naively expect ,
 and can run away extremely rapidly , leading to electrical discharges :
 lightning .
outstanding examples of runaway collisional charging involve
 ice , in thunderstorms both on earth and
 on other planets , and , it is speculated , in the
 solar nebula ; these instances concern granular media whose particles
 also undergo nucleation , growth , and fission , so that they , in effect ,
 reproduce . in this work ,
we demonstrate with a minimal dynamical model
 that secondary nucleation , production of a new particle from an existing
 particle , is a key process in producing runaway electrical charging
 in self - replicating granular matter .
we concomitantly present the
 results of experiments on growing ice in situ from the vapor phase
 within an environmental scanning electron microscope .
we show that
 an effect of the electric field is to induce the formation of fast - growing
 ice  palms
intermediate in morphology between whiskers
 and dendrites ; the ease of breakage of these palmlike formations will
 clearly favor secondary nucleation and hence runaway electrification .  in a thousand seconds , more or less , its volume increases
 a thousandfold , the intensity of its electric fields increases a thousandfold ,
 and its electric energy increases a billionfold  ; thus described
 vonnegut the tremendous metamorphosis a cumulus cloud undergoes to
 become a cumulonimbus or thundercloud .
thundercloud electrification is a consequence of ice particles colliding
 within a cloud and exchanging electrical charge .
charge dipole development
 in a thunderstorm is due to the physical separation of particles with
 opposite charges inside the cloud : larger , heavier particles will
 fall , while smaller , lighter particles will rise in the updraft , owing
 to their different dynamics , and these
 particles carry different charges .
usually ,
 in thunderstorms , the smaller ice particle is an ice crystal and carries
 positive charge aloft in the updraft ; the larger graupel ice particle
 falls with an opposite negative charge , leading to a typical thunderstorm .

we may contrast the foregoing with charging in other granular media , where it has been argued that simple geometry , without growth and
 fission processes , leads to a net transfer of electrons from larger
 to smaller particles , so that smaller
 particles tend to charge negatively and larger ones positively . whether
 this differential charging tendency operates one way or the other
 depends on the microphysics , which differs for different materials ,
 so this polarity differs .
for our present purposes , however , what
 is relevant is that there should exist such a triboelectric charging
 tendency in one sense or the other .
here we build a minimal model
 ( figure 1 ) incorporating solely the collisional
 dynamics of charge transfer plus nucleation , growth , and fission processes ,
 which we aim to have general relevance to self - replicating granular
 media .
anatomy of our minimal model of charging of friable self - replicating
 granular matter through secondary nucleation , incorporating the processes
 of particle growth ( ri  ri + 1 ) , advection
 ( with speed ui ) , collision ,
 charge transfer , and fission ( with probability s ) .
we consider ( figure 1 ) a one - dimensional
 system of length l , within which we place randomly n neutrally charged particles , qi = 0 for i = 1 , ... , n , of size ri extracted
 from a gaussian distribution of sizes with mean r = 1 and standard deviation . these particles grow at a constant
 rate , independent of particle size , that sets the time scale of the
 problem . at the same time , they sediment in an upward flow of constant
 magnitude at their terminal velocity , ui , determined by the instantaneous balance of fluid
 drag and gravitational forces .
the sedimentation speed is normalized
 by the updraft speed ( i.e. , ui = 1 for passive tracers ) and is approximated by a linear function
 of the particle size ri , ui = 1  ( ri / rc ) .
this function is positive ( negative ) for ri below ( above ) a critical value rc .
the sedimentation speed of all particles in the simulation
 is updated every integration time step ; in this way , small particles
 that are initially advected upward by the updraft slow their upward
 motion as they grow and begin moving downward after reaching the threshold rc . when the trajectories of two particles i and j cross , they collide . to overcome
 the 1d limitation of
 the model ,
we allow particles to get past one another after the collision ,
 so that after each time step particles end up in whatever final position
 their velocities prescribe .
both mass and charge are conserved during
 a collision but , while charge is transferred in every collision ( the
 smaller particle leaving the collision positively charged : qi  qi + 1 and qj  qj  1 with ri < rj ) ,
we assign
 a certain probability s for fission to occur for
 each of the two particles involved in a collision .
if fission does
 occur for particle i , a new , neutrally charged particle
 with radius 1 splits from it , reducing its size to ri = ri  1 .
although fracture of particles has been shown
 to lead to additional charging , we left
 this effect out of the model for the sake of simplicity as it does
 not change qualitatively the presented results .
boundary conditions
 are absorbing : particles leaving the system
 through the upper or lower boundary are absorbed there , and do not
 participate further in the dynamics , but their charge accumulates
 to the total charge at the boundaries : qu(l ) = qi for i leaving the system through the upper ( lower ) boundary ,
 respectively .
the total large - scale charge separation is calculated
 as q = qu  ql . for given initial conditions ( set completely
 by the concentration
 of particles ,
= n / l , and
 the initial spread of the size distribution ,  ) , the behavior
 of our minimal model then depends on just two parameters , the critical
 radius rc and the secondary nucleation
 rate s. in what follows , we set rc = 8 ,  = 2 and  = 0.1 and explore the behavior
 of the model with respect to the secondary nucleation rate s. we note that electric forces are not considered in the
 model but implicitly ( through the secondary nucleation rate responsible
 for the process of fission ) .
figure 2 displays the typical transient
 dynamics of the charge distribution in the model .
the figure shows
 an initial stage in the transient dynamics chosen to exemplify how
 the charge separation process operates in the model .
as time passes ,
 as indicated by black arrows , light positively charged particles move
 toward the upper boundary while heavy negatively charged ones move
 in the opposite direction , contributing to a non - negligible dipolar
 large scale charge separation q .
regions where
 localized collisions are produced generate large charges that are
 then separated by differential advection . even at those early stages
 in the process , the global dipolar structure of the system , quantified
 by the large - scale charge difference between the boundaries q , is the dominant field .
figure 3 shows particle size and charge distributions for the upper and lower
 boundaries .
as time passes , light positively charged particles move toward the
 upper boundary while heavy negatively charged ones move in the opposite
 direction , as indicated by arrows , contributing to a non - negligible
 large - scale dipolar charge distribution q .

particle size ( rj )
 and charge ( qj ) distributions
 for the system upper boundary ( left panels ) and lower boundary ( right
 panels ) .
the total charge separation
 q at a finite time step ( which is a measure
 of the speed of the charge - separation process ) displays nonmonotonic
 discontinuous behavior as a function of the secondary nucleation rate s. below a critical value sc , the long - term dynamics reaches an emptying state with no particles
 left in the domain and a finite ( and small ) final charge separation ;
 as there are few secondary nuclei , the initial particles grow and
 collide very little before leaving the system .
occasionally some charge
 is produced , but not much . above sc , the
 number of collisions grows , and with it the charge transfer .
as the
 charge acquired by the particles is correlated with their size , charge
 separation occurs too .
the system approaches a steady state with an
 average nonzero number of particles in the domain and an exponentially
 divergent charge separation , as shown in the inset of figure 4 .
this exponential charge growth is limited in nature
 by electrical discharges ,  lightning  .
the total charge separation q displays nonmonotonic
 behavior as a function of the secondary nucleation rate s. inset : time evolution of q for s = 0.1 shows the exponential growth characteristic of all
 values of s > sc .
however , for secondary - nucleation
 rates much greater than sc , there are
 more and more collisions .
the particles
 undergo more fission into secondary nuclei , and although much charge
 is produced , it does not separate as well ; charge separation is still
 exponentially divergent , but the growth rate decreases beyond sc .
there is thus an intermediate optimal value
 of the secondary nucleation rate to produce the greatest charge separation .

this critical value sc  1/(rc ) is 0.0625 in the simulations ( dashed line
 in figure 4 ) .
a smaller value of rc ( which means a weaker updraft ) requires secondary nucleation
 to occur more often ( larger sc ) in order
 to ensure some particles are advected upward ( leading to charge separation ) ,
 while the initial density of particles ,  , controls the collision
 probability .
it is worth mentioning that even in the limit of very
 high particle density  , in which many collisions occur at early
 stages , charge separation is minimal in the absence of secondary nucleation .

earlier work
 of ours made us suspect that secondary nucleation
 ought to be important in runaway collisional charging .
previously
 we have shown that the nonlinear feedback effects of secondary nucleation
 are responsible for chiral symmetry breaking in experiments involving
 crystallizing a chiral chemical compound from solution .
we showed that secondary nuclei in such stirred crystallization
 experiments are often easily detached whisker or needle crystallites
 growing from a mother crystal , and a runaway process involving the
 formation of secondary nuclei leads to complete chiral symmetry breaking .
water molecules possess a high electric polarizability ; they are
 electrical dipoles and can be highly affected by the presence of an
 external field . during dendrite growth , an electric field can produce
 an ordering of the molecular dipoles and increase the molecular flow
 toward the dendrite tip .
this increases the growth velocity , decreases
 the tip radius and disables the generation of side - branches , producing
 long whiskers .
these effects have long been noted and were studied quantitatively by libbrecht and tanusheva , who measured the tip velocity and found that
 high voltages could multiply the growth rate more than 10-fold .
we hypothesized that this dendrite growth mechanism should be involved
 in promoting secondary nucleation .
thus , we undertook laboratory experiments
 to see whether similarly easily detached forms as in solution crystallization
 experiments are produced in ice under the influence of an electric
 field .
we employed a fei quanta 200 environmental scanning electron
 microscope ( esem ) equipped with a liquid nitrogen cold stage to grow
 ice in situ at low pressures and at temperatures of 90200
 k. the microscope was set up so that the cold finger , together with
 a thermostat , was directly beneath the substrate ( a silicon wafer
 attached with silver glue ) .
we began by evacuating the chamber in
 the high - vacuum mode of the microscope ( 6  10 pa ) and lowering the substrate to the working temperature .
we first
 scanned the uncovered sample substrate , on which we grew an ice film
 by switching to low - vacuum mode and opening the water input microvalve
 at a pressure of 40 pa for some seconds .
we found this was the highest
 pressure at which we could obtain clear images .
we closed the microvalve
 at or before the point when the substrate temperature increases and
 can not be maintained at the working temperature , following which we
 switched back to high - vacuum mode and observed the ice growth in situ . in the electron - microscope chamber ,
a high - voltage electron beam
 is used for imaging , and as we display in figure 5 , we find that the electric field produces rapid dendrite
 growth wherever we charge with electrons by imaging .
a typical ice
 morphology seen under these circumstances is of a form intermediate
 between whiskers and dendrites , which often takes on the aspect of
 a palm tree ; see figure 5a . as we zoom out
 ( figure 5b , c )
, we note that the palm forest
 is found only where we had been imaging ; outside the area of the electron
 beam , we find a relatively flat film of ice , while within the imaged
 zones , three in figure 5c , we find faster ice
 growth and the ice forest .
growth in an
 esem : ( a , b ) at t = 170 k , p = 40
 pa , v = 30 kv , an ice
the forest displays the morphology intermediate between whiskers
 and dendrites typically formed with charged ice .
( c ) in an overview ,
 the three zones where we imaged and charged with electrons stand out ,
 showing the increased growth on the background ice film .
we had noted such palmlike forms in previous experiments
 involving
 growing ice inside an electron microscope , but had not then realized that the electric field was involved in
 their production .
these experiments are necessarily qualititative ,
 being performed within the chamber of an unmodified esem , but we find
 the results suggestive : owing to their geometry , the breakage of these
 structures on collision is likely and will lead to the formation of
 new nucleation centers .
such friable morphologies do not only form
 in ice under electric fields ; snowflakes too have such delicate structures ,
 but an electric field promotes this form of growth .
our minimal physical model of a self - replicating
 granular material
 shows how secondary nuclei from such growth can lead to runaway charging
.
 these effects may be present in ice on earth , in terrestrial thunderstorms , and in astrophysical ices , in the solar nebula , and in thunderstorms on other planets , some of which ,
 for example , on venus , may involve self - replicating granular materials
 other than water ice . it is conceivable that this dynamics is involved
 in the formation of the martian geological structures called razorbacks . while ice is clearly
 the most quotidian example of a friable self - replicating granular
 material , one that breaks easily and continues to grow , other such
 materials can be both sought in different astrophysical environments ,
 and also produced in technological contexts .

Answer:
we
 establish that the nonlinear dynamics of collisions between
 particles favors the charging of an insulating , friable , self - replicating
 granular material that undergoes nucleation , growth , and fission processes ;
 we demonstrate with a minimal dynamical model that secondary nucleation
 produces a positive feedback in an electrification mechanism that
 leads to runaway charging . we discuss ice as an example of such a
 self - replicating granular material : we confirm with laboratory experiments
 in which we grow ice from the vapor phase in situ within an environmental
 scanning electron microscope that charging causes fast - growing and
 easily breakable palmlike structures to form , which when broken off
 may form secondary nuclei .
 we propose that thunderstorms , both terrestrial
 and on other planets , and lightning in the solar nebula are instances
 of such runaway charging arising from this nonlinear dynamics in self - replicating
 granular matter .


Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
the majority of women with menorrhagia , postcoital bleeding , intermenstrual bleeding , or postmenopausal bleeding ultimately undergo diagnostic hysteroscopy with endometrial sampling as part of their assessment , particularly if symptoms persist or pelvic imaging suggests a uterine abnormality .
dilatation and curettage ( d&c ) has been widely considered to be the method of choice for obtaining endometrial samples for histopathological evaluation
. however , the needs for admission and general anesthesia and their associated costs have made this option less favorable . in the outpatient setting , endometrial sampling is an effective and acceptable method for obtaining endometrial samples for histopathological assessment [ 3 , 4 ] .
inadequate sampling is more problematic in postmenopausal women , for whom up to 68% of endometrial samples are reported to be inadequate . in our institution , the only sampling tool available to perform the outpatient sampling procedure is the uterine explora model i - mx120 ( http://www.coopersurgical.com/ ) ( figure 1 ) .
in addition , the device is sterile and disposable ( one - time use ) .
the advantages of using explora rather than d&c as a sampling device include a reduction in hospitalization costs , extra convenience for the patient and physician , and the minimal complications of the procedure .
the purpose of this study is to compare the effectiveness of the explora model i tool with the conventional d&c technique for obtaining adequate endometrial samples that are capable of providing specific and informative histopathologic diagnoses .
after obtaining the approval of our institutional review board , all endometrial samples received at the histopathology department in king khalid university hospital ( kkuh , riyadh , ksa ) between january 2007 and december 2010 were included in this study . a total of 1270 endometrial samples were included ( table 1 ) .
two hundred seventy - four samples ( 21.6% ) were obtained by conventional d&c in the surgical theater , while the remaining 996 samples ( 78.4% ) were obtained by senior obstetrics and gynecology residents who used a standardized biopsy technique in the outpatient procedure rooms . during the usage of the explora model
i , the syringe provided with the instrument was used to create a negative pressure , and the explora was rotated as it was withdrawn . after withdrawal , the tip was cut off , and the tissue was placed in 10% buffered formalin saline fixative and was sent for pathological examination .
the pathologists who interpreted the endometrial samples were blinded to the instrument or method used to obtain the samples .
an inadequate sample was defined as consisting of only blood , cervical mucus , endocervical epithelium , or blood with fragments of endometrial glands or stroma insufficient for histopathological assessment and diagnosis .
the age , gravidity , parity , menstrual history , uterine size , hysteroscopy findings ( when available ) , and the presence or absence of any cervical abnormality were recorded on the request forms , which were reviewed by the investigators . for each of the two methods used ( explora model i and d&c ) , the numbers and percentages of inadequate samples and age group clustering were calculated and statistically analyzed .
of the 1270 endometrial samples obtained , 253 samples ( 19.9% ) were scored as inadequate . of these samples ,
the explora sampler was used to collect 224 samples ( 88.5% ) , whereas 29 samples ( 11.5% ) were obtained by d&c ( figure 2 ) .
thus , the insufficient tissue percentage was higher with the explora ( 17.6% ) than with d&c ( 2.2% ) , which was a statistically significant difference ( p < 0.0001 )
. age group clustering ( i.e. , numbers of premenopausal and postmenopausal women ) of inadequate sample results was also calculated ( figure 3 ) . of the 253 inadequate samples ,
82.6% were from women 45 years of age and older ( i.e. , postmenopausal ) compared to 17.4% in premenopausal women ; the age difference was significant ( p < 0.0001 ) .
the detection rates of endometrial hyperplasia and carcinoma using both methods were assessed and calculated .
of the 73 samples with a diagnosis of endometrial hyperplasia , 50 ( 68.5% ) were diagnosed by d&c , and 23 ( 31.5% ) were diagnosed using the explora sampler .
however , of the 18 samples with a diagnosis of endometrial cancer , the rates of detection were similar between the two methods .
endometrial sampling for the evaluation of dysfunctional uterine bleeding and the diagnosis of endometrial hyperplasia and carcinoma and other indications remains one of the most commonly performed gynecological procedures [ 14 ] . in recent years
, less hazardous and more inexpensive and convenient outpatient sampling methods have replaced the traditional , in - hospital , endometrial curettage .
the advantages of outpatient endometrial biopsy include reduced cost and less risk for the patient , as no anesthesia is required .
furthermore , the discomfort and pain produced by sampling have been reported to be minimal .
however , it is essential to ensure that outpatient endometrial sampling is quantitatively adequate and comparably accurate to conventional dilatation and curettage .
a sample is judged as adequate if a specific diagnosis can be given from the histological examination of the endometrial fragments obtained .
adequacy can be measured by comparison of either outpatient biopsy with curettage histological evaluation or outpatient biopsy with the results of pathological examination of hysterectomy specimens [ 3 , 4 ] .
many techniques for obtaining an endometrial sample without the need for curettage have been described in the literature .
chicago , il , usa ) and the novak biopsy curette with a 10  ml syringe functioning as an aspiratory device , which have been shown to be equally effective compared to d&c in detecting an endometrial pathology [ 69 ] .
however , the vabra aspirator and novak biopsy curette , although widely available and relatively inexpensive , have several disadvantages , including the need for an electric vacuum pump to perform the aspiration in the former technique and the pain caused by both methods . as a result of these drawbacks , smaller inexpensive and
self - contained instruments have been developed and the prototype of this class of endometrial samplers is the pipelle . the pipelle has been shown to have a diagnostic accuracy comparable to that of vabra aspiration and the novak curettage while causing less pain [ 911 ] .
all of these instruments ( i.e. , the vabra aspirator , the novak biopsy curette , and the pipelle ) have low rates of false - negative and insufficient tissue results for the detection of endometrial abnormalities , as determined by comparison to hysterectomy specimens [ 1113 ] .
it was found that pipelle biopsy had a sensitivity of 99.2% in pinpointing high grade cancer and a sensitivity of 93% in detecting low grade malignancies ; the sensitivities defined for d&c were 100% and 97% , respectively . while
excellent agreement  was generally noted between preoperative histology and grade and the final pathology , pre - operative endometrial sampling more commonly provided underestimates of final grade ( low grade versus high grade ) than overestimates .
the explora is somewhat similar in its design to the pipelle , but clinical studies on its effectiveness are scarce , with the effectiveness ranging between 14.6 and 15% according to various studies [ 6 , 15 ] .
our own findings revealed that the rate of obtaining inadequate samples using the explora was much higher ( 17.6% ) than the rates reported in the literature .
however , most of these cases ( 82.6% ) were obtained from postmenopausal women with atrophic endometrial status .
this finding is in keeping with the rates reported by other investigators [ 58 , 16 ] .
this retrospective study suggests that traditional d&c produces better endometrial sample adequacy than the explora technique .
this finding indicates that clinicians performing endometrial sampling would benefit from more experience and training using the explora technique .
additional studies comparing the adequacy of samples obtained with different endometrial sampling techniques and devices are warranted .
furthermore , we recommend using the d&c procedure when the explora - obtained samples are inconclusive or when the use of the explora sampler is accompanied by ultrasound findings that are suspicious of endometrial hyperplasia or carcinoma .

Answer:
aims . our aim is to compare the adequacy and diagnostic yield of samples obtained by the endometrial explora sampler i - mx120 with endometrial specimens obtained by conventional dilatation and curettage ( d&c )
 . methods . a total of 1270 endometrial samples
 were received in the histopathology laboratories at the king khalid university hospital , riyadh , saudi arabia , between 2007 and 2010 . in the outpatient clinic ,
 the uterine explora model i was used to obtain 996 samples .
 the remaining 274 samples were obtained by conventional d&c .
 sample adequacy and the clustering of inadequate specimens according to age groups by the two different techniques were compared and statistically analyzed . results . out of 1270 endometrial samples , 253 ( 19.9% ) were inadequate .
 the uterine explora was used in 88.5% of these inadequate samples ( 253 samples ) , and the remaining 11.5% were obtained by d&c .
 the insufficient tissue incidence was higher with the explora ( 17.6% ) than with the d&c ( 2.2% ) and the difference was statistically significant ( p < 0.0001 ) .
 the ages of the patients , as well as the clinical indications for the procedures , were recorded . conclusion .
 this retrospective study demonstrated better specimen adequacy when d&c was used compared to the higher rate of sample insufficiency obtained with the explora .


Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
medulloblastoma is the most common pediatric brain tumor , with an incidence of ~0.5/100,000 children < 15 years old ( 1 ) .
it is classified as grade iv according to the world health organization ( who ) ( 2 ) .
current treatment consisting of surgery , radiotherapy and adjuvant chemotherapy has a limited role in improving the prognosis of patients ( 3,4 ) . novel therapeutic methods based on the specific mechanism of medulloblastoma carcinogenesis
an increasing number of studies have revealed that micrornas ( mirnas / mirs ) serve a role in tumorigenesis ( 59 ) .
gene expression is regulated by thousands of known mirnas , which bind to imperfect complementary sites within the 3 untranslated regions of their target protein - coding mrnas , and repressing the expression of these genes at the level of mrna stability and translation ( 10 ) .
previous research has revealed that mirnas are involved in the regulation of the majority of physiological and pathological process , including development , life span , and metabolism , and their dysregulation contributes to a number of types of disease , notably cancer ( 11 ) .
these small rnas may function as oncogenes or tumor suppressors by modulating the levels of critical proteins , and their relevance in human disease and therapy is currently under investigation ( 12 ) .
an increasing number of studies have demonstrated abnormal mirna expression levels in the central nervous system ( cns ) of cancer patients , suggesting that mirnas may serve as key regulatory components in cancer of the cns ( 5,10,13 ) .
it was observed that 22 mirnas were upregulated and 26 mirnas were downregulated in the tumor tissue .
ingenuity pathway analysis ( ipa ) was used to analyze the regulatory network of the differentially expressed mirna in medulloblastoma .
it was proposed that the pathways exhibited in the network may have an important role in the tumorigenesis of medulloblastoma .
the data were downloaded from the ncbi gene expression omnibus ( geo ) database ( gse42657 , www.ncbi.nlm.nih.gov/geo ) .
the data include 7 control samples ( consisting of 3 cerebellum and 4 frontal lobe controls ) and 9 medulloblastoma samples .
the data from all samples was normalized using the limma package in r software version 3.3.0 ( https://www.r-project.org/ ) .
the selected samples of this profile are exhibited in table i. the differentially expressed genes ( degs ) were obtained with the thresholds of |logfc|>1.0 and p<0.01 , using linear models and empirical bayes methods for assessing differential expression in microarray experiments in the limma package ( table ii ) .
a heat map of the different groups was produced to visualize the degs and cluster the corresponding groups with the differentially expressed mirnas from the tumor tissue , using the r package gplots ( fig .
the dataset ( 48 differentially expressed mirnas ) was uploaded to the ingenuity pathway analysis software version 2016 ( qiagen , inc . ,
valencia , ca , usa ) , using the microrna target filter to find the targeting information .
a total of 40 micrornas targeting 11,757 mrnas were identified by the filter . the core analysis function ( rapid assessment of the signaling and metabolic pathways , molecular networks , and biological processes that are most markedly perturbed in the dataset of interest ) to analyze the associated network functions of the mirnas .
using mirna microarray data from the geo database , 48 mirnas which are differentially expressed in medulloblastoma were identified , compared with the control group ( table ii ) .
the core analysis demonstrated the molecular network interactions and signaling pathways associated with 28 differentially expressed mirnas of medulloblastoma , and their predicted molecular targets were rebuilt using ipa . the network
organismal injury and abnormalities , reproductive system disease , cancer had an ipa score of 41 , focusing on 17 mirna molecules , and the network  cancer , organismal injury and abnormalities , cell death and survival had an ipa score of 23 , focusing on 11 mirna molecules ( fig .
the most impacted biological processes and diseases regulated by the analyzed mirnas included organismal injury and abnormalities , reproductive system disease and cancer .
the molecular network maps demonstrated that three primary components were identified to be at the central hub of the most significant network with a score of 41 ; these were tumor protein p53 ( tp53 ) , argonaute 2 ( ago2 ) and mitogen activated kinases 3 and 1 ( erk1/2 ) ( fig .
tp53 , sirtuin 1 ( sirt1 ) and y box protein 1 ( ybx1 ) were located in the center of the second network with a core analysis score of 23 ( fig .
the first network included mir-17 - 5p , mir-130a-3p , mir-182 - 5p , mir-18a-5p , mir-19b-3p , mir-4288 , mir-96 - 5p , which were upregulated in the medulloblastoma samples , and mir-128 - 3p , mir-132 - 3p , mir-133a-3p , mir-299a-5p , mir-409 , mir-668 - 3p , which were downregulated . the second notable network ( fig .
2b ) involved upregulated mir-217 - 5p and mir-216a-5p , and downregulated mir-329 , mir-330 and mir-584 , which are associated with the regulation of key regulatory genes in medulloblastoma development , including tp53 , sirt1 and ybx1 .
however , when the cerebellum samples were used as the control , it was observed that 4 mirnas were overexpressed and 5 mirnas were underexpressed in the medulloblastoma ( table iii ) .
the network  cell death and survival , gastrointestinal disease , hepatic system disease had an ipa score of 9 , focusing on 4 mirna molecules ( fig .
mirnas function as master regulators and signal modulators by fine - tuning gene expression in multiple complex pathways .
a number of the mirnas which exhibit dysregulated expression in medulloepithelioma have been reported to serve various roles in carcinogenesis ( 6,7,9 ) . through analysis of a geo mirna expression profiling dataset , mirnas which are over- and underexpressed in medulloblastoma
were identified , including mir-217 , mir-216 , mir-183 , mir-182 and mir-96 , which are upregulated in tumor tissue .
previous research demonstrates that mir-183 - 96 - 182 regulates cell survival , proliferation and migration in medulloblastoma , and increased mir-183 - 96 - 182 expression is associated with aggressive clinical course , high rates of metastasis and poor overall survival ( 8,9,14 ) .
mir-217 and mir-216 were overexpressed in medulloblastoma . however , the role of mir-217 was controversial .
mir-217 is an oncogene that is overexpressed in aggressive human b cell lymphomas ( 15 ) .
however , it may be a tumor suppressor in hepatocellular carcinoma ( 16 ) . in pancreatic intraepithelial neoplasm , pancreatic ductal adenocarcinomas and
further studies are required to determine whether increased expression of mir-217 in medulloblastoma represents an oncogenic effect , or if the dysregulation functions as a potential tumor suppressor . while mir-216 was underexpressed in various types of cancer , including breast cancer , pancreatic cancer and nasopharyngeal carcinoma ( 1921 )
, it may serve as a tumor suppressor to inhibit cell proliferation , invasion and tumor growth .
further studies are required to determine whether increased expression of mir-216 in medulloblastoma represents an oncogenic effect or is a potential tumor suppressor . in the present study ,
marked downregulation of mir-383 , mir-206 , mir-138 , mir-128a / b and mir-133b was identified .
mir-383 , repressing peroxiredoxin 3 at transcriptional and translational levels , suppressed the cell growth of medulloblastoma ( 6 ) .
additionally , mir-206 was downregulated in all the four molecular subgroups of medulloblastoma as well as in cell lines .
orthodenticle homeobox 2 ( otx2 ) , a target gene of mir-206 which is overexpressed in all non - sonic - hedgehog - driven medulloblastomas , is an oncogene in medulloblastoma .
therefore , underexpression of mir-206 contributed to the upregulation of otx2 expression and enhanced growth of medulloblastoma cell lines ( 7 ) .
studies have demonstrated a reduction in the mirnas mir-383 , mir-138 , mir-128a / b , mir-133 , mir-124 and let-7 g in medulloblastoma .
nevertheless , mir-328 , mir-133b , mir-149 , mir-181b and mir-154 were downregulated in the study of ferretti et al ( 5 ) and the present study .
in addition , the present study revealed that mir-433 , mir-488 , mir-584 , mir-329 , mir-299 - 5p , mir-330 , mir-770 - 5p , mir-656 and mir-642 were underexpressed in medulloblastoma , and further research is required to identify whether these mirnas have a specific role in the tumorigenesis of medulloblastoma .
based on microarray analysis , mirnas that distinguish normal brain from medulloblastoma tissue were identified . as presented in the heat map ,
the dysregulated mirnas are more closely associated with the medulloblastoma samples compared with the normal control samples .
additionally , by uploading the mirnas from the first network to the ipa , it was identified that the dysregulated mirnas were associated with key regulatory genes in tumorigenesis , including tp53 , insulin - like growth factor 1 receptor , ago2 and erk1/2 .
the overexpressed mirnas mir-17 - 5p and mir-182 ( log fold change > 2 ) have interactions with tp53 ; studies have demonstrated an association between these mirnas and tp53 in tumorigenesis ( 22,23 ) .
agos are associated with mirnas , due to their function in the rna induced silencing complex ( risc ) , wherein they use small rna guides to recognize targets .
ago2 had an interaction with mirnas that are dysregulated in medulloblastoma , including mir-17 - 5p , mir-128 , mir-96 , mir-433 , mir-383 and mir-138 .
the second network , including mir-217 and mir-216 , which are upregulated in medulloblastoma , exhibits associations with key regulatory genes in medulloblastoma development , including tp53 , sirt1 and ybx1 .
sirt1 is a well understood member of the sirtuin protein class , preventing cell aging and apoptosis of normal cells ( 24,25 ) .
the effects of sirt1 are controversial ; the protein was considered to be a tumor promoter in neuroblastoma , prostate and skin cancer ( 2628 ) , whereas it was considered to be a tumor suppressor in breast and colon cancer ( 29,30 ) .
therefore , sirt1 may serve a role in medulloblastoma and correlate with the formation and prognosis of human medulloblastomas ( 31 ) .
recently , dey et al ( 32 ) proved that ybx1 ( yb1 ) is upregulated across human medulloblastoma subclasses and is required for medulloblastoma cell proliferation .
furthermore , the study identified that the shh : yap : yb1:igf2 axis may be a powerful target for therapeutic intervention in medulloblastoma . when the medulloblastoma samples were compared with the normal cerebellum , 9 dysregulated mirnas were identified .
the 9 mirnas were uploaded to the ipa in order to perform the core analysis .
the network involved 4 downregulated mirnas and was associated with important regulators of tumorigenesis , including met proto - oncogene ( met ) , akt serine - threonine kinase 1 and sterol regulatory element - binding factor 1 ( srebf1 ) .
previous evidence has demonstrated the association between aberrant met signaling and medulloblastoma development ( 33,34 ) .
previous studies have revealed that overexpressed mir-206 may inhibit met in lung cancer ( 35,36 ) , however the function of downregulated mir-206 in medulloblastoma is unknown .
srebf1 is a transcription factor , regulating lipogenesis , which is also involved in tumorigenesis ( 37 ) .
these network components alone are not sufficient to initiate medulloblastoma formation ; the interactions between these dysregulated factors and additional genetic insults promote tumorigenesis . in conclusion , based on the mirna array data in the geo database , mirnas which are differentially expressed in medulloblastoma samples were identified .
certain dysregulated mirnas have been confirmed ; however , further research is required to verify the mirnas which have not been previously identified .
additionally , the ipa core analysis , presenting the interaction of mirnas and counterpart targets , provides a method to understand the tumorigenesis of medulloblastoma .
the results of the present study may provide a potent target for therapeutic intervention or diagnosis in medulloblastomas .

Answer:
medulloblastoma is the most common malignant brain tumor of the central nervous system among children .
 medulloblastoma is an embryonal tumor , of which little is known about the pathogenesis .
 several efforts have been made to understand the molecular aspects of its tumorigenic pathways ; however , these are poorly understood .
 microrna ( mirna ) , a type of non - coding short rna , has been proven to be associated with a number of physiological processes and pathological processes of serious diseases , including brain tumors .
 differentially expressed mirnas serve an important role in numerous types of malignancy .
 the present study aims to define a differentially expressed set of mirnas in medulloblastoma tumor tissue , compared with normal samples , to improve the understanding of the tumorigenesis .
 it was identified that 22 mirnas were upregulated and 26 mirnas were downregulated in the tumor tissue compared with the normal group . however , when the medulloblastoma tissue was compared with normal cerebellum tissue , 9 mirnas were identified to be up or downregulated in the tumor samples .
 the differentially expressed mirnas in the tumor tissue were identified in order to clarify the networks and pathways of tumorigenesis using ingenuity pathway analysis .
 subsequently , key regulatory genes associated with the development of medulloblastoma were identified , including tumor protein p53 , insulin like growth factor 1 receptor , argonaute 2 , mitogen - activated protein kinases 1 and 3 , sirtuin 1 and y box binding protein 1 .


Question:
You will be shown the title of a chemistry paper, together with sections excerpted from the body of the paper. The paper sections may include HTML tags like `<p>` and `</p>`; please ignore these. Your task is to write an abstract for the paper. Your response should include the abstract and no other text.

Title:
A Synthesis of the Chlorosulfolipid Mytilipin A via a Longest Linear Sequence of Seven Steps

Paper sections:

The chlorosulfolipids are a most unusual group of lipids known since the independent reports of chlorinated C22 lipids isolated from the alga Ochromonas danica by the Vagelos and Haines groups in 1969.[1,2] These first compounds were characterized as bis-sulfates of 1,14-docosanediol, with varying levels of chlorination up to the hexachloride, now known as danicalipin A (1, Figure 1). In the decades since, this family has grown to include ill-characterized C24 analogs (also from O. danica),[3] the unusual chlorovinyl sulfate-containing lipid malhamensilipin A (2) that was isolated from the related alga Poterioochromonas malhamensis by Slate and Gerwick,[4] and the mytilipins, a small group of lipids isolated in very small quantities from toxic Adriatic mussels and reported by Fattorusso and co-workers.[5,6] These last compounds include the C15 lipid mytilipin A (3), which has some structural resemblance to danicalipin A and malhamensilipin A, and mytilipins B and C (4 and 5), two C24 lipids with an astounding level of stereochemical complexity that includes 11 chlorine-bearing centers. More recently, Okino has uncovered more natural congeners in the danicalipin series in a careful study of O. danica,[7] and the Sheu group isolated analogs of mytilipin A from an octocoral from the Strait of Taiwan.[8] Given the diversity of sources and structures, it is reasonable to expect that more members will be added to the chlorosulfolipid family in the years to come.[9]

Over the past four years, several groups, including our own, have reported syntheses of members of the chlorosulfolipid family. The Carreira group registered the first synthesis when they disclosed an elegant route to racemic mytilipin A.[10] Shortly thereafter, our group reported the stereochemical elucidation of danicalipin A and its synthesis in racemic form,[11] followed by the structural revision and enantioselective synthesis of malhamensilipin A.[4b,12] These three syntheses featured similar overall strategies with introduction of the polar substituents via alkene oxidation reactions.[13] The Yoshimitsu group developed a substantially different approach, featuring their method for stereospecific deoxydichlorination of enantioenriched epoxides,[14] which culminated in clever asymmetric syntheses of both mytilipin A and danicalipin A,[15] the latter of which was contemporaneous with a third very different, creative approach from the Matsuda group.[16] Finally, the Carreira group recently reported the synthesis of the proposed structure of mytilipin B as shown in Figure 1, and came to the conclusion that this chlorosulfolipid requires stereochemical revision.[17]

We now report a new synthesis of mytilipin A via a longest linear sequence of only seven steps for racemic material, eight for enantioenriched chlorosulfolipid, with several key features: (1) a highly diastereoselective haloallylation of a sensitive α,β-dichloroaldehyde; (2) a kinetic resolution of a complex vinyl epoxide; (3) a convergent olefination via Z-selective alkene cross metathesis; and (4) excellent levels of stereocontrol throughout.

Crotyl alcohol was treated with molecular chlorine in the presence of Et4NCl to afford the anti-dichloride 7; presumably this procedure generates Mioskowski's reagent[18] (Et4NCl3) in situ. Oxidation with the Dess–Martin periodinane followed by a careful workup afforded the sensitive and volatile aldehyde 8 in crude form, which was immediately converted to vinyl epoxide 9. The bromoallylaluminum reagent[19] shown added with high diastereocontrol consistent with both the Felkin–Anh and Cornforth models,[20,21] and the resulting bromohydrin was converted to the epoxide upon treatment with aqueous base. The moderate yield in this case might be attributed to volatility of the intermediate aldehyde and the product vinyl epoxide; in related systems with longer alkyl chains, yields of about 75% have been obtained. Although strategically attractive in the context of the chlorosulfolipids, carbonyl addition reactions to α,β-dichloroaldehydes can be plagued by facile elimination reactions, and only Yoshimitsu has previously embraced this type of C–C bond forming reaction en route to these targets.[15] In our studies, we have found that a variety of allylation reagents that presumably react via closed transition states provide products with high levels of diastereoselectivity and without destruction of the sensitive substrate.

The alkene partner 11 required for the convergent step was obtained in two steps from 8-bromo-1-octene. Formylation of the Grignard reagent derived from 10 followed by Takai chloroolefination[22] afforded 11 in multigram scale.

The key convergent bond-formation—Z-selective alkene cross metathesis[23] using the Grubbs cycloadamantyl catalyst 12[24]—generated Z-vinyl epoxide 13 with complete control of alkene geometry. We attribute the relatively low yield in this particular case to catalyst deactivation by the vinyl epoxide; however, this step compares favorably overall with previous syntheses of this type of epoxyalkene via poorly selective Wittig reactions that require several extra steps.[10–12] Unfortunately, we were unable to achieve effectively more than a single turnover with 12;[25] however, this reaction is notable for the ability to directly introduce the vinyl chloride, which eliminates at least three post-convergence steps.[10,15a] The success of the cross metathesis in the face of possible RCM pathways can be attributed to: 1. the intrinsically slow reactivity of vinyl chlorides; 2. the slow kinetics of cyclooctene formation; and 3. the high kinetic selectivity of catalyst 12 for Z-alkenes, which presumably prevents reaction with the E-vinyl chloride in either RCM or cross metathesis events. Vinyl epoxide chlorinolysis with inversion of configuration[11,12] proceeded smoothly under the conditions shown, providing diene 14. Uncertain about the reactivity of the isolated vinyl chloride relative to the particularly electron-deficient allylic chloride in 14, we were pleased to observe a completely chemoselective, highly diastereoselective (93:7 d.r. of crude product, purified to 97:3), and efficient chlorination using Mioskowski's reagent. The generation of hexachloride product 15 constitutes a formal synthesis of mytilipin A, and sulfation of the secondary alcohol according to Carreira's conditions[10] completes the seven step (longest linear sequence) synthesis of racemic chlorosulfolipid. This route has enabled the preparation of over 100 mg of the target molecule to date, with a nearly 9% yield over the entire sequence. Although the final steps of the synthesis are related to those previously reported by us and the Carreira group, our rapid access to 13 takes advantage of a completely new strategy designed for general access to several of the chlorosulfolipids.

The convergent Z-selective alkene cross metathesis to form 13 is noteworthy for its complete diastereoselectivity if not for its efficiency. To see if the extremely high selectivity we observed was general for vinyl epoxides, as well as to investigate the low catalytic activity of 12 with respect to the specific case in Scheme 1, we tested the reactivity of cis-3,4-epoxy-1-undecene (18) with 1-decene (eq 1). With 10 mol% catalyst 12, complete conversion to Z-vinyl epoxide 19 was observed (83% isolated yield, >20:1 Z:E). With 1 mol% catalyst, the product was isolated in 43% yield (incomplete conversion), with equal selectivity. Therefore, it appears that vinyl epoxides are subject to highly Z-selective cross metathesis with catalyst 12, and that the poor efficiency observed in the convergent step to form 13 is likely specific to chlorinated substrates of type 9.

In principle, adaptation of our route to the enantioselective preparation of mytilipin A simply requires access to enantioenriched dichloroalcohol 7. However, methods for the asymmetric dichlorination of alkenes, including the allylic alcohol substrates pertinent to our synthesis, are not yet at a level of sophistication appropriate for the first step in complex molecule synthesis.[26] We contemplated accessing enantioenriched dichloroalcohols using either the stereospecific deoxydichlorination of an optically active epoxyalcohol derivative according to the method of Yoshimitsu,[14] or by resolution. Because it would add only one step to the sequence, we opted to investigate resolution strategies. Unfortunately, attempts at kinetic resolution of dichloroalcohol 7 (and dichloroaldehyde 8) using a variety of approaches were unsuccessful; however racemic vinyl epoxide 9 could be resolved by adapting the meso-epoxide desymmetrizing chlorinolysis of Denmark and co-workers (Scheme 2).[27] The strong preference for ring-opening of the vinyl epoxide at the allylic position (as opposed to the position proximal to the electron-withdrawing chloride residues) is presumably key to success; a selectivity factor of 13 was realized, allowing for material of 93.5:6.5 e.r. to be obtained at 57% conversion (by NMR analysis) and in 43% isolated yield.[28] On the basis of this result, we have defined an eight-step enantioselective synthesis of mytilipin A.[29,30] More details about this interesting resolution will be forthcoming in a full account.

A few short years ago, the highly chlorinated lipids shown in Figure 1 might have appeared to be intractable problems for chemical synthesis, because of the dearth of previous work on stereochemically complex polychlorinated compounds. Now, with the recent advances made by several groups,[10–16] and with the design and execution of our new direct synthesis described here, it has become clear that the chlorosulfolipids can be assembled in a relatively straightforward fashion. The synthesis of racemic mytilipin A that we report requires only seven linear steps from commercially available starting materials and features only productive chemical transformations. Using kinetic resolution of a vinyl epoxide, enantioenriched chlorosulfolipid can be obtained with only one additional operation. Furthermore, our synthesis demonstrates that α,β-dichloroaldehydes can participate in efficient and highly stereoselective carbonyl addition reactions, and that Z-selective alkene cross metathesis is a powerful method for convergent olefination en route to the chlorosulfolipids. The successful application of these catalysts in this context further documents the ever-expanding reach of metathesis processes for stereocontrolled natural product synthesis.

Answer: The chlorosulfolipid mytilipin A has been synthesized in racemic form in only seven steps and in enantioenriched form in eight steps. Key transformations include a highly diastereoselective bromoallylation of a sensitive \xce\xb1,\xce\xb2-dichloroaldehyde, a kinetic resolution of a complex vinyl epoxide, a convergent and highly Z-selective alkene cross metathesis, and a chemoselective and diastereoselective dichlorination of a complex diene.


Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
anterior cruciate ligament ( acl ) has a primary role in the limitation of anterior translation of the tibia as regards to the femur .
they are also important for the compensation of stability in the acl in the knee lesions and patients with acl .
the hamstring muscle weakness and hamstrings weak relationship with the quadriceps are risk factors for acl injuries .
one of the most commonly used treatments is the method in which knee flexor tendons are used as autograft . as shown in previous studies , after using this method reconstructed knee recovered up to the 90% of flexion muscle strength of counter knee ( harter et al .
, 1990 ; lipscomb et al . , 1982 ; simonian et al . , 1997 ) .
it is also shown in previous studies that semitendinosus which is also used as acl graft has regeneration potential from more proximal and with similar morphology ( eriksson et al . , 2001 ; ferretti et al .
although there is a development of regeneration close to normal morphology ; knee flexors abnormalities in neurological function can be a barrier to motor units function by preventing their healing .
however , morphological factors such as muscle atrophy in these patients is not the only factor that determines the maximum power ; in previous studies , it is shown that despite the absence of morphological abnormalities the afferent feedback deficiency from acl may interfere with the activation of gamma motor unit of the muscles around the knee ( konishi et al .
even if the knee flexor tendon regeneration is morphologically normal and that motor unit complex may prevent the function of the knee flexors by causing neurologic abnormalities .
therefore , while comparing knee flexor muscle strength of patients who underwent acl reconstruction with normal uninjured knee , muscle weakness due to the possibility of neurologic abnormalities can not be ignored .
after acl reconstruction , which muscle groups are more affected from frequently developing thigh muscle atrophy is a matter of debate .
muscle strength tests are used to evaluate recovery of acl after treatment and the effectiveness of treatment .
according to the study carried out , after acl reconstruction using hamstring tendon grafts , weakness in the knee flexor muscle strength can be observed up to 24 months .
in addition , previous studies showed that in patients who underwent acl reconstruction quadriceps muscle torque per unit volume is significantly lower compared the intact knee ( konishi et al . , 2007b ) .
in our study , we aimed to evaluate the effect of thigh circumference difference between patients knees who were administered the acl reconstruction with hamstring tendon autograft and intact knees , on torque between the hamstring and quadriceps muscles .
as is known , development of muscle weakness in quadriceps after acl lesions caused by neurological dysfunction was shown to be a natural consequence . in our study
, we planned to evaluate the effect of thigh circumference difference between operated extremity and intact extremity on knee flexorsmuscle strength .
fifty - five patients ( 54 males , 1 female , mean age 28.156.47 ) who underwent acl reconstruction in our clinic and with at least 6 months follow - up period available were included in our study . while choosing the patients , not having any disease nor interventions previously on intact knees has taken into account .
patients who have symptoms and signs such as discharge , inflammation , instability , locking , limitation of motion , anxiety while exercising were removed from the study .
all operations were applied in teaching and research hospital by the same surgeon . the condition that autogenous hamstring tendon graft usage in acl reconstruction was searched for the patients . in all patients , same postoperative rehabilitation program which is indicated below
for the first week walking with a full load , 090 of passive knee extension , bringing the active flexion , quadriceps and hamstring muscle training , heel shift , straight leg rise ; between 12 weeks , hamstring training in the prone position , asideleg lift , walkingin the water if a swimming pool exist ; between 23 weeks , terminal extension and hamstring stretch studies with weight ; 34 weeks , if knee flexion has reached to 90 the pedals ergonometric work , walking back in the pool ( if possible ) , doing full daily activities ; 612 weeks , rising at finger tips and starting to closed kinetic chain exercises , preparations for the transition to the sport aiming to increase strength , durability and propsiosepsiyo ; in the 3rd month , cycling , running and scissoring in water ; in the 4th month , in addition to weight training activities beginning to proprioceptive and on the stairs activities , doing straight running ; in 68 months beginning to sport - specific movements , ensuring to return to contact sports were taken into account . each patient was laid in the supine position , knees at full extension and relaxed position prior to measurement of the circumference of the thigh muscles .
both thigh circumference were measured and recorded from 15 cm proximal to the upper limit of the patella for measuring . the determined length difference between there constructed knee and the intact knee
power measurements of quadriceps and hamstring muscle groups in patients extremities who underwent operation and who did not in were done by using cybex ii dynamometer ( humac ) . during the measurements the maximum torque ( peak torque ) values at 60/sec , 240/sec infrequency ,
the application of standard equipment , data collection and heating procedures were performed before the measurement .
patients were told to continue their usual daily activities not to do tiring activities in the day before the test . on the test day before the beginning of measurements patients
patients pelvis were stabilized with the help of a belt , thighs were supported with pillows , ankle cuff was placed directly on top of malleolar .
patients forearms were positioned so that the rotational axis of the forearms were aligned with rotational axis of knees . during the test
the range of motion was adjusted to be 0 extension and 90 flexion . in order to get support patients
were allowed to hold seats on the sidebar during the test . before starting the recording of the data patients did three times sample repetition at both angle rates .
concentric exercise were carried out for 5 times in maximal flexion and extension to patients after one minute rest .
first , 60/sec speed after a minute rest the test was continued with 240/sec speed .
several patients developed thigh pain during measurements and measurements were repeated after the test was terminated .
number cruncher statistical system ( ncss ) 2007 and power analysis and sample size ( pass ) 2008 statistical software ( utah , usa ) were used for statistical analysis . besides descriptive statistical methods ( mean , standard deviation , median , frequency , rate , minimum , maximum ) for qualitative comparison of data pearson s chi - square test , fisher - freeman - halton test , fisher s exact test , and yates continuity correction test ( yates adjusted chi - square ) were used for the evaluation of data .
age identifier values and follow - up periods of patients are shown in table 1 .
thigh circumference of intact extremity and operated extremity of patients are shown in table 2 .
peak torque of the mean extensor and flexor muscle strength and percentage values relative to each other , are shown in tables 3 , 4 , and 5 .
statistically significant relationship was observed at the level of 66.0% percent between the thigh diameter difference and cybex extension 60 of patients in negative direction ( while the thigh diameter difference increasing the cybex extension 60 percent decreasing ) ( r : 0,660 ; p=0.001 ; p<0.01 ) .
statistically significant relationship was observed at the level of 55.0% percent between the thigh diameter difference and cybex extension 240 of patients in negative direction ( while the thigh diameter difference increasing the cybex extension 240 percent decreasing ) ( r : 0,550 ; p=0.005 ; p<0.01 ) ( fig .
statistically significant relationship was observed at the level of 55.0% percent between the thigh diameter difference and cybex flexion 60 of patients in negative direction ( while the thigh diameter difference increasing the cybex flexion 60 percent decreasing ) ( r : 0,555 ; p=0.002 ; p<0.01 ) .
it was observed a relation between the thigh diameter difference and cybex flexion 240 of patients in negative direction ( while the thigh diameter difference increasing the cybex flexion 240 percent decreasing ) at the level of 28.1% percent and this situation was found to be statistically significant ( r : 0,281 ; p=0.079 ; p>0.05 ) ( fig .
after our study , in accordance with our findings it is still possible to encounter the thigh atrophy in average 28 months after acl reconstruction surgery even under physical rehabilitation programs and appropriate follow - up . in line with earlier studies , quadriceps muscle mass
is often seen as responsible for the present thigh atrophy , however negative effects of the hamstring muscle group on muscle atrophy which is determined with manual thigh circumference measurements are undeniable .
as shown in previous studies , in patients with acl lesions the development of neurological dysfunction is not available in the knee flexors comparing with quadriceps muscle group .
comparative studies which was done in patients with acl lesion and in patients without any knee problems showed that there was no significant difference between the speed of flexion and torque per unit volume of the knee flexor muscle . despite this ,
in the same study it was found that isokinetic torque that occurred in the knee with acl lesions at 60/sec was less than robust knee ( konishi et al . , 2012 ) .
in addition , it is shown that the acl reconstruction with hamstring tendon is not effective on muscle torque power of knee flexors and flexion speed of these muscles by showing that detection of changes in the robust knee is the same . in the light of these data
, it might lead to think that acl lesions does not cause neurological dysfunction in the knee flexors . in another study
there was a comparison between patients who were administered to the acl reconstruction and patients who did not have any knee problem , it has been identified that muscle torque power on per unit volume of the quadriceps was significantly lower in the patients who were administered to reconstruction .
in addition , quadriceps weakness is associated with the neurologic dysfunction that is developed after acl reconstruction has been shown by other researchers ( hart et al . , 2010 ; rice et al . , 2009 ; snyder - mackler et al .
it has been shown that muscle weakness in the quadriceps that is induced by the acl lesions is a natural result linked to the development of neurological dysfunction . in our study
we have showed the loss of torque power of thigh atrophy on quadriceps at the 60/sec , 240/sec frequency even in the patients who have an appropriate rehabilitation program after acl reconstruction and under going follow - up process .
although , it has been shown in previous studies that acl lesion development in the thigh did not lead to neurological dysfunction on hamstring ; in our measurements , it has been determined statistically that atrophy developed in the thigh is effective on the hamstrings muscle torque power at least as it is on quadriceps , especially 60/sec frequency .
it could not be shown that this weakness is correlated to thigh atrophy as well as quadriceps at 240/sec flexion frequency .
these difficulties are likely to be related to neurological dysfunction occurred in the quadriceps muscles . due to different muscle weakness mechanisms which are developing according to the morphological structure and muscle properties , it is inevitable for the clinician to consider these changes in diagnosis and rehabilitation stages .
the point that we want to emphasize in our study is ; it ca nt be ignored that muscle weakness mechanisms developing in the thigh circumference vary according to the thigh muscle group and knee flexors play an important role in thigh atrophy when determining an appropriate rehabilitation program after anterior cruciate ligament reconstruction application .

Answer:
after anterior cruciate ligament ( acl ) reconstruction , which muscle groups are more affected from frequently developing thigh muscle atrophy is a matter of debate .
 we evaluate the effect of thigh circumference difference between patients knees who were administered the acl reconstruction with hamstring tendon autograft and intact knees , on torque between the hamstring and quadriceps muscles .
 fifty - five patients at least 6 months follow - up period available were included in our study .
 power measurements of quadriceps and hamstring muscle groups in patients extremities were done by using isokinetic dynamometer .
 the maximum torque values at 60/sec , 240/sec in frequency , positions of flexion and extension were determined . in accordance with our findings
 it is still possible to encounter the thigh atrophy in average 28 months after acl reconstruction surgery even under physical rehabilitation programs and appropriate follow - up .
 it is inevitable for the clinician to consider these changes in diagnosis and rehabilitation stages .
 it ca nt be ignored that muscle weakness mechanisms developing in the thigh circumference vary according to the thigh muscle group and knee flexors play an important role in thigh atrophy when determining an appropriate rehabilitation program after reconstruction application .


Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
giant inflammatory ( filiform ) polyposis is an uncommon benign lesion and is usually associated with inflammatory bowel disease ( ibd ) .
long - term inflammation of the colonic mucosa during chronic ibd with alternating periods of ulceration and healing may lead to the formation of finger - like projections [ 1 , 2 ] . in rare cases , a giant inflammatory polyposis forms a large tumor mass [ 3 , 4 , 5 , 6 , 7 ] . on colonoscopy and radiologic studies ,
numerous filiform polyps appear as a  mass of worms or as a  fungating mass ; hence , this condition is easily confused with cancer .
inflammatory polyps or pseudopolyps are the most common lesions observed both in ulcerative colitis ( uc ) and crohn 's disease ( cd ) [ 8 , 9 , 10 , 11 , 12 ] . moreover , in some cases , the polyps contain both mucosal and submucosal tissue , indicating initial inflammatory involvement of the deeper bowel layers .
they are composed of a central core of submucosal connective tissue coated by normal , non - inflamed mucosa . here ,
we report the case of a patient with uc with large tumors obstructing the transverse and descending colon , who presented with severe diarrhea and melena .
a 25-year - old japanese man with an uc history of 2 years and 6 months was successfully treated with prednisolone .
the disease was in remission and his symptoms had been relieved . however , the disease flared up and the patient was admitted to our hospital because of severe abdominal pain and bloody diarrhea .
physical examination revealed direct soreness and masses in the upper and left lower abdominal sites .
blood examination revealed anemia ( hemoglobin level 5.5 g / dl [ normal 11.515.0 ] ) , hypoproteinemia ( protein level 4.6 g / dl [ normal 6.78.3 ] ) and hypoalbuminemia ( albumin level 1.9 g / dl [ normal 3.85.3 ] ) . computed tomography ( ct )
imaging showed bowel wall thickening of the transverse and descending colon , which raised suspicion of wall thickening of several segments of the small bowel .
the ct scan also demonstrated localized high - density areas in the lumen of the transverse and descending colon ( fig .
a colonoscopy revealed a large mass with numerous white - pale reddish polyps of complex shape in the descending colon .
based on this examination , colon carcinoma was strongly suspected , and several biopsies were performed .
histology of the examined sections indicated uncharacteristic inflammatory changes in the mucosa , but no cellular dysplasia .
, we observed one tumor measuring 23  18 cm in the transverse colon and another measuring 14  13 cm in the descending colon .
there were no obvious areas of ulceration , although each tumor had a coral - reef - like surface with numerous soft , finger - like polyps ( up to 5 cm in diameter ) projecting into the lumen .
the cross - section of the tumors showed that narrow strings of tissue were interconnected , forming multiple , variably sized spaces inside the tumors ( fig .
2 ) . the surrounding fat tissue was unaffected , and no suspicious lymph nodes were detected .
microscopic examination revealed that the tumors comprised strings of fibrotic connective tissue , lined by inflamed colonic mucosa , and the surrounding spaces were filled with fecal and mucoid materials .
a fibrovascular core and inflammatory polyposis were evident from the submucosa to the proper muscular layer and the submucosa had partially disappeared in both the elevated and the depressed lesions .
the polyps contained regenerative and hyperplastic muscularis mucosa with an arborized and thickened configuration ( fig .
the crypt architecture was normal , and no epithelial atypia of the polyps was noted . the mucosal inflammation consisted of lymphocytes , plasma cells , eosinophils and lymphoid follicles .
neutrophil infiltration , cryptitis , crypt abscess , which is characteristic of active uc , and paneth cell metaplasia were found in the transverse colon ( fig .
sections through the bowel wall near the mass showed colonic mucosa with regenerative features , including architecturally mildly distorted glands , but without active inflammatory changes ( fig .
finally , histopathological examination of the resected colon led to the diagnosis of giant inflammatory ( filiform ) polyposis associated with uc .
inflammatory polyps are a common complication in patients with ibds such as uc and cd , accounting for approximately 1020% of all cases .
inflammatory polyps may originate from the regenerative mucosa in the remission stage after an acute recurrence of uc or cd . in rare cases ,
numerous large - sized polyps are present , and this condition is known as giant inflammatory ( filiform ) polyposis [ 8 , 9 , 10 , 11 , 12 ] .
these polyps are associated with cd in approximately two - thirds of cases and with uc in one - third of cases .
giant inflammatory polyposis can be localized in one segment of the colon , or numerous polyps can be diffusely involved in the entire colon .
the transverse colon is the most common site , followed by the sigmoid and descending colon , the cecum and the splenic and hepatic flexures . in our case ,
the clinical features of the reported cases indicate that the time from the initial diagnosis of uc to confirmation of giant inflammatory polyposis ranged from 3 to 276 months . in our patient
patients may present with various symptoms , including anemia , weight loss , cramping abdominal pain , diarrhea , passage of blood through the rectum and colonic obstruction .
most patients go undiagnosed until they develop signs and symptoms of obstruction , hemorrhage and anemia [ 1 , 2 , 14 ] .
the pathogenesis of giant inflammatory polyposis is considered to result from enlarged mucosal tags , caused by repeated peristalsis and fecal stream .
giant inflammatory polyposis may be related to postinflammatory regeneration or hyperplastic proliferation of the colonic mucosa between ulcerations .
the histopathological features include inflammatory infiltrates overlying the muscularis mucosae , deep fissure - like ulcers , chronic mucosal inflammation with lymphoid hyperplasia and nerve hyperplasia in the surrounding mucosa [ 1 , 2 , 4 , 5 , 6 , 15 ] .
giant inflammatory polyposis in uc may be a consequence of severe inflammation rather than of increased duration of the disease . in summary , we present the case of a japanese patient with uc who was diagnosed with giant inflammatory polyposis localized in the transverse and descending colon .
severe ulcerative inflammation and its repair process may have caused the development of the giant inflammatory polyps .

Answer:
we report a unique case of giant obstructing inflammatory polyposis associated with ulcerative colitis ( uc ) .
 a 25-year - old japanese man with an uc history of 2 years and 6 months was referred to our institution because of diarrhea and melena .
 his computed tomography scan showed marked dilation of the transverse and descending colon ; therefore , we performed total colectomy .
 macroscopic evaluation of the excised specimen indicated constricting lesions with giant polyposis in the transverse and descending colon .
 the polyposis consisted of narrow worm- or noodle - like polyps that bridged over the irregular ulcers .
 histologic evaluation of the excised specimen indicated transmural inflammation with a thickened proper muscular layer overlaid with inflammatory polyposis . based on these data , a diagnosis of giant inflammatory polyposis
 should be considered in patients who have had uc .
 although giant inflammatory polyposis is considered benign , surgical treatment may be indicated to avoid serious complications .