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:
however , cardiac metastasis is diagnosed in less than 1% of patients with malignant melanoma because less than 10% of these patients present with cardiac symptoms.1 - 3 ) identification of cardiac metastasis from melanoma usually means that the patient is suffering systemic metastasis . unlike typical cardiac metastasized patients , we report a first case of a patient with a metastatic malignant melanoma in the heart without an identifiable primary source or additional metastasis in korea .
a 59-year - old woman was admitted for cough and pleuritic chest pain with no history of malignancy or heart disease . her initial blood pressure was 110/70 mm hg , pulse rate 70 beats / min , respiratory rate 20/min , and body temperature was 36.1. jugular veins were not distended .
laboratory studies , including a complete blood count , liver , and chemical profiles were in normal ranges .
chest computed tomography showed a large amount of pericardial effusion and a mass in the right atrium ( ra ) ( fig .
transthoracic echocardiography showed a large mass measuring 4231 mm in the ra , which did not obstruct tricuspid valve flow .
effusion analysis showed a red blood cell count of 1.910/mm and a white blood cell count of 3300/mm ( lymphocytes , 55% ; neutrophils , 14% ) .
cardiac mri also revealed a large mass surrounding ascending aorta spread into transverse sinus and around pulmonary trunk ( fig .
considering the risk of open heart surgery and poor prognosis of extensive cardiac metastasis , pericardial window operation and epicardial mass biopsy were performed to relieve symptoms and confirm the pathological diagnosis . pathological analysis including immunohistochemistry revealed the final diagnosis to be malignant melanoma ( fig .
positron emission tomography revealed no other distant organ metastasis except for heart and mediastinal lymph nodes .
malignant melanoma has aggressive biological behavior and the greatest tendency for metastasis to the heart.1 ) although autopsy studies reported an incidence of 50% to 71% , cardiac metastasis is diagnosed in less than 1% of patients with malignant melanoma because less than 10% of these patients present with cardiac symptoms.2 ) such metastases most frequently occur after multifocal hematological dissemination and may develop anywhere in the heart.3 ) melanotic metastases can invade the wall of any of the 4 cardiac chambers , and the ra is involved most frequently.4 ) the clinical signs and symptoms of cardiac metastasis are unclear and non - specific , although when present , the clinical signs and symptoms include fatigue , weakness , pericardial effusion , congestive heart failure , cardiac arrhythmia , superior vena cava syndrome , right ventricular outflow and inflow obstruction , and transient ischemic attack.5 ) however , patients with malignant melanoma who have cardiac metastases may present symptoms only caused by tumors in other organ systems . although cardiac involvement occurs during the course of the disease , it is rare that the initial manifestation is cardiac metastasis .
a tumor 's anatomic location and extent of invasion determine the feasibility of surgical intervention , which should optimally be performed during the early stages of the disease.6 ) a complete resection of an intracardiac melanoma prevents potential morbidities that are associated with progressive intracardiac growth , such as superior vena cava syndrome , right ventricular outflow and inflow obstruction , dysrhythmia , cardiac tamponade , and heart failure.6 ) even when total resection is not possible , conservative surgery can relieve symptoms and prevent imminent cardiac failure .
conservative surgery improves the quality of a patient 's life , as in our patient 's case .
although more than 90% of melanomas have a cutaneous origin,7 ) melanomas may sometimes present metastatically in the absence of a primary lesion , termed melanomas of unknown primary origin .
most authors estimate that 2 - 6% of patients are diagnosed with metastatic melanoma of unknown primary site .
in particular , such a metastatic melanoma in the heart such as in this patient without a known primary cutaneous origin is a rare presentation and chiefly an anecdotal finding of metastatic melanoma .
several reported cases can be found in the literature about cardiac involvement with cutaneous primary malignant melanoma and multiple metastasis in korea , as well as worldwide.8)9 ) as far as we know , malignant cardiac melanoma without a primary origin has not yet been reported in korea .
the survival of patients with unknown primary melanoma was demonstrated to be similar to that of patients with known primary tumors when corresponding stages were compared.10 - 12 ) those patients with metastases to any other visceral sites are described to have a 1 year survival rate of 41% and a median survival of approximately 6 months.11)13)14 ) accordingly , we expected that the outcome of this patient might be very unfavorable .
although total resection was not possible because of extensive cardiac metastasis , a pericardial window operation could resolve her symptoms .
after surgery , chemotherapy was planned , including cisplatin , dacarbazine , casmustine , and tamoxifen . however , the patient refused further chemotherapy after completion of two sessions .
as only few reports about cardiac metastasis of malignant melanoma without cutaneous origin have been published , we are uncertain if conservative surgery is associated with prolonged survival and if the role of surgery for survival is worth further investigation .

Answer:
malignant melanoma has a very high propensity to metastasize to the heart . however , melanoma may sometimes present as a metastatic lesion in the absence of a primary lesion , which are called melanomas of unknown primary origin .
 we report a case in which a patient presented with a metastatic maligant melanoma in the right atrium with pericardial effusion and without a primary origin .


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:
many cases of implant placement involve insufficient buccolingual width of the edentulous ridge . the methods used to resolve this issue
are the following : narrow implant placement , horizontal veneer block bone graft , horizontal guided bone regeneration ( gbr ) , and the ridge splitting procedure1,2,3 .
ridge splitting is applied primarily in cases where the bone height is sufficient , but the width is narrow .
the purpose of ridge splitting is to widen the alveolar ridge by taking advantage of the elasticity of bones , and it is frequently performed in the anterior maxillomandibular area .
this surgery restores the morphology of the lingual side of the alveolar bone and obtains not only aesthetic results , but also a housing effect exerted by the cortical bone of the buccolingual side , which improves the osseointegration of implants by providing an ample supply of blood circulation4
. nevertheless , fracture and separation of the buccolingual bone during surgery are potential risks , so it is crucial to minimize these complications .
methods augmenting the alveolar bone to the buccolingual side are often done because ridge splitting involving the use of an osteotome and mallet can induce greenstick fractures of the buccal cortical bone . in the ridge splitting procedure ,
discomfort to patients is often substantial because of malleting , and there is a risk of buccolingual bone fracture when excessive force is delivered .
therefore , the present report introduces and evaluates the clinical results of a procedure that expands the ridge in a stepwise technique using screws of gradually increasing width .
this study was performed after obtaining approval from the institutional review board of the seoul national university bundang hospital ( no .
b-1007 - 105 - 106 ) . in the department of oral and maxillofacial surgery ,
curette , seoul , korea ) , and implants were placed sequentially or simultaneously in 6 patients ( 1 male and 5 females ) .
the age of the patients ranged from 31 to 69 years with a mean age of 55.1 years .
the postsurgical follow - up observation period ranged from 24 to 63 months with an average of 44.7 months .
a midcrestal incision was made in the maxillary and mandibular alveolar bone , and the bone was exposed through the creation of a full thickness flap .
initial drillings were performed in the area of implant placement , and the implant was placed at the proper placement depth using a splitmaster no .
gradually , thicker screws were used relative to the final width and length of the implants .
simultaneous implants were placed with self - tapping and sequential implants were placed with an approximately 3- to 4-month healing period in between . in two cases ,
a groove was created in the alveolar ridge with frios saws ( dentsply implants , mannheim , germany ) or # 15 blades , and alveolar ridge splitting was performed using an osteotome .
then , the implant placement site was expanded to the width of the implant by using expanding screws . in some cases ,
the space between the implants and the bone was filled with graft materials and , if needed , blocking membranes . in one of the ridge expansions
a total of 11 implants were placed : 5 in the maxillary anterior and 3 in the maxillary premolar area.(table 1 ) complications during surgery , such as buccal cortical plate complete fracture , did not develop with the exception of severe edema and post - surgical ecchymosis in one case . in that case ,
osseointegration failure was observed 4 months after the first surgery , so the implant was removed and was replaced immediately . wound dehiscence developed after implant placement , and the implant
after approximately 8 weeks after replacement , a fixed partial prosthesis was installed . during the follow - up observation period , averaging 44.7 months , all 6 patients maintained normal function without any specific problems.(table 2 ) a 31-year - old male patient with a history of right unilateral cleft lip and palate presented to our clinic with a missing right maxillary lateral incisor and alveolar bone loss .
together with orthodontic therapy , a treatment plan was developed that included a symphysis bone graft , oronasal fistula closure surgery , and implant placement .
the first implant surgery was performed after a 6-month healing period following the bone graft . to secure an adequate view , a full thickness flap was created .
the bone height was sufficient for implant placement and the buccolingual width was approximately 3 mm . using splitmaster expanding screws ,
a 4-mm ridge expansion was performed ; subsequently , an implant that was 3.5 mm in diameter and 11 mm in length was placed . to prevent buccal bone fracture ,
on the buccal side , a 2-mm implant thread was exposed , so gbr with xenogeneic bones ( biocera ; osscotec , cheonan , korea ) and barrier membranes ( bioarm ; ace surgical supply , brockton , ma , usa ) was performed in the exposed area . after a 4-month healing period
, the second surgery to maintain the buccal volume was performed through creating a labial pouch and grafting the biocera .
after 3 months of orthodontic treatment for regaining the space of implant prosthesis , a provisional restoration was placed .
after the orthodontic treatment was finished ( nine months after the implant surgery ) , the implant was restored with an all - ceramic crown supported by zirconia abutment post.(figs .
1,2,3,4,5,6 ) a 69-year - old female patient without any history of systemic diseases presented to our clinic with a chief complaint of missing several teeth . under local anesthesia ,
bone height was sufficient for implant placement ; the buccolingual width was as narrow as 3 to 4 mm , bone quality was d3 , and osteoporosis was suspected .
after initial drilling , expansion was performed using splitmaster expanding screws at the left mandibular 2nd premolar and 2nd molar area ; the areas were expanded to 3.8 mm and 4.3 mm , respectively .
two gs ii implants ( osstem , busan , korea ) which were 4 mm in diameter , 11.5 mm in length and 5 mm in diameter , 11.5 mm in length were placed .
as measured by the osstell mentor ( integration diagnostics , savedalen , sweden ) , the primary stability of the implants in the left mandibular 2nd premolar and 2nd molar was 76 and 77 implant stability quotient ( isq ) , respectively .
subsequently , a xenogeneic bone graft ( biocera ) was performed in the space between the bones and the thin area of the buccal side .
the surgery was performed using the one - stage method , and after a healing period of approximately 2 months , the implants were restored with a fixed partial prosthesis.(figs .
a 31-year - old male patient with a history of right unilateral cleft lip and palate presented to our clinic with a missing right maxillary lateral incisor and alveolar bone loss .
together with orthodontic therapy , a treatment plan was developed that included a symphysis bone graft , oronasal fistula closure surgery , and implant placement .
the first implant surgery was performed after a 6-month healing period following the bone graft . to secure an adequate view ,
the bone height was sufficient for implant placement and the buccolingual width was approximately 3 mm . using splitmaster expanding screws ,
a 4-mm ridge expansion was performed ; subsequently , an implant that was 3.5 mm in diameter and 11 mm in length was placed . to prevent buccal bone fracture ,
on the buccal side , a 2-mm implant thread was exposed , so gbr with xenogeneic bones ( biocera ; osscotec , cheonan , korea ) and barrier membranes ( bioarm ; ace surgical supply , brockton , ma , usa ) was performed in the exposed area .
after a 4-month healing period , the second surgery to maintain the buccal volume was performed through creating a labial pouch and grafting the biocera .
after 3 months of orthodontic treatment for regaining the space of implant prosthesis , a provisional restoration was placed .
after the orthodontic treatment was finished ( nine months after the implant surgery ) , the implant was restored with an all - ceramic crown supported by zirconia abutment post.(figs .
a 69-year - old female patient without any history of systemic diseases presented to our clinic with a chief complaint of missing several teeth . under local anesthesia ,
bone height was sufficient for implant placement ; the buccolingual width was as narrow as 3 to 4 mm , bone quality was d3 , and osteoporosis was suspected .
after initial drilling , expansion was performed using splitmaster expanding screws at the left mandibular 2nd premolar and 2nd molar area ; the areas were expanded to 3.8 mm and 4.3 mm , respectively .
two gs ii implants ( osstem , busan , korea ) which were 4 mm in diameter , 11.5 mm in length and 5 mm in diameter , 11.5 mm in length were placed .
as measured by the osstell mentor ( integration diagnostics , savedalen , sweden ) , the primary stability of the implants in the left mandibular 2nd premolar and 2nd molar was 76 and 77 implant stability quotient ( isq ) , respectively .
subsequently , a xenogeneic bone graft ( biocera ) was performed in the space between the bones and the thin area of the buccal side .
the surgery was performed using the one - stage method , and after a healing period of approximately 2 months , the implants were restored with a fixed partial prosthesis.(figs .
since 1990 , it was widely used and referred to in the literature with various terms such as ridge widening , the split crest procedure , and staged ridge splitting5 .
generally , this surgery induces a greenstick fracture in the narrow alveolar ridge with an osteotome .
the procedure forms an implant bed and facilitates the placement of implants with wide diameter .
in addition , bone regeneration is achieved on both sides , so the bone healing capacity is good ; therefore , sufficient osseointegration can be achieved with relatively small volumes of bone .
furthermore , a 3-month waiting period is required at minimum for distraction osteogenesis and 6 months is required for gbr in implant placement . on the other hand , after performing ridge splitting , the first placement surgery can be performed on the same day or within the month .
it is still controversial as to whether a bone graft is required for the space generated after splitting . in simultaneous implant placements ,
it has been reported that in cases with bony gaps smaller than 3 mm , bone graft materials other than collagen sponges are not required7 .
also , implants placed in the space between expanded bones are protected from biodynamic external loading .
furthermore , bony compaction effects can occur as a result of the compression of bony trabeculae . nonetheless , this surgery is a method that uses bone elasticity , so it can only be performed in cases with cancellous bone within the cortical bone on both sides .
therefore the indications of this procedure might be limited when compared with gbr or onlay graft that could be applied in a cancellous bone - deficient area . in cases where the width of the basal bone is too narrow , the primary stability or the slope of edentulous alveolar bone
it has been reported that cases with a residual width of more than 4 mm are ideal for the procedure ; in cases with a width of 3 mm or less , other bone graft procedures should be additionally performed , and the implant should be placed after a certain healing period6 .
moreover , it has been reported that ridge splitting is a procedure that should be applied primarily to the maxilla , as the outcomes are poor in the mandible due to the abundance of cortical bone7 .
however , it has also been reported that if the characteristics of the mandible are well understood and slow expansion is performed manually rather than with a mallet , then successful results can be obtained7 .
chiapasco et al.8 demonstrated gradual bone expansion of 1 mm per day for 4 - 5 days using screw - type tools in the mandible .
chan et al.10 reported that the mean increased ridge width was 0.79 mm in a cadaver study on the ridge width gain through the use of screws . in this study , even in the mandibular molar area , the bone width was expanded to a maximum of 4.3 mm using expanding screws and simultaneously placing implants . even though some of case reports reported the occurrence of cortical bone greenstick fracture after surgery , the separation of bone fragment caused by the occurrence of complete fracture was not reported .
one year after functional loading , good results without the gingival recession or alveolar bone resorption were obtained . in a case with poor d4 bone quality ,
the compaction effect of the bony trabeculae using screw - type tools was observed and resulted in effective primary stability of the implants . in several reports ,
a 97.0%-97.6% success rate of ridge splitting was reported ; however , cortical bone fracture , resorption of the alveolar ridge , nerve injury , and other complications may occur11,12 .
buccal cortical bones are fractured in many cases , particularly when ridge splitting is performed in the mandible with hard bone quality , and this will induce resorption of the alveolar ridge during the bone remodeling process .
the screw - type tools used in this study deliver relatively low amounts of force .
the bone was also expanded sequentially in the deep area , and it was considered to be more effective in preventing cortical bone fracture . in addition , the conventional malleting process was minimized , thereby minimizing head echo and the resulting headaches , injury to the temporomandibular joint , and others .
jensen et al.6 reported that mucoperiosteal elevation should be performed minimally in ridge splitting , and that the use of partial thickness flaps show good results . in this study , and in cases involving the maxillary anterior area where esthetics are required , full - thickness flap elevations were performed in the alveolar ridge and slightly below it .
the ridge expansion technique mentioned in this case report is slightly different from the existing ridge splitting technique .
the ridge splitting technique is a methodology to increase the ridge width by performing the ridge splitting using a chisel after the formation of a groove at the center of ridge crest using a saw or surgical bur and is mainly used in the maxilla .
if the ridge splitting technique is performed in the mandible composed of mainly cortical bone , then it runs the risk of cortical bone fractures . whereas , the ridge expansion technique is a stepwise technique using screws of gradually increasing width , so it has a lower risk of cortical bone fracture than the ridge splitting technique
therefore , ridge expansion technique is considered to be an acceptable method to use on the mandible . in this study ,
one case involving implant placement in the maxillary anterior area developed a complication of failed osseointegration .
however , implant replacement was performed immediately after removal , and successful prosthesis treatments were completed .
buccal cortical bone fracture did not occur in any of the cases . even after the prosthesis were functioning , all adjacent alveolar bones and soft tissues remained stable .

Answer:
implants are typically placed after performing ridge expansion by inserting screws of gradually increasing thickness and good clinical outcomes are often obtained .
 we placed 11 implants in 6 patients , and one implant failed during osseointegration but it was replaced immediately after removal and successful prosthetic treatments were completed . during these surgeries , buccal cortical plate complete fractures do not occur .
 inserting screws for ridge expansion is a successful and predictable technique for implant placement in narrow alveolar bone .


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:
Substoichiometric inhibition of A\xce\xb21-40 aggregation by a tandem A\xce\xb240-1-Gly8-1-40 peptide

Paper sections:
1. INTRODUCTION

The aggregation of amyloid-Î² (AÎ²) is believed to be associated with the onset of Alzheimer's disease and there have been numerous studies of compounds that affect the aggregation process. A large number of compounds have been observed to inhibit aggregation and these have generally been grouped into three classes: those that inhibit oligomerization, those that inhibit oligomerization and fibrillization and those that inhibit fibrillization only (1-9). Among these studies, several investigators have used small peptides that would be expected to bind to full length AÎ² but would be unable to form any structure that could serve as a template for subsequent monomer (or oligomer) addition (10,11). These latter studies were based on the observation of Tjernberg et al. (12) which suggested that the central region of the AÎ² peptide (residues16-20) was responsible for the self-association and subsequent aggregation. These inhibitory peptides include those that are N-methylated (13,14) or cross-linked by a disulfide bond (15) or linked to an oligolysine (16). In general, such small peptides are indeed effective in preventing either oligomer formation or aggregation (17, 18) but the concentration of the peptide inhibitors required to prevent aggregation is high suggesting that the binding of the peptide is weak. Recently, Taylor et al. reported a class of retro-peptides which inhibited aggregation of either AÎ²1-40 or AÎ²1-42 at substoichiometric concentrations (19).

Here we report a novel approach to affect aggregation by using a tandem peptide consisting of two AÎ² molecules linked by a glycine linker in such a way to give the tandem peptide construct NH2-AÎ²40-1-(Gly)8-AÎ²1-40-COOH. In this construct the N-terminal AÎ²40-1 peptide has the reverse sequence of wild-type AÎ² while the C-terminal AÎ² peptide has the forward sequence.

2.1 Preparation of the Tandem peptide and A\xce\xb21-40

In our studies both AÎ²1-40 and the tandem peptide were prepared as a fusion proteins as recently described by Garai et al. (20). The fusion protein of the tandem peptide was purified from inclusion bodies after dissolving in 6 M guanidine-HCl (GdnHCl), passed over a Ni2+-column and refolded on a Sephacryl S100 column in 25 mM HEPES with 100 mM NaCl at pH 7.5. The fusion protein eluted from the S100 column in two main fractions, one monomeric (60%) and the other multimeric (40%). Both fractions were treated with Factor Xa (New England Biolabs,USA) for 6 hrs at room temperature in 25 mM HEPES, pH 7.5 and 100 mM NaCl, using a ratio of Factor Xa to fusion protein of 1:100 (w/w). After cleavage, the peptide was precipitated with 200 Î¼M ZnCl2, dissolved in 6 M GdnHCl and purified by HPLC. The tandem peptide eluted at 33.5-35% in an acetonitrile gradient, was lyophilized and stored at -20 Â°C. The yield of tandem peptide was 1mg/6L cell culture and showed a typical tyrosine fluorescence spectrum. Mass spectrometry of the purified material showed a single peak at a molecular weight of 9097.64 Da compared to the theoretical expected average isotopic mass of 9098 Da (supplementary figure S1). The peptide concentrations were measured by absorbance using values of 1450 M-1cm-1 and 2900 M-1cm-1 at 276 nm for AÎ²1-40 and the tandem peptide, respectively.

2.2 Preparation of Peptide Solution and ThioflavinT assay

The time course of aggregation in the presence and absence of the tandem peptide was measured by Thioflavin T (Figure1). For these experiments, AÎ²1-40 and the tandem peptide at concentrations of 200 Î¼M and 50 Î¼M respectively were dissolved in 5 mM NaOH. A 50 mM borate stock solution at pH 7.8 was then added to this solution to lower the pH to 8. The final concentration of borate buffer was kept at 25 mM. The solution was centrifuged at 14000g for 20-30 minutes and the supernatant solution was used for the experiments. Varying concentration of AÎ²1-40 and the tandem peptide were incubated at 37 Â°C and the extent of aggregation was measured by Thioflavin T.

For ThioflavinT assay, 20 Î¼l of the peptide solution was added in 1ml of glycine buffer (50 mM, pH 9.0) containing 10 Î¼M of ThioflavinT. Solutions were excited at 450 nm and emission was recorded at 490 nm. Before each reading a blank containing no peptide solution was taken to check the baseline. Between each reading the cuvettes were thoroughly rinsed with distilled water and dried to avoid any contamination.

2.3 Atomic Force Microscopy (AFM) of Amyloid fibrils

For AFM studies, 75 Î¼M AÎ²1-40 in the presence and absence of 3 Î¼M tandem peptide was incubated for 4 days at 37 Â°C in 25 mM borate buffer at pH 8.0. 5Î¼L of sample was diluted 20-fold with distilled water and allowed to settle on the freshly cleaved mica surface for 30 min. The majority of the solution was drawn off and the samples dried for 10-15 minutes in vacuo. The images were recorded using AFM MFP-3D-BIO (Asylum Research, Santa Barbara) with a scan resolution of 512Ã512 points/scan at a scan speed of 1 Hz.

2.4 Circular Dichroism Spectra of Tandem pepitide

For secondary structural analysis with CD, a tandem peptide stock solution (50 Î¼M) in 5 mM NaOH solution buffer was diluted 5-fold into 200 mM phosphate buffer at pH 8.0.The CD scans were recorded immediately after dilution using a Jasco J-715 spectropolarimeter. Ten scans from 200 to 260 nm with speed of 20 nm/minute were averaged. A buffer blank was performed under the same conditions and the final spectra were analyzed after buffer blank subtraction.

3.1 The ThioflavinT assay

Figure 1A shows that the onset of fibrillization in the presence of the tandem peptide at a tandem pepide:AÎ²1-40 molar ratio of 1:25 is delayed about 2-fold. At a tandem peptide:AÎ²1-40 molar ratio of 1:10 (Figure 1B), no fluorescence increase is observed after 350 hrs compared to the fibrillization being complete by 175 hrs in the absence of the tandem peptide. The concentrations of AÎ²1-40 used in these experiments are 50 Î¼M and 65 Î¼M respectively, while those of tandem peptides are 2 and 6.5 Î¼M, respectively. As a control experiment, two reference samples containing 2 Î¼M and 6.5 Î¼M of tandem peptide alone were kept under the same experimental conditions. Neither increase in ThioflavinT signal nor any precipitation was observed even after 12 days of incubation.

3.2 Atomic force Microscopy

Figure 2 shows AFM images of AÎ²1-40 in the absence and presence of tandem peptide at a 1:25 ratio. Figure 2A clearly shows large fibrils (~20 Î¼m in length) in the absence of the tandem peptide after 4 days of incubation while no fibril formation was observed in the presence of the tandem peptide (Figure 2B).

3.3 Circular Dichroism spectra of the Tandem peptide

The CD spectrum of the tandem peptide showed a characteristic minimum at 216 nm suggesting a high Î²-sheet propensity (Figure 3). Interestingly, when the tandem peptide was kept for 4-5 days under these conditions at concentration ~10 Î¼M no increase in ThioflavinT signal was observed.

4. Discussion

The experimental results clearly indicate a sub-stoichoimeric inhibition of AÎ²1-40 fibrilization by the tandem peptide. The present study represents a different and unique approach to study the aggregation mechanism of AÎ². The results presented here not only suggest a mechanism for AÎ²1-40 aggregation but also a general procedure for inhibiting other aggregation processes. The substoichiometric inhibition suggests first that the tandem peptide is binding to a form, presumably an oligomer, which is on pathway to form fibrils, and which is present in only low concentration. From the CD data, the tandem peptide shows a high Î²-sheet propensity which might allow specific binding to an intermediate directly involved in fibrillization pathway. On the other hand, it is known that reverse sequence AÎ²40-1 has different properties than that of normal AÎ²1-40. For example, Giordano et. al., have suggested that both the nature of aggregates formed and the mechanism of toxicity differs between the peptides containing the forward and reverse sequences (21). The reverse sequence AÎ²40-1 forms globular aggregates in contrast to the forward sequence which is fibrilar (21). This is indeed what we see in AFM when the tandem peptide aggregates at higher concentration (â¥ 25Î¼M) (supplementary figure S2).

Jan et al. (22) have shown that while AÎ²1-40 appears to retard the formation of mature AÎ²1-42 fibrils, the reverse sequence AÎ²40-1 does not affect fibrillization of protofibrillar AÎ²1-42 indicating the specificity of the interaction. Thus in the complex formed by tandem peptide and the on pathway oligomer(s) involved in fibrilization, the reverse sequence present in the tandem peptide may not allow monomer addition thereby preventing further aggregation.

5. Conclusion

These studies suggest a new approach for understanding the mechanism of fibrillization of intrinsically disordered proteins. Such studies are first of its kind and various permutation of such sequence attachment in AÎ² is presently being pursued in our lab to check their effects on fibrilization. We are also currently in process of implementing tandem constructs in vivo to check its effect on aggregation of AÎ² inside neuronal cells.

Answer: A\xce\xb2 peptides aggregate to form insoluble and neurotoxic fibrils associated with Alzheimer\'s disease. Inhibition of the aggregation has been the subject of numerous studies. Here we describe a novel, substoichiometric inhibitor of A\xce\xb21-40 fibrillization as a tandem dimeric construct consisting of A\xce\xb240-1 (reverse sequence) linked to A\xce\xb21-40 via an eight residue glycine linker. At molar ratios of the tandem peptide to A\xce\xb21-40 of 1:10 to 1:25 inhibition of fibrillization, as measured by Thioflavin T, was observed. We postulate that the tandem construct binds to a fibrillar intermediate but the reverse sequence delays or prevents further monomer association.


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:
we are also grateful to darby proctor for useful comments on a previous version of the manuscript .
the present study was approved by the ethics committee of azabu university ( japan ) ( no .
1303042 ) . this research was supported by the jsps research fellowships for foreign researchers ( no .
p10311 ) and the mext grant - in - aid for scientific research ( no .
26380981 ) to t. r. , the mext grant - in - aid for challenging exploratory research ( no .
23650132 ) to t. h. , and the grant - in - aid for scientific research on innovative areas ( no .

Answer:
in a recent paper,1 we examined whether oxytocin in the domestic dog modulates the maintenance of close social bonds in non - reproductive contexts . we found that exogenous oxytocin promotes positive social behaviors not only toward conspecifics , but also toward human partners .
 here we examined in further detail the effect that oxytocin manipulation has on social play . when sprayed with oxytocin ,
 subjects initiated play sessions more often and played for longer periods of time than when sprayed with saline . furthermore , after oxytocin nasal intake dogs displayed play signals more often than after saline administration , suggesting that oxytocin enhances dogs ' play motivation . to our knowledge
 , this study provides the first evidence that oxytocin promotes social play in the domestic dog .
 we use these results to hypothesize on the potential therapeutic use of oxytocin for promoting social behaviors and treating social deficits in the domestic dog .


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 a : icr ( crl : cd1(icr ) ) and b : icr ( tac : icr ) mice were purchased from two different commercial laboratory animal breeding company in korea .
the mice were housed in a pathogene - free animal facility under a standard 12 h light / dark cycle , maintained in conventional housing conditions at 221 and 5010% relative humidity .
all mice were provided with ad libitum access to standard irradiated chow diet ( purina rodent chow 38057 ) consisting of moisture ( 9.03% ) , crude protein ( 21.52% ) , crude fat ( 5.03% ) , crude fiber ( 4.33% ) , crude ash ( 6.31% ) , calcium ( 1.18% ) , and phosphorus ( 0.35% ) and drinking water .
all animal procedures were conducted in accordance with guidelines of the institutional animal care and use committee , national institute of food and drug safety evaluation ( nifds , cheongju , korea ) .
phylogenetic trees were constructed using the dnapars program of phylip ( phylogeny inference package ) version 3.695 ( http://evolution.genetics.washington.edu/phylip.html ) based on alignment of snps .
seqboot and condense programs of the phylip package were used in bootstrap analysis of 100 resamplings of the data sets .
measurement of body and organ weights was made based on the methods of the international mouse phenotyping consortium .
hematological analysis was determined using by advia 2010i hematology system with autoslide ( siemens , germany ) .
clinical chemical parameters were measured from a single serum sample using a hitachi 7100 automatic analyzer ( hitachi , japan ) .
we noticed that korl : icr had a significant increase in the litter size of the second litter as compared with the first litter .
therefore , the number of offspring of the first litter was taken as to litter size .
time to delivery represents the time period from mating to birth and fertility rate represents a ration between number of female mice giving birth and those used for mating .
cages were observed three times per week and the number of pups born dead or alive and the number of pups weaned in each cage was recorded .
statistical changes in all data were determined using one - way analysis of variance ( anova ) .
the a : icr ( crl : cd1(icr ) ) and b : icr ( tac : icr ) mice were purchased from two different commercial laboratory animal breeding company in korea .
the mice were housed in a pathogene - free animal facility under a standard 12 h light / dark cycle , maintained in conventional housing conditions at 221 and 5010% relative humidity .
all mice were provided with ad libitum access to standard irradiated chow diet ( purina rodent chow 38057 ) consisting of moisture ( 9.03% ) , crude protein ( 21.52% ) , crude fat ( 5.03% ) , crude fiber ( 4.33% ) , crude ash ( 6.31% ) , calcium ( 1.18% ) , and phosphorus ( 0.35% ) and drinking water .
all animal procedures were conducted in accordance with guidelines of the institutional animal care and use committee , national institute of food and drug safety evaluation ( nifds , cheongju , korea ) .
phylogenetic trees were constructed using the dnapars program of phylip ( phylogeny inference package ) version 3.695 ( http://evolution.genetics.washington.edu/phylip.html ) based on alignment of snps .
seqboot and condense programs of the phylip package were used in bootstrap analysis of 100 resamplings of the data sets . the neighbor program of phylip
measurement of body and organ weights was made based on the methods of the international mouse phenotyping consortium .
hematological analysis was determined using by advia 2010i hematology system with autoslide ( siemens , germany ) .
clinical chemical parameters were measured from a single serum sample using a hitachi 7100 automatic analyzer ( hitachi , japan ) .
we noticed that korl : icr had a significant increase in the litter size of the second litter as compared with the first litter .
therefore , the number of offspring of the first litter was taken as to litter size .
time to delivery represents the time period from mating to birth and fertility rate represents a ration between number of female mice giving birth and those used for mating .
cages were observed three times per week and the number of pups born dead or alive and the number of pups weaned in each cage was recorded .
statistical changes in all data were determined using one - way analysis of variance ( anova ) .
the phylogenetic trees based on distance , the minimum genetic distance of korl : icr and other icr showed a genetic structure with three main clusters ( figure 1 ) . from these distance matrices , one can infer the nature of the identified stock differences and the genetic relationships between them .
this indicated that b stock has small genetic diversity compare with a stock and korl stock , and there is large genetic diversity between a stock and b stock .
we measured litter size , body weight , body length , various organ weight , hematology and clinical blood chemistry of the korl : icr compared to other icr .
mouse phenotype analysis , body weight of korl : icr , a : icr and b : icr has been measured during the designated developmental periods ( 3 weeks to 12 weeks ) .
korl : icr and other icr mice experienced similar in body length as well ( figure 2b ) .
female korl : icr mice were experiencing a significant increase in liver , heart and kidney weight compared to a : icr , but no difference with b : icr was observed ( figure 2c ) .
male korl : icr mice had a significant increase in liver , spleen and testis weight compared to a : icr ( figure 2d ) .
the mean litter size of korl : icr mice was 14.52.9 which was higher than commercial icrs ' ( table 1 ) . otherwise , there are no significant differences among the biological phenotypes of korl : icr and other icr .
as summarized in table 2 , 3 , some hematological and biochemical parameters have been observed with sporadically significant differences .
laboratory mice are the essential resource to identify the potency and safety of the drugs and estimate the potency and adverse effects of drugs during the developing stage . according to the effectuation of the nagoya protocol , laboratory mice are not only indispensable for life science studies but also are being considered as important resource . among laboratory mice ,
icr mice are most popular outbred mice broadly used in various fields like toxicology , oncology , pharmacology , pharmaceutical products safety test , and etc . .
swiss mice , that were crossed in 1926 and then adopted by the institute of cancer research in 1974 ( subsequently merged with
commercial production of icr by companies began in 1959 , and the strain was made available to academic and commercial breeders .
currently , many breeders worldwide have possessed their own icr stocks and the icr stocks have been reproduced for their academic or commercial purpose .
the opinions that there might be possible to have differences among icr mice already ensured in various regions of world which have been raised for long term and among mice of the identical stock bred by different breeders have been proposed in some point of view , but there are not sufficient evidences to support these yet .
even though outbred mice are hard to realize the reliability and the repeatability , they are consider to be worked as better resource when the test result is applied to human due to the genetic diversity if compared to inbred mice .
in addition , the advantage of using the icr stocks is extremely high in reproduction rate than the other outbred mice so that it may help the study cost effective .
every icr breeder has adopted and being bred these following common protocols : maintain icr stocks as long as possible , maintain genetic diversity as possible by composing multiple colonies , and minimize the genetic drift .
this study is carried out to establish scientific supports how different in aspect of normal growth curve , breed grad , and clinical blood chemical analysis to ensure the characterization data of icr stock mouse which have been bred by circulation breed approach for more than 50 years .
the breed capacity of both korl : icr mice and commercial icr mice were identified .
the mean litter size of the korl : icr mice were higher than other icr mice . between monthly litter size and litter size per number of pregnancy of the korl : icr mice did not experience a significant difference , but the size of second and third litter were higher than first and fourth litter ( data not shown ) .
the korl : icr mice were having median value of between a : icr and b : icr in a basic phenotype analysis . to tests
evaluation of reactivity drugs , their behavioral changes were observed after administering caffeine and chlorpromazine which activates the central nervous system ; it was possible to identify that the recovery rate of the korl : icr was similar to other icr mice ( data not shown ) .
korl : icr was deduced that there was no significant difference with commercial icrs , and some weight gaps of the organs might be dependent the breeding condition ( feeds , the breeding place ) .
since the comparison studies on laboratory mice have not been remarkably activated , we have faced the difficulty of comparing the study result at this moment .
( 2016 ) suggested that three icr groups , the korl : icr , a : icr and b : icr derived from different sources have an overall similar response of body weight , histopathological structure and inflammation to gastric ulcer inducers .
alcohol induced ulcer model comparison assessment for reviewing the characteristics of the korl : icr were having similar result
. however , the result would be more appropriate to compare with control group rather than the comparison of the absolute value because of a significant difference in certain enzymes .
another implication of the study is that references data ( breeding rate and basic phenotype ) regarding the korl : icr are secured and can be shared with the other researchers .
the korl : icr stocks have been used for decades in terms of conducting lot release project and more , in the national institute of food and drug safety evaluation . in conclusion , we will study secure general documents needed to have as mice resource through this accumulation of various experimental data .

Answer:
mouse is a commonly used animal in life science studies and is classified as outbred if genetically diverse and inbred if genetically homogeneous .
 outbred mouse stocks , are used in toxicology , oncology , infection and pharmacology research .
 the national institute of food and drug safety evaluation ( nifds ; former the korea national institute of health ) have bred icr mice for more than 50 years .
 we investigated to provide users with information and promote accountability to the korl : icr . to secure
 the indigenous data , biological characteristics of korl : icr were identified by comparing with other icr stocks .
 this domestic icr stock was denominated as
 korl : icr. phylogenetic analysis using snps indicated that the population stratification of the korl : icr was allocated different area with other icr .
 in addition , we measured litter size , body weight , body length , various organ weight , hematology and clinical blood chemistry of the korl : icr compared to other icr .
 otherwise , there are no significant differences among the biological phenotypes of korl : icr and other icr .
 these results suggest that as a genetically indigenous source colony , the korl : icr is seperated ( or independent ) stock with other icr . also , we confirmed that there is no difference among the korl : icr and other icr on biological phenotypes .
 therefore , the korl : icr source colony might be a new stock in distinction from other icr , it is a good milestone in securing ownership of the national laboratory animal resource .
 the nifds expects that the korl : icr mice will be useful animal resource for our domestic researchers .


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 analysis is based on food consumption data collected in nine european countries : denmark , finland , germany , ireland , italy , poland , spain , the netherlands , and united kingdom .
the data were collected by an international life science institute ( ilsi ) europe expert group ( 9 )
. the selected micronutrients are vitamin a , retinol , vitamin d , vitamin e , niacin , vitamin b6 , folate , calcium , magnesium , iron , zinc , phosphorus , iodine , selenium , and copper .
data reflect intakes from natural sources plus mandatory fortification ( practiced in denmark , ireland , and poland )  other fortification and supplements are not included .
the survey methods comprise seven - day records or diaries with estimated or weighed amounts of foods ( denmark , ireland , italy , and uk ) and 24 ( poland ) or 48-hour recall ( finland , the netherlands , and spain ) .
germany used a modified diet history and the dutch and spanish recalls were supplied with semiquantitative food frequency questionnaires . the data from spain and the netherlands have been adjusted to correct for short registration period ( 9 ) .
  national dietary surveys with information on year , methodology , survey size , and age range intake of nutrients was calculated using national food composition databases .
the intake data provide data from four groups : children 410 years , children 1117 years , adult women , and adult men .
the analytical process included steps 2 and 3 of the following four steps for each of the selected vitamins and minerals and for each selected gender and age group : calculation of mean intakes from each of the dietary surveys ( an estimate of mean european intake).calculation of the ratio between the 95th percentile and mean intake in each survey.calculation of the average of the ratios.calculation of the common estimate for high intake as the product between steps 1 and 3 ( an estimate of european 95th percentile intake ) .

calculation of mean intakes from each of the dietary surveys ( an estimate of mean european intake ) .
calculation of the common estimate for high intake as the product between steps 1 and 3 ( an estimate of european 95th percentile intake ) .
average ratios for each country and the overall average arranged in ascending order are shown in table 2 .
the results show that for each nutrient the ratio has approximately the same value from one survey to another , implying that the ratio between high and average intake of micronutrients follows a regular pattern across countries and survey methods .
the polish ratios are systematically higher than those of the other countries due to the short registration period , which causes a wider intake distribution .
the spanish and to some extent also the dutch ratios are lower than the others probably because of adjustment of primary data . in the present analysis
average of ratios ( p95:mean intakes ) from national dietary surveys in nine european countries intake is not reported .
note : the overall average is based on ratios from all gender and age groups , i.e. normally four ratios from each country .
overall , the ratios can be divided into three categories : one category with overall ratios of the 95th percentile and mean intake between 1.48 and 1.58 ; this range in ratios is close to the energy ratio ( 1.45 ) and includes the nutrients : magnesium , phosphorus , zinc , iron , vitamin b6 , niacin , and folate.another category has overall ratios in the range between 1.67 and 1.79 and includes the nutrients : calcium , selenium , vitamin e , iodine , and copper.a third category has overall ratios in the range of 2.072.32 and comprises the nutrients : vitamin a , vitamin d , and retinol.in table 3 , ratios of energy and micronutrients for young and older children , and adult females and males are presented .
ratios for the group of young children tend to be slightly lower than the ratios for adults .
the intake distributions of children aged 1117 years are wider and thus the ratios higher because of a wider range in energy requirements in this group .
an exception from this tendency is the ratios of vitamin a , vitamin d , and retinol , which are lower than other group values .

one category with overall ratios of the 95th percentile and mean intake between 1.48 and 1.58 ; this range in ratios is close to the energy ratio ( 1.45 ) and includes the nutrients : magnesium , phosphorus , zinc , iron , vitamin b6 , niacin , and folate .
another category has overall ratios in the range between 1.67 and 1.79 and includes the nutrients : calcium , selenium , vitamin e , iodine , and copper .
a third category has overall ratios in the range of 2.072.32 and comprises the nutrients : vitamin a , vitamin d , and retinol .
average of ratios ( p95:mean intakes ) from all counties divided into age and gender groups note : figures in parentheses are the number of countries contributing to the average .
the results of the present study show that the ratio between high and mean intake for each micronutrient is fairly stable from one survey to another .
the similarity occurs despite differences in dietary habits across countries and despite several differences of methodological nature ( type of dietary survey , food composition data base , sampling procedure , etc . ) .
this similarity probably reflects the biological nature of eating and eating a variety of foods .
we divided the ratios into three rough categories in an attempt to explain the findings .
since most nutrients are widely distributed in rather low concentrations in many foods , their ratios are close to the ratio between the 95th percentile and mean energy intake ( category 1 ) . in category 2 ,
intakes still follow energy intake but the intake distribution may be influenced by a few foods , which are important nutrient sources and has a skewed intake distribution , e.g. milk , which is the major source of calcium .
the third category includes highly skewed intake distributions due to only a few significant food sources of the micronutrient in question .
this effect may explain why the ratios for vitamin a , retinol , and vitamin d are lower among the children aged 1117 years than the three other groups , probably reflecting that most teenagers dislike fish , liver , and carrots  foods very rich in these nutrients .
the only identifiable factors clearly affecting the ratios are the length of registration period and modification of primary data . because of the pragmatic purpose of this study and because excluding , i.e. polish data does not change the overall ratios much , we decided to accept all survey results .
the reason for this was the assumption that most underreporters are individuals found in the lower end of the intake distribution ( i.e. below mean intake ) and that the pattern of underreporting is the same in all populations . if the intakes of underreporters were increased to true levels , the intake distribution would be narrowed probably without any significant increase in levels of high intakes .
this means that the mean values will increase and the ratio p95/mean will be reduced .
the final product between the overall higher mean and lower ratio will be approximately unchanged .
we are fully aware of the limitations of the applied procedure where we used aggregated micronutrient data . with access to the individual data from each country
but even if the calculations are not mathematically ( statistically ) correct they will still create an estimate of high intake , which is sufficiently valid for the purpose of the present study .
the uncertainty is hardly any larger than that of results from any of the single surveys .
one could argue that simply calculating the average of 95th percentiles would be a more simple and direct way to a common estimate of high intake .
this is true and the results would probably be close to the results calculated via the ratios .
another argument against the present approach is the use of mean instead of median values . but using the ratio between 95th percentile and median did not change the final results ( results not shown ) and since it is important to find figures that will satisfy all member states in the eu , we suggest the use of mean values instead of median values . using the present method
makes it possible to include mean intake estimates from dietary surveys that are not able to describe the intake distribution .
this will allow us to use data from all or at least most european countries and thus increase the acceptability of the results across all eu member states .
flynn et al . ( 4 ) used a different approach in their model for calculating safe additions to foods .
they expressed in each survey the high intakes ( 9097.5th percentiles ) as multiples of recommended intakes and used the mean of these multiples as a representative value .
however , this method does not allow use of results from surveys giving only mean intakes . unfortunately the ilsi study does not provide data for all nutrients but we assume that the remaining vitamins and minerals will fit into a similar pattern
. it still has to be shown based on dietary intake data whether this assumption is true , before the proposed model for calculating common european estimates for high intakes of all vitamins and mineral can be implemented in administrative practice .
the average ratio of the 95th percentile and the mean intakes of energy and micronutrients from foods show a remarkable similarity across countries and age groups . for each nutrient it
is possible based on dietary surveys from different countries to calculate a representative european average .
the average ratio of the 95th percentile and the mean intakes is a simple and suitable measure for calculation of an estimate of high intake from an estimated average intake by the four steps described in the methods section .
it is possible to include mean intake estimates from dietary surveys , which are not able to describe the intake distribution .
the authors declare that they have no conflict of interest and have received no funding for the present paper .

Answer:
background : a central element in establishing maximum amount of micronutrients in fortified foods and supplements is to reach to an agreement on how to estimate high intakes of vitamins and minerals from the european diet.objective:to examine whether ratios between the 95th percentile and mean intakes of vitamins and minerals show similarities across different countries independent of dietary habits and survey methods and if so , to suggest a simple and pragmatic way to calculate common estimates of high micronutrient intakes from foods.design:intake data of selected vitamins and minerals from nine european countries were examined for adult females and males and for children aged 410 and 1117 years .
 the ratios between the 95th percentile and mean intakes were calculated for each micronutrient , country , and age group.results:the ratios for each micronutrient follow a fairly regular pattern across countries and survey methods with differences between age groups.the nutrients fall into three categories : nutrients with ratios between 1.45 and 1.58  energy , magnesium , phosphorus , zinc , iron , vitamin b6 , niacin , and folate ; nutrients with ratios between 1.67 and 1.79  calcium , selenium , vitamin e , iodine , and copper ; nutrients with ratios between 2.08 and 2.32  vitamin a , vitamin d , and retinol.conclusion:sufficiently precise estimates of high micronutrient intakes across european countries can be reached by multiplying the overall average of ratios ( p95/mean intakes ) for each micronutrient with the corresponding mean intakes from all available dietary surveys in europe .
 this approach is a simple and pragmatic way to create common european estimates of high micronutrient intakes from foods .


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 beijing genotype is commonly present in russian population and in eurasia as a whole .
this lineage , especially bo\w subline is characterized by high - level virulence , , , . for our analysis , we chose the mycobacterium tuberculosis strain b9741 , isolated from a 33-years - old hiv - positive female patient from irkutsk oblast , russia , with firstly diagnosed fibrocavernous tuberculosis , provided by the scfhhrp , irkutsk , russia .
this strain was resistant to isoniazid ( inh ) , rifampin ( rif ) , streptomycin ( sm ) and pyrazinamide ( pza ) .
genome sequencing was carried out on roche 454 gs junior instrument ( roche , switzerland ) , in the laboratory of bacterial genetics , vigg ras ( moscow , russia ) .
all reads were assembled to an initial draft genome : 4,322,170  bp ( total length ) nucleotides at 13-fold coverage using the gs de novo assembler ( version 3.0 ; roche ) ( table 1 ) .
the automatic functional annotation results were obtained using ncbi prokaryotic genome annotation pipeline ( pgaap ) ( http://www.ncbi.nlm.nih.gov/genomes/static/pipeline.html ) .
the b9741 genome contains 4193 genes ( total ) , 4 rrnas , and 46 trnas .
a total of 250 pseudogenes , 3 noncoding rnas ( ncrnas ) , 1 clustered regularly interspaced short palindromic repeats ( crispr ) were predicted using the pgaap . according to housekeeping gene and toxin - antitoxin analysis , , we classified this strain to belong to b0/w beijing lineage .
we compared our output sequence with dna sequence of the high - virulent m. tuberculosis w-148 strain which belongs to b0/w cluster of beijing group . in this announcement , we focused on genes , which determine virulence and drug resistance .
in addition , we analyzed snps in genes , which are associated with drug resistance to inh , rif , sm , and pza .
analysis we provide the comparison of sequenced dna with b0\w dna sequences and revealed the presence of three polymorphisms at virulence genes .
in the gene mce3f , which essential for survival of mtbs in macrophages and invasion to the host cells , we have found substitution - d410a , in irtb gene , which encode the part of irtab iron importer - a175 t , .
this protein play an essential role for iron homeostasis in stress conditions . and in vapc46 - a38 g , .
thus , identified genes will be used for understanding of m. tuberculosis adaptation to patients with low immune level , including hiv  + patients .
othis whole genome shotgun ( wgs ) project has been deposited at genbank under the accession lvjj01000000 ( mycobacterium tuberculosis strain b9741 ) .
this whole genome shotgun ( wgs ) project has been deposited at genbank under the accession lvjj01000000 ( mycobacterium tuberculosis strain b9741 ) .
the beijing genotype is commonly present in russian population and in eurasia as a whole .
this lineage , especially bo\w subline is characterized by high - level virulence , , , . for our analysis , we chose the mycobacterium tuberculosis strain b9741 , isolated from a 33-years - old hiv - positive female patient from irkutsk oblast , russia , with firstly diagnosed fibrocavernous tuberculosis , provided by the scfhhrp , irkutsk , russia .
this strain was resistant to isoniazid ( inh ) , rifampin ( rif ) , streptomycin ( sm ) and pyrazinamide ( pza ) .
genome sequencing was carried out on roche 454 gs junior instrument ( roche , switzerland ) , in the laboratory of bacterial genetics , vigg ras ( moscow , russia ) .
all reads were assembled to an initial draft genome : 4,322,170  bp ( total length ) nucleotides at 13-fold coverage using the gs de novo assembler ( version 3.0 ; roche ) ( table 1 ) .
the automatic functional annotation results were obtained using ncbi prokaryotic genome annotation pipeline ( pgaap ) ( http://www.ncbi.nlm.nih.gov/genomes/static/pipeline.html ) .
the b9741 genome contains 4193 genes ( total ) , 4 rrnas , and 46 trnas .
a total of 250 pseudogenes , 3 noncoding rnas ( ncrnas ) , 1 clustered regularly interspaced short palindromic repeats ( crispr ) were predicted using the pgaap . according to housekeeping gene and toxin - antitoxin analysis , , we classified this strain to belong to b0/w beijing lineage .
we compared our output sequence with dna sequence of the high - virulent m. tuberculosis w-148 strain which belongs to b0/w cluster of beijing group . in this announcement
we developed the catalog of 342 genes determinate virulence , , . for this analysis ,
in addition , we analyzed snps in genes , which are associated with drug resistance to inh , rif , sm , and pza .
we provide the comparison of sequenced dna with b0\w dna sequences and revealed the presence of three polymorphisms at virulence genes .
we carried out a deeper analysis of these genes involved in virulence . in the gene mce3f ,
which essential for survival of mtbs in macrophages and invasion to the host cells , we have found substitution - d410a , in irtb gene , which encode the part of irtab iron importer - a175 t , .
this protein play an essential role for iron homeostasis in stress conditions . and in vapc46 - a38 g , .
thus , identified genes will be used for understanding of m. tuberculosis adaptation to patients with low immune level , including hiv  + patients .
othis whole genome shotgun ( wgs ) project has been deposited at genbank under the accession lvjj01000000 ( mycobacterium tuberculosis strain b9741 ) .
this whole genome shotgun ( wgs ) project has been deposited at genbank under the accession lvjj01000000 ( mycobacterium tuberculosis strain b9741 ) .
the authors declare that there is no conflict of interests with respect to the work published in this paper .
this research did not receive any specific grant from funding agencies in the public , commercial , or not - for - profit sectors .

Answer:
we report a draft genome sequence of mycobacterium tuberculosis strain b9741 belonging to beijing b0/w lineage isolated from a hiv patient from siberia , russia .
 this clinical isolate showed mdr phenotype and resistance to isoniazid , rifampin , streptomycin and pyrazinamide .
 we analyzed snps associated with virulence and resistance .
 the draft genome sequence and annotation have been deposited at genbank under the accession nz_lvjj00000000 .


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:
acute acalculous cholecystitis ( aac ) is defined as acute inflammation of the gallbladder in the absence of gallstones and has a multifactorial pathogenesis.1 aac occurs in about 10% of all cases of acute cholecystitis .
aac has numerous causes that produce bile stasis and ischemia leading to inflammation and infection of the gallbladder .
aac tends to have a more fulminant course , is frequently associated with gangrene , perforation and empyema , and has high morbidity and mortality.2 aac has traditionally been recognized to occur in patients with serious co - morbid illnesses especially after a major operation , severe trauma , burns , systemic sepsis and prolonged intravenous hyperalimentation.3 however , there has recently been an increasing number of reports in the literature of the occurrence of aac in patients with none of the established risk factors.4 - 6 aac arising as a complication of laparoscopic appendectomy has been reported in just 1 case and it was treated conservatively.7 herein , we present the case of a 38-year - old woman who developed aac after laparoscopic appendectomy .
a 38-year - old woman who was previously in good health came to our emergency room 3 days after she received laparoscopic appendectomy at a local clinic .
she had acute abdominal pain which initially occurred in the epigastric and umbilical area and then migrated to the right lower quadrant after 10 hours and was associated with nausea and anorexia .
acute appendicitis had been diagnosed by abdominal computed tomography ( ct ) and operative findings at another hospital . her abdominal pain and associated symptoms improved after surgery .
body temperature was 37.8. she exhibited tenderness and guarding in the epigastric region and right upper quadrant .
results of the laboratory studies were unremarkable , except for elevated c - reactive protein ( crp ) which was 8.04 mg / dl ( normal range less than 0.5 mg / dl ) .
her body mass index ( bmi ) was 21.7 ( height : 168 cm , weight : 61.2 kg ) .
abdominal ct showed a thickened , contrast - enhanced wall of the gallbladder ( fig .
her abdominal pain subsided and crp decreased to 1.33 mg / dl after the ptgbd .
the patient 's postoperative progress was uneventful , and she was discharged 5 days after surgery .
aac generally occurs in patients after major surgery , in the presence of critical illnesses such as trauma , burns , and sepsis , and in the elderly.1 however there have been recent reports of acalculous cholecystitis in young healthy patients who had none of the established risk factors.6,8 the patient described in this case report was young and healthy and exhibited none of the standard risk factors other than recent surgery , although laparoscopic appendectomy is not considered to be a major operation .
the commonest postulated pathogenesis of aac is bile stasis resulting in a change of bile composition and ischemia.2 factors known to contribute to bile stasis in the postoperative patient are fasting , anesthesia , dehydration , fever , and narcotics for the relief of pain.9 i believe that the most probable mechanism of aac in this woman was bile stasis that resulted from the anesthesia given to her during the appendectomy and the narcotics given for the relief of pain .
aac is difficult to diagnose because clinical signs such as abdominal pain and fever , and laboratory test results are non - specific .
delayed diagnosis of aac is associated with high morbidity and mortality due to the high prevalence of gangrene and perforation.10 early diagnosis and appropriate treatment can improve outcomes in patients with aac.11 the treatment options for aac are cholecystostomy and/or cholecystectomy.9,12 cholecystectomy generally is considered the definitive therapy , and percutaneous cholecystostomy can be performed safely and rapidly.9 standard treatment methods of aac have not yet been established , but it is usually determined by the patient 's condition .
i believe that early cholecystectomy in this case was an effective treatment tool for avoiding potential failure of conservative management and for preventing recurrence , although the patient was young and had none of the risk factors . as mentioned above , laparoscopic appendectomy may mask clinical signs and symptoms of aac .
therefore , when right upper quadrant pain , fever , leukocytosis , and abnormal liver function tests are observed after surgery , physicians should consider the possibility of aac , and promptly check radiological findings .
aac arising as a complication of laparoscopic appendectomy has been reported rarely , especially in young healthy patients .
when abdominal pain , leukocytosis , fever and abnormal results of liver function tests are observed in patients after appendectomy , the possibility of aac should be considered .
prompt recognition and appropriate treatment of aac is necessary to minimize the associated morbidity and mortality .

Answer:
acute acalculous cholecystitis ( aac ) is defined as acute inflammation of the gallbladder in the absence of gallstones .
 aac occurs in patients after major surgery and in the presence of serious co - morbidities such as severe trauma , burns , sepsis , prolonged intravenous hyperalimentation and hemodynamic instability .
 aac is rare in patients with none of the established risk factors .
 we present a case of a 38-year - old woman who developed aac after laparoscopic appendectomy .


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:
resin - based composites are used worldwide in dentistry , mainly because of their aesthetic quality and good physical properties .
since resin composites were first developed , many efforts have been made to improve the clinical behaviour of this restorative material .
several studies have demonstrated that the degree of polymerization of light - cured resin composites depends on many parameters , such as , the specific formulation ( i.e. type and relative amount of monomer , filler and initiator / catalyst ) , the wavelength distribution , the intensity of the incident light and the irradiation time .
although both organic and inorganic phases might influence the material behaviour , the filler particles features and rate of curing are the most important factors related to an improvement in the mechanical properties of the resin composites .
the intended areas of usage of resin composites have traditionally included a trade - off between composites polish ability and strength , based on filler size and loading .
recently , resin composites have been classified according to their filler particle size as hybrid ( 0,5 - 3 m ) , microhybrid ( 0,4 - 1 m ) and microfilled ( 0,04 - 0,4 m ) .
more recently , however , with the introduction of nanotechnology in dentistry , a new class of resin composite , the nanofilled composite resin , is available to clinicians , in an endeavour to provide a material presenting high initial polishing ability combined with superior polish and gloss retention .
the degree of cure of visible light activated dental resins was recognized as important to the clinical success of these materials soon after these materials were introduced .
a curing light intensity output depends on many factors ( light guide , condition of the bulb , battery life ) and the total energy determines the mechanical properties of the resin composites .
also , the distance of the light from the the resin composite is a crucial factor . in the last few years , curing light technology has advanced with the introduction of high intensity halogen lights , plasma arc lights and light emitting diode units ( leds ) , with the aim of fast curing of resin composites and generating less heat . led curing lights
have recently become very popular since they have a number of advantages over conventional halogen units .
traditional modes use high initial irradiance and provide a higher degree of conversion ( dc ) ; on the other hand , a higher shrinkage stress may be induced during polymerization reaction .
gradual polymerization modes have been introduced in order to minimize polymerization shrinkage and consequent marginal gap formation .
physical properties of composite resin are also dependent on the dc of the resin matrix .
a positive correlation has been demonstrated between increasing hardness and increasing dc ; however , it was concluded that an absolute hardness number could not be used to predict dc when different resin composites are compared .
a previously published study showed a significant correlation between the degree of conversion and hardness , modulus of elasticity and flexural strength of dental restorative resins .
direct methods that assess the degree of conversion , such as infrared spectroscopy and laser raman spectroscopy , have not been accepted for routine use as they are complex , expensive and time consuming .
incremental surface hardness has been shown to be an indicator of the degree of conversion and a good correlation between knoops hardness and infrared spectroscopy has also been reported .
it has been used to predict the wear resistance of a material and its ability to abrade or be abraded by opposing tooth structures . to define depth of cure based on top and bottom hardness measurements , it is common to calculate the ratio of bottom / top hardness , and give an arbitrary minimum value for this ratio . in order to consider the bottom surface as adequately cured ,
the current in vitro study evaluated vickers hardness ( vk ) and depth of cure ( hardness ratio ) of three microhybrid , two nanohybrid and one nanofilled resin composites , polymerized with a led curing unit by three different polymerization modes .
six resin composites were selected for the present study and were chosen in accordance with their type of filler particles : three microhybrid ( esthet.x hd , amaris , filtek silorane ) , two nanohybrid ( grandio , ceram.x mono ) and one nanofilled ( filtek supreme xt ) .
the materials evaluated and their manufacturers are shown in table 1 . during the whole experimentation ,
the resin composites were light cured with a led unit , celalux ii ( voco , cuxhaven , germany ) .
three light polymerization modes were used for each material : standard 20 s : 1000 mw / cm for 20 seconds ; standard 40 s : 1000 mw / cm for 40 seconds ; soft - start 40 s : 0 to 1000 mw / cm for 5 seconds + 1000 mw / cm for 35 seconds . the hardness testing methodology used to assess
samples of the respective materials were prepared by placing the material into a stainless steel mold (  7 mm , h 2 mm ) , and were placed on a dark opaque paper background covered with a polyester matrix strip .
the mold was filled with the resin composite and a second polyester matrix strip was placed on the top of the filled mold .
a glass slide was pressed against the upper polyester film to extrude the excess resin composite and to form a flat surface .
the distal end of the light guide was placed against the surface of the matrix strip and positioned concentrically with the mold ; and , the material was then light - cured from the top .
materials used in the study and their manufacturers the cordless curing unit was maintained at full charge before use , and irradiance was checked with a radiometer ( led radiometer , kerr , orange , ca , usa ) .
after polymerization , the samples were stored for 48 hours in complete darkness at 37c and 100% humidity before the vickers hardness test ( vk ) .
the vickers hardness ( vk ) of the surface was determined with a microhardness tester ( durometer zhu 0,2 zwick - roell , ulm , germany ) using a vickers diamond indenter and a 200 g load applied for 15 seconds .
five vk readings were recorded for each sample surface ( top and bottom ) ; and the measurements were made in a sequential pattern , starting with the bottom surface of all specimens , and in 1 mm increments from the specimen centre and extending 2 mm in both x ( east - west [ e - w ] ) and y ( north - south [ n - s ] ) axes .
hardness measurements were not taken at more than 4 mm from the specimen centre to avoid any possible effect of the mold on polymerization . for a given specimen ,
the five hardness values for each surface were averaged and reported as a single value .
the mean vickers hardness and hardness ratio of the specimens were calculated and tabulated using the formula : hardness ratio = vk of bottom surface / vk of top surface .
the mean vickers hardness of top and bottom surfaces and hardness ratio associated with the standard 20 s polymerization mode is shown in table 2 .
the mean vickers hardness of top and bottom surfaces and hardness ratio associated with the standard 40 s polymerization mode is shown in table 3 .
the mean vk of top and bottom surfaces and hardness ratio associated with the soft - start 40 s polymerization mode is shown in table 4 .
the influence of three curing modes ( standard 20 s and 40 s and soft - start 40 s ) on hardness ratio of six composite resins was compared . according to statistical analysis ( t student test ) , it was observed that for all the materials there was no statistical difference ( p > 0.5 ) in hardness values recorded on top surfaces .
a statistical significant difference ( p < 0.01 ) was recorded on the bottom surfaces for all the materials tested ; and this is due to the reduced energy reaching the lower layers , thus affecting the final hardness .
mean vickers hardness of top and bottom surfaces and hardness ratio recorded with the standard 20 s polymerization mode as seen in the study mean vickers hardness of top and bottom surfaces and hardness ratio recorded with the standard 40 s polymerization mode as seen in the study mean vickers hardness of top and bottom surfaces and hardness ratio recorded with the soft - start 40 s polymerization mode as seen in the study hardness ratio values for the different polymerization modes as seen in the study despite this drastic difference between the values recorded on the top and bottom surfaces for all the materials , hardness ratio was higher than the minimum value indicated in literature in order to consider the bottom surface as adequately cured ( 0.80 ) . a statistically significant difference ( p < 0.01 )
was recorded comparing standard 20 s polymerization mode with both standard 40 s and soft - start 40 s polymerization modes for esthet.x hd , amaris and ceram.x mono .
comparing standard 40 s and soft - start 40 s polymerization mode , there was no statistical difference between hardness values recorded on top and bottom surfaces .
resin composites are widely used in restorative dentistry and specifically in posterior restorations , putting the material under constant masticatory stresses .
one of the most important parameters deciding the resin composites resistance to stress is the depth of cure .
the effectiveness of cure depends on the filler particle type , size , quantity and on the parameters ( intensity , time and polymerization modes ) of the light source .
effective cure of light - activated composites is also important to prevent cytotoxicity of inadequately polymerized material .
the optimal degree of curing throughout the bulk of a visible light - activated dental resin composite is acknowledged to be important to the clinical success of a resin composite restoration .
unfortunately , the dentist has no means of monitoring the cure of the resin surfaces not directly exposed to the curing light .
stated that one brand of composite in flowable , hybrid and packable formulations did not achieve a 2 mm depth of cure with 20 s light exposure . de jong et al . demonstrated that with high intensity light - curing units , exposure times of 10s/2 mm increment can be sufficient to obtain under in vitro conditions a high degree of conversion .
these data suggest that a 2 mm buildup layering technique may not result in adequate curing of the bottom layer for such a wide range of materials and that manufacturers need to provide quantitative information about the degree of conversion at specific activation times and light intensities for their entire range of resin materials and shades so that the dentist can devise a placement technique that will ensure adequate cure of the bulk of a restoration .
these findings where in disagreement with some studies that have shown that 2-mm increments were well polymerized .
concluded that the bottom - to - top surface microhardness ratios of a composite resin proved to be an accurate reflection of bottom - to - top degree of conversion ; bottom - to - top microhardness ; and , degree of conversion were independent of composite composition .
the development of new technologies and polymerization modes for photo - activation of restorative composite resins has also caused a great interest among researchers .
however , the real advantages of these techniques are not yet totally known . in the present study , 2-mm thick composite specimens were used as it ensured uniform and maximum polymerization .
the degree to which light - activated composites polymerize is proportional to the amount of light to which they are exposed .
ideally , the degree of polymerization of the composite should be the same throughout its depth and the hardness ratio should be very close or equal to one .
as light passes through the composite , the light intensity is greatly reduced due to light scattering , thus decreasing the effectiveness of cure at the bottom surface .
it was suggested that the hardness ratio should be greater than 0.8% for light activated composites to be adequately polymerized . in the present study ,
the hardness ratio for all the tested materials was over 0.8% for standard 20 s and 40 s and soft - start 40 s polymerization .
denehy et al . found that the top surface hardness of composites was less dependent on light intensity than the bottom surface .
the top surface is actually receiving the maximum energy from the curing light . a statistically significant difference ( p < 0.01 )
was recorded comparing standard 20 s polymerization mode with both , standard 40 s and soft - start 40 s polymerization modes , at top and bottom surfaces , for esthet.x hd , amaris and ceram.x mono .
these results depend on the total amount of energy reaching the composite layer and on chemical composition of the composites . at the the top surface
, it has also been established that even relatively low intensity lights can cure the resin matrix to an extent almost equal to when high intensity lights are used .
the general lack of significance between standard 40 s and soft - start 40 s curing modes in top vickers hardness found in this study corroborate the mentioned studies . at the top surface
, sufficient light energy reaches the photoinitiator , thus starting the polymerization reaction . at the bottom surfaces , a significant difference in vk
was observed for all the materials , but no statistical difference was observed between standard 40 s and soft - start 40 s polymerization modes .
this may be due to the very fast increase ( 5 s ) of light intensity in soft - start polymerization , while total light exposure was very similar between the two polymerization modes . about the properties of the composite resins , the results were generally dependent on the material evaluated , especially with regard to filler features .
suggested that no trend towards the size or shape of fillers affected hardness ; and all materials generally presented different results in comparison with one another .
grandio , for instance , presented the highest values , probably because of its large particles and the highest filler content .
nanofilled filtek supreme xt showed significantly higher hardness values than esthet.x hd , filtek silorane and ceram.x mono , which were all conceived for posterior restorations . in this study
, only one physical property was tested on a limited number of composite resins polymerized with one type of unit .
more research involving the use of other materials and multiple combinations of polymerization modes is warranted .
curing time did not affect hardness ratio values for filtek silorane , grandio and filtek supreme xt .
the effectiveness of cure at the top and bottom surface was not affected by soft - start polymerization mode .

Answer:
aim : the current in vitro study evaluated vickers hardness ( vk ) and depth of cure ( hardness ratio ) of six resin composites , polymerized with a light - emitting diode ( led ) curing unit by different polymerization modes : standard 20 s , standard 40 s , soft - start 40 s.materials and methods : six resin composites were selected for the present study : three microhybrid ( esthet.x hd , amaris , filtek silorane ) , two nanohybrid ( grandio , ceram.x mono ) and one nanofilled ( filtek supreme xt ) .
 the vk of the surface was determined with a microhardness tester using a vickers diamond indenter and a 200 g load applied for 15 seconds .
 the mean vk and hardness ratio of the specimens were calculated using the formula : hardness ratio = vk of bottom surface / vk of top surface.results:for all the materials tested and with all the polymerization modes , hardness ratio was higher than the minimum value indicated in literature in order to consider the bottom surface as adequately cured ( 0.80 ) .
 curing time did not affect hardness ratio values for filtek silorane , grandio and filtek supreme xt.conclusion:the effectiveness of cure at the top and bottom surface was not affected by soft - start polymerization mode .