Fmoc-conjugated PEG-vitamin E2 micelles for tumor-targeted delivery of paclitaxel: enhanced drug-carrier interaction and loading capacity.
The purpose of this study is to develop an improved drug delivery system for enhanced paclitaxel (PTX) loading capacity and formulation stability based on PEG5K-(vitamin E)2 (PEG5K-VE2) system. PEG5K-(fluorenylmethoxycarbonyl)-(vitamin E)2 (PEG5K-FVE2) was synthesized using lysine as the scaffold. PTX-loaded PEG5K-FVE2 micelles were prepared and characterized. Fluorescence intensity of Fmoc in the micelles was measured as an indicator of drug-carrier interaction. Cytotoxicity of the micelle formulations was tested on various tumor cell lines. The therapeutic efficacy and toxicity of PTX-loaded micelles were investigated using a syngeneic mouse model of breast cancer (4T1.2). Our data suggest that the PEG5K-FVE2 micelles have a low CMC value of 4 μg/mL and small sizes (~60 nm). The PTX loading capacity of PEG5K-FVE2 micelles was much higher than that of PEG5K-VE2 micelles. The Fmoc/PTX physical interaction was clearly demonstrated by a fluorescence quenching assay. PTX-loaded PEG5K-FVE2 micelles exerted more potent cytotoxicity than free PTX or Taxol formulation in vitro. Finally, intravenous injection of PTX-loaded PEG5K-FVE2 micelles showed superior anticancer activity compared with PEG5K-VE2 formulation with minimal toxicity in a mouse model of breast cancer. In summary, incorporation of a drug-interactive motif (Fmoc) into PEG5K-VE2 micelles represents an effective strategy to improve the micelle formulation for the delivery of PTX.


Framingham Coronary Heart Disease Risk Score Can be Predicted from Structural Brain Images in Elderly Subjects.
Recent literature has presented evidence that cardiovascular risk factors (CVRF) play an important role on cognitive performance in elderly individuals, both those who are asymptomatic and those who suffer from symptoms of neurodegenerative disorders. Findings from studies applying neuroimaging methods have increasingly reinforced such notion. Studies addressing the impact of CVRF on brain anatomy changes have gained increasing importance, as recent papers have reported gray matter loss predominantly in regions traditionally affected in Alzheimer's disease (AD) and vascular dementia in the presence of a high degree of cardiovascular risk. In the present paper, we explore the association between CVRF and brain changes using pattern recognition techniques applied to structural MRI and the Framingham score (a composite measure of cardiovascular risk largely used in epidemiological studies) in a sample of healthy elderly individuals. We aim to answer the following questions: is it possible to decode (i.e., to learn information regarding cardiovascular risk from structural brain images) enabling individual predictions? Among clinical measures comprising the Framingham score, are there particular risk factors that stand as more predictable from patterns of brain changes? Our main findings are threefold: (i) we verified that structural changes in spatially distributed patterns in the brain enable statistically significant prediction of Framingham scores. This result is still significant when controlling for the presence of the APOE 4 allele (an important genetic risk factor for both AD and cardiovascular disease). (ii) When considering each risk factor singly, we found different levels of correlation between real and predicted factors; however, single factors were not significantly predictable from brain images when considering APOE4 allele presence as covariate. (iii) We found important gender differences, and the possible causes of that finding are discussed.


[Benign peritoneal cystic mesothelioma as differential diagnose of an ovarian dependant tumor. Case report and review of the literature].
Benign cystic mesothelioma is an uncommon lesion of the peritoneum, occurring predominantly in women of reproductive age. The present case is a multitreated perimenopausal woman with lower urinary tract symptoms without clinical improvement despite the treatment, and pelvic pain with physical findings and radiology studies of a probable ovarian mass dependant tumoration, requiring protocolized exploratory laparotomy, finding a benign cystic mesothelioma. Despite the low incidence of this tumoration the gynecologist must be familiar with this disease, because of the high recurrence. Nowadays, steroid hormone receptors typification seems to play an important role to control the recurrence of this tumoration.


Assessing predictive discrimination performance of biomarkers in the presence of treatment-induced dependent censoring.
In medical studies, some therapeutic decisions could lead to dependent censoring for the survival outcome of interest. This is exemplified by a study of paediatric acute liver failure, where death was subject to dependent censoring due to liver transplantation. Existing methods for assessing the predictive performance of biomarkers often pose the independent censoring assumption and are thus not applicable. In this work, we propose to tackle the dependence between the failure event and dependent censoring event using auxiliary information in multiple longitudinal risk factors. We propose estimators of sensitivity, specificity and area under curve, to discern the predictive power of biomarkers for the failure event by removing the disturbance of dependent censoring. Point estimation and inferential procedures were developed by adopting the joint modelling framework. The proposed methods performed satisfactorily in extensive simulation studies. We applied them to examine the predictive value of various biomarkers and risk scores for mortality in the motivating example.


Th17 associated cytokines in sputum samples from patients with cystic fibrosis.
Cystic fibrosis (CF) is a genetic disease leading to chronic bacterial airway infection and inflammation. T helper 17 (Th17) cells are identified by their production of interleukin (IL)-17A, which recruit neutrophils to the site of airway infection. IL-23 is an important inducer of IL-17 and IL-22 production. The aim of this study was to study the role of Th17 cells in CF airway infection by measuring the levels of Th17 associated cytokines in sputum from CF patients with or without airway infection and by comparison with non-CF-controls. In a cross-sectional screening study, cytokine levels were measured with a Th17 multiplex cytokine ELISA. Significantly lower levels of IL-17A and IL-23 were found in sputa from infected CF patients. The lowest levels of IL-17A were found in patients chronically infected with P. aeruginosa, which also had the lowest IL-17/IL-22 ratio, while children had a higher ratio. Children also had higher IL-23 levels than adults. IL-1ß and IL-10 were significantly lower in CF sputum compared to controls. Thus, in our study CF patients with chronic infections had a lower production of Th17 associated cytokines in sputum compared with non-infected CF patients and infected patient without CF.


Occupational hazards education for nursing staff through web-based learning.
This study aims to explore the efficiency of using online education as an intervention measure to prevent occupational hazards in a clinical nursing setting. The subjects were 320 female nursing staff from two hospitals in Taiwan. The questionnaire results indicated that the subjects primarily experienced human factor occupational hazards, as well as psychological and social hazards. Specifically, 73.1% and 69.8% of the subjects suffered from poor sleep quality and low back pain, respectively. After web-based learning, the experimental group had higher post-test scores than the control group in terms of knowledge, attitudes, and practices (KAP). However, there was only a significant difference (p < 0.05) in their knowledge about the prevention of occupational hazards. It is suggested that an online discussion may enhance nursing staff's participation in web-based learning, and further facilitate their comments on negative factors. The findings can highly promote nursing staff's attitudes and practices toward preventing occupational hazards through web-based learning.


HIV Transmission Rates in the United States, 2006-2008.
National HIV incidence for a given year x [I(x)] equals prevalence [P(x)] times the transmission rate [T(x)]. Or, simply rearranging the terms, T(x) = [I(x)/P(x)]*100 (where T(x) is the number of HIV transmissions per 100 persons living with HIV in a given year). The transmission rate is an underutilized measure of the speed at which the epidemic is spreading. Here, we utilize recently updated information about HIV incidence and prevalence in the U.S. to estimate the national HIV transmission rate for 2006 through 2008, and present a novel method to express the level of uncertainty in these estimates. Transmission rate estimates for 2006 through 2008 are as follows (respectively): 4.39 (4.01 to 4.73); 4.90 (4.49 to 5.28); and 4.06 (3.70 to 4.38). Although there are methodological challenges inherent in making these estimates, they do give some indications that the U.S. HIV transmission rate is at a historically low level.


Waveguides consisting of single-crystal lithium niobate thin film and oxidized titanium stripe.
Strip-loaded waveguides were fabricated by the direct oxidation of a titanium film based on the single-crystal lithium niobate. The method avoided the surface roughness problems that are normally introduced during dry etching of waveguide sidewalls. Propagation modes of the composite strip waveguide were analyzed by a full-vectorial finite difference method. The minimum dimensions of the propagation modes were calculated to be 0.7 μm(2) and 1.1 μm(2) for quasi-TM mode and quasi-TE mode at 1550 nm when the thickness of the LN layer and TiO(2) strip was 660 nm and 95 nm, respectively. The optical intensity was as high as 93% and was well confined in the LN layer for quasi-TM polarization. In this experiment, the propagation losses for the composite strip waveguide with 6 μm wide TiO(2) were 14 dB/cm for quasi-TM mode and 5.8 dB/cm for quasi-TE mode, respectively. The compact hybrid structures have the potential to be utilized for compact photonic integrated devices.


Cytotoxic T lymphocytes and natural killer cells display impaired cytotoxic functions and reduced activation in patients with alcoholic hepatitis.
The dynamics and role of cytotoxic T lymphocytes (CTLs), natural killer (NK) cells, and NKT cells in the life-threatening inflammatory disease alcoholic hepatitis is largely unknown. These cells directly kill infected and damaged cells through, e.g., degranulation and interferon-γ (IFNγ) production, but cause tissue damage if overactivated. They also assist tissue repair via IL-22 production. We, therefore, aimed to investigate the frequency, functionality, and activation state of such cells in alcoholic hepatitis. We analyzed blood samples from 24 severe alcoholic hepatitis patients followed for 30 days after diagnosis. Ten healthy abstinent volunteers and 10 stable abstinent alcoholic cirrhosis patients were controls. Using flow cytometry we assessed cell frequencies, NK cell degranulation capacity following K562 cell stimulation, activation by natural killer group 2 D (NKG2D) expression, and IL-22 and IFNγ production. In alcoholic hepatitis we found a decreased frequency of CTLs compared with healthy controls (P < 0.001) and a similar trend for NK cells (P = 0.089). The NK cell degranulation capacity was reduced by 25% compared with healthy controls (P = 0.02) and by 50% compared with cirrhosis patients (P = 0.04). Accordingly, the NKG2D receptor expression was markedly decreased on NK cells, CTLs, and NKT cells (P < 0.05, all). The frequencies of IL-22-producing CTLs and NK cells were doubled compared with healthy controls (P < 0.05, all) but not different from cirrhosis patients. This exploratory study for the first time showed impaired cellular cytotoxicity and activation in alcoholic hepatitis. This is unlikely to cause hepatocyte death but may contribute toward the severe immune incompetence. The results warrant detailed and mechanistic studies.


Unmet healthcare need, gender, and health inequalities in Canada.
Unmet healthcare need should be rare in nations with a universally accessible publicly funded healthcare system such as Canada. This however is not the case. This study examines the extent to which predictors of such need are consistent with various paradigmatic approaches (e.g., structural-critical, social capital, social support, and lifestyle) that consider such issues. Analyses of data from a probability sample of 2536 urban residents in British Columbia specified the relationship of unmet need with socioeconomic issues such as income, gender, and housing tenure, community issues such as social networks and social support, and traditional lifestyle or behavioural risk factors. The structural-critical model concerned with socio-demographics provided the most parsimonious explanation for having an unmet healthcare need. Consistent with a structural-critical approach, gender was found to be a reliable predictor of having an unmet health need in each of the models tested. Increasing federal transfers to healthcare and providing childcare and other community supports that are of special value for women may help to reduce unmet healthcare need.


[Which antibiotics should one choose for prophylaxis in vascular surgery?].
Although the principle and duration of prophylactic antibiotic therapy in prosthetic vascular surgery are fairly widely accepted, the choice of antibiotic is still open to discussion. During two successive periods, identical groups of patients received peri-operative prophylaxis with, during period I (455 cases) oxacillin alone and during period II (537 cases) combined treatment with oxacillin and amikacin. The aim of the study was to evaluate efficacy of the association and to draw general conclusions on choice of antibiotic. The addition of amikacin reduced frequency of infection in elective operations, particularly aorto-ilio-femoral prostheses (0.5% as against 1.24%), but not in operations conducted as emergencies. In addition, frequency of infection due to BGN fell only slightly. Finally, combined therapy with oxacillin-amikacin had 2 disadvantages: impossibility of using these antibiotics for prophylaxis alone as provided for in the protocol, and its high cost. Factors of choice of antibiotic should be: efficacy against germs encountered, which can vary from year to year, rarity of toxic or side effects, good tissue diffusion, the rare need for therapeutic use and a low cost.


Facioscapulohumeral muscular dystrophy (FSHD) and multiple sclerosis: a case report.
Facioscapulohumeral muscular dystrophy 1 (FSHD1) is an autosomal dominant neuromuscular disorder, associated with reduction of tandemly arrayed repetitive DNA elements D4Z4 (DRA), at 4q35. Few cases, especially carriers of 1-3 DRA show a syndromic form. Anecdotally the association of FSHD with multiple sclerosis (MS) is reported. Herein we report a 33 years old Caucasian with a molecular diagnosis of FSHD1 with classical phenotype (clinical category A2) and concomitant white matter lesions suggestive of MS. White matter lesions in patients with FSHD have often been described but rarely investigated in order to evaluate a possible diagnosis of MS. We think that MS and FSHD remain clearly distinct diseases, but growing evidences show a widespread and variable activation of the immune system in patients suffering from FSHD probably an hypotheses on a potential common pathogenetic mechanism between these two disorders could should be better investigated.


Antioxidants, nutritional supplements and life-threatening diseases.
Antioxidants are a complex and diverse group of molecules that protect key biological sites from oxidative damage. They usually act by removing or inactivating chemical intermediates that produce the ultimate oxidant. Different sites in the body have evolved to use highly specialised strategies to deal with free radicals and other reactive oxygen intermediates. Recent epidemiological evidence suggests that the development of life-threatening disease, such as cancer and heart disease, is linked to our dietary intake of micronutrients including antioxidants. Modification of dietary habits together with supplementation may provide a simple yet profound way to reduce deaths from these two major diseases. Sound scientific evidence to support a curative role for antioxidants in life-threatening diseases, however, is lacking.


Burn wound closure with cultured autologous keratinocytes and fibroblasts attached to a collagen-glycosaminoglycan substrate.
Improved survival of patients with extensive burn injuries requires the development of better techniques for timely and permanent closure of the full-thickness wound. We developed procedures for establishing confluent, stratified layers of cultured, autologous keratinocytes on the surface of a modified collagen-glycosaminoglycan membrane that contains autologous fibroblasts. We transferred the composite grafts onto limited areas of excised full-thickness burn wounds of four patients with extensive burn injuries. Our results indicate that this composite graft material has acceptable "take," with formation of a basement membrane within 9 days of graft placement. Use of this technique for major wound coverage may offer a significant advance in the care of extensively burned patients and also may be useful for providing skin for reconstructive surgery.


[Genetic constitution differences in patients with various forms of alcoholism].
Four groups of alcoholics were identified, according to the structure of psychopathological disturbances outside the acute period of abstinence and progression of the disease. There were inter-group differences in the level of familial history of alcoholism, alcoholic psychoses and psychic diseases, as well as in the mean values of some parameters of dermatoglyphics of palms, colour perception and taste perception of phenylthiocarbamide. The used clinical criteria of patients' distribution reflect the constitutional-genetic differences between them, which should be taken into consideration in developing differential pharmacotherapy.


Assessing landscape scale wildfire exposure for highly valued resources in a Mediterranean area.
We used a fire simulation modeling approach to assess landscape scale wildfire exposure for highly valued resources and assets (HVR) on a fire-prone area of 680 km(2) located in central Sardinia, Italy. The study area was affected by several wildfires in the last half century: some large and intense fire events threatened wildland urban interfaces as well as other socioeconomic and cultural values. Historical wildfire and weather data were used to inform wildfire simulations, which were based on the minimum travel time algorithm as implemented in FlamMap. We simulated 90,000 fires that replicated recent large fire events in the area spreading under severe weather conditions to generate detailed maps of wildfire likelihood and intensity. Then, we linked fire modeling outputs to a geospatial risk assessment framework focusing on buffer areas around HVR. The results highlighted a large variation in burn probability and fire intensity in the vicinity of HVRs, and allowed us to identify the areas most exposed to wildfires and thus to a higher potential damage. Fire intensity in the HVR buffers was mainly related to fuel types, while wind direction, topographic features, and historically based ignition pattern were the key factors affecting fire likelihood. The methodology presented in this work can have numerous applications, in the study area and elsewhere, particularly to address and inform fire risk management, landscape planning and people safety on the vicinity of HVRs.


Mechanism of thermal decomposition of tetrabromobisphenol A (TBBA).
This study presents a detailed investigation into the gas-phase thermal decomposition of tetrabromobisphenol A (TBBA), that is, the most widely used brominated flame retardant (BFR). Elimination of one of the methyl groups characterizes the sole dominant channel in the self-decomposition of the TBBA molecule at all temperatures. A high-pressure rate constant for this reaction is fitted to k(T) = 2.09 × 10(10)T(1.93) exp(-37000/T) s(-1). The high A factor and low activation energy for this reaction arise from the formation of a delocalized radical upon the loss of a methyl group. We calculate rate constants for the bimolecular reactions of TBBA with H, Br, and CH3 radicals. Kinetic and mechanistic data provided herein should be instrumental to gain further understanding of the fate of TBBA during thermal degradation of materials laden with this BFR.


Comparison of mortality of brachycephalic dogs undergoing partial staphylectomy using conventional incisional, carbon dioxide laser, or bipolar vessel sealing device.
To compare mortality of dogs undergoing partial staphylectomy using conventional incisional, carbon dioxide (CO2 ) laser, and bipolar vessel sealing device (BVSD) techniques for the treatment of brachycephalic obstructive airway syndrome (BOAS). Retrospective multicenter cohort study. A total of 606 client-owned English bulldogs, French bulldogs, and pugs. Medical records from 2011 to 2021 were reviewed for signalment, history, surgical technique, length of hospitalization, and complications. Multivariate statistical analysis was performed to compare odds of mortality between the three techniques of staphylectomy. The overall mortality rate was 24/606 (4.0%). Of those 24 dogs, staphylectomy was performed with BVSD technique in 13 cases, with CO2 laser in nine, and using conventional incisional technique in two. Nine dogs were graded II or III laryngeal collapse, 14 were graded I, and one was unknown. BVSD technique was associated with mortality prior to discharge compared to the other two techniques (OR = 6.0, 95% CI: 1.3-28.4, p = .023). No differences were detected between conventional incisional and CO2 laser techniques. Concurrent higher grade (stage II or III) laryngeal collapse was independently associated with mortality prior to discharge (OR = 4.6, 95% CI: 1.8-11.8, p = .002). The use of BVSD and grade of laryngeal collapse were associated with a higher risk of perioperative mortality. Clinical studies using a randomized trial design should be conducted to further determine the putative influence of surgical instrumentation in the perioperative mortality rate following multilevel surgery in dogs with BOAS.


Tempo and timing of ecological trait divergence in bird speciation.
Organismal traits may evolve either gradually or in rapid pulses, but the relative importance of these modes in the generation of species differences is unclear. Additionally, while pulsed evolution is frequently assumed to be associated with speciation events, few studies have explicitly examined how the tempo of trait divergence varies with respect to different geographical phases of speciation, starting with geographic isolation and ending, in many cases, with spatial overlap (sympatry). Here we address these issues by combining divergence time estimates, trait measurements and geographic range data for 952 avian sister species pairs worldwide to examine the tempo and timing of trait divergence in recent speciation events. We show that patterns of divergence in key ecological traits are not gradual, but instead seem to follow a pattern of relative stasis interspersed with evolutionary pulses of varying magnitude. We also find evidence that evolutionary pulses generally precede sympatry, and that greater trait disparity is associated with sympatry. These findings suggest that early pulses of trait divergence promote subsequent transitions to sympatry, rather than occurring after sympatry has been established. Incorporating models with evolutionary pulses of varying magnitude into speciation theory may explain why some species pairs achieve rapid sympatry whereas others undergo prolonged geographical exclusion.


[Hypercalcemia in childhood. A boy with asymptomatic hypocalciuric hypercalcemia].
The diagnostic work-up of a patient with (familial) hypocalciuric hypercalcemia (FHH) is discussed. The patient showed no clinical signs of hypercalcemia. There were no indications of vitamin D intoxication. In the first degree family members no hypercalcemia was found. Physical examination was normal. In contrast to hyperparathyroidism, FHH is usually symptomless. Furthermore, FHH is characterized by a normal chloride/phosphate ratio, a normal, but relatively high, serum parathyroid hormone level, a relatively low urinary calcium excretion, a calcium-creatinine clearance ratio less than 0.01 and a normal cyclic AMP excretion.


Evaluation of leishmanin skin test reaction in different variants of cutaneous leishmaniasis.
Cutaneous leishmaniasis (CL) is a parasitic disease which has different clinical forms. The aim of this study is to compare the response to leishmanin skin test (LST) in three forms of CL including plaque type, lupoid type, and sporotrichoid type. This was a descriptive cross-sectional study. The patients enrolled in this study had three clinical forms of CL confirmed by positive smear of their lesions and then LST was performed for them. Results were categorized as negative (0-5 mm induration), positive (6-14 mm), and strongly positive (≥15 mm). The data were documented in the patients' files and analyzed with SPSS windows software version 16 (Inc.Chicago, USA). 200 patients were enrolled in the study. In the group with plaque type, 86% had a positive LST, 13.3% were negative, and 0.7% were strongly positive. In the lupoid group, these figures were 45.8%, 8.4%, 45.8%, respectively. In the sporotrichoid group, LST was positive in 27.3%, negative in 72.7%, and none of the patients had a strongly positive reaction (P < 0.05). The most of the positive LST were belong to plaque and lupoid groups, the most of strongly positive were belong to lupoid, and the most of negative LST were related with sporotrichoid type. It can be suggested that lupoid and sporotrichoid types of CL are parts of a continuous spectrum of the disease with an enhanced cellular immunity in lupoid form and a decreased state in sporotrichoid type.


Factor analytic and item response theory evaluation of the Penn State Worry Questionnaire in women with cancer.
Cancer survivors frequently experience worry about a variety of topics, including fear of recurrence. However, general measures of worry still require examination of reliability for this vulnerable population. This study utilized modern psychometric methods to examine the reliability of a worry measure in women with breast or gynecologic cancer. Women with cancer (n = 332) completed the 16-item Penn State Worry Questionnaire (PSWQ), which has an abbreviated 8-item version (PSWQ-A). Categorical confirmatory factor analysis (CCFA) was used to determine the factor structure and item response theory (IRT) was used to examine score reliability. CCFA supported a two-factor structure with 11 positively worded items and the 5 negatively worded items loading on different factors. IRT analysis of the 11 positively worded items showed that each was contributing meaningful information to the overall scores. The 11 positively worded items and the PSWQ-A produced the most reliable scores for levels of worry ranging from one θ below to two θ above the mean. The 11 positively worded items of the PSWQ and the 8-item PSWQ-A were suitable for use in cancer patients while the full PSWQ was unsuitable due to inclusion of the negatively worded items. Future research should consider measuring worry when examining distress in cancer survivors.


Assessing the efficacy of aqueous garlic extract, sodium nitrite and sodium thiosulfate against prolonged oral cyanide exposure in rabbits.
This study was aimed to compare the efficacy of aqueous garlic extract, sodium nitrite (SNT), sodium thiosulfate (STS) and hydroxocobalamin against oral cyanide exposure in rabbits. For this purpose, forty two adult male rabbits were divided randomly into 7 groups of 6 animals (A-G) each. Rabbits in group A were offered feed only and served as negative control, while the rabbits in group B received feed plus potassium cyanide (KCN) at 3mg/kg orally and were kept as positive control. Animals in group C received feed, KCN and intraperitoneal injection (IP) of aqueous garlic extract at 500mg/kg. Rabbits in group D were given feed, KCN and IP injection of STS at 600mg/kg. Members in group E received feed, KCN and IP injection of both aqueous garlic extract at 500mg/kg and SNT at 20mg/kg. Animals in group F were given feed, KCN and IP injection of both STS at 600mg/kg and SNT at 20mg/kg, while the rabbits in group G received feed, KCN and IP injection of hydroxocobalamin at 300mg/kg. The treatments were given to respective groups for 40 days. The efficacy of the antidotes was measured on the basis of changes in biochemical profile of rabbits in each group. In this study, hydroxocobalamin was found to be significantly more effective cyanide (CNI) antidote than garlic, STS, SNT plus garlic extract, or SNT and STS, either alone or in combination. A combination of SNT and garlic extract was the second most effective CNI antidote. The efficacy of garlic alone was significantly higher than STS alone or in combination with SNT. The efficacy of combined SNT and STS was superior to STS alone in treating rabbits with CNI toxicity. In conclusion, aqueous garlic extract alone or in combination with STS can effectively be used against cyanide toxicity.


Hybrid origin of European commercial pigs examined by an in-depth haplotype analysis on chromosome 1.
Although all farm animals have an original source of domestication, a large variety of modern breeds exist that are phenotypically highly distinct from the ancestral wild population. This phenomenon can be the result of artificial selection or gene flow from other sources into the domesticated population. The Eurasian wild boar (Sus scrofa) has been domesticated at least twice in two geographically distinct regions during the Neolithic revolution when hunting shifted to farming. Prior to the establishment of the commercial European pig breeds we know today, some 200 years ago Chinese pigs were imported into Europe to improve local European pigs. Commercial European domesticated pigs are genetically more diverse than European wild boars, although historically the latter represents the source population for domestication. In this study we examine the cause of the higher diversity within the genomes of European commercial pigs compared to their wild ancestors by testing two different hypotheses. In the first hypothesis we consider that European commercial pigs are a mix of different European wild populations as a result of movement throughout Europe, hereby acquiring haplotypes from all over the European continent. As an alternative hypothesis, we examine whether the introgression of Asian haplotypes into European breeds during the Industrial Revolution caused the observed increase in diversity. By using re-sequence data for chromosome 1 of 136 pigs and wild boars, we show that an Asian introgression of about 20% into the genome of European commercial pigs explains the majority of the increase in genetic diversity. These findings confirm that the Asian hybridization, that was used to improve production traits of local breeds, left its signature in the genome of the commercial pigs we know today.


African Swine Fever in a commercial pig farm: Outbreak investigation and an approach for identifying the source of infection.
African Swine Fever (ASF) is a contagious disease of domestic and wild pigs caused by the African Swine Fever Virus (ASFV). The disease has spread globally in recent years with serious economic consequences to pork production. This report describes an ASF outbreak that occurred in a large-scale Chinese commercial pig farm. The outbreak started in 2018 and presents the spatial and temporal spread of infection in an intensive pig farm. Pig houses adjacent to exit rooms had a higher risk of infection (Odds ratio = 14.4, 95%CI: 1.5-140). Introduction of disease is presumed to have occurred through a contaminated vehicle used in the sale of pigs with poor productivity. This investigation shows the process of ASFV infection and spread in a facility with presumed adequate biosecurity measures. These findings may benefit others in the control of ASF in large-scale pig farms.


Knockdown of RNF6 inhibits gastric cancer cell growth by suppressing STAT3 signaling.
RNF6, an E3 ligase, has been reported to play an important role in the tumorigenesis in several tissues, but its role in gastric cancer is still unknown. In this study, we aimed to investigate the biological function and molecular mechanisms of RNF6 in gastric cancer. The expression levels of RNF6 were detected by quantitative real-time PCR (qRT-PCR) and immunoblotting in gastric cancer tissues and cell lines. Cell Counting Kit-8 assay was performed to evaluate cell proliferation. Cell apoptosis was analyzed by flow cytometer and immunoblotting. Luciferase assay, immunoblotting and qRT-PCR were performed to explore the activation of STAT3. Immunoprecipitation was performed to evaluate the ubiquitination of SHP-1. In this study, RNF6 was found to be upregulated in both primary tissues and cell lines of gastric cancer. Knockdown or overexpression of RNF6 inhibited or promoted cell growth of gastric cancer cells. Knockdown of RNF6 also induced the cleavage of PARP and promoted cell apoptosis in gastric cancer cells. In addition, knockdown of RNF6 also increased the cytotoxicity of doxorubicin against gastric cancer. Moreover, knockdown of RNF6 inhibited STAT3-derived luciferase activity and downregulated the phosphorylation of STAT3, but upregulated the protein level of SHP-1. Knockdown of RNF6 downregulated the expression of MCL1 and XIAP, which are target genes of STAT3. Further studies showed that RNF6 regulated the stability of SHP-1 by inducing its polyubiquitination. These results demonstrated that RNF6 was highly expressed in gastric cancer and regulated the growth of gastric cancer cells by affecting SHP-1/STAT3 signaling, which suggested that RNF6 could be a novel target for gastric cancer therapy.


Racial/ethnic differences in the epidemiology of ovarian cancer: a pooled analysis of 12 case-control studies.
Ovarian cancer incidence differs substantially by race/ethnicity, but the reasons for this are not well understood. Data were pooled from the African American Cancer Epidemiology Study (AACES) and 11 case-control studies in the Ovarian Cancer Association Consortium (OCAC) to examine racial/ethnic differences in epidemiological characteristics with suspected involvement in epithelial ovarian cancer (EOC) aetiology. We used multivariable logistic regression to estimate associations for 17 reproductive, hormonal and lifestyle characteristics and EOC risk by race/ethnicity among 10 924 women with invasive EOC (8918 Non-Hispanic Whites, 433 Hispanics, 911 Blacks, 662 Asian/Pacific Islanders) and 16 150 controls (13 619 Non-Hispanic Whites, 533 Hispanics, 1233 Blacks, 765 Asian/Pacific Islanders). Likelihood ratio tests were used to evaluate heterogeneity in the risk factor associations by race/ethnicity. We observed statistically significant racial/ethnic heterogeneity for hysterectomy and EOC risk (P = 0.008), where the largest odds ratio (OR) was observed in Black women [OR = 1.64, 95% confidence interval (CI) = 1.34-2.02] compared with other racial/ethnic groups. Although not statistically significant, the associations for parity, first-degree family history of ovarian or breast cancer, and endometriosis varied by race/ethnicity. Asian/Pacific Islanders had the greatest magnitude of association for parity (≥3 births: OR = 0.38, 95% CI = 0.28-0.54), and Black women had the largest ORs for family history (OR = 1.77, 95% CI = 1.42-2.21) and endometriosis (OR = 2.42, 95% CI = 1.65-3.55). Although racial/ethnic heterogeneity was observed for hysterectomy, our findings support the validity of EOC risk factors across all racial/ethnic groups, and further suggest that any racial/ethnic population with a higher prevalence of a modifiable risk factor should be targeted to disseminate information about prevention.


[Free microvascular fibula graft for skeletal reconstruction after tumor resections in the forearm -- experience with five cases].
Plastic-reconstructive surgery for upper extremity tumors not only follows the fundamental principles of oncologic surgery, but also requires attention to functional and aesthetic aspects. For soft tissue reconstruction, a variety of surgical options are available, whereas for the reconstruction of extensive bony defects only the free microvascular fibular transplant appears to be a reasonable method. Its advantages are its slim shape and variable length, the possibility of achieving a stable osteosynthesis suitable for early physiotherapy, and low donor site morbidity, even if the fibula is harvested as an osteoseptocutaneous flap. Between 1994 and 2000, five patients underwent a free fibula transplantation for radius reconstruction. In all cases, a two-stage reconstructive approach with initial tumor biopsy was chosen. The resected tumors were two osteosarcomas, one extraosseous Ewing sarcoma, one aneurysmatic bone cyst and one desmoplastic fibroma. Surgical and pathohistological tumor-free margins were achieved in all cases (R(0)). Two patients received an osteocutaneous graft. All grafts were revascularized to the radial artery and subcutaneous veins. The transplanted fibula grafts were between 10 cm and 17 cm in length. All proximal osteosyntheses were performed fibuloradially, the distal stabilizations were fibulo-scapho-lunate (2 x) and fibulo-radial (3 x), depending on the extent of resection. All microvascular transplants survived completely and showed a stable osseous integration, both clinically and radiologically. Depending on the postoperative course, an adapted intensive physiotherapy regimen yielded good or satisfactory function. In the follow-up of up to seven years in one case a tumor recurrence (osteosarcoma, 35 months post-operatively) required forearm amputation. The reconstruction of tumor-associated wide bony defects in the upper extremity with a free microvascular fibula graft allows for a successful therapy with respect to oncologic, functional and aesthetic considerations.


Wolbachia detection in Aedes aegypti using MALDI-TOF MS coupled to artificial intelligence.
The mosquito Aedes aegypti is the major vector of arboviruses like dengue, Zika and chikungunya viruses. Attempts to reduce arboviruses emergence focusing on Ae. aegypti control has proven challenging due to the increase of insecticide resistances. An emerging strategy which consists of releasing Ae. aegypti artificially infected with Wolbachia in natural mosquito populations is currently being developed. The monitoring of Wolbachia-positive Ae. aegypti in the field is performed in order to ensure the program effectiveness. Here, the reliability of the Matrix‑Assisted Laser Desorption Ionization‑Time Of Flight (MALDI‑TOF) coupled with the machine learning methods like Convolutional Neural Network (CNN) to detect Wolbachia in field Ae. aegypti was assessed for the first time. For this purpose, laboratory reared and field Ae. aegypti were analyzed. The results showed that the CNN recognized Ae. aegypti spectral patterns associated with Wolbachia-infection. The MALDI-TOF coupled with the CNN (sensitivity = 93%, specificity = 99%, accuracy = 97%) was more efficient than the loop-mediated isothermal amplification (LAMP), and as efficient as qPCR for Wolbachia detection. It therefore represents an interesting method to evaluate the prevalence of Wolbachia in field Ae. aegypti mosquitoes.


Use of interventional bronchoscopic treatment in small cell lung cancer.
Small cell lung cancer (SCLC) constitutes 15%-25% of all lung cancers. Their treatment approach is different from nonsmall cell lung cancer. Central airway obstruction develops at the time of diagnosis or eventually at some time as the disease progress. Quick relief of symptoms with chemotherapy will cause to postpone interventional bronchoscopy which divest patient from benefits of this procedure. There is a few data about the use of interventional bronchoscopy in SCLC. Between January 2005 and December 2012, rigid bronchoscopy under general anaesthesia was done in a total of 944 cases. Among them, 52 consecutive SCLC cases were evaluated retrospectively. Survival was calculated from the date of application of therapeutic bronchoscopy using statistical software. From the 52 cases (41 males) mean age of the patients were 56,87 ± 10,16 (range 34-78). Most common obstruction areas were distal trachea and carina invasion involving both main bronchus (n: 12; 23%). Most common method used was mechanical desobstruction after coagulation with diode diode laser or APC. A total of 16 stents was applied to 15 of the cases from 52 cases (28.8%). Most common used stent was silicon Y stent (n: 11). Most common complication during the procedure was bleeding that was mild in 11 cases and massive in 1. One patient died during the procedure (1.9%). Multimodal interventional bronchoscopic methods seem to be a last option but may be useful in the management of advanced airway obstruction in the setting of SCLC. The choice of modality may be chosen depending upon individual patient characteristics as appropriate.


Functional expression of IgG-Fc receptors in human airway smooth muscle cells.
IgE-Fc receptors and IgG-Fc receptors are expressed on hematopoietic cells, but some evidence suggests that these receptors are also found on nonhematopoietic cells, including human airway smooth muscle (hASM) cells. Our study characterizes the expression of IgE-Fc receptors (FcεRI/CD23) and IgG-Fc receptors (FcγRs-I, -II, and -III) in cultured hASM cells by flow cytometry and Western blotting, and the functional activity of receptors was determined through quantification of cell proliferation and released cytokines. Expression of Fc receptor-linked intracellular signaling proteins and phosphorylation of the mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinase 1/2 and p38(MAPK) in hASM cells was examined by Western blotting. Expression of FcεRI and CD23 was not detectable in hASM cells. However, FcγRI and FcγRII were shown to be expressed on these cells. Specific antibodies, validated using transfected cell lines, revealed that the inhibitory IgG receptor, FcγRIIb, was the most abundant Fc receptor subtype expressed. Although cross-linking FcγR with heat-aggregated γ globulin (HAGG) did not induce detectable cell stimulation, pretreating hASM cells with HAGG significantly inhibited IL-1α-induced increases in cytokine levels and basic fibroblast growth factor-induced cell proliferation. This inhibitory effect of HAGG was abrogated by preincubation of cells with an anti-FcγRIIb antigen-binding fragment (Fab). Expression of proteins involved in the canonical FcγRIIb inhibitory signaling pathway was established in hASM cells. Pretreatment of hASM cells with HAGG significantly inhibited IL-1α- and basic fibroblast growth factor-induced extracellular signal-regulated kinase 1/2 and p38(MAPK) phosphorylation. This study identifies functional expression of FcγRIIb in hASM cells, with the potential to suppress their remodeling and immunomodulatory roles.


Childhood traumatic experiences and the association with marijuana and cocaine use in adolescence through adulthood.
Examination of longitudinal relationships between childhood traumatic experiences and drug use across the life-course at the national level, with control of confounding by other forms of trauma, is needed. We aimed to estimate the prevalence of nine typologies of childhood traumas and the cumulative number experienced, correlation between traumas and associations between individual and cumulative number of traumas with drug use during adolescence, emerging adulthood and adulthood. Secondary data analysis using the National Longitudinal Study of Adolescent to Adult Health. United States. A nationally representative sample of individuals in grades 7-12 (aged 11-21 years) during 1994-95, who were re-interviewed during emerging adulthood (2001-02; aged 18-28) and adulthood (2007-08; aged 24-34). The analytical sample comprised 12 288 participants with data at all three waves. Nine typologies of childhood traumas: neglect; emotional, physical and sexual abuse; parental incarceration and binge drinking; and witnessing, being threatened with and experiencing violence. Indicators of each were summed to measure cumulative dose. Outcomes were marijuana and cocaine use during adolescence, emerging adulthood and adulthood. Approximately half experienced at least one childhood trauma; traumas were not highly correlated. We observed a dose-response relationship between the number of traumas and drug use in adolescence [marijuana, adjusted odds ratio (aOR) one trauma versus none = 1.65, 95% confidence interval (CI) = 1.42, 1.92; two traumas = 2.58, 95% CI = 2.17, 3.06; ≥ four traumas = 6.92, 95% CI = 5.17, 9.26; cocaine, aOR one trauma = 1.87, 95% CI = 1.23, 2.84; two traumas = 2.80, 95% CI = 1.74, 4.51; ≥ four traumas = 9.54, 95% CI = 5.93, 15.38]. Similar dose-response relationships with drug use were observed in emerging adulthood and adulthood. Each individual trauma was associated independently with either marijuana or cocaine use in adolescence, emerging adulthood and/or adulthood. Childhood trauma is prevalent in the United States, and individual types as well as the total number experienced are associated significantly with marijuana and cocaine use throughout the life-course.


Modulation of Cl-, K+, and nonselective cation conductances by taurine in olfactory receptor neurons of the mudpuppy Necturus maculosus.
Odors are transduced by processes that modulate the membrane conductance of olfactory receptor neurons. Olfactory neurons from the aquatic salamander, Necturus maculosus, were acutely isolated without enzymes and studied with a resistive whole-cell method to minimize loss of soluble intracellular constituents. 55 of 224 neurons responded to the test compound taurine at concentrations between 10 nM and 100 microM. Four different conductance changes were elicited by taurine: an increased Cl- conductance (33%), an increased nonselective cation conductance (15%), a decreased Cl- conductance (15%), and a decreased K+ conductance (15%); in addition, responses too small to be characterized were elicited in some neurons. In most cases, taurine appeared to modulate only a single conductance in any particular cell. Modulation of each conductance was dose dependent, and each response ran down quickly in the normal whole-cell mode, presumably due to washout of a diffusible component in the transduction pathway. Modulation of taurine-sensitive conductances caused either inhibitory or excitatory responses. A similar diversity of responses in vivo would produce a complex pattern of electrical activity that could encode the identity and characteristics of an odor.


Geometry of the valence transition induced surface reconstruction of Sm(0001).
We present a structural determination of the surface reconstruction of the Sm(0001) surface using surface x-ray diffraction, scanning tunneling microscopy, and ab initio calculations. The reconstruction is associated with a large (22%) expansion of the atomic radius for the top monolayer surface Sm atoms. The mechanism driving the surface reconstruction in Sm is unique among all elements and is connected to the strong correlations of the 4f electrons in Sm and the intermediate valence observed in certain Sm compounds. The atoms constituting the top monolayer of Sm(0001) have vastly different chemical properties compared to the layer underneath and behave as if they were an adsorbate of a different chemical species.


Factors Related to Postoperative Pain Trajectories following Total Knee Arthroplasty: A Longitudinal Study of Patients Admitted to a Russian Orthopaedic Clinic.
This study explores sociodemographic, clinical, and surgical factors in relation to pain trajectories during the first 3 days following total knee arthroplasty (TKA). 100 patients (mean age 63.5 ± 7.8 years and 93% female) consecutively admitted for uncomplicated primary TKA were prospectively included. Postoperative pain was assessed using pain diaries. Measures of preoperative pain, symptoms, daily functioning, quality of life, comorbidities, knee function, perioperative characteristics, and physical/biochemical parameters were also evaluated. All pain ratings decreased in the three days following surgery (p < .001) as well as the reported number of daily hours in moderate/severe pain (p < .001). Women reported more pain than men (p = .009). Pain trajectories did not differ by education, employment, cohabitation, or any patient clinical and biochemical characteristics but were significantly related to preoperative anxiety (p = .029). Patients reporting moderate/severe pain prior to surgery also reported more hours in moderate/severe pain on days 0-3 postoperatively (p = .029). Patients with surgeries longer than 90 min reported more hours of moderate/severe pain compared with patients who had shorter surgeries (p = .008), and similar results were observed for ratings of pain with activity (p = .012). In this sample, only female gender, higher levels of preoperative pain and anxiety, and longer surgical duration were associated with increased pain after TKA.


Vortex rectenna powered by environmental fluctuations.
A rectenna, standing for a rectifying antenna, is an apparatus which generates d.c. electricity from electric fluctuations. It is expected to realize wireless power transmission as well as energy harvesting from environmental radio waves. To realize such rectification, devices that are made up of internal atomic asymmetry such as an asymmetric junction have been necessary so far. Here we report a material that spontaneously generates electricity by rectifying environmental fluctuations without using atomic asymmetry. The sample is a common superconductor without lowered crystalline symmetry, but, just by putting it in an asymmetric magnetic environment, it turns into a rectifier and starts generating electricity. Superconducting vortex strings only annihilate and nucleate at surfaces, and this allows the bulk electrons to feel surface fluctuations in an asymmetric environment: a vortex rectenna. The rectification and generation can be switched on and off with only a slight change in temperature or external magnetic fields.


Case Report: Circulating Tumor DNA Fraction Analysis Using Ultra-Low-Pass Whole-Genome Sequencing Correlates Response to Chemoradiation and Recurrence in Stage IV Small-Cell Carcinoma of the Cervix - A Longitudinal Study.
Neuroendocrine carcinoma of the cervix is a rare and aggressive form of cervical cancer that presents with frequent metastasis at diagnosis and high recurrence rates. Primary treatment is multimodal, which often includes chemotherapy with or without radiation therapy. There are no data available to guide treatment for recurrence, and second-line therapies are extrapolated from small-cell lung carcinoma data. Close monitoring of these patients for recurrence is paramount. Evaluation of circulating tumor DNA (ctDNA) in the peripheral blood is an attractive approach due to its non-invasive nature. Ultra-low-pass whole-genome sequencing (ULP-WGS) can assess tumor burden and response to therapy and predict recurrence; however, data are lacking regarding the role of ULP-WGS in small-cell carcinoma of the cervix. This study demonstrates a patient whose response to chemotherapy and cancer recurrence was accurately monitored by ctDNA analysis using ULP-WGS and confirmed with radiologic imaging findings.


Effects of Dietary Intake of Japanese Mushrooms on Visceral Fat Accumulation and Gut Microbiota in Mice.
A lot of Japanese people are generally known for having a healthy diet, and consume a variety of mushrooms daily. Many studies have reported anti-obesity effects of mushrooms, but few have investigated the effects of consuming a variety of edible mushroom types together in realistic quantities. In this study, we investigated whether supplementation with a variety of mushroom types affects visceral fat accumulation and gut microbiota in mice. The most popular mushroom varieties in Japan were lyophilized and mixed according to their local production ratios. C57BL/6J mice were fed a normal diet, high-fat (HF) diet, HF with 0.5% mushroom mixture (equivalent to 100 g mushrooms/day in humans) or HF with 3% mushroom mixture (equivalent to 600 g mushrooms/day in humans) for 4 weeks. The mice were then sacrificed, and blood samples, tissue samples and feces were collected. Our results show that mushroom intake suppressed visceral fat accumulation and increased the relative abundance of some short chain fatty acid- and lactic acid-producing gut bacteria. These findings suggest that mushroom intake is an effective strategy for obesity prevention.


Polystyrene-supported (2S)-(-)-3-exo-piperazinoisoborneol: an efficient catalyst for the batch and continuous flow production of enantiopure alcohols.
A polystyrene-supported analog (PS-PIB) of 3-exo-morpholinoisoborneol (MIB), designed for increased chemical stability, has been synthesized and used as a ligand in the asymmetric alkylation of aldehydes with Et(2)Zn. The supported ligand turned out to be highly active and enantioselective for a broad scope of substrates (92-99% ee), allowing repeated recycling. A single-pass, continuous flow process implemented with PS-PIB shows only a marginal decrease in conversion after 30 h of operation.


[Narratives about the process of recovering from addiction: the perspective of family members attending care services].
Addiction treatment services usually prioritize the recovery of the user, despite the fact that problematic consumption often leads to distress among families that requires attention. The purpose of this study is to identify types of narratives constructed by relatives of people with substance dependence disorders regarding their condition and recovery process. Additionally, we seek to understand the conditions that facilitate or hinder the recovery process from the perspective of family members. Seven in-depth interviews were conducted with a narrative approach. Progressive, stable, and regressive narratives were identified, corresponding to various stages in the addiction and recovery processes. These narratives revealed different forms of distress, obstacles to treatment, and critical junctures with respect to attending care services. Families represent a valuable resource for user recovery, and therefore must be included in the treatment process.


The Role of Animacy in Turkish Relative Clause Production and Distribution.
Relative clause (RC) production has been a major tool used for understanding language production mechanism in experimental linguistics. The present study analyzes language production mechanisms in Turkish by utilizing animacy effect on RC production. A picture description task was applied to two participant groups. The data were combined and analyzed to see how animacy influenced RC formation. The outcomes were also compared to the distributions of RC use in corpus data. Both participant and corpus data demonstrated significant level of passivization for RCs with animate heads, strongly affirming the grammatical function assignment proposal by Bock and Warren (Cognition 21(1):47-67, 1985) as well as the premise of Production-Distribution-Comprehension account (MacDonald in Front Psychol 4:226, 2013), emphasizing the relationship between language production mechanisms and typology. However, the corpus data were observed to have higher numbers of passivization with animate condition. Accordingly, a coarse comparison of the participant RC production proportions in the current study with some other crosslinguistic research suggests that some language-specific or discourse-related interventions can also compete with the animacy accessibility during the sentence planning procedure, which needs an extra inquiry especially in Turkish language.


Effect of complete protein 4.1R deficiency on ion transport properties of murine erythrocytes.
Moderate hemolytic anemia, abnormal erythrocyte morphology (spherocytosis), and decreased membrane stability are observed in mice with complete deficiency of all erythroid protein 4.1 protein isoforms (4.1(-/-); Shi TS et al. J Clin Invest 103: 331, 1999). We have examined the effects of erythroid protein 4.1 (4.1R) deficiency on erythrocyte cation transport and volume regulation. 4.1(-/-) mice exhibited erythrocyte dehydration that was associated with reduced cellular K and increased Na content. Increased Na permeability was observed in these mice, mostly mediated by Na/H exchange with normal Na-K pump and Na-K-2Cl cotransport activities. The Na/H exchange of 4.1(-/-) erythrocytes was markedly activated by exposure to hypertonic conditions (18.2 +/- 3.2 in 4.1(-/-) vs. 9.8 +/- 1.3 mmol/10(13) cell x h in control mice), with an abnormal dependence on osmolality (EC(50) = 417 +/- 42 in 4.1(-/-) vs. 460 +/- 35 mosmol/kgH(2)O in control mice), suggestive of an upregulated functional state. While the affinity for internal protons was not altered (K(0.5) = 489.7 +/- 0.7 vs. 537.0 +/- 0.56 nM in control mice), the V(max) of the H-induced Na/H exchange activity was markedly elevated in 4.1(-/-) erythrocytes (V(max) 91.47 +/- 7.2 compared with 46.52 +/- 5.4 mmol/10(13) cell x h in control mice). Na/H exchange activation by okadaic acid was absent in 4.1(-/-) erythrocytes. Altogether, these results suggest that erythroid protein 4.1 plays a major role in volume regulation and physiologically downregulates Na/H exchange in mouse erythrocytes. Upregulation of the Na/H exchange is an important contributor to the elevated cell Na content of 4.1(-/-) erythrocytes.


Therapeutic options in acute severe ulcerative colitis.
Ulcerative colitis is a relapsing-remitting inflammatory disease affecting the colon and is associated with considerable morbidity. In acute severe attacks, there continues to be an associated mortality rate of 1-2%, even in specialist units. During an acute severe exacerbation, approximately two-thirds of patients will respond to intravenous corticosteroid therapy, the accepted first-line therapy in such cases. For steroid-refractory patients, options are limited to surgery (colectomy) or second-line agents, such as ciclosporin or infliximab, used in an attempt to salvage the colon. Considerable debate exists over the optimal management of such patients. During the last decade, an increased understanding of the pathogenesis of inflammatory bowel disease has led to the rapid development of other biological agents, such as basiliximab and visilizumab. Novel methods, such as leucopheresis, have been studied and other established immunomodulatory agents, such as tacrolimus, have also been suggested. The purpose of this review is to highlight some of the areas of recent development in the treatment of acute severe ulcerative colitis and review important safety data, with a particular emphasis on biological agents.


Case report: Immunotherapy plus chemotherapy and stereotactic ablative radiotherapy (ICSABR): a novel treatment combination for Epstein-Barr virus-associated lymphoepithelioma-like intrahepatic cholangiocarcinoma.
Epstein-Barr virus-associated lymphoepithelioma-like intrahepatic cholangiocarcinoma (EBVa LEL-ICC) is a rare tumor, characterized by a rich tumor immune microenvironment (TIME). While this tumor is reportedly sensitive to immunotherapy, its response has been inconsistent. This decreased sensitivity was associated with reduced TIME abundance. We report the case of a 53-year-old woman with EBVa LEL-ICC having reduced TIME abundance. The patient presented with a liver lesion, which was detected using ultrasound. Initially, the tumor was sensitive to immunotherapy and chemotherapy (IC), but resistance developed after a short interval. Subsequently, stereotactic ablative radiotherapy (SABR) was added to the patient's treatment, which now consisted of ICSABR. Successful tumor shrinkage was achieved with the combination therapy regimen. Thus, surgery and ICSABR are effective adjuncts to the first-line IC therapy in improving the survival rate of patients with EBVa LEL-ICC. The results of this study support multidisciplinary treatment as a viable treatment strategy for EBVa LEL-ICC.


Collateral arterial blood supply to the pregnant uterus in the sheep.
The common internal iliac artery in the sheep gives rise to the arteries which are the primary source of blood to the uterus. We have used a vascular occluder placed on the common internal iliac artery of the pregnant sheep to induce and study the effects of chronic fetal hypoxaemia. We have noted that uterine blood flow and fetal oxygenation improve within 5 d of occlusion of the common internal iliac artery. To investigate the basis of this observation we performed serial angiograms and postmortem examinations of the uterine arterial circulation in pregnant sheep under normal conditions and after 7 d of blood flow occlusion. We identified distal anastomoses on the surface of the uterus between the middle uterine and internal pudendal arteries by way of the urogenital arteries and their branches. Furthermore, the internal pudendal artery filled retrogradely through other branches when the vessel was ligated at its origin. The development of a collateral circulation to the uterus in response to chronic common internal iliac artery occlusion is a physiological adaptation to maintain an adequate supply of blood to the uterus and thus to maintain fetal oxygen delivery.


Viral bacterial artificial chromosomes: generation, mutagenesis, and removal of mini-F sequences.
Maintenance and manipulation of large DNA and RNA virus genomes had presented an obstacle for virological research. BAC vectors provided a solution to both problems as they can harbor large DNA sequences and can efficiently be modified using well-established mutagenesis techniques in Escherichia coli. Numerous DNA virus genomes of herpesvirus and pox virus were cloned into mini-F vectors. In addition, several reverse genetic systems for RNA viruses such as members of Coronaviridae and Flaviviridae could be established based on BAC constructs. Transfection into susceptible eukaryotic cells of virus DNA cloned as a BAC allows reconstitution of recombinant viruses. In this paper, we provide an overview on the strategies that can be used for the generation of virus BAC vectors and also on systems that are currently available for various virus species. Furthermore, we address common mutagenesis techniques that allow modification of BACs from single-nucleotide substitutions to deletion of viral genes or insertion of foreign sequences. Finally, we review the reconstitution of viruses from BAC vectors and the removal of the bacterial sequences from the virus genome during this process.


Liver transplantation for hepatocellular carcinoma: current update on treatment and allocation.
This review discusses the current imaging modalities and criteria used to diagnose, and the role of liver transplantation as well as nonsurgical hepatic-directed therapies to treat hepatocellular carcinoma in the setting of chronic liver disease. There has been continual evolution of guidelines, policies, and algorithms for the imaging diagnosis of hepatocellular carcinoma, particularly the Liver Imaging Reporting and Data System. The use of liver-directed therapy as a bridge to transplant is now common practice. Recently, patients have waited 6 months from listing before being granted a Model for End-Stage Liver Disease exception score of 28, with an increase every 3 months to a maximum score of 34. This policy change was developed to reduce disparities in outcomes for patients undergoing liver transplantation. The use of liver transplantation to treat hepatocellular carcinoma within the Milan criteria has good outcomes with a 5-year disease-free survival rate comparable to patients transplanted without malignancy. The development of guidelines both for the radiologic diagnosis and staging of the primary tumor and guidelines for assessing response to treatment allows for a more unified approach to the management of patients. With the partnership of oncologists, hepatologists, radiologists, pathologists, and surgeons, the outcomes of liver transplantation as treatment for hepatocellular continue to improve.


Psoriasis infiltrating cell immunophenotype: changes induced by PUVA or corticosteroid treatment in T-cell subsets, Langerhans' cells and interdigitating cells.
The effects of PUVA or corticosteroid treatment on the distribution pattern of immunocompetent cells in psoriasis symptomatic skin were investigated. A total of 29 biopsies, taken before and a regular intervals during treatment, were studied in a two-stage immunoperoxidase technique using monoclonal antibodies directed against T cells, their major subsets, interdigitating cells, and Langerhans' cells. T cell exocytosis was not affected by PUVA or corticosteroid treatment. Instead, both treatment regimens led to an initial increase in interbasally localized T8+ suppressor/cytotoxic T cells. Increased T4/T8 ratios within the subepidermal infiltrates were restored to normal except in one case, who did not respond to PUVA-treatment. Epidermal and dermal T6+ Langerhans' cells decreased to almost absent. RFD1+ interdigitating cells had the same tendency, except in the PUVA-non-responding patient. Treatment of psoriasis with PUVA or corticosteroids thus results in a normalization of an initial immune imbalance in infiltrating immunocompetent cells. A working hypothesis on psoriasis immunopathogenesis and its restoration by treatment is presented.


Occupational exposure to polychlorinated dibenzo-p-dioxins and dibenzofurans, dioxin-like polychlorinated biphenyls, and polychlorinated naphthalenes in workplaces of secondary nonferrous metallurgical facilities in China.
The concentrations of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), dioxin-like polychlorinated biphenyls (dl-PCBs), and polychlorinated naphthalenes (PCNs) were determined in workplace air from eight secondary nonferrous metal processing plants to investigate occupational exposure to these toxic compounds. The total estimated daily intakes of PCDD/Fs and dl-PCBs for workers by inhalation in the workplace were in the range of 0.15-9.91 and 0.13-8.59 pg of WHO-TEQ/kg of body weight (bw) for moderate and light activities, respectively. The daily inhalation doses for workers in the workplaces of three investigated plants exceeded the tolerable daily intake recommended by the World Health Organization. These results indicate that the risk of occupational exposure to dioxins by inhalation in the workplace of plants investigated was considerably high. For PCNs, the daily inhalation doses for workers in the workplace were in the range of 0.005-4.46 and 0.004-3.87 pg of TEQ/kg of bw for moderate and light activities, respectively, which were lower than those of dioxins. To identify the source of PCDD/Fs, PCBs, and PCNs in workplace air, their homologue profiles were compared with those in stack gas from the plants investigated. It was found that significant dioxin contamination in workplace air was mainly attributed to the emission of fugitive gas from smelting furnaces during reclamation processes.


Wenckebach periodicity in single atrioventricular nodal cells from the rabbit heart.
Previous studies have suggested that Wenckebach periodicity in cardiac tissues may occur because of discontinuous propagation across junctional areas in which there is high intercellular resistivity or different cell types. Under these conditions, the impulse may stop altogether at a given junction, or may renew its propagation but only after a step delay imposed by the diastolic time-dependent recovery in the excitability of cells distal to that junction. Accordingly, Wenckebach periodicity in the atrioventricular node may be explained in terms of electrotonically mediated delay in the activation of the nodal cells. To test this hypothesis, we have studied recovery of excitability, and susceptibility to rate-dependent activation failure in single myocytes isolated from the adult rabbit atrioventricular node. Recordings were obtained by using the patch technique in the whole-cell, current clamp configuration. Repetitive stimulation of single atrioventricular nodal myocytes with depolarizing current pulses of critical amplitude yielded frequency-dependent stimulus response patterns that ranged from 1:1, through various Wenckebachlike periodicities (e.g., 5:4 and 4:3) to 2:1 and 3:1. Both typical and atypical Wenckebach structures were demonstrated, as well as "complex" patterns (e.g., reverse Wenckebach or alternating Wenckebach) previously ascribed to multiple levels of block. The diastolic recovery of excitability curve, determined by application of repetitive stimuli at cycle lengths that were longer than the action potential duration, showed a monotonic function with a refractory period outlasting the action potential duration (i.e., postrepolarization refractoriness). Abbreviation of the stimulation cycle length to values below those of the action potential duration revealed the existence of a period of supernormal excitability during the repolarizing phase of the action potential. In either case, the stimulus response patterns obtained were a direct consequence of the shape of the recovery of excitability curve. The monotonic portion of the recovery curve was fitted to an empirical equation that when iterated reproduced the stimulus response patterns observed in the atrioventricular nodal cell. Our data demonstrate that recovery of excitability after an action potential is indeed a function of the diastolic interval, and that this slow process sets the conditions for the development of Wenckebach periodicity in the atrioventricular node.


CYTOCHROME OXIDASE IN NORMAL AND REGENERATING NEURONS.
Manometric determinations of cytochrome oxidase activity were carried out on grey matter from the thalamus and anterior horn of cats and monkeys under various experimental conditions. The thalamus of the cat was studied following the degeneration of virtually all the thalamic neurons secondary to decortication. In comparing the deneuronated thalamus with the normal one, it was found that approximately 34 per cent of the cytochrome oxidase activity was contributed by the neurons and the balance by neuroglia and mesodermal tissues which on the operated side remained comparable to that of the normal side. Total activity of the normal thalamus averaged 5.52 units per mg. of dry weight where I unit is defined as the amount of cytochrome oxidase required to produce a net oxygen consumption of 10 c.mm. per hour under the specified conditions of the experiment. The grey matter of the anterior horns of the spinal cord was isolated by a special technique and its cytochrome oxidase activity was compared with anterior horns in which motoneurons had been stimulated to regenerative activity by section of peripheral nerves. Each animal was studied in relation to an anterior horn which was normal and one in which only the functional state of the motoneurons had been changed. Average normal levels of 2.23 units were found for cat anterior horn and 0.69 units for the monkey. Reductions of cytochrome oxidase activity in the range of 22 to 23 per cent were observed for both cat and monkey following nerve section. In the latter the time sequence was carefully studied in relation to the cytological cycle known as chromatolysis and a virus refractory state previously described by us. It was found that maximal reduction of cytochrome oxidase activity coincided with maximal refractoriness of the cells to poliomyelitis virus (30 to 70 days following nerve section). Neither of these states could be correlated in time with maximal chromatolysis (10 to 15 days).


Transcranial direct current stimulation of 20- and 30-minutes combined with sertraline for the treatment of depression.
Transcranial direct current stimulation (tDCS) can be an effective treatment for depression, however, the duration of the stimulation session, among other parameters, needs to be optimized. 69 mild to moderately depressed patients (age 37.6±10.5years, 19 men) were randomized into three groups - 30-, 20-minute or sham tDCS. 10 daily sessions of anodal/sham tDCS of the left DLPFC (0.5mA; electrode 3,5×7cm) combined with 50mg/day of sertraline were performed. Mood, cognition and BDNF level were assessed before and after the treatment. A significant difference between groups was observed in the percent change of the Hamilton Depression Rating Scale (F(2, 66)=10.1; p<0.001). Sham group (43.4%±18.1) had a smaller improvement compared to the 30-minute (63.8%±13.4; 95% CI: 11.23-29.44; p=0.00003) and 20-minute group (53.2%±15.3; 95% CI: 0.21-19.26; p=0.045). 30-minute group had significantly greater percent improvement than 20-minute group (95% CI: 1.74-19.46; p=0.02). Responders constituted 89%, 68%, and 50% and remitters - 70%, 27%, and 35% in the 30-, 20-minute and sham groups, respectively. A significant difference in the number of responders was observed between 30-minute vs. sham group (odds ratio=8; 95% CI, 2.59-24.69; p=0.001), in remission rate - between 30-minute vs. sham (odds ratio=4.40; 95% CI, 2.02-9.57; p=0.02) and vs. 20-minute (odds ratio=6.33; 95% CI, 2.85-14.10; p=0.003) groups. Two hypomania cases and one case of blood pressure elevation were detected in the 20-minute group. Among neuropsychological tests, only the change in Digit Span Backwards test showed a significant interaction between groups (TIME*GROUP; F(2, 65)=6,6, p=0.002); a greater improvement was observed in both active groups compared to sham (p<0.05). The change in BDNF level after the treatment did not show the significant difference between groups. tDCS of 20- or 30-minutes combined with sertraline are efficient for the treatment of mild and moderate depression; the effect of 30min stimulation exceeds the one obtained from 20min.


A dynamic nonlinearity and spatial phase specificity in macaque V1 neurons.
While studying the visual response dynamics of neurons in the macaque primary visual cortex (V1), we found a nonlinearity of temporal response that influences the visual functions of V1 neurons. Simple cells were recorded in all layers of V1; the nonlinearity was strongest in neurons located in layer 2/3. We recorded the spike responses to optimal sinusoidal gratings that were displayed for 100 ms, a temporal step response. The step responses were measured at many spatial phases of the grating stimulus. To judge whether simple cell behavior was consistent with linear temporal integration, the decay of the 100 ms step response at the preferred spatial phase was used to predict the step response at the opposite spatial phase. Responses in layers 4B and 4C were mostly consistent with a linear-plus-static-nonlinearity cascade model. However, this was not true in layer 2/3 where most cells had little or no step responses at the opposite spatial phase. Many layer 2/3 cells had transient preferred-phase responses but did not respond at the offset of the opposite-phase stimuli, indicating a dynamic nonlinearity. A different stimulus sequence, rapidly presented random sinusoids, also produced the same effect, with layer 2/3 simple cells exhibiting elevated spike rates in response to stimuli at one spatial phase but not 180 degrees away. The presence of a dynamic nonlinearity in the responses of V1 simple cells indicates that first-order analyses often capture only a fraction of neuronal behavior. The visual implication of our results is that simple cells in layer 2/3 are spatial phase-sensitive detectors that respond to contrast boundaries of one sign but not the opposite.


A review of deep tissue injury development, detection, and prevention: shear savvy.
Pressure ulcer prevention strategies include the prevention, and early recognition, of deep tissue injury (DTI), which can evolve into a Stage III or Stage IV pressure ulcer. In addition to their role in pressure-induced ischemia, shearing forces are believed to contribute substantially to the risk of DTI. Because the visual manifestation of a DTI may not occur until many hours after tissues were damaged, research to explore methods for early detection is on-going. For example, rhabdomyolysis is a common complication of deep tissue damage; its detection via blood chemistry and urinalysis is explored as a possible diagnostic tool of early DTI in anatomical areas where muscle is present. Substances released from injured muscle cells have a predictable time frame for detection in blood and urine, possibly enabling the clinician to estimate the time of the tissue death. Several small case studies suggest the potential validity and reliability of ultrasoun for visualizing soft tissue damage also deserve further research. While recommendations to reduce mechanical pressure and shearing damage in high-risk patients remain unchanged, their implementation is not always practical, feasible, or congruent with the overall plan of patient care. Early detection of existing tissue damage will help clinicians implement appropriate care plans that also may prevent further damage. Research to evaluate the validity, reliability, sensitivity, and specificity of diagnostic studies to detect pressure-related tissue death is warranted.


Palladium-catalyzed benzene arylation: incorporation of catalytic pivalic acid as a proton shuttle and a key element in catalyst design.
A palladium-pivalic acid cocatalyst system has been developed that exhibits unprecedented reactivity in direct arylation. This reactivity is illustrated with the first examples of high yielding direct metalation-arylation reactions of a completely unactivated arene, benzene. Experimental and computational evidence indicates that the pivalate anion is a key component in the palladation/C-H bond breaking event, that it lowers the energy of C-H bond cleavage and acts as a catalytic proton shuttle from benzene to the stoichiometric carbonate base. Eight examples of substituted aryl bromides are included which undergo direct arylation with benzene in 55-85% yield.


Microphthalmia-Associated Transcription Factor-Dependent Melanoma Cell Adhesion Molecule Activation Promotes Peritoneal Metastasis of Ovarian Cancer.
Ovarian cancer (OvCa) is one of the leading causes of death due to its high metastasis rate to the peritoneum. Recurrent peritoneal tumors also develop despite the use of conventional platinum-based chemotherapies. Therefore, it is still important to explore the factors associated with peritoneal metastasis, as these predict the prognosis of patients with OvCa. In this study, we investigated the function of microphthalmia-associated transcription factor (MITF), which contributes to the development of melanoma, in epithelial ovarian cancer (OvCa). High MITF expression was significantly associated with a poor prognosis in OvCa. Notably, MITF contributed to the motility and invasion of OvCa cells, and specifically with their peri-mesothelial migration. In addition, MITF-positive cells expressed the melanoma cell adhesion molecule (MCAM/CD146), which was initially identified as a marker of melanoma progression and metastasis, and MCAM expression was regulated by MITF. MCAM was also identified as a significant prognostic factor for poor progression-free survival in patients with OvCa. Collectively, our results suggest that MITF is a novel therapeutic target that potentially promotes peritoneal metastasis of OvCa.


Clozapine-induced myocarditis: electronic health register analysis of incidence, timing, clinical markers and diagnostic accuracy.
Clozapine is associated with increased risk of myocarditis. However, many common side-effects of clozapine overlap with the clinical manifestations of myocarditis. As a result, there is uncertainty about which signs, symptoms and investigations are important in distinguishing myocarditis from benign adverse effects of clozapine. Clarity on this issue is important, since missing a diagnosis of myocarditis or discontinuing clozapine unnecessarily may both have devastating consequences. To examine the clinical characteristics of clozapine-induced myocarditis and to identify which signs and symptoms distinguish true myocarditis from other clozapine adverse effects. A retrospective analysis of the record database for 247 621 patients was performed. A natural language processing algorithm identified the instances of patients in which myocarditis was suspected. The anonymised case notes for the patients of each suspected instance were then manually examined, and those whose instances were ambiguous were referred for an independent assessment by up to three cardiologists. Patients with suspected instances were classified as having confirmed myocarditis, myocarditis ruled out or undetermined. Of 254 instances in 228 patients with suspected myocarditis, 11.4% (n = 29 instances) were confirmed as probable myocarditis. Troponin and C-reactive protein (CRP) had excellent diagnostic value (area under the curve 0.975 and 0.896, respectively), whereas tachycardia was of little diagnostic value. All confirmed instances occurred within 42 days of clozapine initiation. Suspicion of myocarditis can lead to unnecessary discontinuation of clozapine. The 'critical period' for myocarditis emergence is the first 6 weeks, and clinical signs including tachycardia are of low specificity. Elevated CRP and troponin are the best markers for the need for further evaluation.


The anabolic steroid methandienone targets the hypothalamic-pituitary-testicular axis and myostatin signaling in a rat training model.
There is increasing evidence that the biological activity of myostatin (MSTN), a negative regulator of muscle growth, is affected by training but also anabolic steroids. In this study, we analyzed the effects of the frequently abused anabolic steroid methandienone (Md) on the hypothalamic-pituitary-testicular axis and androgen-sensitive tissues in intact rats performing a treadmill training to simulate the situation of abusing athletes. The anabolic effects were correlated with the expression of members of the MSTN signaling cascade. Md treatment resulted in a significant stimulation of anabolic activity of the levator ani muscle, which was further increased by training, while prostate and seminal vesicle weights decreased in conformance with hormone concentrations of LH and testosterone. In gastrocnemius muscle, mRNA expression of genes of the MSTN signaling cascade (MSTN, Smad7 and MyoD) was reduced by training but not after Md treatment, in soleus muscle MSTN and its inhibitors, follistatin (FLST) and Smad-7 were only affected after training in combination with Md treatment. In summary, our data demonstrate that Md treatment of intact rats results in anabolic effects which are enhanced in combination with physical activity. Interestingly, the anabolic activity on the levator ani was increased in combination with training, although the levator ani muscle was not specifically stimulated by our training protocol. In the m. gastrocnemius and soleus, the anabolic effects correlate with changes in the expression patterns of genes involved in MSTN signaling. Our data provide evidence that the decrease in the weight of androgen-sensitive sexual glands, observed after Md treatment, is caused by a suppression of endogenous testosterone synthesis. These observations provide new insights into the molecular mechanisms of the interaction between anabolic steroids, training and MSTN signaling during skeletal muscle adaptation.


Job requirements compared to medical school education: differences between graduates from problem-based learning and conventional curricula.
Problem-based Learning (PBL) has been suggested as a key educational method of knowledge acquisition to improve medical education. We sought to evaluate the differences in medical school education between graduates from PBL-based and conventional curricula and to what extent these curricula fit job requirements. Graduates from all German medical schools who graduated between 1996 and 2002 were eligible for this study. Graduates self-assessed nine competencies as required at their day-to-day work and as taught in medical school on a 6-point Likert scale. Results were compared between graduates from a PBL-based curriculum (University Witten/Herdecke) and conventional curricula. Three schools were excluded because of low response rates. Baseline demographics between graduates of the PBL-based curriculum (n = 101, 49% female) and the conventional curricula (n = 4720, 49% female) were similar. No major differences were observed regarding job requirements with priorities for "Independent learning/working" and "Practical medical skills". All competencies were rated to be better taught in PBL-based curriculum compared to the conventional curricula (all p < 0.001), except for "Medical knowledge" and "Research competence". Comparing competencies required at work and taught in medical school, PBL was associated with benefits in "Interdisciplinary thinking" (Delta + 0.88), "Independent learning/working" (Delta + 0.57), "Psycho-social competence" (Delta + 0.56), "Teamwork" (Delta + 0.39) and "Problem-solving skills" (Delta + 0.36), whereas "Research competence" (Delta--1.23) and "Business competence" (Delta--1.44) in the PBL-based curriculum needed improvement. Among medical graduates in Germany, PBL demonstrated benefits with regard to competencies which were highly required in the job of physicians. Research and business competence deserve closer attention in future curricular development.


Evaluation and treatment of lipid disorders in women.
The latest report from the National Cholesterol Education Program has reaffirmed that the primary lipid goal for the prevention of atherosclerotic vascular disease (AVD) is to achieve a normal low-density lipoprotein (LDL) cholesterol (<130 mg/dL) by diet in normal individuals, and by diet and statin therapy in patients with multiple risk factors. Patients with any clinical AVD (which includes diabetes) will need a statin to achieve an optimal LDL cholesterol (<100 mg/dL). The recent Heart Protection Study might revise our thinking further. Patients at high risk achieved a reduction in mortality and vascular events taking simvastatin 40 mg, even if they had a low baseline LDL value. Individuals with the metabolic syndrome and insulin resistance do not typically have a very high LDL, but rather have elevated triglycerides and a low high-density lipoprotein (HDL) cholesterol. They, too, need to be treated with a statin, first to achieve an appropriate LDL goal. This is insufficient if the triglyceride value exceeds 200 mg/dL. They should be treated to achieve a non-HDL cholesterol goal (equal to total cholesterol minus HDL cholesterol) that is 30 mg/dL higher than the LDL goal.


Exploiting conformationally constrained peptidomimetics and an efficient human-compatible delivery system in synthetic vaccine design.
Peptide and protein mimetics are potentially of great value in synthetic vaccine design. The mimetics should function by stimulating the immune system to produce antibodies that recognize the intact parasite. Also the mimetics should be presented to the immune system in a way that leads to efficient antibody production. Here we investigate the application of cyclic peptidomimetics presented on immunopotentiating reconstituted influenza virosomes (IRIVs), a form of antigen delivery that is licensed already for human clinical use, in synthetic vaccine design. We focus on the central (NPNA)(n) repeat region of the circumsporozoite (CS) protein of the malaria parasite Plasmodium falciparum as a model system. Cyclic peptidomimetics of the NPNA repeats were incorporated into both an IRIV and (for comparison) a multiple-antigen peptide (MAP). Both IRIV and MAP delivery forms induced mimetic-specific humoral immune responses in mice, but only with the mimetic-IRIV preparations did a significant fraction of the elicited antibodies cross-react with sporozoites. The results demonstrate that IRIVs are a delivery system suitable for the efficient induction of antibody responses against conformational epitopes by use of cyclic template-bound peptidomimetics. Combined with combinatorial chemistry, this approach may have great potential for the rapid optimization of molecularly defined synthetic vaccine candidates against a wide variety of infectious agents.


Promyelocytic leukemia protein (PML) and stem cells: from cancer to pluripotency.
The promyelocytic leukemia protein (PML) is the core organizer of cognate nuclear bodies (PML-NBs). Through physical interaction or modification of diverse protein clients, PML-NBs regulate a multitude of - often antithetical- biological processes such as antiviral and stress response, inhibition of cell proliferation and autophagy, and promotion of apoptosis or senescence. Although PML was originally recognized as a tumor-suppressive factor, more recent studies have revealed a "double-faced" agent role for PML. Indeed, PML displayed tumor cell pro-survival and pro-migratory functions via inhibition of migration suppressing molecules or promotion of transforming growth factor beta (TGF-β) mediated Epithelial-Mesenchymal Transition (EMT) that may promote cancer cell dissemination. In this line, PML was found to correlate with poor patient prognosis in distinct tumor contexts. Furthermore, in the last decade, a number of publications have implicated PML in the physiology of normal or cancer stem cells (CSCs). Promyelocytic leukemia protein activates fatty acid oxidation (FAO), a metabolic mechanism required for the asymmetric divisions and maintenance of hematopoietic stem cells (HSCs). In embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), PML is required for maintenance of the naïve and acquisition of the induced pluripotency state, respectively. Correspondingly, PML ablation causes significant morphological gene expression and lineage choice changes. In this review, we focus on the mechanisms orchestrated by PML and PML-NBs in cancer and healthy stem cells, from cell physiology to the regulation of chromatin dynamics.


ATP1A1 -linked diseases require a malfunctioning protein product from one allele.
Heterozygous germline variants in ATP1A1 , the gene encoding the α1 subunit of the Na + /K + -ATPase (NKA), have been linked to diseases including primary hyperaldosteronism and the peripheral neuropathy Charcot-Marie-Tooth disease (CMT). ATP1A1 variants that cause CMT induce loss-of-function of NKA. This heterodimeric (αβ) enzyme hydrolyzes ATP to establish transmembrane electrochemical gradients of Na + and K + that are essential for electrical signaling and cell survival. Of the 4 catalytic subunit isoforms, α1 is ubiquitously expressed and is the predominant paralog in peripheral axons. Human population sequencing datasets indicate strong negative selection against both missense and protein-null ATP1A1 variants. To test whether haploinsufficiency generated by heterozygous protein-null alleles are sufficient to cause disease, we tested the neuromuscular characteristics of heterozygous Atp1a1 +/- knockout mice and their wildtype littermates, while also evaluating if exercise increased CMT penetrance. We found that Atp1a1 +/- mice were phenotypically normal up to 18 months of age. Consistent with the observations in mice, we report clinical phenotyping of a healthy adult human who lacks any clinical features of known ATP1A1 -related diseases despite carrying a protein-null early truncation variant, p.Y148*. Taken together, these results suggest that a malfunctioning gene product is required for disease induction by ATP1A1 variants and that if any pathology is associated with protein-null variants, they may display low penetrance or high age of onset.


Structure-function relationship of working memory activity with hippocampal and prefrontal cortex volumes.
A rapidly increasing number of studies are quantifying the system-level network architecture of the human brain based on structural-to-structural and functional-to-functional relationships. However, a largely unexplored area is the nature and existence of "cross-modal" structural-functional relationships, in which, for example, the volume (or other morphological property) of one brain region is related to the functional response to a given task either in that same brain region, or another brain region. The present study investigated whether the gray matter volume of a selected group of structures (superior, middle, and inferior frontal gyri, thalamus, and hippocampus) was correlated with the fMRI response to a working memory task, within a mask of regions previously identified as involved with working memory. The subjects included individuals with schizophrenia, their siblings, and healthy controls (n = 154 total). Using rigorous permutation testing to define the null distribution, we found that the volume of the superior and middle frontal gyri was correlated with working memory activity within clusters in the intraparietal sulcus (i.e., dorsal parietal cortex) and that the volume of the hippocampus was correlated with working memory activity within clusters in the dorsal anterior cingulate cortex and left inferior frontal gyrus. However, we did not find evidence that the identified structure-function relationships differed between subject groups. These results show that long-distance structural-functional relationships exist within the human brain. The study of such cross-modal relationships represents an additional approach for studying systems-level interregional brain networks.


Cover cropping can be a stronger determinant than host crop identity for arbuscular mycorrhizal fungal communities colonizing maize and soybean.
Understanding the role of communities of arbuscular mycorrhizal fungi (AMF) in agricultural systems is imperative for enhancing crop production. The key variables influencing change in AMF communities are the type of cover crop species or the type of subsequent host crop species. However, how maize and soybean performance is related to the diversity of AMF communities in cover cropping systems remains unclear. We therefore investigated which cover cropping or host identity is the most important factor in shaping AMF community structure in subsequent crop roots using an Illumina Miseq platform amplicon sequencing. In this study, we established three cover crop systems (Italian ryegrass, hairy vetch, and brown mustard) or bare fallow prior to planting maize and soybean as cash crops. After cover cropping, we divided the cover crop experimental plots into two subsequent crop plots (maize and soybean) to understand which cover cropping or host crop identity is an important factor for determining the AMF communities and diversity both in maize and soybeans. We found that most of the operational taxonomic units (OTUs) in root samples were common in both maize and soybean, and the proportion of common generalists in this experiment for maize and soybean roots was 79.5% according to the multinomial species classification method (CLAM test). The proportion of OTUs specifically detected in only maize and soybean was 9.6% and 10.8%, respectively. Additionally, the cover cropping noticeably altered the AMF community structure in the maize and soybean roots. However, the differentiation of AMF communities between maize and soybean was not significantly different. Our results suggest cover cropping prior to planting maize and soybean may be a strong factor for shaping AMF community structure in subsequent maize and soybean roots rather than two host crop identities. Additionally, we could not determine the suitable rotational combination for cover crops and subsequent maize and soybean crops to improve the diversity of the AMF communities in their roots. However, our findings may have implications for understanding suitable rotational combinations between cover crops and subsequent cash crops and further research should investigate in-depth the benefit of AMF on cash crop performances in cover crop rotational systems.


The association between primary ovarian insufficiency and osteoporosis in the Canadian Longitudinal Study on Aging.
The objective of this study is to describe the association of premature ovarian insufficiency (POI) and early menopause on bone mineral density (BMD) and osteoporosis in a large cohort of women living in Canada. Cross-sectional baseline data from a deeply characterized cohort (female participants) of the Canadian Longitudinal Study on Aging was used. Additional bio-psycho-social characteristics that may influence bone health and the development of osteoporosis were explored. The mean age of women at the time of baseline assessment was 65 years (N = 12,339). When comparing women with POI to those with early and normal age of menopause, there was no difference in hip BMD between groups, but women in the POI group were more likely to have a higher rate of self-reported osteoporosis (21.9% vs 16.7%) and have used osteoporosis drugs (11.39% vs 7.63%). After adjustment, POI was found to increase the odds of osteoporosis, as diagnosed using BMD. Current cigarette smoking was found to influence this association. Protective factors included obesity and current hormone therapy use, but not the duration of hormone therapy use. Women in the POI group were more likely to be obese, have decreased physical activity, and were more likely to be current smokers. These results confirm findings from smaller cohorts illustrating that POI is associated with osteoporosis. Increasing understanding of the sequelae associated with an earlier loss of ovarian function will aid in targeting earlier screening and intervention strategies for women in Canada and abroad.