Immunity against HIV/AIDS, malaria, and tuberculosis during co-infections with neglected infectious diseases: recommendations for the European Union research priorities.
Infectious diseases remain a major health and socioeconomic problem in many low-income countries, particularly in sub-Saharan Africa. For many years, the three most devastating diseases, HIV/AIDS, malaria, and tuberculosis (TB) have received most of the world's attention. However, in rural and impoverished urban areas, a number of infectious diseases remain neglected and cause massive suffering. It has been calculated that a group of 13 neglected infectious diseases affects over one billion people, corresponding to a sixth of the world's population. These diseases include infections with different types of worms and parasites, cholera, and sleeping sickness, and can cause significant mortality and severe disabilities in low-income countries. For most of these diseases, vaccines are either not available, poorly effective, or too expensive. Moreover, these neglected diseases often occur in individuals who are also affected by HIV/AIDS, malaria, or TB, making the problem even more serious and indicating that co-infections are the rule rather than the exception in many geographical areas. To address the importance of combating co-infections, scientists from 14 different countries in Africa and Europe met in Addis Ababa, Ethiopia, on September 9-11, 2007. The message coming from these scientists is that the only possibility for winning the fight against infections in low-income countries is by studying, in the most global way possible, the complex interaction between different infections and conditions of malnourishment. The new scientific and technical tools of the post-genomic era can allow us to reach this goal. However, a concomitant effort in improving education and social conditions will be needed to make the scientific findings effective.


Bras for Breast Support After Sternotomy: Patient Satisfaction and Wear Compliance.
For women undergoing median sternotomy, especially those with a bra cup size C or larger, breast support can reduce pain, wound breakdown, and infection. This study addressed a gap in research, identifying the best bra after sternotomy in terms of patient satisfaction and wear compliance. To evaluate larger-breasted women's satisfaction and compliance with wearing 3 commercially available front-closure bras-with a hook-loop closure (the hospital's standard of care), a zipper closure, or a hook-eye closure-after cardiac surgery. This study used a posttest-only, 3-group randomized controlled design. A convenience sample of participants were sized and randomly assigned a product that was placed immediately postoperatively. Participants agreed to wear the bra at least 20 h/d until the provider cleared them for less wear. At inpatient day 5 or discharge, and at the follow-up outpatient visit, subjects completed investigator-developed surveys. Data were analyzed from 60 participants by using the χ2 test and Kruskal-Wallis analysis of variance; also, patterns were identified within written comments. Participants were most satisfied with the hook-eye front-closure product before (P = .05) and after (P = .02) discharge. Participants recommended the hook-eye and zipper products over the hook-loop bra (H = 8.39, P = .02). Wear compliance was strongest in the group wearing the hook-eye bra. The hook-eye closure product had the most satisfaction and greatest wear compliance, and it received the highest recommendation. A practice change was made to fit and place the hook-eye bra in the operating room immediately after surgery.


Longitudinal mechanical tension induces growth in the small bowel of juvenile rats.
The aim of our study was to apply longitudinal force to the small bowel to increase the length of intestine in juvenile rats. Fifty juvenile rats had double barrelled, blind loop ostomies created using an isolated segment of bowel. Our intestinal lengthening device was inserted into one of the loops and the second loop served as a control. Once the device was deployed, the experimental, control, and in situ segments of bowel were evaluated for length, weight, histology, and disaccharidase enzyme activity. Mechanical tension increased intestinal length by 149%. The lengthened bowel also exhibited a greater total weight (218%), greater mucosal weight (122%), and increased protein mass (164%) compared with the control limb of bowel. Histologically, there was a markedly increased thickness of the muscularis propria in the lengthened bowel (200% increase compared with the control limb). Functionally, we found increased total disaccharidase activity in the lengthened bowel (between 47% and 350%, depending on the particular enzyme tested; p<0.01). Mechanical tension induces intestinal growth by increasing length, weight of the bowel and mucosa, and protein mass. Histological changes, such as increases in Paneth cells, suggest that increased proliferation and reorganisation of the mucosa and muscularis propria are a response to mechanical tension. Functionally, increased intestinal length corresponds with increased disaccharidase activity, thus implying potential increased absorptive capacity of the lengthened bowel.


A regional-scale assessment of using metabolic scaling theory to predict ecosystem properties.
Metabolic scaling theory (MST) is one of ecology's most high-profile general models and can be used to link size distributions and productivity in forest systems. Much of MST's foundation is based on size distributions following a power law function with a scaling exponent of -2, a property assumed to be consistent in steady-state ecosystems. We tested the theory's generality by comparing actual size distributions with those predicted using MST parameters assumed to be general. We then used environmental variables and functional traits to explain deviation from theoretical expectations. Finally, we compared values of relative productivity predicted using MST with a remote-sensed measure of productivity. We found that fire-prone heath communities deviated from MST-predicted size distributions, whereas fire-sensitive rainforests largely agreed with the theory. Scaling exponents ranged from -1.4 to -5.3. Deviation from the power law assumption was best explained by specific leaf area, which varies along fire frequency and moisture gradients. While MST may hold in low-disturbance systems, we show that it cannot be applied under many environmental contexts. The theory should remain general, but understanding the factors driving deviation from MST and subsequent refinements is required if it is to be applied robustly across larger scales.


Hydrocephalus surveillance following shunt placement or endoscopic third ventriculostomy: a survey of surgeons in the Hydrocephalus Clinical Research Networks.
Late failure is a well-documented complication of cerebrospinal fluid shunt placement and, less commonly, endoscopic third ventriculostomy (ETV). However, standards regarding the frequency of clinical and radiological follow-up in these patients have not been defined. Here, the authors report on their survey of surgeons at sites for the Hydrocephalus Clinical Research Network (HCRN) or its implementation/quality improvement arm (HCRNq) to provide a cross-sectional overview of practice patterns. A 24-question survey was developed using the Research Electronic Data Capture (REDCap) platform and was distributed to the 138 pediatric neurosurgeons across 39 centers who participate in the HCRN or HCRNq. Survey questions were organized into three sections: 1) Demographics (5 questions), 2) Shunt Surveillance (12 questions), and 3) ETV Surveillance (7 questions). A total of 122 complete responses were obtained, for an overall response rate of 88%. The majority of respondents have been in practice for more than 10 years (58%) and exclusively treat pediatric patients (79%). Most respondents consider hydrocephalus to have stabilized 1 month (21%) or 3 months (39%) after shunt surgery, and once stability is achieved, 72% then ask patients to return for routine clinical follow-up annually. Overall, 83% recommend lifelong clinical follow-up after shunt placement. Additionally, 75% obtain routine imaging studies in asymptomatic patients, although the specific imaging modality and frequency of imaging vary. The management of an asymptomatic increase in ventricle size or an asymptomatic catheter fracture also varies widely. Many respondents believe that hydrocephalus takes longer to stabilize after ETV than after shunt placement, reporting that they consider hydrocephalus to have stabilized 3 (28%), 6 (33%), or 12 (28%) months after an ETV. Although 68% of respondents have patients return annually for routine clinical follow-up after an ETV, only 56% recommend lifelong follow-up. The proportion of respondents who perform lifelong follow-up increases with greater practice experience (p = 0.01). Overall, 67% of respondents obtain routine imaging studies in asymptomatic patients after an ETV, with "rapid" MRI the study of choice for most respondents. While there is a general consensus among pediatric neurosurgeons across North America that hydrocephalus patients should have long-term follow-up after shunt placement, radiological surveillance is characterized by considerable variety, as is follow-up after an ETV. Future work should focus on evaluating whether any one of these surveillance protocols is associated with improved outcomes.


Association of Apolipoprotein C3 Genetic Polymorphisms with the Risk of Ischemic Stroke in the Northern Chinese Han Population.
The apolipoprotein C3 (APOC3) gene, which is a member of the APOA1/C3/A4/A5 gene cluster, plays a crucial role in lipid metabolism. Dyslipidemia is an important risk factor for ischemic stroke. In the present study, we performed a hospital-based case-control study of 895 ischemic stroke patients and 883 control subjects to examine the effects of four APOC3 single nucleotide polymorphisms (SNPs) (rs2854116, rs2854117, rs4520 and rs5128) on the risk of ischemic stroke in a northern Chinese Han population. The SNaPshot Multiplex sequencing assay was used for SNP genotyping, and the potential association of genotype distributions and allele frequencies with ischemic stroke was analyzed statistically. Compared with the GG genotype, the CC+GC genotype of rs5128 was significantly associated with an increased risk in females (adjusted OR = 3.38, 95% CI = 1.82-6.28, P <0.01) after all of the risk factors were adjusted for with logistic regression analyses. A similar relationship was found between the rs4520 polymorphism and ischemic stroke risk in Han Chinese women. Under a recessive genetic model, the TT+TC genotypes of this variant increased ischemic stroke risk (adjusted OR = 2.05; 95% CI = 1.28-3.29; P <0.01). Haplotype analysis revealed that in males, the T-C-T-C haplotype of rs2854116-rs2854117-rs4520-rs5128 was significantly more frequent in the ischemic stroke group than in the control group (OR = 1.49, 95% CI = 1.18-1.87, P<0.01). The results of our study indicate that the APOC3 polymorphisms contribute to ischemic stroke susceptibility in females in the northern Chinese Han population.


Modulational instability in a layered Kerr medium: theory and experiment.
We present the first experimental investigation of modulational instability in a layered Kerr medium. The particularly interesting and appealing feature of our configuration, consisting of alternating glass-air layers, is the piecewise-constant nature of the material properties, which allows a theoretical linear stability analysis leading to a Kronig-Penney equation whose forbidden bands correspond to the modulationally unstable regimes. We find very good quantitative agreement between theoretical, numerical, and experimental diagnostics of the modulational instability. Because of the periodicity in the evolution variable arising from the layered medium, there are multiple instability regions rather than just one as in a uniform medium.


Effects of mechanical stretching on trabecular matrix metalloproteinases.
The homeostatic mechanisms responsible for intraocular pressure (IOP) regulation are not understood. Studies were conducted to evaluate the hypothesis that trabecular meshwork (TM) cells sense increases in IOP as stretching or distortion of their extracellular matrix (ECM) and respond by increasing ECM turnover enzymes. Flow rates were increased in perfused human anterior segment organ cultures and the matrix metalloproteinase (MMP) levels and IOP were evaluated. Human TMs in stationary anterior segment organ culture were mechanically stretched, and MMP levels were analyzed. TM cells were grown on membranes, which were then stretched, and MMP levels were evaluated. Western immunoblots, zymography, and confocal immunohistochemistry were used to evaluate changes in MMPs and their tissue inhibitors, the TIMPS: Doubling the flow rate in perfused human organ cultures increased gelatinase A levels in the perfusate by 30% to 50% without affecting gelatinase B or stromelysin levels. Immediately after doubling the flow rate, the measured IOP doubled. However, over the next few days the IOP gradually returned to the initial level, although the flow rate was maintained at double the initial value. Stretching stationary organ cultures or stretching TM cells grown on membranes resulted in similar increases in gelatinase A without changes in gelatinase B or stromelysin levels. The gelatinase A increases occurred between 24 and 72 hours and were approximately proportional to the degree of stretching. Although coating the membranes with different ECM molecule affected the gelatinase A response, the optimum response occurred when the cells had been grown long enough to produce their own ECM. By Western immunoblot and confocal immunohistochemistry, the stretch-induced increases in gelatinase A were accompanied by strong decreases in TIMP-2 levels and moderate increases in one membrane type MMP, MT1-MMP. After mechanical stretching of the membrane, gelatinase A, MT1-MMP and TIMP-2 all exhibited a similar punctate immunostaining pattern over the TM cell surface. These results are compatible with the hypothesis that elevations in IOP are sensed by TM cells as ECM stretch/distortion. TM cells respond by increasing gelatinase A and MT1-MMP, while decreasing TIMP-2 levels. This will increase ECM turnover rates, reduce the trabecular resistance to aqueous humor outflow, and restore normal IOP levels. This hypothesis provides a regulatory feedback mechanism for IOP homeostasis.


Deferred radiotherapy and upfront procarbazine-ACNU-vincristine administration for 1p19q codeleted oligodendroglial tumors are associated with favorable outcome without compromising patient performance, regardless of WHO grade.
Recently updated phase III trials revealed the favorable effect of add-on procarbazine-lomustine-vincristine chemotherapy (CT) to radiotherapy (RT) in treating anaplastic oligodendrogliomas with 1p19q codeletion (codel). However, the underlying rationality of deferring RT and upfront CT administration for these tumors is yet to be elucidated. Here, we retrospectively analyzed the long-term outcome of our case series with oligodendroglial tumors treated with deferred RT and upfront procarbazine+nimustine+vincristine (PAV) in the introduction administration. We enrolled 36 patients with newly diagnosed oligodendroglial tumors (17, grade II and 19, grade III) treated during 1999-2012 and followed up for a median period of 69.0 months. Their clinical and genetic prognostic factors were analyzed, and progression-free survival, overall survival (OS), and deterioration-free survival (DFS) were evaluated. Regardless of the WHO grade, the 25 patients with 1p19q codel tumors never received RT initially, and of these 25, 23 received PAV treatment upfront. The 75% OS of patients with 1p19q codel tumor was 135.3 months (did not reach the median OS), indicating a favorable outcome. Multivariate analysis revealed that IDH mutation and 1p19q, not WHO grade, are independent prognostic factors; furthermore, IDH and 1p19q status stratified the cohort into 3 groups with significantly different OS. The DFS explained the prolonged survival without declining performance in patients with both grade II and III 1p19q codel tumors. Deferred RT and upfront PAV treatment for 1p19q codel oligodendrogliomas were associated with favorable outcomes without compromising performance status, regardless of WHO grade.


A synthetic lethal interaction between K-Ras oncogenes and Cdk4 unveils a therapeutic strategy for non-small cell lung carcinoma.
We have unveiled a synthetic lethal interaction between K-Ras oncogenes and Cdk4 in a mouse tumor model that closely recapitulates human non-small cell lung carcinoma (NSCLC). Ablation of Cdk4, but not Cdk2 or Cdk6, induces an immediate senescence response only in lung cells that express an endogenous K-Ras oncogene. No such response occurs in lungs expressing a single Cdk4 allele or in other K-Ras-expressing tissues. More importantly, targeting Cdk4 alleles in advanced tumors detectable by computed tomography scanning also induces senescence and prevents tumor progression. These observations suggest that robust and selective pharmacological inhibition of Cdk4 may provide therapeutic benefit for NSCLC patients carrying K-RAS oncogenes.


Effects of feeding conditions on gene expression in chicken breast muscle.
Chicken meat quality is becoming increasingly important among breeders and consumers. To understand the effect of feeding conditions on chicken meat quality, we investigated the profiles of genes expressed in chicken breast muscle. Using RNA sequencing, we identified 336, 321, and 387 differentially expressed genes among Chengkou, Daninghe, and Qingjiaoma chickens under scatter- and captivity-feeding conditions. Twenty-two genes differentially expressed between different feeding conditions were shown to be common among the three breeds. Seven of these genes were assessed by real-time quantitative PCR, which confirmed the findings of RNA sequencing and suggested that the results were viable. The differentially expressed genes showed enrichment for a series of significant pathways, including energy metabolism, xenobiotics biodegradation and metabolism, and the immune system. These results provide a solid foundation for elucidating the molecular mechanisms underlying chicken meat quality.


Regioselective dehydration of α-hydroxymethyl tetrahydrofurans using Burgess' reagent under microwave irradiation.
We here present a highly efficient and high yielding procedure for the preparation of 2-vinyl tetrahydrofurans starting from α-hydroxymethyl tetrahydrofurans. Best results for this dehydration were achieved using Burgess' reagent in dioxane under microwave irradiation. A range of functional groups as well as different cyclic and bicyclic frameworks were found to be compatible with the reaction conditions. The desired products were obtained within minutes in good to high yields and excellent regioselectivity.


Cross-species transmission of poultry pathogens in backyard farms: ducks as carriers of chicken viruses.
In backyard farms of Lao People's Democratic Republic, mixed-species rearing of poultry is a breeding-ground for cross-species transmission. Here, the epidemiology of viruses circulating among backyard poultry in Vientiane Province was assessed to guide future control strategies. Oral/tracheal and cloacal swabs, collected from 605 poultry (308 ducks, 297 chickens) between 2011 and 2015, were screened by PCR for Newcastle disease virus (NDV), coronavirus (CoV) and chicken anaemia virus (CAV). Chicken sera were screened for anti-NDV antibodies by ELISA. Statistical and phylogenetic analyses revealed transmission patterns and relationships. Closely related strains co-circulated in chickens and ducks. While CoV RNA was detected in oral/tracheal swabs of 9.3% of the chickens and 2.4% of the ducks, rates were higher in faecal swabs of both species (27.3% and 48.2%). RNA of infectious bronchitis virus (IBV) and duck CoV was found in faecal swabs of chickens (19.7% and 7.1%) and ducks (4.1% and 44.1%). Moreover, DNA of the generally chicken-specific CAV was detected in oral/tracheal swabs of chickens (18.1%) and, sporadically, of ducks (2.4%). Despite serological evidence of NDV circulation or vaccination (86.9%), NDV RNA was not detected. We found a high prevalence and indication for cross-species transmission of different CoV strains in backyard poultry. Interestingly, ducks served as biological, or at least mechanical, carriers of viral strains closely related not only to IBV, but also to CAV. Bird containment and poultry species separation could be first steps to avoid cross-species transmission and emergence of novel strains with broad host range and enhanced pathogenicity. RESEARCH HIGHLIGHTS High rates of avian viruses were detected by PCR in backyard poultry from Lao PDR. Diverse coronavirus and chicken anemia virus strains co-circulated. Phylogenetic analyses suggested virus transmission between chickens and ducks. Serological evidence of Newcastle disease was found, but viral RNA was not detected.


Effects of Combined Aerobic and Resistance Exercise on Exercise Capacity, Muscle Strength and Quality of Life in HIV-Infected Patients: A Systematic Review and Meta-Analysis.
Many HIV-infected patients demonstrate disability and lower aerobic capacity. The inclusion of resistance training combined with aerobic exercise in a single program is known as combined aerobic and resistance exercise (CARE) and seems to be an effective strategy to improve muscle weakness, as well as aerobic capacity in HIV-infected patients. We performed a meta-analysis to investigate the effects of CARE in HIV-infected patients. We searched MEDLINE, Cochrane Controlled Trials Register, EMBASE, CINAHL (from the earliest date available to august 2014) for controlled trials that evaluated the effects of CARE in HIV-infected patients. Weighted mean differences (WMD) and 95% confidence intervals (CIs) were calculated, and heterogeneity was assessed using the I2 test. Seven studies met the study criteria. CARE resulted in improvement in Peak VO2 WMD (4.48 mL·kg-1·min-1 95% CI: 2.95 to 6.0), muscle strength of the knee extensors WMD (25.06 Kg 95% CI: 10.46 to 39.66) and elbow flexors WMD (4.44 Kg 95% CI: 1.22 to 7.67) compared with no exercise group. The meta-analyses also showed significant improvement in Health status, Energy/Vitality and physical function domains of quality of life for participants in the CARE group compared with no exercise group. A nonsignificant improvement in social function domain of quality of life was found for participants in the CARE group compared with no exercise group. Combined aerobic and resistance exercise may improve peak VO2, muscle strength and health status, energy and physical function domains of quality of life and should be considered as a component of care of HIV-infected individuals.


Maternal-fetal interactions and the maintenance of HLA polymorphism.
There is some empirical evidence that a fetus with an HLA antigen not present in its mother has a higher survival than a fetus sharing antigens with its mother. We have developed both single locus and two-locus theoretical models to examine this mode of selection. First, this immunologically based model appears to have the potential to maintain many alleles at a single locus and to result in an excess of heterozygotes when selection is strong. Second, substantial gametic disequilibrium is maintained between alleles at two loci for this selection mode when recombination is that observed between HLA loci A, B, and DR. Overall, it appears that this mode of selection has the potential to strongly affect genetic variation in the HLA region.


Understanding parent perceptions of healthy physical activity for their child with a chronic medical condition: A cross-sectional study.
We sought to determine the prevalence of, and identify factors associated with, parent questions about physical activity for their child with a chronic cardiac, respiratory, or rheumatologic condition. This cross-sectional study of 56 children (32 [57%] female), 3 to 18 years of age, with chronic cardiac (n=21), respiratory (n=18), or rheumatologic (n=17) conditions involved a parent questionnaire about their child's physical activity participation and measurement of the child's activity with an omni-directional accelerometer for 1 week. Parents of 20 (36%) children had at least one question about their child's physical activity participation, and the prevalence of questions did not vary by age (Wald chi square = 0.77, P=0.38), gender (Wald chi square = 0.11, P=0.74), or clinic (Wald chi square = 1.77, P=0.41). Parent questions were associated (P = 0.04) with lower levels of activity for boys (95% confidence interval [CI] for estimated marginal means: With questions: 197, 395; Without questions: 346, 500) and higher levels of activity for girls (95% CI for estimated marginal means: With questions: 268, 448; Without questions: 239, 369). A multivariable logistic regression model found that parents with questions had higher odds of having a child who was less well (odds ratio [OR]=19.9 for unwell, OR=5.6 for generally well with some symptoms versus well and asymptomatic) and had a history of cardiac arrhythmia (OR=7.6). Over one-third of parents reported having questions about physical activity for their child with a chronic medical condition, suggesting substantial uncertainty even among children reported as active. Presence of parent uncertainty is associated with parent reports of the child being unwell or a history of cardiac arrhythmia. By asking parents if they have questions about their child's activity, health care professionals may be better able to identify inactive boys and overprotective attitudes toward active girls.


Phase II trial of paclitaxel, ifosfamide, and cisplatin in patients with recurrent head and neck squamous cell carcinoma.
To assess the activity and toxicity profile of combined taxol (paclitaxel), ifosfamide, and platinum (cisplatin) (TIP) in patients with recurrent or metastatic squamous cell carcinoma (SCC) of the head and neck. Recurrent or metastatic head and neck SCC patients received paclitaxel 175 mg/m2 in a 3-hour infusion on day 1; ifosfamide 1,000 mg/m2 in a 2-hour infusion on days 1 through 3; mesna 600 mg/m2 on days 1 through 3; and cisplatin 60 mg/m2 on day 1, repeated every 3 to 4 weeks. All were premedicated with dexamethasone, diphenhydramine, and cimetidine. Prophylactic hematopoietic growth factors were not permitted. Fifty-two patients were assessable for response and toxicity; 53 for survival (local-regional recurrence alone in 57% and distant metastasis with or without local-regional recurrence in 43%). Overall response rate was 58% (30 of 52) of patients; complete response rate was 17% (nine of 52) of patients, with six complete responses that continued for a median 15.7+ months. Median follow-up of all patients was 17.7 months. Median survival was 8.8 months (95% confidence interval [CI] 8.1 to 17.5 months). Toxicity was relatively well tolerated and caused no deaths. The most frequent moderate-to-severe toxicity (90% of patients) was transient grades 3 to 4 neutropenia; neutropenic fever occurred in 27%. Grade 3 peripheral neuropathy occurred in three patients, none had grade 4. Grade 3 mucositis occurred in only one patient, none had grade 4. TIP had major activity in this setting, with a 58% objective response rate, 17% complete response rate, durable complete responses (six of nine persisting), and relatively well-tolerated toxicity, with no toxic deaths. The activity of TIP, a novel taxol-cisplatin-based regimen, in recurrent or metastatic head and neck SCC should be confirmed in a phase III trial.


Replication stress interferes with histone recycling and predeposition marking of new histones.
To restore chromatin on new DNA during replication, recycling of histones evicted ahead of the fork is combined with new histone deposition. The Asf1 histone chaperone, which buffers excess histones under stress, is a key player in this process. Yet how histones handled by human Asf1 are modified remains unclear. Here we identify marks on histones H3-H4 bound to Asf1 and changes induced upon replication stress. In S phase, distinct cytosolic and nuclear Asf1b complexes show ubiquitous H4K5K12diAc and heterogeneous H3 marks, including K9me1, K14ac, K18ac, and K56ac. Upon acute replication arrest, the predeposition mark H3K9me1 and modifications typical of chromatin accumulate in Asf1 complexes. In parallel, ssDNA is generated at replication sites, consistent with evicted histones being trapped with Asf1. During recovery, histones stored with Asf1 are rapidly used as replication resumes. This shows that replication stress interferes with predeposition marking and histone recycling with potential impact on epigenetic stability.


Social Constructions of Rape at Columbia University and Barnard College, 1955-90.
Sex on college campuses has fascinated scholars, reporters, and the public since the advent of coeducational higher education in the middle of the nineteenth century. But the emergence of rape on campus as a public problem is relatively recent. This article reveals the changing social constructions of campus rape as a public problem through a detailed examination of newspaper reporting on this issue as it unfolded at Columbia University and Barnard College between 1955 and 1990. Adapting Joseph R. Gusfield's classic formulation of public problem construction, we show the ways police and other judicial and law enforcement authorities, feminists, university faculty, student groups, university administrators, and health professionals and institutions have struggled over ownership of how the problem should be defined and described, attribution of responsibility for addressing the problem, and prescriptions for what is to be done. Our findings show how beginning in the late 1960s and early 1970s, the simultaneous swelling of the women's liberation movement and the exponential integration of women into previously male-dominated institutions of higher education and medicine catalyzed the creation of new kinds of knowledge, institutions, and expertise to address rape and sexual violence more broadly on college campuses. New actors-feminists and health professionals-layered frames of gender and health over those of crime and punishment to fundamentally transform how we understand rape on campus, and beyond.


The age of extremes: concentrated affluence and poverty in the twenty-first century.
Urbanization, rising income inequality, and increasing class segregation have produced a geographic concentration of affluence and poverty throughout the world, creating a radical change in the geographic basis of human society. As the density of poverty rises in the environment of the world's poor, so will their exposure to crime, disease, violence, and family disruption. Meanwhile the spatial concentration of affluence will enhance the benefits and privileges of the rich. In the twenty-first century the advantages and disadvantages of one's class position will be compounded and re-inforced through ecological mechanisms made possible by the geographic concentration of affluence and poverty, creating a deeply divided and increasingly violent social world.


Inward rectification of resting and opiate-activated potassium currents in rat locus coeruleus neurons.
Intracellular recordings were made from rat locus coeruleus neurons in vitro, and membrane currents were measured at potentials from -50 to -130 mV. In the absence of any applied agonists, the slope conductance of the cells increased 3-fold when the cell was hyperpolarized from -60 to -120 mV. This conductance increase was complete within 5 msec of the onset of a hyperpolarizing command and was subsequently independent of time for several seconds. The conductance increase was blocked by cesium chloride (1-2 mM), rubidium chloride (1-2 mM), or barium chloride (1-100 microM). The membrane potential range over which the conductance increased was centered at the potassium equilibrium potential (EK; extracellular potassium concentration, 2.5-10.5 mM): the current/voltage (I/V) relation of the cell could be well described by supposing that there were 2 potassium conductances, one voltage independent (G1) and the other (inward rectifier, Gir) activated according to the expression Gir = Gir,max/(1 + exp[(V - EK)/k]), where k ranged from 15 mV in 2.5 mM potassium to 6 mV in 10.5 mM potassium. The additional membrane potassium conductance that developed when agonists at mu-opioid and alpha 2-adrenoceptors were applied also became larger with membrane hyperpolarization, and this voltage dependence was also reduced or blocked by rubidium, cesium, and barium; in the presence of these agonists the current also reached its final value within 5 msec. However, the conductance increased by the agonists (Gag) was not well expressed by simply increasing the values of G1 and Gir,max. It was best described by a potassium conductance that increased according to Gag,max/(1 + exp[(V - Vm)/k]), where Vm (the potential at which the conductance was half-maximum) was close to the resting potential of the cell.(ABSTRACT TRUNCATED AT 400 WORDS)


Crystal structure of a G:T/U mismatch-specific DNA glycosylase: mismatch recognition by complementary-strand interactions.
G:U mismatches resulting from deamination of cytosine are the most common promutagenic lesions occurring in DNA. Uracil is removed in a base-excision repair pathway by uracil DNA-glycosylase (UDG), which excises uracil from both single- and double-stranded DNA. Recently, a biochemically distinct family of DNA repair enzymes has been identified, which excises both uracil and thymine, but only from mispairs with guanine. Crystal structures of the mismatch-specific uracil DNA-glycosylase (MUG) from E. coli, and of a DNA complex, reveal a remarkable structural and functional homology to UDGs despite low sequence identity. Details of the MUG structure explain its thymine DNA-glycosylase activity and the specificity for G:U/T mispairs, which derives from direct recognition of guanine on the complementary strand.


Analysis of body fluid mixtures by mtDNA sequencing: An inter-laboratory study of the GEP-ISFG working group.
The mitochondrial DNA (mtDNA) working group of the GEP-ISFG (Spanish and Portuguese Group of the International Society for Forensic Genetics) carried out an inter-laboratory exercise consisting of the analysis of mtDNA sequencing patterns in mixed stains (saliva/semen and blood/semen). Mixtures were prepared with saliva or blood from a female donor and three different semen dilutions (pure, 1:10 and 1:20) in order to simulate forensic casework. All labs extracted the DNA by preferential lysis and amplified and sequenced the first mtDNA hypervariable region (HVS-I). Autosomal and Y-STR markers were also analysed in order to compare nuclear and mitochondrial results from the same DNA extracts. A mixed stain prepared using semen from a vasectomized individual was also analysed. The results were reasonably consistent among labs for the first fractions but not for the second ones, for which some laboratories reported contamination problems. In the first fractions, both the female and male haplotypes were generally detected in those samples prepared with undiluted semen. In contrast, most of the mixtures prepared with diluted semen only yielded the female haplotype, suggesting that the mtDNA copy number per cell is smaller in semen than in saliva or blood. Although the detection level of the male component decreased in accordance with the degree of semen dilution, it was found that the loss of signal was not consistently uniform throughout each electropherogram. Moreover, differences between mixtures prepared from different donors and different body fluids were also observed. We conclude that the particular characteristics of each mixed stain can deeply influence the interpretation of the mtDNA evidence in forensic mixtures (leading in some cases to false exclusions). In this sense, the implementation of preliminary tests with the aim of identifying the fluids involved in the mixture is an essential tool. In addition, in order to prevent incorrect conclusions in the interpretation of electropherograms we strongly recommend: (i) the use of additional sequencing primers to confirm the sequencing results and (ii) interpreting the results to the light of the phylogenetic perspective.


ACOG Simulation Working Group: A Needs Assessment of Simulation Training in OB/GYN Residencies and Recommendations for Future Research.
To evaluate current availability and needs of simulation training among obstetrics/gynecology (OB/GYN) residency programs. Cross-sectional survey. Accreditation Council for Graduate Medical Education accredited OB/GYN residency programs in the United States. Residency program directors, gynecology simulation faculty, obstetrics simulation faculty, and fourth-year residents. Of 673 invited participants, 251 (37.3%) completed the survey. Among the survey responses, OB procedures were more broadly represented compared to the GYN procedures for simulation teaching: 8 (50%) of 16 OB procedures versus 4 (18.2%) of 22 GYN procedures had simulation teaching. Among the simulated procedures, a majority of residents and faculty reported that simulation teaching was available for operative vaginal delivery, postpartum hemorrhage, shoulder dystocia, perineal laceration repair, conventional laparoscopic procedures, and robotic surgery. There were significant differences between residents and faculty perceptions regarding the availability and needs of simulated procedures with a minority of residents having knowledge of Council on Resident Education in Obstetrics and Gynecology (47.2%) and American College of Obstetrics and Gynecology (27.8%) simulation tools compared to the majority of faculty (84.7% and 72.1%, respectively). More than 80% of trainees and faculty reported they felt the average graduating resident could perform vaginal, laparoscopic, and abdominal hysterectomies independently. Simulation is now widely available for both gynecologic and obstetric procedures, but there remains tremendous heterogeneity between programs and the perceptions of residents, program directors, and faculty. The variations in simulation training and readiness for performing different procedures following residency support the need for objective, validated assessments of actual performance to better guide resident learning and faculty teaching efforts.


[Suicide trends in Colombia, 1985-2002].
To report trends in mortality from suicide in Colombia from 1985 to 2002 by sex, age group, and method, and determine the number of Years of Potential Life Lost (YPLL) to suicide during this period. Age- and sex-specific and age-adjusted crude mortality rates were calculated based on mortality and population information available from the official database of the Department of National Statistics Administration, Colombia. YPLL were estimated and adjusted for societal impact, age, and poor quality of mortality records. The results were tabulated according to codes X600-X849 and Y870 from the International Statistical Classification of Disease and Related Health Problems, 10th revision (ICD-10), and codes E950-E959 from the 9th revision (ICD-9). Suicide rates have been climbing in Colombia since 1998, particularly among young adults and males. The highest rates among males were in the age groups 20-29 years of age and over 70 years of age, and rates increased over time. Among females, the highest rates were recorded for the group 10-19 years of age. The YPLL rose in proportion with the increase in suicides, from 0.81% in 1981 to 2.20% in 2002. Among males, the most common methods used were firearms and explosives, hanging, and poison, with a relative increase in hanging; whereas among females, poison was most common. A rising trend in suicide rates in Colombia was confirmed, especially among the productive segment of the population, which has resulted in a marked increase in YPLL.


Responses to pandemic (H1N1) 2009, Australia.
In 2007, adults in Australia were interviewed about their willingness to comply with potential health interventions during a hypothetical influenza outbreak. After the first wave of pandemic (H1N1) 2009 in Australia, many of the same respondents were interviewed about behavior and protection measures they actually adopted. Of the original 1,155 respondents, follow-up interviews were conducted for 830 (71.9%). Overall, 20.4% of respondents in 2009 had recently experienced influenza-like illness, 77.7% perceived pandemic (H1N1) 2009 to be mild, and 77.8% reported low anxiety. Only 14.5% could correctly answer 4 questions about influenza virus transmission, symptoms, and infection control. Some reported increasing handwashing (46.6%) and covering coughs and sneezes (27.8%) to reduce transmission. Compared with intentions reported in 2007, stated compliance with quarantine or isolation measures in 2009 remained high. However, only respondents who perceived pandemic (H1N1) 2009 as serious or who had attained higher educational levels expressed intention to comply with social distancing measures.


A cluster randomized controlled trial of a structured training programme for caregivers of inpatients after stroke (TRACS).
The majority of stroke patients are discharged home dependent on informal caregivers, usually family members, to provide assistance with activities of daily living, including bathing, dressing, and toileting. Many caregivers feel unprepared for this role, and this may have a detrimental effect on both the patient and caregiver. To evaluate whether a structured, competency-based training programme for caregivers improves physical and psychological outcomes for patients and their caregivers after disabling stroke, and to determine if such a training programme is cost-effective. A cluster randomized controlled trial. The trial aims to recruit 25 patient and caregiver dyads from each of the 36 participating stroke rehabilitation units. Stroke units have been randomized to either the intervention or control group with randomization stratified by geographical region and quality of care. The intervention is the London Stroke Carer Training Course developed and evaluated in a previous single-centre study. The London Stroke Carer Training Course comprises a number of caregiver training sessions and competency assessment delivered while the patient is in the hospital and one follow-up session after discharge. The multidisciplinary teams in the units randomized to the intervention group have been trained to incorporate delivery of the London Stroke Carer Training Course into ward practice, while those randomized to the control group have continued to provide usual care according to national guidelines. The primary outcomes are extended activities of daily living for the patient and caregiver burden measured at six-months after recruitment. Secondary outcomes include mood and cost-effectiveness, with final follow-up at 12 months.


Prevalence of hemolysin genes and comparison of ehxA subtype patterns in Shiga toxin-producing Escherichia coli (STEC) and non-STEC strains from clinical, food, and animal sources.
Shiga toxin-producing Escherichia coli (STEC) belonging to certain serogroups (e.g., O157 and O26) can cause serious conditions like hemolytic-uremic syndrome (HUS), but other strains might be equally pathogenic. While virulence factors, like stx and eae, have been well studied, little is known about the prevalence of the E. coli hemolysin genes (hlyA, ehxA, e-hlyA, and sheA) in association with these factors. Hemolysins are potential virulence factors, and ehxA and hlyA have been associated with human illness, but the significance of sheA is unknown. Hence, 435 E. coli strains belonging to 62 different O serogroups were characterized to investigate gene presence and phenotypic expression of hemolysis. We further investigated ehxA subtype patterns in E. coli isolates from clinical, animal, and food sources. While sheA and ehxA were widely distributed, e-hlyA and hlyA were rarely found. Most strains (86.7%) were hemolytic, and significantly more hemolytic (95%) than nonhemolytic strains (49%) carried stx and/or eae (P < 0.0001). ehxA subtyping, as performed by using PCR in combination with restriction fragment length polymorphism analysis, resulted in six closely related subtypes (>94.2%), with subtypes A/D being eae-negative STECs and subtypes B, C, E, and F eae positive. Unexpectedly, ehxA subtype patterns differed significantly between isolates collected from different sources (P < 0.0001), suggesting that simple linear models of exposure and transmission need modification; animal isolates carried mostly subtypes A/C (39.3%/42.9%), food isolates carried mainly subtype A (81.9%), and clinical isolates carried mainly subtype C (66.4%). Certain O serogroups correlated with particular ehxA subtypes: subtype A with O104, O113, and O8; B exclusively with O157; C with O26, O111, and O121.


Crosstalk between SUMO and ubiquitin on PCNA is mediated by recruitment of the helicase Srs2p.
Posttranslational modification of proliferating cell nuclear antigen (PCNA), an essential processivity clamp for DNA polymerases, by ubiquitin and SUMO contributes to the coordination of DNA replication, damage tolerance, and mutagenesis. Whereas ubiquitination in response to DNA damage promotes the bypass of replication-blocking lesions, sumoylation during S phase is damage independent. As both modifiers target the same site on PCNA, an antagonistic action of SUMO on ubiquitin-dependent DNA damage tolerance has been proposed. We now present evidence that the apparent negative effect of SUMO on lesion bypass is not due to competition with ubiquitination but is rather mediated by the helicase Srs2p, which affects genome stability by suppressing unscheduled homologous recombination. We show that Srs2p physically interacts with sumoylated PCNA, which contributes to the recruitment of the helicase to replication forks. Our findings suggest a mechanism by which SUMO and ubiquitin cooperatively control the choice of pathway for the processing of DNA lesions during replication.


Neurological manifestations of COVID-19 and other coronavirus infections: A systematic review.
Increasing research reports neurological manifestations of COVID-19 patients. SARS-CoV-2 shares homology with other human coronaviruses that have also had nervous system involvement. To review the neurological aspects of SARS-cov2 and other coronavirus, including transmission pathways, mechanisms of invasion into the nervous system, and mechanisms of neurological disease. We conducted a systematic review of articles in PubMed, SCOPUS and EMBASE data bases. Reviewed evidence is presented in sections of this manuscript which includes pathogenesis, neuro-invasion, encephalitis, Guillain-Barré, ADEM, multiple sclerosis, polyneuropathy, and cerebrovascular disease. A total 67 studies were included in the final analysis of experimental studies, case reports, series of cases, cohort studies, and systematic reviews related to neurological manifestations of SARS- CoV-2 and other human coronavirus infections. The SARS-CoV-2 receptor is expressed in the nervous system. Common reported symptoms included hyposmia, headaches, weakness, altered consciousness. Encephalitis, demyelination, neuropathy, and stroke have been associated with COVID-19. Infection through the cribriform plate and olfactory bulb and dissemination through trans-synaptic transfer are some of the mechanisms proposed. Invasion of the medullary cardiorespiratory center by SARS-CoV-2 may contribute to the refractory respiratory failure observed in critically-ill COVID-19 patients. An increasing number of reports of COVID-19 patients with neurological disorders add to emergent experimental models with neuro-invasion as a reasonable concern that SARS-CoV-2 is a new neuropathogen. How it may cause acute and chronic neurologic disorders needs to be clarified in future research.


The course of headache in idiopathic intracranial hypertension: a 12-month prospective follow-up study.
Our aim was to prospectively describe the course of headache during the first year of idiopathic intracranial hypertension (IIH). Patients with newly diagnosed IIH were consecutively included from December 2010 to June 2013. Treatment according to standard guidelines was initiated. Headache history was obtained by headache diaries and standardized interviews performed at baseline and after 1, 2, 3 and 12 months. Parallel changes in papilledema were assessed by optical coherence tomography (OCT). All patients had comprehensive neuro-ophthalmological examinations including automated perimetry. Forty-four patients were included. Thirty-five patients completed the 12-month follow-up. Dramatic improvement in headache occurred within the first weeks after diagnosis. After 1 year, 15 patients reported no or only infrequent headache. However, 15 of the remaining 20 patients reported sustained chronic headache. Early age of onset and high diagnostic intracranial pressure (ICP) were associated with better headache outcome (≤1 headache days/month) after a year. Papilledema decreased rapidly within the first 2 months of diagnosis. After 1 year, OCT measures had normalized. Visual outcome was excellent in most patients. Although headache in 43% of patients responded well to ICP management, sustained long-term headache was seen in the remaining patients, despite resolution of papilledema. Headache in IIH may thus be attributed to more complex mechanisms than ICP elevation alone. High ICP and young age were associated with better headache outcome. Early treatment according to standard guidelines seems sufficient to ensure excellent visual outcome in the vast majority of patients.


RNA Sequencing Reveals that Kaposi Sarcoma-Associated Herpesvirus Infection Mimics Hypoxia Gene Expression Signature.
Kaposi sarcoma-associated herpesvirus (KSHV) causes several tumors and hyperproliferative disorders. Hypoxia and hypoxia-inducible factors (HIFs) activate latent and lytic KSHV genes, and several KSHV proteins increase the cellular levels of HIF. Here, we used RNA sequencing, qRT-PCR, Taqman assays, and pathway analysis to explore the miRNA and mRNA response of uninfected and KSHV-infected cells to hypoxia, to compare this with the genetic changes seen in chronic latent KSHV infection, and to explore the degree to which hypoxia and KSHV infection interact in modulating mRNA and miRNA expression. We found that the gene expression signatures for KSHV infection and hypoxia have a 34% overlap. Moreover, there were considerable similarities between the genes up-regulated by hypoxia in uninfected (SLK) and in KSHV-infected (SLKK) cells. hsa-miR-210, a HIF-target known to have pro-angiogenic and anti-apoptotic properties, was significantly up-regulated by both KSHV infection and hypoxia using Taqman assays. Interestingly, expression of KSHV-encoded miRNAs was not affected by hypoxia. These results demonstrate that KSHV harnesses a part of the hypoxic cellular response and that a substantial portion of hypoxia-induced changes in cellular gene expression are induced by KSHV infection. Therefore, targeting hypoxic pathways may be a useful way to develop therapeutic strategies for KSHV-related diseases.


Endoplasmic reticulum-associated degradation of the human type 2 iodothyronine deiodinase (D2) is mediated via an association between mammalian UBC7 and the carboxyl region of D2.
The type 2 iodothyronine selenodeiodinase (D2) is an endoplasmic reticulum (ER)-resident selenoprotein that activates T4 to T3, playing a critical role in thyroid homeostasis. D2 has an approximately 45-min half-life due to selective ubiquitin-mediated ER-associated degradation (ERAD), a process of particular interest because it is accelerated by exposure to D2 substrates, T4 or rT3. The present in vitro binding studies indicate that glutathione-S-transferase (GST)-human D2 fusion proteins specifically associate with a mammalian homolog of the ubiquitin conjugase UBC7 (MmUBC7), with localization to amino acids 169-234 of D2. Coexpression of D2 with an inactive D2 mutant or a truncated version containing amino acids 169-234 stabilizes D2 half-life, supporting the importance of the carboxyl region of D2 for ERAD. Mammalian UBC6 (MmUBC6) does not directly associate with D2 but can associate with a complex containing UBC7 and D2. At the same time, functional studies in human embryonic kidney-293 cells indicate that D2 activity half-life and protein levels are stabilized only when inactive mutants of both UBC6 and UBC7 are overexpressed with D2, suggesting that redundancy may exist at the level of the E2 for both basal and substrate-accelerated D2 ERAD. In conclusion, D2 ERAD in human cells proceeds via an association between UBC7 and the carboxyl region of D2, a unique mechanism for the control of thyroid hormone activation.


Future research directions to identify causes of the increasing incidence rate of congenital hypothyroidism in the United States.
A workshop to evaluate the reported increasing trend in the incidence rate of primary congenital hypothyroidism (CH) identified by newborn screening was held February 27 and 28, 2008, in Atlanta, Georgia, and was sponsored by the Centers for Disease Control and Prevention, the Health Resources and Services Administration, and the National Newborn Screening and Genetics Resource Center. Through a series of presentations and discussions, this group of experts considered a variety of factors that could be contributing to the perceived increasing trend of the CH-incidence rate, the gaps in knowledge that need to be overcome to identify the causes of the observed trend, and possible future research activities that might resolve the uncertainties surrounding the increasing incidence rate of CH in the United States. On the basis of these discussions, workshop participants concluded that the initial focus of future efforts should be to determine if the increasing CH-incidence rate persists once there is standardization of the diagnostic criteria for the classification of CH versus transient hypothyroidism. In discussions, workshop participants suggested that if the increasing incidence rate of CH could not be explained by definitional issues, then future research could focus on the identification and evaluation of risk factors for CH that might be changing among the US population and, thus, contributing to the observed increasing incidence rate of CH.


Bacteriophage- based tests for the detection of Mycobacterium tuberculosis in clinical specimens: a systematic review and meta- analysis.
Sputum microscopy, the most important conventional test for tuberculosis, is specific in settings with high burden of tuberculosis and low prevalence of non tuberculous mycobacteria. However, the test lacks sensitivity. Although bacteriophage-based tests for tuberculosis have shown promising results, their overall accuracy has not been systematically evaluated. We did a systematic review and meta-analysis of published studies to evaluate the accuracy of phage-based tests for the direct detection of M. tuberculosis in clinical specimens. To identify studies, we searched Medline, EMBASE, Web of science and BIOSIS, and contacted authors, experts and test manufacturers. Thirteen studies, all based on phage amplification method, met our inclusion criteria. Overall accuracy was evaluated using forest plots, summary receiver operating (SROC) curves, and subgroup analyses. The data suggest that phage-based assays have high specificity (range 0.83 to 1.00), but modest and variable sensitivity (range 0.21 to 0.88). The sensitivity ranged between 0.29 and 0.87 among smear-positive, and 0.13 to 0.78 among smear-negative specimens. The specificity ranged between 0.60 and 0.88 among smear-positive and 0.89 to 0.99 among smear-negative specimens. SROC analyses suggest that overall accuracy of phage-based assays is slightly higher than smear microscopy in direct head-to-head comparisons. Phage-based assays have high specificity but lower and variable sensitivity. Their performance characteristics are similar to sputum microscopy. Phage assays cannot replace conventional diagnostic tests such as microscopy and culture at this time. Further research is required to identify methods that can enhance the sensitivity of phage-based assays without compromising the high specificity.


Carbon metabolism of intracellular bacteria.
Bacterial metabolism has been studied intensively since the first observations of these 'animalcules' by Leeuwenhoek and their isolation in pure cultures by Pasteur. Metabolic studies have traditionally focused on a small number of model organisms, primarily the Gram negative bacillus Escherichia coli, adapted to artificial culture conditions in the laboratory. Comparatively little is known about the physiology and metabolism of wild microorganisms living in their natural habitats. For approximately 500-1000 species of commensals and symbionts, and a smaller number of pathogenic bacteria, that habitat is the human body. Emerging evidence suggests that the metabolism of bacteria grown in vivo differs profoundly from their metabolism in axenic cultures.


Preoperative Treatment of Locally Advanced Rectal Cancer.
Pelvic radiation plus sensitizing chemotherapy with a fluoropyrimidine (chemoradiotherapy) before surgery is standard care for locally advanced rectal cancer in North America. Whether neoadjuvant chemotherapy with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) can be used in lieu of chemoradiotherapy is uncertain. We conducted a multicenter, unblinded, noninferiority, randomized trial of neoadjuvant FOLFOX (with chemoradiotherapy given only if the primary tumor decreased in size by <20% or if FOLFOX was discontinued because of side effects) as compared with chemoradiotherapy. Adults with rectal cancer that had been clinically staged as T2 node-positive, T3 node-negative, or T3 node-positive who were candidates for sphincter-sparing surgery were eligible to participate. The primary end point was disease-free survival. Noninferiority would be claimed if the upper limit of the two-sided 90.2% confidence interval of the hazard ratio for disease recurrence or death did not exceed 1.29. Secondary end points included overall survival, local recurrence (in a time-to-event analysis), complete pathological resection, complete response, and toxic effects. From June 2012 through December 2018, a total of 1194 patients underwent randomization and 1128 started treatment; among those who started treatment, 585 were in the FOLFOX group and 543 in the chemoradiotherapy group. At a median follow-up of 58 months, FOLFOX was noninferior to chemoradiotherapy for disease-free survival (hazard ratio for disease recurrence or death, 0.92; 90.2% confidence interval [CI], 0.74 to 1.14; P = 0.005 for noninferiority). Five-year disease-free survival was 80.8% (95% CI, 77.9 to 83.7) in the FOLFOX group and 78.6% (95% CI, 75.4 to 81.8) in the chemoradiotherapy group. The groups were similar with respect to overall survival (hazard ratio for death, 1.04; 95% CI, 0.74 to 1.44) and local recurrence (hazard ratio, 1.18; 95% CI, 0.44 to 3.16). In the FOLFOX group, 53 patients (9.1%) received preoperative chemoradiotherapy and 8 (1.4%) received postoperative chemoradiotherapy. In patients with locally advanced rectal cancer who were eligible for sphincter-sparing surgery, preoperative FOLFOX was noninferior to preoperative chemoradiotherapy with respect to disease-free survival. (Funded by the National Cancer Institute; PROSPECT ClinicalTrials.gov number, NCT01515787.).


Exploring the Relationship Between Callous-Unemotional Traits, Empathy Processing and Affective Valence in a General Population.
Callous-Unemotional (CU) traits are personality attributes, which are associated with a deficit of affective valence and reduced empathetic responding in high CU trait clinical populations. The aim of the research was to explore whether a similar pattern of empathy and emotional responding correlated with CU trait manifestation in the general population. A total of 124 participants completed the Inventory of Callous-Unemotional Traits, the Interpersonal Reactivity Index, the Empathy Quotient, an expression recognition task, and a measure of affective response. Negative correlations with CU trait score were observed for both cognitive empathy and emotional empathy. Accuracy in the identification of fearful expressions presented a negative association with CU trait score. Self-rating of affective valence, when viewing both positive and negative images, indicated a universal reduction in emotional response associated with increased CU trait manifestation.


Efficiency and equity considerations in the preferences of health policy-makers in Israel.
There is a traditional tension in public policy between the maximization of welfare from given resources (efficiency) and considerations related to the distribution of welfare among the population and to social justice (equity). The aim of this paper is to measure the relative weights of the efficiency- and equity-enhancing criteria in the preferences of health policy-makers in Israel, and to compare the Israeli results with those of other countries. We used the criteria of efficiency and equity which were adopted in a previous international study, adapted to Israel. The equity criteria, as defined in the international study, are: severity of the disease, age (young vs. elderly), and the extent to which the poor are subsidized. Efficiency is represented by the criteria: the potential number of beneficiaries, the extent of the health benefits to the patient, and the results of economic assessments (cost per QALY gained). We contacted 147 policy-makers, 65 of whom completed the survey (a response rate of 44%). Using Discrete Choice Experiment (DCE) methodology by 1000Minds software, we estimated the relative weights of these seven criteria, and predicted the desirability of technologies characterized by profiles of the criteria. The overall weight attached to the four efficiency criteria was 46% and that of the three equity criteria was 54%. The most important criteria were "financing of the technology is required so that the poor will be able to receive it" and the level of individual benefit. "The technology is intended to be used by the elderly" criterion appeared as the least important, taking the seventh place. Policy-makers who had experience as members of the Basket Committee appear to prefer efficiency criteria more than those who had never participated in the Basket Committee deliberations. While the efficiency consideration gained preference in most countries studied, Israel is unique in its balance between the weights attached to equity and efficiency considerations by health policy-makers. The study explored the trade-off between efficiency and equity considerations in the preferences of health policy-makers in Israel. The way these declarative preferences have been expressed in actual policy decisions remains to be explored.


Assessing equity in clinical practice guidelines.
Recognition of the need for systematically developed clinical practice guidelines (CPGs) has increased dramatically over the past 20 years. CPGs have focused primarily on the effectiveness of interventions, explicitly or implicitly addressing the following question: Will adherence to a recommendation do more good than harm? At times they have also focused on the cost-effectiveness of interventions: Are the net benefits worth the costs? They rarely have focused on equity: Are the recommendations fair? The Knowledge Plus Project of the International Clinical Epidemiology Network attempts to improve the process of CPG development by formulating strategies to consider not just technical issues (effectiveness, and efficiency) but sociopolitical dimensions as well (equity and local appropriateness). This article discusses a proposed lens for users to evaluate how well CPGs address issues of equity.


Analysis of Fatalities During Maintenance and Repair Operations in the U.S. Mining Sector.
Maintenance and repair work in mining is particularly hazardous and yet has received little focus in ergonomics research. In this article, an attempt has been made to determine if patterns can be identified to categorize maintenance and repair fatalities in mining, to compare occurrence of fatalities between coal and metal/nonmetal sectors, and to use this information to identify safety deficiencies and associated proposed remedial measures. A classification scheme was developed to identify patterns in fatalities, including proximal causes, tasks, and contributing factors. This scheme was tested to ensure adequacy of the categories, and fatalities were categorized using the scheme. All testing and categorization were done by two of the authors to ensure reliability of the coding scheme. Patterns were successfully identified to categorize the fatalities, and these patterns were different between coal and metal/nonmetal mines. Coal mines had a greater proportion of electrical-related fatalities, while more fatalities related to potential energy occurred at metal/nonmetal mines. Most of the fatalities were caused by the victim coming into contact with an object or machine or the victim falling from height, and they occurred most often while the victim was performing maintenance or repair on equipment, cleaning, or removing blockages. The most frequent factors contributing to these incidents were failure to properly de-energize or lock out/tag out equipment, violation of work procedures, missing or inadequate safety equipment, and failure to block equipment properly. The classification approach used was successful in identifying hazard patterns during maintenance and repair fatalities in mining. These patterns identify areas to focus attention when developing interventions to prevent the occurrence of future fatalities.


On the calibration of continuous, high-precision delta18O and delta2H measurements using an off-axis integrated cavity output spectrometer.
The (18)O and (2)H of water vapor serve as powerful tracers of hydrological processes. The typical method for determining water vapor delta(18)O and delta(2)H involves cryogenic trapping and isotope ratio mass spectrometry. Even with recent technical advances, these methods cannot resolve vapor composition at high temporal resolutions. In recent years, a few groups have developed continuous laser absorption spectroscopy (LAS) approaches for measuring delta(18)O and delta(2)H which achieve accuracy levels similar to those of lab-based mass spectrometry methods. Unfortunately, most LAS systems need cryogenic cooling and constant calibration to a reference gas, and have substantial power requirements, making them unsuitable for long-term field deployment at remote field sites. A new method called Off-Axis Integrated Cavity Output Spectroscopy (OA-ICOS) has been developed which requires extremely low-energy consumption and neither reference gas nor cryogenic cooling. In this report, we develop a relatively simple pumping system coupled to a dew point generator to calibrate an ICOS-based instrument (Los Gatos Research Water Vapor Isotope Analyzer (WVIA) DLT-100) under various pressures using liquid water with known isotopic signatures. Results show that the WVIA can be successfully calibrated using this customized system for different pressure settings, which ensure that this instrument can be combined with other gas-sampling systems. The precisions of this instrument and the associated calibration method can reach approximately 0.08 per thousand for delta(18)O and approximately 0.4 per thousand for delta(2)H. Compared with conventional mass spectrometry and other LAS-based methods, the OA-ICOS technique provides a promising alternative tool for continuous water vapor isotopic measurements in field deployments.


Structural color films with lotus effects, superhydrophilicity, and tunable stop-bands.
The structural blue color of a Morpho butterfly originates from the diffraction of light and interference effects due to the presence of the microstructures on the wing of the butterfly. Structural color on the surface of a damselfish reversibly changes between green and blue. Inspired by these creatures, we have been trying to prepare high-quality and functional structural color films. We describe our efforts in this Account. A useful technique to prepare such structural color films in colloidal solution is a "lifting" method, which allows us to quickly fabricate brilliant colloidal crystal films. The thicknesses of the films can be controlled by precisely adjusting the particle concentration and the lifting speed. Moreover, in order to prepare a complicated structure, we have used template methods. Indeed, we have successfully prepared the inverse structure of the wing of a Morpho butterfly with this technique. Initially, however, our structural color films had a whitish appearance due to the scattering of light by defects in the colloidal crystal film. Later, we were able to prepare a non-whitish structural color film by doping an appropriate dye in the colloidal particles to absorb the scattering light. In addition to the structural blue color, the wing of the Morpho butterfly has superhydrophobic properties. According to Wenzel's equation, the hydrophobic and hydrophilic properties are enhanced when the roughness of the hydrophobic and hydrophilic surface is increased, respectively. Based on this mechanism, we have successfully prepared structural color films with superhydrophobic properties, as well as with superhydrophilic properties. Another important property that can be seen in nature is tunable structural color, such as the color change that can be seen on the surface of a damselfish. In order to mimic such color change, we have developed several tunable structural color films. In particular, we have successfully prepared phototunable photonic crystals using photoresponsive azobenzene derivatives. In order to apply these structural color films, we developed a technique for patterning them by taking advantage of the wettability of the substrate surface. These materials can be used in the future for self-cleaning pigments and tunable photonic crystals.


Two-dimensional HYSCORE spectroscopy of superoxidized manganese catalase: a model for the oxygen-evolving complex of photosystem II.
The solar water-splitting protein complex, photosystem II (PSII), catalyzes one of the most energetically demanding reactions in Nature by using light energy to drive a catalyst capable of oxidizing water. The water oxidation reaction takes place at the tetra-nuclear manganese calcium-oxo (Mn4Ca-oxo) cluster at the heart of the oxygen-evolving complex (OEC) of PSII. Previous studies have determined the magnetic interactions between the paramagnetic Mn4Ca-oxo cluster and its environment in the S2 state of the OEC. The assignments for the electron-nuclear magnetic interactions that were observed in these studies were facilitated by the use of synthetic dimanganese di-μ-oxo complexes. However, there is an immense need to understand the effects of the protein environment on the coordination geometry of the Mn4Ca-oxo cluster in the OEC of PSII. In the present study, we use a proteinaceous model system to examine the protein ligands that are coordinated to the dimanganese catalytic center of manganese catalase from Lactobacillus plantarum. We utilize two-dimensional hyperfine sublevel correlation (2D HYSCORE) spectroscopy to detect the weak magnetic interactions of the paramagnetic dinuclear manganese catalytic center of superoxidized manganese catalase with the nitrogen and proton atoms of the surrounding protein environment. We obtain a complete set of hyperfine interaction parameters for the protons of a water molecule that is directly coordinated to the dinuclear manganese center. We also obtain a complete set of hyperfine and quadrupolar interaction parameters for two histidine ligands as well as a coordinated azide ligand, in azide-treated superoxidized manganese catalase. On the basis of the values of the hyperfine interaction parameters of the dimanganese model, manganese catalase, and those of the S2 state of the OEC of PSII, for the first time, we discuss the impact of a proteinaceous environment on the coordination geometry of multinuclear manganese clusters.


Facilitated transport of L-phenylalanine across blood-nerve barrier of rat peripheral nerve.
L-Phenylalanine transport across the blood-nerve barrier was studied by perfusing Ringer solution containing trace amounts of L-[14C]phenylalanine and [3H]dextran (a vascular marker) through the hindlimb of an anesthetized rat. At the end of perfusion, a segment of sciatic nerve was removed, frozen, desheathed, and processed for radioactivity counting. The permeability-surface area product of the blood-nerve barrier (PABNB) to L-[14C]phenylalanine decreased from 58 +/- 9 X 10(-5) to 1.7 +/- 0.3 X 10(-5) (SE) ml.s-1.g wet wt-1, as the perfusate concentration of unlabeled L-phenylalanine was increased to 10 mM. D-Phenylalanine had less of an inhibitory effect on L-[14C]phenylalanine uptake than did L-phenylalanine. PABNB did not change in the presence of 50 mM alpha-(methylamino)isobutyric acid (MeAIB) in the perfusion medium, nor by replacing NaCl by Tris.HCl. However, addition of 50 mM 2-aminobicyclo(2,2,1)heptane-2-carboxylic acid (BCH) reduced PABNB to 2.1 +/- 0.3 X 10(-5) ml.s-1.g wet wt-1 (n = 4). PA at epiperineurial barrier (PAper) of L-[14C]phenylalanine at the epiperineurial barrier, determined from in situ incubation, was 1.4 +/- 0.2 X 10(-5) ml.s-1.g wet wt-1 (n = 6) and was unaffected by 10 mM L-phenylalanine concentration in the incubation medium. The results demonstrate for the first time carrier-mediated transport system for L-phenylalanine at the blood-nerve barrier of the rat peripheral nerve.


Muscle forces during locomotion in kangaroo rats: force platform and tendon buckle measurements compared.
The muscle forces and stresses occurring during normal locomotor activity in kangaroo rats are compared with the peak isometric force developed by the same muscles in situ. Two methods were used simultaneously to determine the stresses (force/cross-sectional area) acting in the ankle extensors during steady-speed hopping and during jumps when animals were startled: a direct measurement using a force buckle surgically implanted around a tendon; and an indirect measurement using a force platform/ciné analysis technique. We obtained essentially the same values with the two techniques. We found that at slow speeds (0.7 m s-1) the ankle extensor muscles of kangaroo rats exerted 20% of the maximum isometric force developed when the muscles were stimulated via the tibial nerve. This increased to 53% at higher speeds (1.9 m s-1). At the animals's preferred hopping speed (1.5 m s-1), peak force was approximately 40% of maximum isometric force. In jumps when animals were startled, peak forces as high as 175% of the maximal elicited isometric force were recorded. These high forces always occurred when the muscles were being stretched. It appears that kangaroo rats utilize nearly the entire range of muscle force possible during normal locomotor events (i.e. up to 175% of maximum isometric force when muscles are stretched).


Auxin as a player in the biocontrol of Fusarium head blight disease of barley and its potential as a disease control agent.
Mechanisms involved in the biological control of plant diseases are varied and complex. Hormones, including the auxin indole acetic acid (IAA) and abscisic acid (ABA), are essential regulators of a multitude of biological functions, including plant responses to biotic and abiotic stressors. This study set out to determine what hormones might play a role in Pseudomonas fluorescens -mediated control of Fusarium head blight (FHB) disease of barley and to determine if biocontrol-associated hormones directly affect disease development. A previous study distinguished bacterium-responsive genes from bacterium-primed genes, distinguished by the fact that the latter are only up-regulated when both P. fluorescens and the pathogen Fusarium culmorum are present. In silico analysis of the promoter sequences available for a subset of the bacterium-primed genes identified several hormones, including IAA and ABA as potential regulators of transcription. Treatment with the bacterium or pathogen resulted in increased IAA and ABA levels in head tissue; both microbes had additive effects on the accumulation of IAA but not of ABA. The microbe-induced accumulation of ABA preceded that of IAA. Gene expression analysis showed that both hormones up-regulated the accumulation of bacterium-primed genes. But IAA, more than ABA up-regulated the transcription of the ABA biosynthesis gene NCED or the signalling gene Pi2, both of which were previously shown to be bacterium-responsive rather than primed. Application of IAA, but not of ABA reduced both disease severity and yield loss caused by F. culmorum, but neither hormone affect in vitro fungal growth. Both IAA and ABA are involved in the P. fluorescens-mediated control of FHB disease of barley. Gene expression studies also support the hypothesis that IAA plays a role in the primed response to F. culmorum. This hypothesis was validated by the fact that pre-application of IAA reduced both symptoms and yield loss asssociated with the disease. This is the first evidence that IAA plays a role in the control of FHB disease and in the bacterial priming of host defences.


HIV-1 drug discovery: targeting folded RNA structures with branched peptides.
Human immunodeficiency virus type 1 (HIV-1) is an RNA virus that is prone to high rates of mutation. While the disease is managed with current antiretroviral therapies, drugs with a new mode of action are needed. A strategy towards this goal is aimed at targeting the native three-dimensional fold of conserved RNA structures. This perspective highlights medium-sized peptides and peptidomimetics used to target two conserved RNA structures of HIV-1. In particular, branched peptides have the capacity to bind in a multivalent fashion, utilizing a large surface area to achieve the necessary affinity and selectivity toward the target RNA.


Sex differences in the composition of weight gain and loss in overweight and obese adults.
Sex differences in the ratio of fat mass (FM):fat-free mass (FFM) during weight change should differentially affect the extent of weight change during energy imbalance in men and women. In the present study, we determined FM and FFM contents by dual-energy X-ray absorptiometry and calculated the P-ratios (protein energy/total energy) of excess weight and weight loss during a randomised controlled trial of four commercial weight loss regimens. Overweight and obese women (n 210) and men (n 77) were studied at baseline and at 2 and 6 months during weight loss on four dietary regimens: Dr Atkins' New Diet Revolution; The Slim-Fast Plan; Weight-Watchers programme; Rosemary Conley's Diet and Fitness Plan. At baseline, the percentage of FFM (%FFM) and P-ratios of excess weight were 40 % and 0·071 for men and 27 % and 0·039 for women. At 2 months, men had lost twice as much weight as women and three times more FFM than women, indicating higher FFM content and P-ratios of weight loss for men, 0·052, than for women, 0·029, with no dietary effects. Between 2 and 6 months, the rate at which weight was lost decreased and the %FFM of weight loss decreased to similar low levels in men (7 %) and women (5 %): i.e. P-ratios of 0·009 and 0·006, respectively, with no dietary effects. Thus, for men compared with women, there were greater FFM content and P-ratios of weight change, which could partly, but not completely, explain their greater weight loss at 2 months. However, protein-conserving adaptations occur with increasing weight loss and over time, more extensively in men, eventually eliminating any sex difference in the composition of weight loss.


INTIMATE PARTNER VIOLENCE RISK AMONG VICTIMS OF YOUTH VIOLENCE: ARE EARLY UNIONS BAD, BENEFICIAL, OR BENIGN?
Youth violent victimization (YVV) is a risk factor for precocious exits from adolescence via early coresidential union formation. It remains unclear, however, whether these early unions 1) are associated with intimate partner violence (IPV) victimization, 2) interrupt victim continuity or victim-offender overlap through protective and prosocial bonds, or 3) are inconsequential. By using data from the National Longitudinal Study of Adolescent to Adult Health (N = 11,928; 18-34 years of age), we examine competing hypotheses for the effect of early union timing among victims of youth violence (n = 2,479)-differentiating across victimization only, perpetration only, and mutually combative relationships and considering variation by gender. The results from multinomial logistic regression models indicate that YVV increases the risk of IPV victimization in first unions, regardless of union timing; the null effect of timing indicates that delaying union formation would not reduce youth victims' increased risk of continued victimization. Gender-stratified analyses reveal that earlier unions can protect women against IPV perpetration, but this is partly the result of an increased risk of IPV victimization. The findings suggest that YVV has significant transformative consequences, leading to subsequent victimization by coresidential partners, and this association might be exacerbated among female victims who form early unions. We conclude by discussing directions for future research.


A robust gene selection method for microarray-based cancer classification.
Gene selection is of vital importance in molecular classification of cancer using high-dimensional gene expression data. Because of the distinct characteristics inherent to specific cancerous gene expression profiles, developing flexible and robust feature selection methods is extremely crucial. We investigated the properties of one feature selection approach proposed in our previous work, which was the generalization of the feature selection method based on the depended degree of attribute in rough sets. We compared the feature selection method with the established methods: the depended degree, chi-square, information gain, Relief-F and symmetric uncertainty, and analyzed its properties through a series of classification experiments. The results revealed that our method was superior to the canonical depended degree of attribute based method in robustness and applicability. Moreover, the method was comparable to the other four commonly used methods. More importantly, the method can exhibit the inherent classification difficulty with respect to different gene expression datasets, indicating the inherent biology of specific cancers.


Long-term inhibition of human T-lymphotropic virus type III/lymphadenopathy-associated virus (human immunodeficiency virus) DNA synthesis and RNA expression in T cells protected by 2',3'-dideoxynucleosides in vitro.
We report that 2',3'-dideoxyadenosine and 2',3'-dideoxycytidine inhibit retroviral DNA synthesis and mRNA expression in T cells exposed to the virus that causes acquired immunodeficiency syndrome, and afford such cells long-term protection in vitro under conditions of substantial viral excess. Both 2',3'-dideoxyadenosine and 2',3'-dideoxycytidine appear to completely block reverse transcription from viral RNA to viral DNA. Viral mRNA expression is also not detected in cells protected by the drugs throughout 30 days of culture following exposure to the virus. Purine and pyrimidine analogues as 2',3'-dideoxynucleoside-5'-triphosphate serve as substrates for the human T-lymphotropic virus type III/lymphadenopathy-associated virus reverse transcriptase to elongate a DNA chain by one residue, after which the chain is terminated. Cloned normal helper/inducer T cells exposed to a cytopathic dose of the virus, but protected by the drugs, respond normally to specific antigen in vitro. These results suggest that the drugs could be promising agents for further studies in the experimental treatment of patients infected with retroviruses.


Review: placenta-specific microRNAs in exosomes - good things come in nano-packages.
MicroRNAs (miRNAs) are small noncoding RNA gene products that commonly regulate mRNA expression by repression of translation and/or transcript decay. Whereas common and unique types of miRNAs are expressed by the placenta during pregnancy, the functions of most placental miRNA species are unknown. In addition to their intracellular silencing function, miRNAs are also released to the extracellular space and systemic circulation, where they can potentially target cells to regulate mRNA and protein expression, providing a non-hormonal means of intercellular communication that contributes to tissue homeostasis and disease pathophysiology. This review centers on extracellular miRNAs that originate in trophoblasts and that could mediate crosstalk between the feto-placental unit and the mother during pregnancy. We specifically detail the function of miRNAs from the primate-specific chromosome 19 miRNA cluster. These miRNAs are highly expressed in human placentas and in the serum of pregnant women. They are also packaged into extracellular vesicles of diverse sizes, including exosomes, and endow non-trophoblastic cells with resistance to a variety of viruses.


Period3 structural variation: a circadian biomarker associated with breast cancer in young women.
Circadian disruption has been indicated as a risk factor for breast cancer in recent epidemiologic studies. A novel finding in circadian biology is that genes responsible for circadian rhythm also regulate many other biological pathways, including cell proliferation, cell cycle regulation, and apoptosis. Therefore, mutations in circadian genes could conceivably result in deregulation of these processes and contribute to tumor development, and be markers for susceptibility to human cancer. In this study, we investigated the association between an exonic length variation in a circadian gene, Period3 (Per3), and breast cancer risk using blood samples collected from a recently completed breast cancer case-control study in Connecticut. There were 389 Caucasian cases and 432 Caucasian controls included in our analysis. We found that the variant Per3 genotype (heterozygous + homozygous 5-repeat alleles) was associated with an increased risk of breast cancer among premenopausal women (odds ratio, 1.7; 95% confidence interval, 1.0-3.0). Our finding suggests that the circadian genes might be a novel panel of potential biomarkers for breast cancer and worth further investigation.


Anti-CD20 Therapy Acts via FcγRIIIA to Diminish Responsiveness of Human Natural Killer Cells.
Natural killer (NK) immune cells mediate antibody-dependent cellular cytotoxicity (ADCC) by aggregating FcγRIIIA/CD16, contributing significantly to the therapeutic effect of CD20 monoclonal antibodies (mAb). In this study, we show that CD16 ligation on primary human NK cells by the anti-CD20 mAb rituximab or ofatumumab stably impairs the spontaneous cytotoxic response attributable to cross-tolerance of several unrelated NK-activating receptors (including NKG2D, DNAM-1, NKp46, and 2B4). Similar effects were obtained from NK cells isolated from patients with chronic lymphocytic leukemia in an autologous setting. NK cells rendered hyporesponsive in this manner were deficient in the ability of these cross-tolerized receptors to phosphorylate effector signaling molecules critical for NK cytotoxicity, including SLP-76, PLCγ2, and Vav1. These effects were associated with long-lasting recruitment of the tyrosine phosphatase SHP-1 to the CD16 receptor complex. Notably, pharmacologic inhibition of SHP-1 with sodium stibogluconate counteracted CD20 mAb-induced NK hyporesponsiveness, unveiling an unrecognized role for CD16 as a bifunctional receptor capable of engendering long-lasting NK cell inhibitory signals. Our work defines a novel mechanism of immune exhaustion induced by CD20 mAb in human NK cells, with potentially negative implications in CD20 mAb-treated patients where NK cells are partly responsible for clinical efficacy.


M1-activated macrophages migration, a marker of aortic atheroma progression: a preclinical MRI study in mice.
M1-activated Macrophages (M1M) play a major role in atherosclerotic lesions of aortic arch, promoting proinflammatory response. In vivo trafficking of M1M in aortic plaques is therefore critical. M1M from bone marrow cell culture were magnetically labeled, using iron nanoparticles, intravenously injected and followed up with 3 day magnetic resonance imaging (MRI) in mice developing macrophage-laden atheroma (ApoE2 knock-in mice). M1M recruitment in aortic arch lesions was assessed both by MRI and histology. In all ApoE2 knock-in mice injected with labeled cells, high resolution MRI showed localized signal loss regions in the thickened aortic wall, with a maximal effect at day 2 (-34% +/- 7.3% P < 0.001 compared with baseline). This was confirmed with Prussian blue (iron) staining and corresponded to M1M (Major Histo-compatibility Complex II positive). Clear different intraplaque and adventitial dynamic distribution profiles of labeled cells were observed during the 3 days. M1M dynamic MRI is a promising marker to noninvasively assess the macrophage trafficking underlying aortic arch plaque progression.


Selective trihydroxylated azepane inhibitors of NagZ, a glycosidase involved in Pseudomonas aeruginosa resistance to β-lactam antibiotics.
The synthesis of a series of d-gluco-like configured 4,5,6-trihydroxyazepanes bearing a triazole, a sulfonamide or a fluorinated acetamide moiety at C-3 is described. These synthetic derivatives have been tested for their ability to selectively inhibit the muropeptide recycling glucosaminidase NagZ and to thereby increase sensitivity of Pseudomonas aeruginosa to β-lactams, a pathway with substantial therapeutic potential. While introduction of triazole and sulfamide groups failed to lead to glucosaminidase inhibitors, the NHCOCF3 analog proved to be a selective inhibitor of NagZ over other glucosaminidases including human O-GlcNAcase and lysosomal hexosaminidases HexA and B.


Deconstructing the differences: a comparison of GBD 2010 and CHERG's approach to estimating the mortality burden of diarrhea, pneumonia, and their etiologies.
Pneumonia and diarrhea are leading causes of death for children under five (U5). It is challenging to estimate the total number of deaths and cause-specific mortality fractions. Two major efforts, one led by the Institute for Health Metrics and Evaluation (IHME) and the other led by the World Health Organization (WHO)/Child Health Epidemiology Reference Group (CHERG) created estimates for the burden of disease due to these two syndromes, yet their estimates differed greatly for 2010. This paper discusses three main drivers of the differences: data sources, data processing, and covariates used for modelling. The paper discusses differences in the model assumptions for etiology-specific estimates and presents recommendations for improving future models. IHME's Global Burden of Disease (GBD) 2010 study estimated 6.8 million U5 deaths compared to 7.6 million U5 deaths from CHERG. The proportional differences between the pneumonia and diarrhea burden estimates from the two groups are much larger; GBD 2010 estimated 0.847 million and CHERG estimated 1.396 million due to pneumonia. Compared to CHERG, GBD 2010 used broader inclusion criteria for verbal autopsy and vital registration data. GBD 2010 and CHERG used different data processing procedures and therefore attributed the causes of neonatal death differently. The major difference in pneumonia etiologies modeling approach was the inclusion of observational study data; GBD 2010 included observational studies. CHERG relied on vaccine efficacy studies. Greater transparency in modeling methods and more timely access to data sources are needed. In October 2013, the Bill & Melinda Gates Foundation (BMGF) hosted an expert meeting to examine possible approaches for better estimation. The group recommended examining the impact of data by systematically excluding sources in their models. GBD 2.0 will use a counterfactual approach for estimating mortality from pathogens due to specific etiologies to overcome bias of the methods used in GBD 2010 going forward.


How Varroa Parasitism Affects the Immunological and Nutritional Status of the Honey Bee, Apis mellifera.
We investigated the effect of the parasitic mite Varroa destructor on the immunological and nutritional condition of honey bees, Apis mellifera, from the perspective of the individual bee and the colony. Pupae, newly-emerged adults and foraging adults were sampled from honey bee colonies at one site in S. Texas, USA. Varroa‑infested bees displayed elevated titer of Deformed Wing Virus (DWV), suggestive of depressed capacity to limit viral replication. Expression of genes coding three anti-microbial peptides (defensin1, abaecin, hymenoptaecin) was either not significantly different between Varroa-infested and uninfested bees or was significantly elevated in Varroa-infested bees, varying with sampling date and bee developmental age. The effect of Varroa on nutritional indices of the bees was complex, with protein, triglyceride, glycogen and sugar levels strongly influenced by life-stage of the bee and individual colony. Protein content was depressed and free amino acid content elevated in Varroa-infested pupae, suggesting that protein synthesis, and consequently growth, may be limited in these insects. No simple relationship between the values of nutritional and immune-related indices was observed, and colony-scale effects were indicated by the reduced weight of pupae in colonies with high Varroa abundance, irrespective of whether the individual pupa bore Varroa.


The expression of a carbon concentrating mechanism in Chlamydomonas acidophila under variable phosphorus, iron, and CO2 concentrations.
The CO(2) acquisition was analyzed in Chlamydomonas acidophila at pH 2.4 in a range of medium P and Fe concentrations and at high and low CO(2) condition. The inorganic carbon concentrating factor (CCF) was related to cellular P quota (Q(p)), maximum CO(2)-uptake rate by photosynthesis (V(max,O2)), half saturation constant for CO(2) uptake (K(0.5)), and medium Fe concentration. There was no effect of the medium Fe concentration on the CCF. The CCF increased with increasing Q(p) in both high and low CO(2) grown algae, but maximum Q(p) was 6-fold higher in the low CO(2) cells. In high CO(2) conditions, the CCF was low, ranging between 0.8 and 3.5. High CCF values up to 9.1 were only observed in CO(2)-limited cells, but P- and CO(2)-colimited cells had a low CCF. High CCF did not relate with a low K(0.5) as all CO(2)-limited cells had a low K(0.5) (<4 μM CO(2)). High C(i)-pools in cells with high Q(p) suggested the presence of an active CO(2)-uptake mechanism. The CCF also increased with increasing V(max,O2) which reflect an adaptation to the nutrient in highest demand (CO(2)) under balanced growth conditions. It is proposed that the size of the CCF in C. acidophila is more strongly related to porter density for CO(2) uptake (reflected in V(max,O2)) and less- to high-affinity CO(2) uptake (low K(0.5)) at balanced growth. In addition, high CCF can only be realized with high Q(p).


Contributing to Understand the Crosstalk between Brain and Periphery in Methylmercury Intoxication: Neurotoxicity and Extracellular Vesicles.
Human exposure to methylmercury (MeHg) is currently high in regions such as the Amazon. Understanding the molecular changes associated with MeHg-induced neurotoxicity and the crosstalk with the periphery is essential to support early diagnoses. This work aimed to evaluate cellular and molecular changes associated with behavioral alterations in MeHg acute exposure and the possible changes in extracellular vesicles (EVs) number and S100β content. Adults male Wistar rats were orally treated with 5 mg/kg for four days. Behavioral performance, molecular and histological changes in the cerebellum, and plasma EVs were assessed. MeHg-intoxicated animals performed significantly worse in behavioral tests. MeHg increased the number of GFAP+ cells and GFAP and S100β mRNA expression in the cerebellum but no change in NeuN+ or IBA-1+ cells number was detected. The number of exosomes isolated from plasma were decreased by the metal. S100B mRNA was detected in circulating plasma EVs cargo in MeHg exposure. Though preliminary, our results suggest astrocytic reactivity is displaying a protective role once there was no neuronal death. Interestingly, the reduction in exosomes number could be a new mechanism associated with MeHg-induced neurotoxicity and plasma EVs could represent a source of future biomarkers in MeHg intoxication.