Monoclonal antibodies detect different distribution patterns of IL-8 receptor A and IL-8 receptor B on human peripheral blood leukocytes.
mAbs previously reported to be specific for IL-8R type A (IL-8R-A) and mAbs specific for IL-8R type B (IL-8R-B), which are described in this paper, were used to investigate the expression of each receptor on various types of cells. We generated mAbs specific for IL-8R-B, 4D1, and 10H2 by immunizing mice with 293 cells that expressed IL-8R-B and by selecting hybridoma cell lines that secreted mAbs that bind to human neutrophils. Flow cytometry showed that mAbs 4D1 and 10H2 were specific for IL-8R-B, as determined by their exclusive binding to 293-27 cells that expressed IL-8R-B, but not to 293-71 cells that expressed IL-8R-A. Epitopes recognized by these IL-8R-B-specific mAbs were shown to be within the N-terminal residues 1-18 of the IL-8R-B on the basis of their binding to various N-terminal peptides, as measured by ELISA. These IL-8R-B-specific mAbs were able to inhibit up to 90 and 50% of the 125I-labeled IL-8 binding to 293-27 cells and human neutrophils, respectively. The combination of mAb 9H1 (anti-IL-8R-A) and mAb 10H2 (anti-IL-8R-B) inhibited approximately 70% of 125I-labeled IL-8 binding to human neutrophils. Flow cytometry showed a wide range of donor variation in the expression levels of IL-8R-A and IL-8R-B on various human peripheral blood leukocytes. All neutrophils, all monocytes, and 5 to 25% of total lymphocytes (CD8+ T cells and CD56+ NK cells) expressed IL-8R. Neutrophils expressed the highest level of both IL-8R-A and IL-8R-B, at an approximately equal ratio, whereas monocytes and IL-8R+ lymphocytes expressed higher levels of IL-8R-B than IL-8R-A. Double-color flow cytometric analysis showed that 7 to 42% of CD8+ T cells and 39 to 76% of CD56+ NK cells, but no CD 20+ B cells or CD4+ T cells, expressed IL-8R.


The ameliorative effect of CangFu Daotan Decoction on polycystic ovary syndrome of rodent model is associated with m6A methylation and Wnt/β-catenin pathway.
Objective: This study investigates the effects of CangFu Daotan Decoction (CDD) on m6A methylation and Wnt/β-catenin pathway in rats with polycystic ovary syndrome (PCOS).Methods: The PCOS rat model was established by letrozole gavage. The rats were fed high-fat chow, and their body weight and blood glucose were recorded. The expressions of follicle-stimulating hormone(FSH), luteinizing hormone(LH), and testosterone(T) were quantified by ELISA. Chemical components in CDD were analyzed using UPLC-Q/TOF-MS. Based on network pharmacology methods, related targets of CDD on PCOS were screened. An enrichment analysis according to Tokyo Encyclopedia of Genes and Genomes (KEGG) was conducted to predict the potential signaling pathway of CDD in PCOS. The expressions of Wnt-1, β-Catenin, GSK-3β, C-MYC, Beclin1, LC3II, Bax, and PCNA were detected by western blotting. The expressions of Mettl3, Mettl14, Fto, Alkbh5, Ythdf1, and Ythdf2 were monitored by RT-PCR. The expressions of Mettl3, Fto, and Ythdf1 were detected by western blotting.Results: Letrozole and a high-fat diet induced ovarian dysfunction in rats, which was attenuated by CDD. CDD decreased blood glucose, LH, and T concentrations and increased FSH expression in PCOS. After removing duplicates, a total of 71 compounds were identified by UHPLC-Q/TOF-MS, among which terpenoids and flavonoids account for the main proportion. The clustering analysis showed that the active site of CDD might be in the Wnt/β-catenin pathway. CDD decreased the expressions of Wnt-1, β-Catenin, GSK-3β, C-MYC, Beclin1, LC3II, and Bax and increased PCNA expression in the ovarian tissue of PCOS rats. CDD decreased the m6A gene expressions of Mettl3, Mettl14, Fto, Alkbh5, Ythdf1, and Ythdf2 in peripheral blood and ovarian tissue of PCOS rats. CDD reduced the m6A proteins expressions of Mettl3, Fto, and Ythdf1 in the ovarian tissue of PCOS rats.Conclusion: CDD can regulate m6A modification and inhibit the Wnt/β-catenin signaling pathway in PCOS rats, thereby reducing body weight, lowering blood glucose levels, improving sex hormone disorders, and decreasing autophagy and apoptosis in ovarian tissue to promote the recovery of ovarian morphology.


Secretory leucocyte protease inhibitor inhibits interferon-gamma-induced cathepsin S expression.
We have demonstrated that bronchoalveolar lavage fluid from chronic obstructive pulmonary disease patients contains higher levels of interferon-gamma compared with controls. Interferon-gamma is a potent inducer of various cathepsins and matrix metalloproteases. Therefore, we postulated that interferon-gamma could induce protease expression by macrophages in acute and chronic lung disease. Chronic obstructive pulmonary disease patients had greater levels of cathepsin S and matrix metalloprotease-12 in their bronchoalveolar lavage fluid. Macrophages incubated with chronic obstructive pulmonary disease bronchoalveolar lavage fluid exhibited increased expression of cathepsin S and matrix metalloprotease-12, which was inhibited by the addition of interferon-gamma-neutralizing immunoglobulin. Human secretory leukocyte protease inhibitor is an 11.7-kDa cationic non-glycosylated antiprotease synthesized and secreted by cells at the site of inflammation. We have demonstrated that secretory leukocyte protease inhibitor can inhibit interferon-gamma-induced cathepsin S production by macrophages. Pretreatment of macrophages with secretory leukocyte protease inhibitor inhibited interferon-gamma-induced inhibitor kappaB beta degradation and activation of nuclear factor kappaB. Secretory leukocyte protease inhibitor may prove to be therapeutically important as a potential inhibitor of protease expression in chronic obstructive pulmonary disease.


Neurodevelopmental and Metabolomic Responses from Prenatal Coexposure to Perfluorooctanesulfonate (PFOS) and Methylmercury (MeHg) in Sprague-Dawley Rats.
Methylmercury (MeHg) and perfluorooctanesulfonate (PFOS) are major contaminants of human blood that are both common in dietary fish, thereby raising questions about their combined impact on human development. Here, pregnant Sprague-Dawley rats ingested a daily dose, from gestational day 1 through to weaning, of either 1 mg/kg bw PFOS (PFOS-only), 1 mg/kg MeHg (MeHg-only), a mixture of 0.1 mg/kg PFOS and 1 mg/kg MeHg (Low-Mix), or of 1 mg/kg of PFOS and 1 mg/kg MeHg (High-Mix). Newborns were monitored for physical milestones and reflexive developmental responses, and in juveniles the spontaneous activity, anxiety, memory, and cognition were assessed. Targeted metabolomics of 199 analytes was applied to sectioned brain regions of juvenile offspring. Newborns in the High-Mix group had decreased weight gain as well as delayed reflexes and innate behavioral responses compared to controls and individual chemical groups indicating a toxicological interaction on early development. In juveniles, cumulative mixture effects increased in a dose-dependent manner in tests of anxiety-like behavior. However, other developmental test results suggested antagonism, as PFOS-only and MeHg-only juveniles had increased hyperactivity and thigmotaxic behavior, respectively, but fewer effects in Low-Mix and High-Mix groups. Consistent with these behavioral observations, a pattern of antagonism was also observed in neurochemicals measured in rat cortex, as PFOS-only and MeHg-only juveniles had altered concentrations of metabolites (e.g., lipids, amino acids, and biogenic amines), while no changes were evident in the combined exposures. The cortical metabolites altered in PFOS-only and MeHg-only exposed groups are involved in inhibitory and excitatory neurotransmission. These proof-of-principle findings at relatively high doses indicate the potential for toxicological interaction between PFOS and MeHg, with developmental-stage specific effects. Future mixture studies at lower doses are warranted, and prospective human birth cohorts should consider possible confounding effects from PFOS and mercury exposure on neurodevelopment.


The sportsman readjustment after transcontinental flight: a study on marathon runners.
The aim of the study was to evaluate the synchronizing effect of physical activity on the rest-activity cycle after a flight across different time zones, investigating the parameters linked to sleep. The purpose of this study is to evaluate the synchronizing effect of physical activity on the sleep-activity parameters after a flight across different time zones. Eighteen volunteers flew from Milan to New York for the 2007 New York City Marathon. A training program, that consisted of running sessions three times a week for one month, was planned for the twelve athletes that participated in the marathon. The athletes were divided in two groups: Morning Training Group (MTG), trained from 7:00 to 9:00; Evening Training Group (ETG) from 19:00 to 21:00. The Control Group (CG), of 6 non-athletes, did not train before the flight and did not participate in the marathon. In New York, both groups of athletes trained in the morning. Two Actigraph monitoring sessions were performed in all three groups, before the Milan-New York flight and during the stay in New York. The actigraphy made it possible to calculate sleep and activity-specific parameters; sleep and activity patterns were continuously monitored using an actometer on the wrist of the non-dominant hand. Sleep analysis done on the first night in New York showed a significant difference (P<0.05) in the Movement and Fragmentation Index (MFI) between MTG and ETG. In CG and MTG, the MFI increased after the flight, while in ETG, the MFI decreased. Activity analysis demonstrated that, in ETG, evening physical activity in Milan associated with morning activity in New York produced a shift in the Cosine Peak of the rhythm of activity. Physical activity can have a positive effect both on sleep, by improving quality, as well as on the circadian rhythm of activity, by encouraging re-synchronization after the flight.


Number of HIV-1 founder variants is determined by the recency of the source partner infection.
During sexual transmission, the high genetic diversity of HIV-1 within an individual is frequently reduced to one founder variant that initiates infection. Understanding the drivers of this bottleneck is crucial to developing effective infection control strategies. Little is known about the importance of the source partner during this bottleneck. To test the hypothesis that the source partner affects the number of HIV founder variants, we developed a phylodynamic model calibrated using genetic and epidemiological data on all existing transmission pairs for whom the direction of transmission and the infection stage of the source partner are known. Our results suggest that acquiring infection from someone in the acute (early) stage of infection increases the risk of multiple-founder variant transmission compared with acquiring infection from someone in the chronic (later) stage of infection. This study provides the first direct test of source partner characteristics to explain the low frequency of multiple-founder strain infections.


All in its proper time: monitoring the emergence of a memory bias for novel, arousing-negative words in individuals with high and low trait anxiety.
The well-established memory bias for arousing-negative stimuli seems to be enhanced in high trait-anxious persons and persons suffering from anxiety disorders. We monitored the emergence and development of such a bias during and after learning, in high and low trait anxious participants. A word-learning paradigm was applied, consisting of spoken pseudowords paired either with arousing-negative or neutral pictures. Learning performance during training evidenced a short-lived advantage for arousing-negative associated words, which was not present at the end of training. Cued recall and valence ratings revealed a memory bias for pseudowords that had been paired with arousing-negative pictures, immediately after learning and two weeks later. This held even for items that were not explicitly remembered. High anxious individuals evidenced a stronger memory bias in the cued-recall test, and their ratings were also more negative overall compared to low anxious persons. Both effects were evident, even when explicit recall was controlled for. Regarding the memory bias in anxiety prone persons, explicit memory seems to play a more crucial role than implicit memory. The study stresses the need for several time points of bias measurement during the course of learning and retrieval, as well as the employment of different measures for learning success.


Risk factors, confounding, and the illusion of statistical control.
When experimental designs are premature, impractical, or impossible, researchers must rely on statistical methods to adjust for potentially confounding effects. Such procedures, however, are quite fallible. We examine several errors that often follow the use of statistical adjustment. The first is inferring a factor is causal because it predicts an outcome even after "statistical control" for other factors. This inference is fallacious when (as usual) such control involves removing the linear contribution of imperfectly measured variables, or when some confounders remain unmeasured. The converse fallacy is inferring a factor is not causally important because its association with the outcome is attenuated or eliminated by the inclusion of covariates in the adjustment process. This attenuation may only reflect that the covariates treated as confounders are actually mediators (intermediates) and critical to the causal chain from the study factor to the study outcome. Other problems arise due to mismeasurement of the study factor or outcome, or because these study variables are only proxies for underlying constructs. Statistical adjustment serves a useful function, but it cannot transform observational studies into natural experiments, and involves far more subjective judgment than many users realize.


Comparative susceptibility of Atlantic salmon, lake trout and rainbow trout to Myxobolus cerebralis in controlled laboratory exposures.
The susceptibility of lake trout Salvelinus namaycush, rainbow trout Oncorhynchus mykiss and Atlantic salmon Salmo salar to Myxobolus cerebralis, the causative agent of whirling disease, was compared in controlled laboratory exposures. A total of 450 (225 for each dose) fry for each species were exposed to a low (200 spores per fish) or high (2000 spores per fish) dose of the infective triactinomyxon. At 22 wk post-exposure, 60 fish from each group, as well as controls for each species, were examined for clinical signs (whirling behavior, blacktail, deformed heads and skeletal deformities), microscopic lesions, and presence of spores. Rainbow trout were highly susceptible to infection, with 100% being positive for spores and with microscopic pathological changes in both exposure groups. Rainbow trout were the only species to show whirling behavior and blacktail. Atlantic salmon were less susceptible, with only 44 and 61% being positive for spores, respectively, in the low and high dose groups, while 68 and 75%, respectively, had microscopic pathology associated with cartilage damage. Rainbow trout heads contained mean spore concentrations of 2.2 (low dose) or 4.0 (high dose) x 10(6) spores g tissue(-1). The means for positive Atlantic salmon (not including zero values) were 1.7 (low) and 7.4 (high) x 10(4) spores g tissue(-1). Lake trout showed no clinical signs of infection, were negative for spores in both groups and showed no histopathological signs of M. cerebralis infection.


Robot-assisted thoracoscopic lymphadenectomy along the left recurrent laryngeal nerve for esophageal squamous cell carcinoma in the prone position: technical report and short-term outcomes.
Meticulous mediastinal lymphadenectomy frequently induces recurrent laryngeal nerve palsy (RLNP). Surgical robots with impressive dexterity and precise dissection skills have been developed to help surgeons perform operations. The objective of this study was to determine the impact on short-term outcomes of robot-assisted thoracoscopic radical esophagectomy performed on patients in the prone position for the treatment of esophageal squamous cell carcinoma, including its impact on RLNP. A single-institution nonrandomized prospective study was performed. The patients (n = 36) with resectable esophageal squamous cell carcinoma were divided into two groups: patients who agreed to robot-assisted thoracoscopic esophagectomy with total mediastinal lymphadenectomy performed in the prone position (n = 16, robot-assisted group) without insurance reimbursement, and those who agreed to undergo the same operation without robot assistance but with health insurance coverage (n = 20, control group). These patients were observed for 30 days following surgery to assess short-term surgical outcomes, including the incidence of vocal cord palsy, hoarseness, and aspiration. Robot assistance significantly reduced the incidence of vocal cord palsy (p = 0.018) and hoarseness (p = 0.015) and the time on the ventilator (p = 0.025). There was no in-hospital mortality in either group. There were no significant differences between the two groups with respect to patient background, except for the use of preoperative therapy (robot-assisted group <control, p = 0.003). There were no significant differences in estimated blood loss, operating time, number of dissected lymph nodes, completeness of resection, or the incidence of the other complications, except for anastomotic leakage (p = 0.038). Robot-assisted thoracoscopic esophagectomy with total mediastinal lymphadenectomy is feasible and safe. This method shows promise in preventing RLNP.


Long-acting injectable versus oral antipsychotics in schizophrenia: a systematic review and meta-analysis of mirror-image studies.
Recent, large, randomized controlled trials (RCTs) showed no benefit of long-acting injectable (LAI) antipsychotics over oral antipsychotics in preventing relapse in schizophrenia, nor did a recent meta-analysis incorporating these studies. However, RCTs might enroll a disproportionate number of patients with better treatment adherence and lower illness severity. Mirror-image studies, which compare periods of oral antipsychotic versus LAI treatment in the same patients, might therefore better reflect the real-world impact of LAIs. A systematic literature search without language restriction was conducted using MEDLINE/PubMed, Cochrane Library, Web of Science, PsycINFO, and CINAHL until May 31, 2012. Search terms included synonyms of (1) antipsychotic(s) AND (2) schizophrenia and related disorders AND (3) depot, (long-acting) injection(s), microsphere, decanoate, palmitate, enanthate. Of 5,483 identified citations, 607 articles were fully inspected, and 582 were ineligible. Finally, 25 mirror-image studies from 28 countries that followed 5,940 patients with schizophrenia for ≥ 12 months (≥ 6 months each on oral antipsychotic and LAI treatment) met the inclusion criteria and were analyzed. Coprimary outcomes were hospitalization risk and number of hospitalizations. Secondary outcomes included hospitalization days and length of stay. LAIs showed strong superiority over oral antipsychotics in preventing hospitalization (16 studies, N = 4,066; risk ratio = 0.43; 95% CI, 0.35-0.53; P < .001) and in decreasing the number of hospitalizations (15 studies, 6,342 person-years; rate ratio = 0.38; 95% CI, 0.28-0.51; P < .001). This strong advantage was also observed for secondary outcomes and in multiple clinically relevant subpopulations and treatment groups. Results from mirror-image studies in patients eligible for clinical use of LAIs showed strong superiority of LAIs compared to oral antipsychotics in preventing hospitalization. The results were in contrast to the recent meta-analysis of RCTs, which showed no superiority of LAIs. Given the possible biases in mirror-image studies, such as expectation bias, natural illness course, and time effect, a cautious interpretation is required. Nevertheless, the population in mirror-image studies better reflects the population receiving LAIs in clinical practice.


Atrial fibrillation after cardiac surgery/cardiopulmonary bypass is associated with monocyte activation.
Atrial fibrillation (AF) contributes significantly to morbidity and mortality in as many as one-third of patients after cardiac surgery that requires cardiopulmonary bypass (CPB). Recent data suggest that inflammatory infiltration of the myocardium may predispose to AF. We conducted an exploratory pilot study to determine if there was an association between the perioperative leukocyte inflammatory response to cardiac surgery/CPB and postoperative AF. We enrolled 72 patients undergoing cardiac surgery with CPB; all patients were in sinus rhythm before surgery. Leukocyte activation (CD11b upregulation) was perioperatively measured in monocytes and neutrophils (PMN). Preoperative C-reactive protein (CRP) and perioperative neutrophil myeloperoxidase (MPO) were also monitored for inflammation, and troponin I was assayed for perioperative cardiac muscle damage. All markers were evaluated for differences between the subset of patients who developed AF versus those who remained in normal sinus rhythm after surgery. All 72 patients completed the study. Postoperative AF developed in 26 (36%) patients. Perioperative monocyte CD11b upregulation was significantly increased in patients who developed AF (P = 0.01), but increases in PMN CD11b were not significantly associated with AF (P = 0.057). The increase in both monocyte and PMN counts after aortic cross-clamp release was significantly associated with postoperative AF (P = 0.007 and P = 0.005, respectively). By contrast, preoperative CRP and perioperative MPO did not differ between AF and normal rhythm patients. Similarly, the peak value of troponin I did not differ between groups. In this pilot study of cardiac surgery/CPB patients, perioperative upregulation of the monocyte adhesion receptor, CD11b, and higher circulating monocyte and PMN numbers were associated with postoperative AF, suggesting that the induction of cellular inflammation during cardiac surgery/CPB may contribute to this pathophysiology.


Crisis communication: learning from the 1998 LPG near miss in Stockholm.
The authors examine current trends in urban risks and resilience in relation to hazardous material transports in general, and crisis communication and the Stockholm liquefied petroleum gas (LPG) near miss in 1998 in particular. The article discusses how current dynamics affecting urban areas, such as the decay in terms of increased condensation and limited expansion alternatives combined with industry site contamination and transports of hazardous materials on old worn-out physical infrastructure, work together to produce high-risk factors and increase urban vulnerability in large parts of the world today. Crisis communication takes a particularly pronounced role in the article as challenges in communication and confidence maintenance under conditions of information uncertainty and limited information control are explored. The LPG near miss case illustrates a Swedish case of urban risk and the tight coupling to hazardous material transports. The case also serves as a current example of Swedish resilience and lack of preparedness in urban crises, with particular observations and lessons learned in regards to crisis communication.


Virus Cooperation, ZIKV Viremia and in Utero Fetus Infection.
With growth and exponential globe trotter traveling of the human population, and many more conducive factors, the likelihood of merging and melting viruses capable of infecting humans in a cooperative fashion, has increased markedly. Hence, viruses that were limited to a particular region of the planet, or to certain population groups, have become capable of infecting humans on a pandemic scale. Some viruses not only can infect pregnant women, but also expand to the amnotic fluid and fetus. With this review, we will reflect upon some examples of known viral cooperations, as well as new ones that have the potential for compromising human health and survival of the fetus in utero.


Comparative study of tissue deposition of omega-3 fatty acids from polar-lipid rich oil of the microalgae Nannochloropsis oculata with krill oil in rats.
Long-chain omega-3 polyunsaturated fatty acids (LC n-3 PUFA) exert health benefits which are dependent upon their incorporation into blood, cells and tissues. Plasma and tissue deposition of LC n-3 PUFA from oils extracted from the micro-algae Nannochloropsis oculata and from krill were compared in rats. The algal oil provides eicosapentaenoic acid (EPA) partly conjugated (15%) to phospholipids and glycolipids but no docosahexaenoic acid (DHA), whereas krill oil provides both EPA and DHA conjugated in part (40%) to phospholipids. Rats fed a standard diet received either krill oil or polar-lipid rich algal oil by gavage daily for 7 days (5 ml oil per kg body weight each day). Fatty acid concentrations were analyzed in plasma, brain and liver, and two adipose depots since these represent transport, functional and storage pools of fatty acids, respectively. When measuring total LC n-3 PUFA (sum of EPA, docosapentaenoic acid (DPA) and DHA), there was no statistically significant difference between the algal oil and krill oil for plasma, brain, liver and gonadal adipose tissue. Concentrations of LC n-3 PUFA were higher in the retroperitoneal adipose tissue from the algal oil group. Tissue uptake of LC n-3 PUFA from an algal oil containing 15% polar lipids (glycolipids and phospholipids) was found to be equivalent to krill oil containing 40% phospholipids. This may be due to glycolipids forming smaller micelles during ingestive hydrolysis than phospholipids. Ingestion of fatty acids with glycolipids may improve bioavailability, but this needs to be further explored.


Evaluation of vegetable protein in canine diets: Assessment of performance and apparent ileal amino acid digestibility using a broiler model.
Recent technological advances in the human food industry with respect to meat processing have decreased the availability of animal proteins to the pet food industry which typically formulates diets with an excess of animal protein. In the long term, this is not sustainable; thus, alternative protein sources need to be investigated. This study examined three canine diets, comparing a typical animal protein-based diet (control) with two experimental diets where the animal protein was substituted in part with vegetable protein (formulated based either on total protein or amino acid content) using a broiler model. Each diet was fed to six cages each containing two birds from day 15, 18 cages in total (36 birds). Excreta were collected from days 19 to 21. On day 23, birds were euthanized and weighed, and their ileal digesta were collected and pooled for each cage. In addition, one leg per cage was collected for evaluation of muscle mass. Results showed no significant difference in animal performance (feed intake or live weight gain) or muscle to leg proportion across the diets. Birds fed the control diet and the diet balanced for amino acid content exhibited the greatest coefficients of apparent metabolizability for nitrogen (p < .001). Birds fed the diets that contained partial replacement of animal with vegetable protein generally had greater ileal digestibility of amino acids compared to birds fed the control (animal protein) diet. Analysis of excreta showed no dietary difference in terms of dry matter content; however, birds fed the diet balanced for total protein and the diet balanced for amino acid content had significantly greater excreta nitrogen than the control (p = .038). Overall, the study suggests vegetable proteins when formulated based on amino acid content are a viable alternative to animal proteins in canine diets.


Is the thrifty genotype hypothesis supported by evidence based on confirmed type 2 diabetes- and obesity-susceptibility variants?
According to the thrifty genotype hypothesis, the high prevalence of type 2 diabetes and obesity is a consequence of genetic variants that have undergone positive selection during historical periods of erratic food supply. The recent expansion in the number of validated type 2 diabetes- and obesity-susceptibility loci, coupled with access to empirical data, enables us to look for evidence in support (or otherwise) of the thrifty genotype hypothesis using proven loci. We employed a range of tests to obtain complementary views of the evidence for selection: we determined whether the risk allele at associated 'index' single-nucleotide polymorphisms is derived or ancestral, calculated the integrated haplotype score (iHS) and assessed the population differentiation statistic fixation index (F (ST)) for 17 type 2 diabetes and 13 obesity loci. We found no evidence for significant differences for the derived/ancestral allele test. None of the studied loci showed strong evidence for selection based on the iHS score. We find a high F (ST) for rs7901695 at TCF7L2, the largest type 2 diabetes effect size found to date. Our results provide some evidence for selection at specific loci, but there are no consistent patterns of selection that provide conclusive confirmation of the thrifty genotype hypothesis. Discovery of more signals and more causal variants for type 2 diabetes and obesity is likely to allow more detailed examination of these issues.


Submolecular electronic mapping of single cysteine molecules by in situ scanning tunneling imaging.
We have used L-cysteine (Cys) as a model system to study the surface electronic structures of single molecules at the submolecular level in aqueous buffer solution by a combination of electrochemical scanning tunneling microscopy (in situ STM), electrochemistry including voltammetry and chronocoulometry, and density functional theory (DFT) computations. Cys molecules were assembled on single-crystal Au(110) surfaces to form a highly ordered monolayer with a periodic lattice structure of c(2x2) in which each unit contains two molecules; this conclusion is confirmed by the results of calculations based on a slab model for the metal surface. The ordered monolayer offers a platform for submolecular scale electronic mapping that is an issue of fundamental interest but remains a challenge in STM imaging science and surface chemistry. Single Cys molecules were mapped as three electronic subunits contributed mainly from three chemical moieties: thiol (-SH), carboxylic (-COOH), and amine (-NH2) groups. The contrasts of the three subunits depend on the environment (e.g., pH), which affects the electronic structure of adsorbed species. From the DFT computations focused on single molecules, rational analysis of the electronic structures is achieved to delineate the main factors that determine electronic contrasts in the STM images. These factors include the molecular orientation, the chemical nature of the elements or groups in the molecule, and the interaction of the elements with the substrate and tip. The computational images recast as constant-current-height profiles show that the most favorable molecular orientation is the adsorption of cysteine as a radical in zwitterionic form located on the bridge between the Au(110) atomic rows and with the amine and carboxyl group toward the solution bulk. The correlation between physical location and electronic contrast of the adsorbed molecules was also revealed by the computational data. The present study shows that cysteine packing in the adlayer on Au(110) from the liquid environment is in contrast to that from the ultrahigh-vacuum environment, suggesting solvent plays a role during molecular assembly.


BVES is required for maintenance of colonic epithelial integrity in experimental colitis by modifying intestinal permeability.
Blood vessel epicardial substance (BVES), or POPDC1, is a tight junction-associated transmembrane protein that modulates epithelial-to-mesenchymal transition (EMT) via junctional signaling pathways. There have been no in vivo studies investigating the role of BVES in colitis. We hypothesized that BVES is critical for maintaining colonic epithelial integrity. At baseline, Bves-/- mouse colons demonstrate increased crypt height, elevated proliferation, decreased apoptosis, altered intestinal lineage allocation, and dysregulation of tight junctions with functional deficits in permeability and altered intestinal immunity. Bves-/- mice inoculated with Citrobacter rodentium had greater colonic injury, increased colonic and mesenteric lymph node bacterial colonization, and altered immune responses after infection. We propose that increased bacterial colonization and translocation result in amplified immune responses and worsened injury. Similarly, dextran sodium sulfate (DSS) treatment resulted in greater histologic injury in Bves-/- mice. Two different human cell lines (Caco2 and HEK293Ts) co-cultured with enteropathogenic E. coli showed increased attaching/effacing lesions in the absence of BVES. Finally, BVES mRNA levels were reduced in human ulcerative colitis (UC) biopsy specimens. Collectively, these studies suggest that BVES plays a protective role both in ulcerative and infectious colitis and identify BVES as a critical protector of colonic mucosal integrity.


Transcription factor Sox11 is essential for both embryonic and adult neurogenesis.
Neurogenesis requires neural progenitor cell (NPC) proliferation, neuronal migration, and differentiation. During embryonic development, neurons are generated in specific areas of the developing neuroepithelium and migrate to their appropriate positions. In the adult brain, neurogenesis continues in the subgranular zone (SGZ) of the hippocampal dentate gyrus and the subventricular zone (SVZ) of the lateral ventricle. Although neurogenesis is fundamental to brain development and function, our understanding of the molecular mechanisms that regulate neurogenesis is still limited. In this study, we generated a Sox11 floxed allele and a Sox11 null allele in mice using the Cre-loxP technology. We first analyzed the role of the transcription factor Sox11 in embryonic neurogenesis using Sox11 null embryos. We also examined the role of Sox11 in adult hippocampal neurogenesis using Sox11 conditional knockout mice in which Sox11 is specifically deleted in adult NPCs. Sox11 null embryos developed small and disorganized brains, accompanied by transient proliferation deficits in NPCs. Deletion of Sox11 in adult NPCs blunted proliferation in the SGZ. Using functional genomics, we identified potential downstream target genes of Sox11. Taken together, our work provides evidence that Sox11 is required for both embryonic and adult neurogenesis, and identifies potential downstream target genes.


Valproic acid activates notch-1 signaling and regulates the neuroendocrine phenotype in carcinoid cancer cells.
Carcinoid tumors are neuroendocrine malignancies that frequently metastasize and secrete hormones that cause debilitating symptoms in patients. In this study we report the effects of valproic acid (VPA), a drug long used for the treatment of epilepsy, on the growth and neuroendocrine phenotype of human carcinoid cancer cells. VPA treatment of gastrointestinal and pulmonary carcinoid cells resulted in a dose-dependent inhibition of cancer cell growth. Western blot analysis revealed degradation of cyclin D1 and an increase in cyclin-dependent kinases p21 and p27 with VPA treatment. Flow cytometry confirmed that the mechanism of VPA-induced growth inhibition is G(1) phase cell cycle arrest. Furthermore, VPA suppressed expression of the neuroendocrine tumor marker chromogranin A. In addition to these effects, VPA also increased levels of full-length Notch-1 and the active Notch-1 intracellular domain. Luciferase reporter assays incorporating the centromere-binding factor 1 (CBF-1) binding site and the achaete-scute complex-like 1 (ASCL-1) promoter confirmed the functional activity of VPA-induced Notch-1. Transfection of Notch-1 small-interfering RNA into carcinoid tumor cells blocked the effects of VPA on Notch-1 activation, ASCL-1 suppression, p21 induction, and cell growth inhibition. VPA also suppressed growth of carcinoid tumors in vivo in a mouse tumor xenograft experiment. These findings confirm the important role of Notch-1 in regulating the growth and neuroendocrine phenotype of carcinoid tumor cells. On the basis of this study, a clinical trial of VPA for patients with advanced carcinoid cancer will be conducted. Disclosure of potential conflicts of interest is found at the end of this article.


Multiple slow waves and relevant transverse transmission and confinement in chirped photonic crystals.
The dispersion properties of rod-type chirped photonic crystals (PhCs) and non-channeled transmission in the direction of the variation of structural parameters from one cell of such a PhC to another are studied. Two types of configurations that enable multiple slow waves but differ in the utilized chirping scheme are compared. It is demonstrated that the multiple, nearly flat bands with a group index of refraction exceeding 180 can be obtained. For these bands, transmission is characterized by multiple narrow peaks of perfect transmission, strong field enhancement inside the slab, and large values of the Q-factor. Among the bands, there are some that show negative phase velocity. Symmetry with respect to the slab mid-plane must be kept in order to obtain constructive interferences that are necessary for reflection-free transmission. It is shown that 15 and more slow wave bands can be obtained in one configuration. The corresponding transmission peaks are well separated from each other, being the only significant feature of the transmission spectrum, while the Q-factor can exceed 10⁵. The observed features are preserved in a wide range of the incidence angle variation. They can be used for tuning the locations and spectral widths of the transmission peaks. Some comparisons with the chirped multilayer structures have been carried out.


Antimicrobial Peptide Modifications against Clinically Isolated Antibiotic-Resistant Salmonella.
Antimicrobial peptides are promising molecules to address the global antibiotic resistance problem, however, optimization to achieve favorable potency and safety is required. Here, a peptide-template modification approach was employed to design physicochemical variants based on net charge, hydrophobicity, enantiomer, and terminal group. All variants of the scorpion venom peptide BmKn-2 with amphipathic α-helical cationic structure exhibited an increased antibacterial potency when evaluated against multidrug-resistant Salmonella isolates at a MIC range of 4-8 µM. They revealed antibiofilm activity in a dose-dependent manner. Sheep red blood cells were used to evaluate hemolytic and cell selectivity properties. Peptide Kn2-5R-NH2, dKn2-5R-NH2, and 2F-Kn2-5R-NH2 (variants with +6 charges carrying amidated C-terminus) showed stronger antibacterial activity than Kn2-5R (a variant with +5 charges bearing free-carboxyl group at C-terminus). Peptide dKn2-5R-NH2 (d-enantiomer) exhibited slightly weaker antibacterial activity with much less hemolytic activity (higher hemolytic concentration 50) than Kn2-5R-NH2 (l-enantiomer). Furthermore, peptide Kn2-5R with the least hydrophobicity had the lowest hemolytic activity and showed the highest specificity to Salmonella (the highest selectivity index). This study also explained the relationship of peptide physicochemical properties and bioactivities that would fulfill and accelerate progress in peptide antibiotic research and development.


Helps from flipped classroom in learning suturing skill: The medical students' perspective.
Today, flipped classroom (FC) has been widely used in medical education. However, the effectiveness of FC remains controversial. The variation may cause by different subjects or different course design. Moreover, those studies did not explain how the association among different domains of learning objective was in FCs. The purpose of this study was to explore the help of learning domains from a FC of suturing skill in year-5 medical students. This study determined sample size according to statistical power. A minimum number of 77 participants for regression analysis are needed. Therefore, this study enrolled 78 medical students in a 2-hour suturing course, which consisted of pre-class video and in-class instruction. Both simple and mattress suturing were taught. The students received an anonymous survey with questionnaire of Help from Instruction Questionnaire for Clinical Skills (HIQ-CS) after the course. The HIQ-CS was developed by medical education team according to Bloom's taxonomy, and its reliability was favorable (Cronbach's ^l = 0.839). Factor loadings among all items in the HIQ-CS was also favorable (0.790 to 0.849). This study determined consensus of students' perspective by median (Me) and interquartile range (IQR), and tested mediation among different learning domains by regression. The results showed medical students agreed FC can help them in learning suturing (Me = 4, IQR = 1). The cognitive help (β = .526, p < .001) was completely mediated by psychomotor help (β = .399, p < .001) and affective help (β = .413, p < .001) to overall helps in FC. The affective help (β = .617, p < .001) was partially mediated by psychomotor help to overall helps in FC. FC may help students in learning suturing skill in different domains. Our model explains the cognitive help from FC provides an important foundation for the helps of other domains. Although the model should be examined by different curricula and measurements in future, the model of help from instruction in our study provided an innovated concept and framework in medical education.


The Effect of Krill Oil Supplementation on Exercise Performance and Markers of Immune Function.
Krill oil is a rich source of the long-chain n-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which may alter immune function after exercise. The aim of the study was to determine the effects of krill oil supplementation on post exercise immune function and performance. Nineteen males and 18 females (age: 25.8 ± 5.3 years; mean ± S.D.) were randomly assigned to 2 g/day of krill oil (n = 18) or placebo (n = 19) supplementation for 6 weeks. A maximal incremental exercise test and cycling time trial (time to complete set amount of work) were performed pre-supplementation with the time trial repeated post-supplementation. Blood samples collected pre- and post- supplementation at rest, and immediately, 1 and 3h post-exercise. Plasma IL-6 and thiobarbituric acid reactive substances (TBARS) concentrations and, erythrocyte fatty acid composition were measured. Natural killer (NK) cell cytotoxic activity and peripheral blood mononuclear cell (PBMC) IL-2, IL-4, IL-10, IL-17 and IFNγ production were also measured. No effects of gender were noted for any variable. PBMC IL-2 and NK cell cytotoxic activity were greater (P < 0.05) 3h post exercise in the krill oil compared to the control group. Plasma IL-6 and TBARS, PBMC IL-4, IL-10, IL-17 and IFNγ production, along with performance and physiological measures during exercise, were not different between groups. Six weeks of krill oil supplementation can increase PBMC IL-2 production and NK cell cytotoxic activity 3h post-exercise in both healthy young males and females. Krill oil does not modify exercise performance.


Synaesthetic photisms influence visual perception.
When C, a digit-color synaesthete, views black digits, she reports that each digit elicits a highly specific color (a photism), which is experienced as though the color was externally projected onto the digit. We evaluated this claim by assessing whether C's photisms influenced her ability to perceive visually presented digits. C identified and localized target digits presented against backgrounds that were either congruent or incongruent with the color of her photism for the digits. The results showed that C was poorer at identifying and localizing digits on congruent than incongruent trials. Such differences in performance between congruent and incongruent trials were not found with nonsynaesthete control participants. These results suggest that C's colored photisms influence her perception of black digits. We propose a model in which color information influences the perception of digits through reentrant pathways in the visual system.


Peripheral compartment innate immune response to Haemophilus influenzae and Streptococcus pneumoniae in chronic obstructive pulmonary disease patients.
Alterations in innate immunity that predispose to chronic obstructive pulmonary disease (COPD) exacerbations are poorly understood. We examined innate immunity gene expression in peripheral blood polymorphonuclear leukocytes (PMN) and monocytes stimulated by Haemophilus influenzae and Streptococcus pneumoniae. Thirty COPD patients (15 rapid and 15 non-rapid lung function decliners) and 15 smokers without COPD were studied. Protein expression of IL-8, IL-6, TNF-α and IFN-γ (especially monocytes) increased with bacterial challenge. In monocytes stimulated with S. pneumoniae, TNF-α protein expression was higher in COPD (non-rapid decliners) than in smokers. In co-cultures of monocytes and PMN, mRNA expression of TGF-β1 and MYD88 was up-regulated, and CD14, TLR2 and IFN-γ down-regulated with H. influenzae challenge. TNF-α mRNA expression was increased with H. influenzae challenge in COPD. Cytokine responses were similar between rapid and non-rapid decliners. TNF-α expression was up-regulated in non-rapid decliners in response to H. influenzae (monocytes) and S. pneumoniae (co-culture of monocytes and PMN). Exposure to bacterial pathogens causes characteristic innate immune responses in peripheral blood monocytes and PMN in COPD. Bacterial exposure significantly alters the expression of TNF-α in COPD patients, although not consistently. There did not appear to be major differences in innate immune responses between rapid and non-rapid decliners.


The evaluation in terms of sarcopenia of patients with fibromyalgia syndrome.
Fibromyalgia syndrome (FMS) is an extra-articular rheumatic illness, characterized by widespread body pain and decreased muscle function. Generalized loss of muscle mass and strength is named as sarcopenia. The objective of this study was to evaluate patients with FMS regarding sarcopenia. This was a cross sectional, case-controlled, single-blinded, and single-centered study. The FMS patients were assessed by Fibromyalgia Impact Questionnaire (FIQ), visual analog scale (VAS), Beck Depression Index (BDI), and Pittsburg Sleep Quality Scale (PSQI). All the participants were evaluated for sarcopenia by bioimpedance analysis (BIA), anthropometric measurements, handgrip strength, and the parameters of walking speed. In this study, 82 patients with FMS and 38 healthy control female subjects were included. VAS, BDI, and PSQI scores were statistically higher in the FMS group than the control group (p < 0.001). Handgrip strength (HS) and walking speed (WS) scores in the group with FMS were statistically lower than the control group (p = 0.023, p < 0.001 respectively). VAS score of FMS patients was significantly correlated with BIA, body mass index, waist circumference, HS, and WS scores (r = 0.284, p = 0.012; r = 0.228, p = 0.045; r = 0.249, p = 0.028; r = - 0.361, p = 0.001; and r = - 0.230, p = 0.043 respectively). Also FIQ in patients was significantly correlated with BIA, waist circumference, HS, WS, and body mass index (r = 0.267, p = 0.018; r = 0.291, p = 0.010; r = - 0.319, p = 0.004; r = - 0.360, p = 0.001; and r = 0.304, p = 0.007 respectively). Evaluation of female patients with primary FMS by the sarcopenia parameters could contribute a more objective evaluation during the patients' follow-up.


Small amounts of sub-visible aggregates enhance the immunogenic potential of monoclonal antibody therapeutics.
Determine the effect of minute quantities of sub-visible aggregates on the in vitro immunogenicity of clinically relevant protein therapeutics. Monoclonal chimeric (rituximab) and humanized (trastuzumab) antibodies were subjected to fine-tuned stress conditions to achieve low levels (<3% of total protein) of sub-visible aggregates. The effect of stimulating human dendritic cells (DC) and CD4(+) T cells with the aggregates was measured in vitro using cytokine secretion, proliferation and confocal microscopy. Due to its intrinsic high clinical immunogenicity, aggregation of rituximab had minimal effects on DC activation and T cell responses compared to monomeric rituximab. However, in the case of trastuzumab (low clinical immunogenicity) small quantities of aggregates led to potent CD4(+) T cell proliferation as a result of strong cytokine and co-stimulatory signals derived from DC. Consistent with this, confocal studies showed that stir-stressed rituximab was rapidly internalised and associated with late endosomes of DC. These data link minute amounts of aggregates with activation of the innate immune response, involving DC, resulting in T cell activation. Thus, when protein therapeutics with little or no clinical immunogenicity, such as trastuzumab, contain minute amounts of sub-visible aggregates, they are associated with significantly increased potential risk of clinical immunogenicity.


Design of Crotoxin-Based Peptides with Potentiator Activity Targeting the ΔF508NBD1 Cystic Fibrosis Transmembrane Conductance Regulator.
We have previously shown that the CBb subunit of crotoxin, a β-neurotoxin with phospholipase A2 (PLA2) activity, targets the human ΔF508CFTR chloride channel implicated in cystic fibrosis (CF). By direct binding to the nucleotide binding domain 1 (NBD1) of ΔF508CFTR, this neurotoxic PLA2 acts as a potentiator increasing chloride channel current and corrects the trafficking defect of misfolded ΔF508CFTR inside the cell. Here, for a therapeutics development of new anti-cystic fibrosis agents, we use a structure-based in silico approach to design peptides mimicking the CBb-ΔF508NBD1 interface. Combining biophysical and electrophysiological methods, we identify several peptides that interact with the ΔF508NBD1 domain and reveal their effects as potentiators on phosphorylated ΔF508CFTR. Moreover, protein-peptide interactions and electrophysiological studies allowed us to identify key residues of ΔF508NBD1 governing the interactions with the novel potentiators. The designed peptides bind to the same region as CBb phospholipase A2 on ΔF508NBD1 and potentiate chloride channel activity. Certain peptides also show an additive effect towards the clinically approved VX-770 potentiator. The identified CF therapeutics peptides represent a novel class of CFTR potentiators and illustrate a strategy leading to reproducing the effect of specific protein-protein interactions.


A New Family of Diverse Skin Peptides from the Microhylid Frog Genus Phrynomantis.
A wide range of frogs produce skin poisons composed of bioactive peptides for defence against pathogens, parasites and predators. While several frog families have been thoroughly screened for skin-secreted peptides, others, like the Microhylidae, have remained mostly unexplored. Previous studies of microhylids found no evidence of peptide secretion, suggesting that this defence adaptation was evolutionarily lost. We conducted transcriptome analyses of the skins of Phrynomantis bifasciatus and Phrynomantis microps, two African microhylid species long suspected to be poisonous. Our analyses reveal 17 evolutionary related transcripts that diversified from to those of cytolytic peptides found in other frog families. The 19 peptides predicted to be processed from these transcripts, named phrynomantins, show a striking structural diversity that is distinct from any previously identified frog skin peptide. Functional analyses of five phrynomantins confirm the loss of a cytolytic function and the absence of insecticidal or proinflammatory activity, suggesting that they represent an evolutionary transition to a new, yet unknown function. Our study shows that peptides have been retained in the defence poison of at least one microhylid lineage and encourages research on similarly understudied taxa to further elucidate the diversity and evolution of skin defence molecules.


Low-frequency noise in bilayer MoS(2) transistor.
Low-frequency noise is a significant limitation on the performance of nanoscale electronic devices. This limitation is especially important for devices based on two-dimensional (2D) materials such as graphene and transition metal dichalcogenides (TMDs), which have atomically thin bodies and, hence, are severely affected by surface contaminants. Here, we investigate the low-frequency noise of transistors based on molybdenum disulfide (MoS2), which is a typical example of TMD. The noise measurements performed on bilayer MoS2 channel transistors show a noise peak in the gate-voltage dependence data, which has also been reported for graphene. To understand the peak, a trap decay-time based model is developed by revisiting the carrier number fluctuation model. Our analysis reveals that the peak originates from the fact that the decay time of the traps for a 2D device channel is governed by the van der Waals bonds between the 2D material and the surroundings. Our model is generic to all 2D materials and can be applied to explain the V, M and Λ shaped dependence of noise on the gate voltage in graphene transistors, as well as the noise shape dependency on the number of atomic layers of other 2D materials. Since the van der Waals bonding between the surface traps and 2D materials is weak, in accordance with the developed physical model, an annealing process is shown to significantly reduce the trap density, thereby reducing the low-frequency noise.


Isolated subtalar arthrodesis.
The purposes of this retrospective study were to review the results of isolated subtalar arthrodesis in adults and to identify factors influencing the union rate. The hypotheses were that (1) the overall outcome is acceptable but is not as favorable as previously reported, (2) complication rates, especially the nonunion rate, are higher than previously reported, and (3) factors contributing to a less favorable union rate can be identified. Between January 1988 and July 1995, 184 consecutive isolated subtalar arthrodeses were performed in 174 adults (115 men and fifty-nine women) whose average age was forty-three years (range, eighteen to seventy-nine years). Eighty patients (46 percent) were smokers. The indications for the procedure included posttraumatic arthritis after a fracture of the calcaneus (109 feet), a fracture of the talus (thirteen feet), or a subtalar dislocation (thirteen feet); primary subtalar arthritis (thirteen feet); failure of a previous subtalar arthrodesis (twenty-eight feet); and residual congenital deformity (eight feet). Rigid internal fixation with one or two screws was used for all feet. Bone graft was used in 145 feet; the types of graft material included cancellous autograft (ninety-four feet), structural autograft (twenty-nine feet), cancellous allograft (seventeen feet), and structural allograft (five feet). Bone graft was not used in the remaining thirty-nine feet. Clinical and radiographic follow-up examinations were performed for 148 (80 percent) of the 184 feet at an average of fifty-one months (range, twenty-four to 130 months) postoperatively. The average ankle-hindfoot score according to the modified scale of the American Orthopaedic Foot and Ankle Society (maximum possible score, 94 points) improved from 24 points preoperatively to 70 points at follow-up. Thirty feet had clinical evidence of nonunion. The union rate was 84 percent (154 of 184) overall, 86 percent (134 of 156) after primary arthrodesis, and 71 percent (twenty of twenty-eight) after revision arthrodesis. The union rate was 92 percent (ninety-three of 101 feet) for nonsmokers and 73 percent (sixty-one of eighty-three feet) for smokers (p < 0.05). Intraoperative inspection revealed that 42 percent (seventy-eight) of the 184 feet had evidence of more than two millimeters of avascular bone at the subtalar joint; all thirty nonunions occurred in this group (p < 0.05). A nonunion occurred in three of the five feet that had been treated with structural allograft and in two of the six feet in which the subtalar arthrodesis had been performed adjacent to the site of a previous ankle arthrodesis. After elimination of the subgroups of feet in patients who smoked, those that had had a failure of a previous subtalar arthrodesis, those that had been treated with a structural graft, and those that had had the subtalar arthrodesis adjacent to the site of a previous ankle arthrodesis, the union rate improved to 96 percent (seventy-three of seventy-six). Complications other than nonunion included prominent hardware requiring screw removal (thirty-six of 184 feet; 20 percent), lateral impingement (fifteen of 148 feet; 10 percent), symptomatic valgus malalignment (five of 148 feet; 3 percent), symptomatic varus malalignment (four of 148 feet; 3 percent), and infection (five of 184 feet; 3 percent). To the best of our knowledge, the present study includes the largest reported series of isolated subtalar arthrodeses in adults. Our results suggest that the outcome following isolated subtalar arthrodesis is not as favorable as has been reported in previous studies. The rate of union was significantly diminished by smoking, the presence of more than two millimeters of avascular bone at the arthrodesis site, and the failure of a previous subtalar arthrodesis (p < 0.05 for all). Other factors that probably affect the union rate include the use of structural allograft and performance of the arthrodesis adjac


Career transition and dental school faculty development program.
Academic dentistry, as a career track, is not attracting sufficient numbers of new recruits to maintain a corps of skilled dental educators. The Faculty Development Program (FDP) at the University of Texas Health Science Center at San Antonio Dental School received federal funds to institute a 7-component program to enhance faculty recruitment and retention and provide training in skills associated with success in academics including:(1) a Teaching Excellence and Academic Skills (TExAS)Fellowship, (2) training in research methodology,evidence-based practice research, and information management, (3) an annual dental hygiene faculty development workshop for dental hygiene faculty, (4) a Teaching Honors Program and Academic Dental Careers Fellowship to cultivate students' interest in educational careers, (5) an Interprofessional Primary Care Rotation,(6) advanced education support toward a master's degree in public health, and (7) a key focus of the entire FDP, an annual Career Transition Workshop to facilitate movement from the practice arena to the educational arm of the profession.The Career Transition Workshop is a cap stone for the FDP; its goal is to build a bridge from practice to academic environment. It will provide guidance for private practice, public health, and military dentists and hygienists considering a career transition into academic dentistry. Topics will be addressed including: academic culture, preparation for the academic environment,academic responsibilities, terms of employment,compensation and benefits, career planning, and job search / interviewing. Instructors for the workshop will include dental school faculty who have transitioned from the practice, military, and public health sectors into dental education.Objectives of the Overall Faculty Development Program:• Provide training in teaching and research skills,career planning, and leadership in order to address faculty shortages in dental schools and under representation of minority faculty.• Provide resident and faculty training in cultural and linguistic competency.• Develop and conduct a collaborative inter professional education project with a Pediatric Medicine department, a nursing school, and other health professions' education programs.• Provide faculty and residents with financial support to pursue a master's degree in public health; and • Provide support and assistance for dental practitioners desiring to explore a transition into the educational environment.


A comparison of mycophenolate mofetil and calcineurin inhibitor as maintenance immunosuppression for kidney transplant recipients: A meta-analysis of randomized controlled trials
We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the comparison and its timing between mycophenolate mofetil (MMF) and calcineurin inhibitor (CNI) as maintenance immunosuppression for kidney transplant recipients. The RCTs of MMF versus CNI as maintenance immunosuppression for kidney transplant recipients were searched from PubMed, Embase, Cochrane Central Register of Controlled Trials (CCRCT), and ClinicalTrials.gov. After screening relevant RCTs, two authors independently assessed the quality of included studies and performed a meta-analysis using RevMan5.3. Relative risk (RR) was used to report dichotomous data, while mean difference (MD) with 95% confidence interval (CI) was used to report continuous outcomes. The analysis was conducted using the random-effect model due to the expected heterogeneity among different studies. Four subgroups were allocated to compare MMF with CNI as maintenance immunosuppression: (1) after 3 months of CNI-based therapy, (2) after 6 months of CNI-based therapy, (3) after 12 months of CNI-based therapy, and (4) in recipients with allograft dysfunction. Twelve RCTs with 950 renal transplant recipients were included. This meta-analysis presented the following results upon comparison between MMF and CNI as maintenance immunosuppression for kidney transplant recipients: (1) MMF significantly improved the glomerular filtration rate (GFR) not only in the comparison performed after 3, 6, or 12 months of CNI-based therapy but also in the comparison of recipients with allograft dysfunction, (2) MMF may increase the risk of acute rejection in the comparison performed after 3 months of CNI-based therapy, but no increase was noted in the comparison performed after 6 or 12 months of CNI- based therapy. Our present meta-analysis suggested that MMF followed at least 6 months of CNI-based therapy is an effective maintenance immunosuppressive regimen for kidney transplant recipients to improve renal function but not increase rejection.


Measuring treatment response in psychotic depression: the Psychotic Depression Assessment Scale (PDAS) takes both depressive and psychotic symptoms into account.
There is no established psychometric instrument dedicated to the measurement of severity in psychotic depression (PD). The aim of this study was to investigate whether a new composite rating scale, the Psychotic Depression Assessment Scale (PDAS), covering both the psychotic and the depressive domains of PD, could detect differences in effect between two psychopharmacological treatment regimens. We reanalyzed the data from the Study of Pharmacotherapy of Psychotic Depression (STOP-PD), which compared the effect of Olanzapine+Sertraline (n=129) versus Olanzapine+Placebo (n=130). The response to the two regimens was compared using both a mixed effects model and effect size statistics on the total scores of three rating scales: the 17-item Hamilton Depression Rating Scale (HAM-D17), its 6-item melancholia subscale (HAM-D6), and the 11-item PDAS consisting of the HAM-D6 plus five items from the Brief Psychiatric Rating Scale covering psychotic symptoms. According to both statistical approaches, the PDAS, the HAM-D17 and the HAM-D6 were all able to detect significant differences in treatment effect between Olanzapine+Sertraline and Olanzapine+Placebo (Olanzapine+Sertraline being superior). Notably, 45% of the trial participants were at least "probable psychotic" at their last assessment in the trial. The STOP-PD was not designed specifically to answer the research questions of the present study. The Psychotic Depression Assessment Scale (PDAS) is a sensitive measure of treatment response in PD. The fact that 45% of the patients still experienced psychotic symptoms at their last trial assessment emphasizes the need to include items pertaining to psychotic symptoms in rating scales for PD.


Use and efficacy of tuberculosis infection control practices at hospitals with previous outbreaks of multidrug-resistant tuberculosis.
To evaluate the implementation and efficacy of selected Centers for Disease Control and Prevention guidelines for preventing spread of Mycobacterium tuberculosis. Analysis of prospective observational data. Two medical centers where outbreaks of multidrug-resistant tuberculosis (TB) had occurred. All hospital inpatients who had active TB or who were placed in TB isolation and healthcare workers who were assigned to selected wards on which TB patients were treated. During 1995 to 1997, study personnel prospectively recorded information on patients who had TB or were in TB isolation, performed observations of TB isolation rooms, and recorded tuberculin skin-test results of healthcare workers. Genetic typing of M tuberculosis isolates was performed by restriction fragment-length polymorphism analysis. We found that only 8.6% of patients placed in TB isolation proved to have TB; yet, 19% of patients with pulmonary TB were not isolated on the first day of hospital admission. Specimens were ordered for acid-fast bacillus smear and results received promptly, and most TB isolation rooms were under negative pressure. Among persons entering TB isolation rooms, 44.2% to 97.1% used an appropriate (particulate, high-efficiency particulate air or N95) respirator, depending on the hospital and year; others entering the rooms used a surgical mask or nothing. We did not find evidence of transmission of TB among healthcare workers (based on tuberculin skin-test results) or patients (based on epidemiological investigation and genetic typing). We found problems in implementation of some TB infection control measures, but no evidence of healthcare-associated transmission, possibly in part because of limitations in the number of patients and workers studied. Similar evaluations should be performed at hospitals treating TB patients to find inadequacies and guide improvements in infection control.


Colorectal cancer with Synchronous liver-limited Metastases: the protocol of an Inception Cohort study (CoSMIC).
Colorectal cancer is the fourth most common cancer in the UK and an important cause of cancer-related death. In 20% of patients, there is metastasis to the liver or beyond at the time of diagnosis. The management of synchronous disease is complex. Conventional surgery removes the colorectal primary first, followed by chemotherapy, with resection of liver metastases as a final step. Advances in the availability and safety of liver surgery, anaesthesia and critical care have made two alternative options feasible. The first is synchronous resection of the primary and liver metastases. The second is resection of the metastatic disease as the first step, termed the reverse or liver-first approach. Currently, evidence is inadequate to inform the selection of care pathway for patients with colorectal cancer and synchronous liver-limited metastases. Specifically, optimal pathways are not defined and there is a dearth of prospectively recorded cohort-defining factors influencing treatment selection or outcome. Colorectal cancer with Synchronous liver-limited Metastases: an Inception Cohort (CoSMIC) is an inception cohort study of patients with a new diagnosis of colorectal cancer with synchronous liver-limited metastases. The sequence of treatment received, and factors influencing treatment decisions, will be evaluated against European Society of Medical Oncology guidelines. Clinical data will be collected, and quality of life, morbidity, mortality and long-term outcome compared for different treatment sequences adjusted for prognostic factors. Disease-free survival or progression will be measured at 1, 2 and 5 years. A nested qualitative study will ascertain patient experiences and clinician perspectives on delivery of care. The full study protocol was independently peer reviewed by Professor Kees de Jong (University of Maastricht, Holland). CoSMIC has ethical approval from the National Health Service Research Ethics Committee (14/NW/1397). Results will be disseminated to healthcare professionals and patient groups, and may be used to design a definitive trial addressing areas of equipoise in treatment pathways, as well as optimising current pathways to improve outcomes and experiences. NCT02456285, pre-results.


Quantitative Bio-Imaging Tools to Dissect the Interplay of Membrane and Cytoskeletal Actin Dynamics in Immune Cells.
Cellular function is reliant on the dynamic interplay between the plasma membrane and the actin cytoskeleton. This critical relationship is of particular importance in immune cells, where both the cytoskeleton and the plasma membrane work in concert to organize and potentiate immune signaling events. Despite their importance, there remains a critical gap in understanding how these respective dynamics are coupled, and how this coupling in turn may influence immune cell function from the bottom up. In this review, we highlight recent optical technologies that could provide strategies to investigate the simultaneous dynamics of both the cytoskeleton and membrane as well as their interplay, focusing on current and future applications in immune cells. We provide a guide of the spatio-temporal scale of each technique as well as highlighting novel probes and labels that have the potential to provide insights into membrane and cytoskeletal dynamics. The quantitative biophysical tools presented here provide a new and exciting route to uncover the relationship between plasma membrane and cytoskeletal dynamics that underlies immune cell function.


Effects of twenty-minute 3G mobile phone irradiation on event related potential components and early gamma synchronization in auditory oddball paradigm.
We investigated the potential effects of 20 min irradiation from a new generation Universal Mobile Telecommunication System (UMTS) 3G mobile phone on human event related potentials (ERPs) in an auditory oddball paradigm. In a double-blind task design, subjects were exposed to either genuine or sham irradiation in two separate sessions. Before and after irradiation subjects were presented with a random series of 50 ms tone burst (frequent standards: 1 kHz, P=0.8, rare deviants: 1.5 kHz, P=0.2) at a mean repetition rate of 1500 ms while electroencephalogram (EEG) was recorded. The subjects' task was to silently count the appearance of targets. The amplitude and latency of the N100, N200, P200 and P300 components for targets and standards were analyzed in 29 subjects. We found no significant effects of electromagnetic field (EMF) irradiation on the amplitude and latency of the above ERP components. In order to study possible effects of EMF on attentional processes, we applied a wavelet-based time-frequency method to analyze the early gamma component of brain responses to auditory stimuli. We found that the early evoked gamma activity was insensitive to UMTS RF exposition. Our results support the notion, that a single 20 min irradiation from new generation 3G mobile phones does not induce measurable changes in latency or amplitude of ERP components or in oscillatory gamma-band activity in an auditory oddball paradigm.


Randomized Controlled Immunotherapy Clinical Trials for GBM Challenged.
Immunotherapies represent a promising strategy for glioblastoma multiforme (GBM) treatment. Different immunotherapies include the use of checkpoint inhibitors, adoptive cell therapies such as chimeric antigen receptor (CAR) T cells, and vaccines such as dendritic cell vaccines. Antibodies have also been used as toxin or radioactive particle delivery vehicles to eliminate target cells in the treatment of GBM. Oncolytic viral therapy and other immunogenic cell death-inducing treatments bridge the antitumor strategy with immunization and installation of immune control over the disease. These strategies should be included in the standard treatment protocol for GBM. Some immunotherapies are individualized in terms of the medicinal product, the immune target, and the immune tumor-host contact. Current individualized immunotherapy strategies focus on combinations of approaches. Standardization appears to be impossible in the face of complex controlled trial designs. To define appropriate control groups, stratification according to the Recursive Partitioning Analysis classification, MGMT promotor methylation, epigenetic GBM sub-typing, tumor microenvironment, systemic immune functioning before and after radiochemotherapy, and the need for/type of symptom-relieving drugs is required. Moreover, maintenance of a fixed treatment protocol for a dynamic, deadly cancer disease in a permanently changing tumor-host immune context might be inappropriate. This complexity is illustrated using our own data on individualized multimodal immunotherapies for GBM. Individualized medicines, including multimodal immunotherapies, are a rational and optimal yet also flexible approach to induce long-term tumor control. However, innovative methods are needed to assess the efficacy of complex individualized treatments and implement them more quickly into the general health system.


Comparative evaluation of shear bond strength of different bracket base designs in dry and wet environments.
One hundred and thirty five extracted premolars were selected and bonded with three types of brackets with different bracket base designs viz. Gemini (foil mesh), Miniature twin (Laser etched) and Mini Dynalocks (Integral base). These brackets were bonded with Transbond XT adhesive using two types of primers viz. Conventional Transbond XT in dry conditions and M.I.P in dry and wet environments. The specimens were tested for SBS using Instron machine at C.I.P.E.T. (Amritsar), Punjab. Results were statistically analyzed. The Miniature twin brackets revealed higher SBS values as compared to Gemini and Mini Dynalock in dry and wet conditions. All the groups showed higher SBS values in dry conditions as compared to wet conditions respectively. The Gemini and Mini Dynalock brackets showed very little difference of SBS values. Miniature twin brackets with laser etched bracket base in dry and wet environments have revealed the highest SBS values. All the groups have revealed clinically acceptable SBS value of above 8 MPa in moist conditions.


Ibotenic acid lesion of nucleus basalis magnocellularis differentially affects cholinergic, glutamatergic and GABAergic markers in cortical rat brain regions.
The present study was undertaken to study the effect of reduced cortical cholinergic activity on gamma-aminobutyric acid (GABA)ergic and glutamatergic mechanisms in cholinoceptive cortical target regions which are assumed to play an important role for realizing cognitive functions. The densities of cortical muscarinic cholinergic receptor subtypes and corresponding receptor genes m1 through m4, N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) and kainate glutamate receptor subtypes as well as GABAA and benzodiazepine receptors were measured in rats 1 week after unilateral ibotenic acid lesion of the nucleus basalis magnocellularis (Nbm) applying quantitative receptor autoradiography and in situ hybridization. Ibotenic acid lesion resulted in a striking loss of acetylcholinesterase (AChE) staining in the lesioned Nbm which is associated with a 60% decrease in AChE staining and a 30% reduction in [3H]hemicholinium-3 binding in frontal and parietal cortical regions as well fore- and hindlimb areas ipsilateral to the lesion, being more prominent in the more rostral cortical regions. M1-muscarinic cholinergic receptor binding was not changed in any of the cortical regions studied 1 week after lesion. M2-muscarinic receptor binding levels are slightly increased in the parietal cortex only. The lesion-induced increase in parietal cortical M2-muscarinic receptor binding is complemented by an increase in the hybridization signal for the corresponding m4-mRNA transcript. In cortical regions displaying a reduced activity of AChE and decreased levels of high-affinity choline uptake sites due to forebrain cholinergic lesion, NMDA receptor binding was markedly reduced in comparison to the unlesioned brain side whereas AMPA and kainate binding has been significantly increased in these regions. Muscimol binding to GABAA receptors was increased in the rostral portions of frontal and parietal cortices as compared with the unlesioned brain side. Binding levels of benzodiazepine receptors were not affected by the lesion in any of the cortical regions studied. The differential changes in glutamate and GABA receptor subtypes following lesion might be regarded as the consequence of a cortical reorganization compensating for the reduced cholinergic presynaptic input. The data further suggest that presynaptic cortical cholinergic deficits might affect both glutamatergic and GABAergic functions with different intensity and different directions.


Harnessing prions as test agents for the development of broad-range disinfectants.
The development of disinfectants with broad-range efficacy against bacteria, viruses, fungi, protozoa and prions constitutes an ongoing challenge. Prions, the causative agents of transmissible spongiform encephalopathies (TSEs) such as Creutzfeldt-Jakob disease (CJD) or its variant (vCJD) rank among the pathogens with the highest resistance to disinfection. Pilot studies have shown that procedures devised for prion disinfection were also highly effective against microbial pathogens. This fueled the idea to systematically exploit prions as test pathogens for the identification of new potential broad-range disinfectants. Prions essentially consist of misfolded, aggregated prion protein (PrP) and putatively replicate by nucleation-dependent, or seeded PrP polymerization. Recently, we have been able to establish PrP seeding activity as a quantitative in vitro indicator for the disinfection of 263K scrapie prions on steel wires used as surrogates for medical instruments. The seeding activity on wires re-processed in different disinfectants could be (1) biochemically determined by quantitative protein misfolding cyclic amplification (qPMCA), (2) biologically detected after qPMCA in a cell assay and (3) correctly translated into residual titres of scrapie infectivity. Our approach will substantially facilitate the identification of disinfectants with efficacy against prions as promising candidates for a further microbiological validation of broad-range activity.


Beyond existence and aiming outside the laboratory: estimating frequency-dependent and pay-off-biased social learning strategies.
The existence of social learning has been confirmed in diverse taxa, from apes to guppies. In order to advance our understanding of the consequences of social transmission and evolution of behaviour, however, we require statistical tools that can distinguish among diverse social learning strategies. In this paper, we advance two main ideas. First, social learning is diverse, in the sense that individuals can take advantage of different kinds of information and combine them in different ways. Examining learning strategies for different information conditions illuminates the more detailed design of social learning. We construct and analyse an evolutionary model of diverse social learning heuristics, in order to generate predictions and illustrate the impact of design differences on an organism's fitness. Second, in order to eventually escape the laboratory and apply social learning models to natural behaviour, we require statistical methods that do not depend upon tight experimental control. Therefore, we examine strategic social learning in an experimental setting in which the social information itself is endogenous to the experimental group, as it is in natural settings. We develop statistical models for distinguishing among different strategic uses of social information. The experimental data strongly suggest that most participants employ a hierarchical strategy that uses both average observed pay-offs of options as well as frequency information, the same model predicted by our evolutionary analysis to dominate a wide range of conditions.


European core curriculum in cariology for undergraduate dental students.
As dental caries prevalence is still high in many populations and groups of both children and adults worldwide, and as caries continues to be responsible for significant health, social and economic impacts, there is an urgent need for dental students to receive a systematic education in cariology based upon current best evidence. Although European curriculum guidelines for undergraduate students have been prepared in other dental fields over the last decade, none exist for cariology. Thus the European Organisation for Caries Research (ORCA) formed a task force to work with the Association of Dental Education in Europe (ADEE) on a European Core Curriculum in Cariology. In 2010, a workshop to develop such a curriculum was organised in Berlin, Germany, with 75 participants from 24 European and 3 North-South American countries. The Curriculum was debated by five pre-identified working groups: I The Knowledge Base; II Risk Assessment, Diagnosis and Synthesis; III Decision-making and Preventive Non-surgical Therapy; IV Decision-making and Surgical Therapy; and V Evidence-based Cariology in Clinical and Public Health Practice and then finalised jointly by the group chairs. According to this Curriculum, on graduation, a dentist must be competent at applying knowledge and understanding of the biological, medical, basic and applied clinical sciences in order to recognise caries and make decisions about its prevention and management in individuals and populations. This document, which presents several major and numerous supporting competences, does not confine itself to dental caries alone, but refers also to dental erosion/non-erosive wear and other dental hard tissue disorders.


Insertion and pore formation driven by adsorption of proteins onto lipid bilayer membrane-water interfaces.
We describe the binding of proteins to lipid bilayers in the case for which binding can occur either by adsorption to the lipid bilayer membrane-water interface or by direct insertion into the bilayer itself. We examine in particular the case when the insertion and pore formation are driven by the adsorption process using scaled particle theory. The adsorbed proteins form a two-dimensional "surface gas" at the lipid bilayer membrane-water interface that exerts a lateral pressure on the lipid bilayer membrane. Under conditions of strong intrinsic binding and a high degree of interfacial converge, this pressure can become high enough to overcome the energy barrier for protein insertion. Under these conditions, a subtle equilibrium exists between the adsorbed and inserted proteins. We propose that this provides a control mechanism for reversible insertion and pore formation of proteins such as melittin and magainin. Next, we discuss experimental data for the binding isotherms of cytochrome c to charged lipid membranes in the light of our theory and predict that cytochrome c inserts into charged lipid bilayers at low ionic strength. This prediction is supported by titration calorimetry results that are reported here. We were furthermore able to describe the observed binding isotherms of the pore-forming peptides endotoxin (alpha 5-helix) and of pardaxin to zwitterionic vesicles from our theory by assuming adsorption/insertion equilibrium.


miR-21-3p inhibits autophagy of bovine granulosa cells by targeting VEGFA via PI3K/AKT signaling.
It is well documented that granulosa cell apoptosis is the main reason for follicular atresia and death; however, increasing evidence suggests that autophagy plays an important role in the fate of granulosa cells. miR-21-3p regulates many fundamental biological processes and is pivotal in the autophagy of tumor cells; nevertheless, the autophagy in cattle ovary and how miR-21-3p regulates the follicular cells is unknown. In this study, we aimed to elucidate the autophagy and the role of miR-21-3p in cattle ovary using bovine primary ovarian granulosa cells (BGCs). The results showed the autophagy for the first time in BGCs in large follicle according to autophagic gene transcript of LC3, BECN-1, ATG3, protein expression of LC3, P62 and LC3 puncta, a standard marker for autophagosomes. miR-21-3p was identified as a novel miRNA that repressed BGCs autophagy according to the results from plasmids transfection of miR-21-3p mimics and inhibitor. Meanwhile, VEGFA was confirmed to be a validated target of miR-21-3p in BGCs using luciferase reporter assays and the results of VEGFA expression decreased with transfection of miR-21-3p mimics, while it increased with transfection of miR-21-3p inhibitor. In addition, small interference-mediated knockdown of VEGFA significantly inhibits BGCs autophagy signaling; however, overexpression of VEGFA in BGCs promoted autophagy in the presence of miR-21-3p. Finally, the results of AKT and its phosphorylation suggested that miR-21-3p suppressed VEGFA expression through downregulating AKT phosphorylation signaling. In summary, this study demonstrates that miR-21-3p inhibits BGCs autophagy by targeting VEGFA and attenuating PI3K/AKT signaling.


A strategic screening approach to identify transformation products of organic micropollutants formed in natural waters.
Many transformation products (TPs) from organic micropollutants are not included in routine environmental monitoring programs due to limited knowledge of their occurrence and fate. An efficient method to identify and prioritize critical compounds in terms of environmental relevance is needed. In this study, we applied a strategic screening approach based on a case-control concept to identify TPs formed along wastewater-impacted rivers. Time-integrated samples were collected over one week at both ends of a river stretch downstream of a wastewater treatment plant (WWTP) outfall and were analyzed by ultrahigh performance liquid chromatography interfaced with quadrupole time-of-flight mass spectrometry (UHPLC-QToF-MS/MS). The screening procedure of the high-resolution MS (HRMS) datasets consisted of three major steps: (i) screening for parent compounds (PCs) attenuated along the stretch; (ii) prediction of potential TPs from these PCs; and (iii) screening for TPs from this list with an increasing trend along the stretch. In total, 32 PCs decreased along the investigated river stretches. From these PCs, eight TPs had increasing concentrations along the studied stretches and could be tentatively identified. The identification of one TP (benzamide) was confirmed by its corresponding reference standard, while no standards were available for the remaining TPs.


COCO-CL: hierarchical clustering of homology relations based on evolutionary correlations.
Determining orthology relations among genes across multiple genomes is an important problem in the post-genomic era. Identifying orthologous genes can not only help predict functional annotations for newly sequenced or poorly characterized genomes, but can also help predict new protein-protein interactions. Unfortunately, determining orthology relation through computational methods is not straightforward due to the presence of paralogs. Traditional approaches have relied on pairwise sequence comparisons to construct graphs, which were then partitioned into putative clusters of orthologous groups. These methods do not attempt to preserve the non-transitivity and hierarchic nature of the orthology relation. We propose a new method, COCO-CL, for hierarchical clustering of homology relations and identification of orthologous groups of genes. Unlike previous approaches, which are based on pairwise sequence comparisons, our method explores the correlation of evolutionary histories of individual genes in a more global context. COCO-CL can be used as a semi-independent method to delineate the orthology/paralogy relation for a refined set of homologous proteins obtained using a less-conservative clustering approach, or as a refiner that removes putative out-paralogs from clusters computed using a more inclusive approach. We analyze our clustering results manually, with support from literature and functional annotations. Since our orthology determination procedure does not employ a species tree to infer duplication events, it can be used in situations when the species tree is unknown or uncertain. firstname.lastname@example.com, email@example.com Supplementary materials are available at Bioinformatics online.


Risk factors for chronic kidney disease: an update.
Chronic kidney disease has become a serious public health issue. There are currently over 1.4 million patients receiving renal replacement therapy worldwide. One way to reduce the economic burden of chronic kidney disease would be early intervention. In order to achieve this, we should be able to identify individuals with increased risk of renal disease. An individual's genetic and phenotypic make-up puts him/her at risk for kidney disease. Factors such as race, gender, age, and family history are highly important. For instance, being of African-American decent, older age, low birth weight and family history of kidney disease are considered to be strong risk factors for chronic kidney disease. Moreover, smoking, obesity, hypertension, and diabetes mellitus can also lead to kidney disease. An uncontrolled diabetic and/or hypertensive patient can easily and quickly progress to an end-stage kidney disease patient. Exposure to heavy metals, excessive alcohol consumption, smoking, and the use of analgesic medications also constitute risks. Experiencing acute kidney injury, a history of cardiovascular disease, hyperlipidemia, metabolic syndrome, hepatitis C virus, HIV infection, and malignancy are further risk factors. Determination of serum creatinine levels and urinalysis in patients with chronic kidney disease risk will usually be sufficient for initial screening.


Endocannabinoid Signaling in Autism.
Autism spectrum disorder (ASD) is a complex behavioral condition with onset during early childhood and a lifelong course in the vast majority of cases. To date, no behavioral, genetic, brain imaging, or electrophysiological test can specifically validate a clinical diagnosis of ASD. However, these medical procedures are often implemented in order to screen for syndromic forms of the disorder (i.e., autism comorbid with known medical conditions). In the last 25 years a good deal of information has been accumulated on the main components of the "endocannabinoid (eCB) system", a rather complex ensemble of lipid signals ("endocannabinoids"), their target receptors, purported transporters, and metabolic enzymes. It has been clearly documented that eCB signaling plays a key role in many human health and disease conditions of the central nervous system, thus opening the avenue to the therapeutic exploitation of eCB-oriented drugs for the treatment of psychiatric, neurodegenerative, and neuroinflammatory disorders. Here we present a modern view of the eCB system, and alterations of its main components in human patients and animal models relevant to ASD. This review will thus provide a critical perspective necessary to explore the potential exploitation of distinct elements of eCB system as targets of innovative therapeutics against ASD.


Skin color-based video segmentation under time-varying illumination.
A novel approach for real-time skin segmentation in video sequences is described. The approach enables reliable skin segmentation despite wide variation in illumination during tracking. An explicit second order Markov model is used to predict evolution of the skin-color (HSV) histogram over time. Histograms are dynamically updated based on feedback from the current segmentation and predictions of the Markov model. The evolution of the skin-color distribution at each frame is parameterized by translation, scaling, and rotation in color space. Consequent changes in geometric parameterization of the distribution are propagated by warping and resampling the histogram. The parameters of the discrete-time dynamic Markov model are estimated using Maximum Likelihood Estimation and also evolve over time. The accuracy of the new dynamic skin color segmentation algorithm is compared to that obtained via a static color model. Segmentation accuracy is evaluated using labeled ground-truth video sequences taken from staged experiments and popular movies. An overall increase in segmentation accuracy of up to 24 percent is observed in 17 out of 21 test sequences. In all but one case, the skin-color classification rates for our system were higher, with background classification rates comparable to those of the static segmentation.


Comprehensive analysis of microRNA expression in regionalized human neural progenitor cells reveals microRNA-10 as a caudalizing factor.
MicroRNAs (miRNAs) have been implicated in regulating multiple processes during brain development in various species. However, the function of miRNAs in human brain development remains largely unexplored. Here, we provide a comprehensive analysis of miRNA expression of regionalized neural progenitor cells derived from human embryonic stem cells and human foetal brain. We found miR-92b-3p and miR-130b-5p to be specifically associated with neural progenitors and several miRNAs that display both age-specific and region-specific expression patterns. Among these miRNAs, we identified miR-10 to be specifically expressed in the human hindbrain and spinal cord, while being absent from rostral regions. We found that miR-10 regulates a large number of genes enriched for functions including transcription, actin cytoskeleton and ephrin receptor signalling. When overexpressed, miR-10 influences caudalization of human neural progenitor cells. Together, these data confirm a role for miRNAs in establishing different human neural progenitor populations. This dataset also provides a comprehensive resource for future studies investigating the functional role of different miRNAs in human brain development.


Allogenic mesenchymal stem cells transplantation in refractory systemic lupus erythematosus: a pilot clinical study.
To determine the safety and efficacy of allogeneic mesenchymal stem cell transplantation (MSCT) in refractory systemic lupus erythematosus (SLE). A total of 15 patients with persistently active SLE underwent MSCT. Outcome was evaluated by changes in the SLE disease activity index (SLEDAI), serological features (anti-nuclear antibodies and anti-double-stranded DNA (anti-dsDNA)), renal function and percentage of peripheral blood regulatory T cells. From 11 March 2007 to 4 November 2008, 15 patients with persistently active SLE were enrolled and underwent MSCT. The mean follow-up period was 17.2+/-9.5 months. A total of 13 patients have been followed for more than 12 months. All patients clinically improved following treatment with mesenchymal stem cells with a marked decrease in the SLEDAI score and 24 h proteinuria. At 12-month follow-up, SLEDAI scores decreased from 12.2+/-3.3 to 3.2+/-2.8 and proteinuria decreased from 2505.0+/-1323.9 to 858.0+/-800.7 mg/24 h (all p<0.05, by paired t test, n=12). At 1-year follow-up in 13 patients, 2 had a relapse of proteinuria, while the other 11 continue to have decreased disease activity on minimal treatment. Anti-dsDNA levels decreased. Improvement in glomerular filtration rate was noted in two patients in which formal testing was performed. Non-renal-related manifestations also improved significantly. No serious adverse events were reported. Allogeneic MSCT in patients with refractory lupus resulted in amelioration of disease activity, improvement in serological markers and stabilisation of renal function. MSCT appears beneficial in treatment of patients with SLE refractory to conventional treatment options.


Human immunodeficiency virus type 1 protease regulation of tat activity is essential for efficient reverse transcription and replication.
The human immunodeficiency virus type 1 (HIV-1) Tat protein enhances reverse transcription, but it is not known whether Tat acts directly on the reverse transcription complex or through indirect mechanisms. Since processing of Tat by HIV protease (PR) might mask its presence and, at least in part, explain this lack of data, we asked whether Tat can be cleaved by PR. We used a rabbit reticulocyte lysate (RRL) system to make Tat and PR. HIV-1 PR is expressed as a Gag-Pol fusion protein, and a PR-inactivated Gag-Pol is also expressed as a control. We showed that Tat is specifically cleaved in the presence of PR, producing a protein of approximately 5 kDa. This result suggested that the cleavage site was located in or near the Tat basic domain (amino acids 49 to 57), which we have previously shown to be important in reverse transcription. We created a panel of alanine-scanning mutations from amino acids 45 to 54 in Tat and evaluated functional parameters, including transactivation, reverse transcription, and cleavage by HIV-1 PR. We showed that amino acids 49 to 52 (RKKR) are absolutely required for Tat function in reverse transcription, that mutation of this domain blocks cleavage by HIV-1 PR, and that other pairwise mutations in this region modulate reverse transcription and proteolysis in strikingly similar degrees. Mutation of Tat Y47G48 to AA also down-regulated Tat-stimulated reverse transcription but had little effect on transactivation or proteolysis by HIV PR, suggesting that Y47 is critical for reverse transcription. We altered the tat gene of the laboratory strain NL4-3 to Y47D and Y47N so that overlapping reading frames were not affected and showed that Y47D greatly diminished virus replication and conveyed a reverse transcription defect. We hypothesize that a novel, cleaved form of Tat is present in the virion and that it requires Y47 for its role in support of efficient reverse transcription.