Effects of ambient oxygen and size-selective mortality on growth and maturation in guppies.
Growth, onset of maturity and investment in reproduction are key traits for understanding variation in life-history strategies. Many environmental factors affect variation in these traits, but for fish, hypoxia and size-dependent mortality have become increasingly important because of human activities, such as increased nutrient enrichment (eutrophication), climate warming and selective fishing. Here, we study experimentally the effect of oxygen availability on maturation and growth in guppies (Poecilia reticulata) from two different selected lines, one subjected to positive and the other negative size-dependent fishing. This is the first study to assess the effects of both reduced ambient oxygen and size-dependent mortality in fish. We show that reduced ambient oxygen led to stunting, early maturation and high reproductive investment. Likewise, lineages that had been exposed to high mortality of larger-sized individuals displayed earlier maturation at smaller size, greater investment in reproduction and faster growth. These life-history changes were particularly evident for males. The widely reported trends towards earlier maturation in wild fish populations are often interpreted as resulting from size-selective fishing. Our results highlight that reduced ambient oxygen, which has received little experimental investigation to date, can lead to similar phenotypic changes. Thus, changes in ambient oxygen levels can be a confounding factor that occurs in parallel with fishing, complicating the causal interpretation of changes in life-history traits. We believe that better disentangling of the effects of these two extrinsic factors, which increasingly affect many freshwater and marine ecosystems, is important for making more informed management decisions.


The context of HLA-DR/CD18 complex in the plasma membrane governs HLA-DR-derived signals in activated monocytes.
HLA-DR-derived signals in activated monocytes mediate both pro-inflammatory cytokine production and caspase-independent death, and have been postulated to play a role in inflammation and in its resolution, respectively. Herein, using the monocytic/macrophagic human cell line THP-1 primed with IFNgamma (IFNgamma-primed THP-1), we investigated how HLA-DR may integrate both signals. Our inhibition studies demonstrated that if cell death is dependent on PKCbeta activation, the induction of TNFalpha gene expression relies on PTK activation, in particular the Src family of kinases, but both cell responses implicate the beta2-integrin CD18. Accordingly, sequential immunoprecipitation experiments demonstrated that following engagement of HLA-DR on IFNgamma-primed THP-1 cells, the HLA-DR/CD18 complex physically associates with PKCbeta and with PTK. Pharmacological disruption of lipid rafts microdomains abolished the assembly of HLA-DR/CD18/PTK signaling complex, HLA-DR-mediated tyrosine activation, and the PTK-dependent TNFalpha expression in IFNgamma-primed THP-1 cells. In contrast, HLA-DR/CD18/PKCbeta complex was still formed and able to mediate cell death after cholesterol depletion of these cells. These results indicate that while the integrity of lipid rafts is necessary for the transduction of cytokine gene expression through the HLA-DR/CD18 complex, it is not necessary for the induction of the HLA-DR/CD18-dependent cell death. Thus, our study provides experimental evidence indicating the compartmentalization of HLA-DR/CD18 complex within or outside lipid rafts as a mechanism through which HLA-DR can integrate both PTK and PKCbeta signals leading to activation and death, respectively, of activated monocytes. This might provide new insights into how MHC class II signaling may regulate inflammatory response.


Polarization properties of polymer-dispersed liquid-crystal film with small nematic droplets.
The polarization state of light transmitted through a polymer-dispersed liquid-crystal film with small, spherical, nonabsorbing, partially oriented nematic droplets is theoretically investigated. The model used is based on the effective medium approach. Scattering properties of a single droplet are described by the Rayleigh-Gans approximation. Propagation of coherent light is described within the framework of the Twersky theory. To describe the orientation of liquid-crystal molecules inside droplets and liquid-crystal droplets in a sample, the concept of multilevel order parameters is employed. Conditions for circular and linear polarization of the transmitted light are determined and investigated.


Benchmarking calving management practices on western Canada cow-calf operations.
Benchmarking current calving management practices and herd demographics in the western Canadian cow-calf production system helps to fill the gap in knowledge and understanding of how this production system works. Further investigation into the relationships between management decisions and calf health may guide the development of management practices and protocols to improve calf health, especially in compromised calves after a difficult birth. Therefore, the objectives of this cross-sectional study were to describe current calving management practices on western Canadian cow-calf ranches and to investigate the association of herd demographics with herd-level incidence of calving assistance, morbidity, mortality, and use of calving and colostrum management practices. Cow-calf producers were surveyed in January 2017 regarding herd inventory and management practices during the 2016 calving season. Ninety-seven of 110 producers enrolled in the western Canadian Cow-Calf Surveillance Network responded. Average herd-level incidence of assisted calvings was 4.9% (13.5% heifers, 3.2% cows), stillbirths was 2.1% (3.3% heifers, 1.9% cows), preweaning mortality was 4.5%, and preweaning treatment for disease was 9.4% (3.0% neonatal calf diarrhea, 3.8% bovine respiratory disease, 2.6% other diseases). Greater than 90% of producers assisted calvings and would intervene with colostrum consumption if the calf did not appear to have nursed from its dam. Late calving herds (i.e., started calving in March or later) had significantly lower average herd-level incidence of assistance, treatment for disease, and mortality (P < 0.05). In earlier calving herds (i.e., started calving in January or February) producers had shorter intervals between checking on dams for signs of calving or intervening to assist with a calving (P < 0.05). In early calving herds, producers were more likely to perform hands-on colostrum management techniques such as placing the cow and calf together or feeding stored, frozen colostrum (P < 0.05). There were no associations between herd size and herd-level incidences or management techniques (P > 0.05). This study suggests that in western Canada earlier calving herds are more intensively managed, whereas later calving herds are more extensively managed. Herd demographics may be important to consider when investigating factors associated with management strategies, health, and productivity in cow-calf herds.


Identification of HLA-DR alpha chain residues critical for binding of the toxic shock syndrome toxin superantigen.
Staphylococcal toxic shock syndrome toxin 1 (TSST-1) binds to major histocompatibility complex class II molecules, and the toxin-class II complexes induce proliferation of T cells expressing V beta 2 sequences. To define the residues involved in TSST-1 binding, a set of transfectants expressing 21 HLA-DR alpha chain mutants were analyzed for their abilities to bind and present TSST-1 and to present an antigenic peptide. Mutations at DR alpha positions 36 and 39 markedly decreased the ability of the DR7 molecule to bind and present TSST-1 but did not affect the ability to present an antigenic peptide. These data indicate that DR alpha residues 36 and 39, predicted to be located on an outer loop, are important in the formation of the TSST-1 binding site on DR molecules.


Using routine intelligence to target inspection of healthcare providers in England.
The Healthcare Commission, the national regulator for the National Health Service in England, has to assess providers (NHS trusts) on compliance with core standards in a way that targets appropriate local inspection resources. To develop and evaluate a system for targeting inspections in 2006 of 44 standards in 567 healthcare organisations. A wide range of available information was structured as a series of indicators (called items) that mapped to the standards. Each item was scored on a common scale (a modified Z-score), and these scores were aggregated to indicate risks of undeclared non-compliance for all trusts and standards. In addition, local qualitative intelligence was coded and scored. The information sets used comprised 463 875 observations structured in 1689 specific items, drawn from 83 different data streams. Follow-up inspections were undertaken on the 10% of trusts with the highest-risk scores (where the trust had declared compliance with a standard) and an additional 10% of trusts randomly selected from the remainder. The success of the targeting was measured by the number of trust declarations that were "qualified" following inspection. In the risk-based sample, the proportion of inspected standards that were qualified (26%) was significantly higher than in the random sample (13%). The success rate for targeting varied between standards and care sectors. This innovative approach to using information to target inspection activity achieved its overall aims. The method worked better for some standards and in some settings than for others, and is being improved in the light of experience gained. Such applications are increasingly important as modern regulators strive to be targeted and proportionate in their activities.


Hepatic arterial mapping by multidetector computed tomographic angiography in living donor liver transplantation.
Our aims were to present the hepatic arterial variations that were detected with computed tomographic angiography (CTA) and confirmed by operation in living liver donors and to emphasize the usefulness of CTA in the assessment of hepatic arterial anatomy. The donors of 100 patients (46 women and 54 men) who had undergone a living donor liver transplantation in a (blinded) hospital between July 2004 and June 2007 were evaluated. The age of the donors ranged from 18 to 63 years (mean, 39 years). The CTA images obtained by a 16-slice multidetector CT before the transplantation procedure were retrospectively evaluated for arterial variations, and the results were compared with the results of the operation. In 59 donors (59%), classic hepatic arterial anatomy was observed. In the remaining 41 donors (41%), various arterial variations were determined. In 11 of the donors (11%), variations were not compatible with the description of Michel's classification. In all of our patients, CTA findings were confirmed with operational findings. Our complication rate was 1%. Only 1 of the patients who had undergone the transplantation developed hepatic arterial thrombus, and the remaining 99 patients had no arterial complications. The course of the vascular structures before live donor liver transplantation is essential for planning and success of the operation. Our study showed that multidetector CTA can be used successfully in hepatic artery imaging of liver transplantation donors as a noninvasive method.


Genomics and future biological weapons: the need for preventive action by the biomedical community.
There is an increasing concern within both the scientific and security communities that the ongoing revolution in biology has great potential to be misused in offensive biological weapons programs. In light of the 11 September tragedy, we can no longer afford to be complacent about the possibility of biological terrorism. Here we review the major relevant trends in genomics research and development, and discuss how these capabilities might be misused in the design of new bioweapons. We also discuss how the breakthroughs that have come from the genomics revolution may be used to enhance detection, protection and treatment so that biological warfare agents are never used.


Multiplexed massively parallel SELEX for characterization of human transcription factor binding specificities.
The genetic code-the binding specificity of all transfer-RNAs--defines how protein primary structure is determined by DNA sequence. DNA also dictates when and where proteins are expressed, and this information is encoded in a pattern of specific sequence motifs that are recognized by transcription factors. However, the DNA-binding specificity is only known for a small fraction of the approximately 1400 human transcription factors (TFs). We describe here a high-throughput method for analyzing transcription factor binding specificity that is based on systematic evolution of ligands by exponential enrichment (SELEX) and massively parallel sequencing. The method is optimized for analysis of large numbers of TFs in parallel through the use of affinity-tagged proteins, barcoded selection oligonucleotides, and multiplexed sequencing. Data are analyzed by a new bioinformatic platform that uses the hundreds of thousands of sequencing reads obtained to control the quality of the experiments and to generate binding motifs for the TFs. The described technology allows higher throughput and identification of much longer binding profiles than current microarray-based methods. In addition, as our method is based on proteins expressed in mammalian cells, it can also be used to characterize DNA-binding preferences of full-length proteins or proteins requiring post-translational modifications. We validate the method by determining binding specificities of 14 different classes of TFs and by confirming the specificities for NFATC1 and RFX3 using ChIP-seq. Our results reveal unexpected dimeric modes of binding for several factors that were thought to preferentially bind DNA as monomers.


Policy opportunities and limitations of evidence-based planning for immunization: lessons learnt from a field trial in Bangladesh.
Despite success in scaling up immunization, the national immunization programme in Bangladesh remains challenged by persisting inequities in health access related to geographic location and social factors, including income and education status. In order to tackle these inequities in access, the national immunization programme has conducted a field trial of the evidence-based planning model in Bangladesh between 2011 and 2013, in 11 low-performing districts and 3 city corporations. The main elements of this intervention included bottleneck analysis in local areas, action planning and budgeting to correct the bottlenecks, and establishment of a monitoring system to track progress. Coverage improved in 8 out of 14 districts post intervention. The main success factors associated with the intervention included more analytic approaches to situation assessment and taking action on health inequities at the local level, as well as more considered use of local data to track immunization drop-outs. The main factors associated with coverage declines in trial areas (6 districts) included poor financial resourcing and supervisory support, and gaps and turnover in human resources. In order to sustain and improve coverage, it will be necessary in future to link pro-equity approaches to subdistrict planning to higher-level health-system-strengthening strategy and planning systems. This will ensure that local area planners have the required resources, comprehensive operational plans and political support to sustain implementation of corrective actions to address identified system bottlenecks and inequities in health access at the local level.


Ocular neuromyotonia: clinical features, physiological mechanisms, and response to therapy.
Ocular neuromyotonia (ONM) is a rare disorder characterized by episodic diplopia, occurring either spontaneously or following sustained eccentric gaze. Most patients have had prior radiation therapy to the sellar and parasellar region. ONM is thought to reflect impaired muscle relaxation due to inappropriate discharges from oculomotor, trochlear, or abducens neurons or axons with unstable cell membranes. Patients with ONM often benefit from membrane stabilizing agents such as carbamazepine. Here we describe a 71-year-old man, with no history of radiation therapy, who for 18 months had had transient episodic diplopia that occurred after down gaze. Clinical examination indicated ONM in muscles supplied by the right oculomotor nerve. Binocular scleral search coil eye movement recordings revealed a defect not only of muscle relaxation but also of maximal muscle contraction. The patient was treated with carbamazepine 200 mg per day with complete resolution of his symptoms. ONM may be more common than previously recognized, and patients with unexplained transient episodic diplopia should be specifically tested for diplopia and ocular misalignment following sustained eccentric gaze.


SFPQ promotes an oncogenic transcriptomic state in melanoma.
The multifunctional protein, splicing factor, proline- and glutamine-rich (SFPQ) has been implicated in numerous cancers often due to interaction with coding and non-coding RNAs, however, its role in melanoma remains unclear. We report that knockdown of SFPQ expression in melanoma cells decelerates several cancer-associated cell phenotypes, including cell growth, migration, epithelial to mesenchymal transition, apoptosis, and glycolysis. RIP-seq analysis revealed that the SFPQ-RNA interactome is reprogrammed in melanoma cells and specifically enriched with key melanoma-associated coding and long non-coding transcripts, including SOX10, AMIGO2 and LINC00511 and in most cases SFPQ is required for the efficient expression of these genes. Functional analysis of two SFPQ-enriched lncRNA, LINC00511 and LINC01234, demonstrated that these genes independently contribute to the melanoma phenotype and a more detailed analysis of LINC00511 indicated that this occurs in part via modulation of the miR-625-5p/PKM2 axis. Importantly, analysis of a large clinical cohort revealed that elevated expression of SFPQ in primary melanoma tumours may have utility as a prognostic biomarker. Together, these data suggest that SFPQ is an important driver of melanoma, likely due to SFPQ-RNA interactions promoting the expression of numerous oncogenic transcripts.


Mediastinal lymph node enlargement in idiopathic pulmonary fibrosis: relationships with disease progression and pulmonary function trends.
Evidence of mediastinal Lymph Node Enlargement (LNE) on CT scan is a common finding in idiopathic pulmonary fibrosis (IPF). We sought to investigate whether the involvement of mediastinal lymph nodes is associated with accelerated disease progression, and explored the changes occurring in mediastinal lymph nodes during the radiological follow up of these patients. This retrospective study included IPF patients referred to a single ILD centre in Italy. A consensus-based assessment of mediastinal LNE on chest CT scan was performed by two thoracic radiologists. Kaplan-Meier curves and multivariate Cox proportional hazards regression were used to assess hazard ratios for mortality and disease progression (defined as categorical FVC decline ≥10%). The annualized rates of change in functional parameters for each patient were calculated using mixed linear models. The study population consisted of 152 IPF patients, of whom 135 (89%) received antifibrotic treatment for IPF during the study follow up. Patients having evidence of 3 or more enlarged mediastinal lymph nodes on baseline CT scan showed increased rates of mortality (HR 5.03, 95% CI 1.86-13.62, p ≤ 0.001) and significant disease progression (HR 2.99, 95% CI 1.22-7.33, p = 0.17) as compared to patients without LNE, after adjusting for GAP stage. Among 62 patients with LNE who underwent a follow up CT scan of the chest and received antifibrotic treatment, 57 (92%) maintained evidence mediastinal LNE over time. Diffuse mediastinal lymph node involvement predicts clinically meaningful functional deterioration in patients with IPF.


Regulation of the infraabdominal regions of the bithorax complex of Drosophila by gap genes.
The expression of the abdominal-A and Abdominal-B genes of the bithorax complex of Drosophila is controlled by cis-regulatory infraabdominal regions. The activation of these regions along the anteroposterior axis of the embryo determines where abdominal-A and Abdominal-B are transcribed. There is spatially restricted transcription of the infraabdominal regions (infraabdominal transcripts) that may reflect this specific activation. We show that the gap genes hunchback, Krüppel, tailless and knirps control abdominal-A and Abdominal-B expression early in development. The restriction of abdominal-A and Abdominal-B transcription is preceded by (and requires) the spatially localized activation of regulatory regions, which can be detected by the distribution of infraabdominal transcripts. The activation of these regions (except the infraabdominal-8 one) could require no specific gap gene. Instead, a general mechanism of activation, combined with repression by gap genes in the anteroposterior axis, seems to be responsible for delimiting infraabdominal active domains. The gradients of the hunchback and Krüppel products seem to be key elements in this restricted activation.


High and far: biases in the location of protected areas.
About an eighth of the earth's land surface is in protected areas (hereafter "PAs"), most created during the 20(th) century. Natural landscapes are critical for species persistence and PAs can play a major role in conservation and in climate policy. Such contributions may be harder than expected to implement if new PAs are constrained to the same kinds of locations that PAs currently occupy. Quantitatively extending the perception that PAs occupy "rock and ice", we show that across 147 nations PA networks are biased towards places that are unlikely to face land conversion pressures even in the absence of protection. We test each country's PA network for bias in elevation, slope, distances to roads and cities, and suitability for agriculture. Further, within each country's set of PAs, we also ask if the level of protection is biased in these ways. We find that the significant majority of national PA networks are biased to higher elevations, steeper slopes and greater distances to roads and cities. Also, within a country, PAs with higher protection status are more biased than are the PAs with lower protection statuses. In sum, PAs are biased towards where they can least prevent land conversion (even if they offer perfect protection). These globally comprehensive results extend findings from nation-level analyses. They imply that siting rules such as the Convention on Biological Diversity's 2010 Target [to protect 10% of all ecoregions] might raise PA impacts if applied at the country level. In light of the potential for global carbon-based payments for avoided deforestation or REDD, these results suggest that attention to threat could improve outcomes from the creation and management of PAs.


Data-driven identification of complex disease phenotypes.
Disease interaction in multimorbid patients is relevant to treatment and prognosis, yet poorly understood. In the present work, we combine approaches from network science, machine learning and computational phenotyping to assess interactions between two or more diseases in a transparent way across the full diagnostic spectrum. We demonstrate that health states of hospitalized patients can be better characterized by including higher-order features capturing interactions between more than two diseases. We identify a meaningful set of higher-order diagnosis features that account for synergistic disease interactions in a population-wide (N = 9 M) medical claims dataset. We construct a generalized disease network where (higher-order) diagnosis features are linked if they predict similar diagnoses across the whole diagnostic spectrum. The fact that specific diagnoses are generally represented multiple times in the network allows for the identification of putatively different disease phenotypes that may reflect different disease aetiologies. At the example of obesity, we demonstrate the purely data-driven detection of two complex phenotypes of obesity. As indicated by a matched comparison between patients having these phenotypes, we show that these phenotypes show specific characteristics of what has been controversially discussed in the medical literature as metabolically healthy and unhealthy obesity, respectively. The findings also suggest that metabolically healthy patients show some progression towards more unhealthy obesity over time, a finding that is consistent with longitudinal studies indicating a transient nature of metabolically healthy obesity. The disease network is available for exploration at https://disease.network/.


An overview on the field of micro- and nanotechnologies for synthetic Peptide-based vaccines.
The development of synthetic peptide-based vaccines has many advantages in comparison with vaccines based on live attenuated organisms, inactivated or killed organism, or toxins. Peptide-based vaccines cannot revert to a virulent form, allow a better conservation, and are produced more easily and safely. However, they generate a weaker immune response than other vaccines, and the inclusion of adjuvants and/or the use of vaccine delivery systems is almost always needed. Among vaccine delivery systems, micro- and nanoparticulated ones are attractive, because their particulate nature can increase cross-presentation of the peptide. In addition, they can be passively or actively targeted to antigen presenting cells. Furthermore, particulate adjuvants are able to directly activate innate immune system in vivo. Here, we summarize micro- and nanoparticulated vaccine delivery systems used in the field of synthetic peptide-based vaccines as well as strategies to increase their immunogenicity.


Pharmacological targeting of peptidylarginine deiminase 4 prevents cancer-associated kidney injury in mice.
Renal insufficiency is a frequent cancer-associated problem affecting more than half of all cancer patients at the time of diagnosis. To minimize nephrotoxic effects the dosage of anticancer drugs are reduced in these patients, leading to sub-optimal treatment efficacy. Despite the severity of this cancer-associated pathology, the molecular mechanisms, as well as therapeutic options, are still largely lacking. We here show that formation of intravascular tumor-induced neutrophil extracellular traps (NETs) is a cause of kidney injury in tumor-bearing mice. Analysis of clinical biomarkers for kidney function revealed impaired creatinine clearance and elevated total protein levels in urine from tumor-bearing mice. Electron microscopy analysis of the kidneys from mice with cancer showed reversible pathological signs such as mesangial hypercellularity, while permanent damage such as fibrosis or necrosis was not observed. Removal of NETs by treatment with DNase I, or pharmacological inhibition of the enzyme peptidylarginine deiminase 4 (PAD4), was sufficient to restore renal function in mice with cancer. Tumor-induced systemic inflammation and impaired perfusion of peripheral vessels could be reverted by the PAD4 inhibitor. In conclusion, the current study identifies NETosis as a previously unknown cause of cancer-associated renal dysfunction and describes a novel promising approach to prevent renal failure in individuals with cancer.


Thermoelectric properties of Se and Zn/Cd/Sn double substituted Co4Sb12 skutterudite compounds.
Double-doped skutterudite Co4Sb12 compounds are reported as a good n-type thermoelectric system which operate in the mid-temperature range. Instead of filling the skutterudite phase to minimize the thermal conductivity, it is proposed to induce disorder in the pnicogen rings by the substitution of Zn/Cd/Sn and Se. Structural analyses of the prepared compounds were carried out by Rietveld refinement process. The compounds show overall reduction in thermal conductivity, particularly the lattice part. Since vibration modes of heat-carrying phonons predominantly fall within the frequency range of the pnicogen rings, double substitutions on those pnicogen rings are particularly helpful in distracting the thermal transport. As larger mass difference and strain fluctuations can more efficiently scatter the heat-carrying phonons through short mean free path, it drastically restrains the thermal transport of the compounds, and this effect has been successfully demonstrated using the Debye-Callaway-Klemens model. Smooth electrical transport behavior is observed in all the samples and the power factor values are quite comparable to reported values. Phonon scattering mechanism and local distortion in the structure of the compounds is also evaluated by Raman analysis. Collectively, a high peak ZT of ∼0.7 and ∼0.65 at 673 K is obtained for Co4Sb11.86Se0.1Zn0.04 and Co4Sb11.86Se0.1Sn0.04 compounds which shows more than 50% enhancement relative to the pristine Co4Sb12 system.


Preferences of Canadian Patients and Physicians for Treatment of HR+/HER2- Advanced Breast Cancer.
(1) Background: Past research suggests that patients with advanced breast cancer prefer treatments with improved clinical outcomes and lower risk of side effects. Evidence on preferences of Canadian patients and physicians for treatments for advanced breast cancer is limited. (2) Methods: Patients' and physicians' preferences for treatments for HR+/HER2-, pre-/peri-menopausal advanced breast cancer were assessed by an online discrete choice experiment (DCE). Treatment alternatives were characterized by seven attributes regarding dosing, efficacy, and toxicities, with levels corresponding to those for ribociclib plus a non-steroidal aromatase inhibitor (NSAI), NSAI, and tamoxifen. For patients, impacts of advanced breast cancer on quality of life (QOL) and ability to work/perform activities of daily living also were assessed. Patients were recruited by a Canadian breast cancer patient advocacy group through email and social media. Physicians were recruited by email. (3) Results: Among 118 patients starting the survey, 23 completed ≥ 1 DCE question (19%). Among 271 physicians who were sent the e-mail invitation, 21 completed ≥ 1 DCE question (8%). For both patients and physicians, the increased probability of remaining alive and without cancer progression over 2 years was the most important attribute. A treatment with attributes consistent with ribociclib plus NSAI was chosen by patients and physicians in 70% and 88% of the time, respectively. A substantial proportion of patients reported worrying about future diagnostic tests and their cancer getting worse; (4) Conclusions: Canadian patients and physicians are generally concordant in preference for advanced breast cancer treatments, preferring ribociclib plus NSAI to other options.


Inhibition of CD39 enzymatic function at the surface of tumor cells alleviates their immunosuppressive activity.
The ectonucleotidases CD39 and CD73 hydrolyze extracellular adenosine triphosphate (ATP) and adenosine diphosphate (ADP) to generate adenosine, which binds to adenosine receptors and inhibits T-cell and natural killer (NK)-cell responses, thereby suppressing the immune system. The generation of adenosine via the CD39/CD73 pathway is recognized as a major mechanism of regulatory T cell (Treg) immunosuppressive function. The number of CD39⁺ Tregs is increased in some human cancers, and the importance of CD39⁺ Tregs in promoting tumor growth and metastasis has been demonstrated using several in vivo models. Here, we addressed whether CD39 is expressed by tumor cells and whether CD39⁺ tumor cells mediate immunosuppression via the adenosine pathway. Immunohistochemical staining of normal and tumor tissues revealed that CD39 expression is significantly higher in several types of human cancer than in normal tissues. In cancer specimens, CD39 is expressed by infiltrating lymphocytes, the tumor stroma, and tumor cells. Furthermore, the expression of CD39 at the cell surface of tumor cells was directly demonstrated via flow cytometry of human cancer cell lines. CD39 in cancer cells displays ATPase activity and, together with CD73, generates adenosine. CD39⁺CD73⁺ cancer cells inhibited the proliferation of CD4 and CD8 T cells and the generation of cytotoxic effector CD8 T cells (CTL) in a CD39- and adenosine-dependent manner. Treatment with a CD39 inhibitor or blocking antibody alleviated the tumor-induced inhibition of CD4 and CD8 T-cell proliferation and increased CTL- and NK cell-mediated cytotoxicity. In conclusion, interfering with the CD39-adenosine pathway may represent a novel immunotherapeutic strategy for inhibiting tumor cell-mediated immunosuppression.


Understanding coping strategies during pregnancy and the postpartum period: a qualitative study of women living with HIV in rural Uganda.
In sub-Saharan Africa, 58% of adults living with HIV are women. In Uganda, HIV prevalence is 8.3% for women compared to 6.1% for men. Access to antiretroviral therapy (ART) and prevention of mother to child transmission (PMTCT) programs have enabled women living with HIV (WLWH) to have children with minimal risk of perinatal transmission. Nevertheless, pregnant WLWH face many challenges. We explored women's perceptions of how they cope with the challenges of pregnancy and the postpartum period as HIV-infected women. We conducted semi-structured interviews with postpartum WLWH accessing ART who had a pregnancy within 2 years prior to recruitment between February-August, 2014. Childbearing associated stressors and coping strategies were discussed. We used content analysis to identify major themes and NVivo 10 software facilitated data analysis. Twenty women were interviewed with median age 33 (IQR: 28-35) years, CD4 cell count 677 cells/mm3 (IQR: 440-767), number of live births 4 (IQR: 2-6), and number of living children 3 (IQR: 2-4.3). We summarize five identified coping strategies within a socio-ecological framework according to Bronfenbrenner's Ecological Model. Coping strategies on the individual level included acceptance of self and HIV status, and self-reliance. On the interpersonal level, participants reported coping through support from partners, family, and friends. On the organizational level, participants reported coping through HIV-related healthcare delivery and system supports. At the community level, women reported coping through support from church and spirituality. The results highlight coping strategies used by WLWH to manage the myriad challenges faced during pregnancy and the postpartum period. Intervention programs for WLWH must emphasize psychosocial care and incorporate strategies that address psychosocial challenges in the HIV care package in order to optimize well-being. Additionally policies that support networks of WLWH should be put in place and funding support should be provided through existing funding mechanisms in order to respond to the needs and challenges of WLWH. Programmes that support WLWH for economic empowerment and improved livelihoods should be strengthened across all regions in the country.


Torsion sensor based on inter-core mode coupling in seven-core fiber.
We proposed a novel torsion sensor based on inter-core mode coupling in seven-core fiber (SCF). The torsion sensor is fabricated by tapering a commercially available SCF spliced with two single mode fibers. Waist diameter and length of the taper structure were experimentally optimized to achieve good transmission spectrum. Based on this structure, the torsion measurement was conducted, and the experimental results demonstrated that the transmission spectrum shows a red shift with the fiber twist. The torsion sensitivity increases with the twisting angle, which can achieve as high as 1.00 nm/°. The direction of wavelength shift was observed to be opposite when twisting the tapered SCF in clockwise and counter-clockwise direction, demonstrating its capability to discriminate the rotation orientation. Moreover, all the measurements were repeated in attempts to confirm its stable performance as well as high accuracy. Mode coupling dynamics and theory of optical anisotropy in twisted fiber are adopted to discuss the sensitivity performance, which agrees well with experimental results. The novel torsion sensor could provide a promising candidate for the applications requiring accurate rotation.


Are individual differences quantitative or qualitative? An integrated behavioral and fMRI MIMIC approach.
In cognitive neuroscience there is a growing interest in individual differences. We propose the Multiple Indicators Multiple Causes (MIMIC) model of combined behavioral and fMRI data to determine whether such differences are quantitative or qualitative in nature. A simulation study revealed the MIMIC model to have adequate power for this goal, and parameter recovery to be satisfactory. The MIMIC model was illustrated with a re-analysis of Van Duijvenvoorde et al. (2016) and Blankenstein et al. (2018) decision making data. This showed individual differences in Van Duijvenvoorde et al. (2016) to originate in qualitative differences in decision strategies. Parameters indicated some individuals to use an expected value decision strategy, while others used a loss minimizing strategy, distinguished by individual differences in vmPFC activity. Individual differences in Blankenstein et al. (2018) were explained by quantitative differences in risk aversion. Parameters showed that more risk averse individuals preferred safe over risky choices, as predicted by heightened vmPFC activity. We advocate using the MIMIC model to empirically determine, rather than assume, the nature of individual differences in combined behavioral and fMRI datasets.


Combined inhibition of estrogen-dependent human breast carcinoma by soy and tea bioactive components in mice.
Breast cancer is significantly less prevalent among Asian women, whose diets contain high intake of soy products and tea. The objective of our present study was to identify the combined effects of dietary soy phytochemicals and tea components on breast tumor progression in a clinically relevant in vivo model of MCF-7 androgen-dependent human breast tumor in female SCID mice. MCF-7 tumor growth, tumor cell proliferation and apoptosis, microvessel density, and expressions of tumor estrogen receptors were compared in mice treated with genistin-rich soy isoflavones (GSI), soy phytochemical concentrate (SPC), black tea (BT), green tea (GT), SPC/BT combination and SPC/GT combination. GSI and SPC led to dose-dependent inhibition of MCF-7 tumor growth via inhibition of cancer cell proliferation in vivo. GT showed more potent anti-breast tumor activity than BT. GT infusion at 1.5 g tealeaf/100 mL water produced significant (p < 0.05) reductions of 56% in final tumor weight. GT plus SPC at 0.1% of the diet further reduced final tumor weight by 72% (p < 0.005). Analysis of serum and tumor biomarkers showed that the combined effects of SPC and GT inhibited tumor angiogenesis, and reduced estrogen receptor (ER)-alpha and serum levels of insulin-like growth factor (IGF)-I. Our study suggests that dietary SPC plus GT may be used as a potential effective dietary regimen for inhibiting progression of estrogen-dependent breast cancer.


Salivary Redox Biomarkers in Selected Neurodegenerative Diseases.
Neurodegenerative diseases (NDDs), such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, are disorders, which cause irreversible and progressive deterioration of the central nervous system. The pathophysiology of NDDs is still not fully explained; nevertheless, oxidative stress is considered as a critical mediator of cerebral degeneration, brain inflammation, as well as neuronal apoptosis. Therefore, it is not surprising that redox biomarkers are increasingly used in the diagnosis of neurodegenerative diseases. As saliva is a very easy to obtain bioliquid, it seems promising to use this biomaterial in the diagnosis of NDDs. Saliva collection is easy, cheap, stress-free, and non-infectious, and it does not require the help of a specialised medical personnel. Additionally, the concentrations of many salivary redox biomarkers correlate with their content in blood serum as well as the degree of disease progression, which makes them non-invasive indicators of NDDs. This paper reviews the latest knowledge concerning the use of salivary redox biomarkers in the diagnosis and prognosis of selected neurodegenerative diseases.


Spectroscopic properties of the 1.4 microm emission of Tm3+ ions in TeO2-WO3-PbO glasses.
In this work, we report the spectroscopic properties of the infrared 3H4-->3F4 emission of Tm3+ ions in two different compositions of glasses based on TeO2, WO3, and PbO for three Tm2O3 concentrations (0.1,0.5, and 1 wt%). Judd-Ofelt intensity parameters have been determined and used to calculate the radiative transition probabilities and radiative lifetimes. The infrared emission at around 1490 nm corresponding to the 3H4-->F4 transition has two noticeable features if compared to fluoride glasses used for S-band amplifiers. On one hand, it is broader by nearly 30 nm, and on the other, the stimulated emission cross section is twice the value for fluoride glasses. Both the relative intensity ratio of the 1490 nm emission to 1820 nm and the measured lifetime of the 3H4 level decrease as concentration increases, due to the existence of energy transfer via cross-relaxation among Tm3+ ions. The analysis of the decays from the 3H4 level with increasing concentration indicates the presence of a dipole-dipole quenching process assisted by energy migration.


Direct identification and enrichment of retinal stem cells/progenitors by Hoechst dye efflux assay.
The present study describes a method for isolating neural stem cells/progenitors directly from the freshly dissociated embryonic retina (prospective identification) and compares their characteristics with those enriched from mitogen-exposed embryonic retinal cell culture. Cell dissociates from embryonic rat retina and mitogen-exposed embryonic retinal cultures were stained with Hoechst 33342 fluorescent dye. The emission patterns of cells were analyzed in both blue and red wavelength using flow cytometry to enrich cells that retained or excluded the dye. The phenotype characteristics and differentiation potential of enriched cells were analyzed by immunocytochemical, RT-PCR, and electrophysiological analyses. The Hoechst dye efflux assay identified a minor population of cells, called side population (SP) cells, in fresh retinal dissociates. These cells that preferentially excluded the Hoechst 33342 fluorescent dye were proliferative and expressed both neural progenitor and retinal progenitor markers. The retinal SP cells generated functional neurons and glia and possessed the ability to differentiate along lineages of different late-born retinal cell types. Cells of similar phenotypes and potential were observed in the SP obtained from mitogen-exposed retinal culture. The Hoechst dye efflux assay represents an effective method for direct identification of retinal stem cells/progenitors. These results demonstrate that the prospectively isolated retinal stem cells/progenitors and those enriched as SP cells from mitogen-exposed retinal cell culture may be similar in their properties and potential.


Nitric oxide leads to cytoskeletal reorganization in the retinal pigment epithelium under oxidative stress.
Light is a risk factor for various eye diseases, including age-related macular degeneration (AMD) and retinitis pigmentosa (RP). We aim to understand how cytoskeletal proteins in the retinal pigment epithetlium (RPE) respond to oxidative stress, including light and how these responses affect apoptotic signaling. Previously, proteomic analysis revealed that the expression levels of vimentin and serine/threonine protein phosphatase 2A (PP2A) are significantly increased when mice are exposed under continuous light for 7 days compared to a condition of 12 hrs light/dark cycling exposure using retina degeneration 1 (rd1) model. When melatonin is administered to animals while they are exposed to continuous light, the levels of vimentin and PP2A return to a normal level. Vimentin is a substrate of PP2A that directly binds to vimentin and dephosphorylates it. The current study shows that upregulation of PP2Ac (catalytic subunit) phosphorylation negatively correlates with vimentin phosphorylation under stress condition. Stabilization of vimentin appears to be achieved by decreased PP2Ac phosphorylation by nitric oxide induction. We tested our hypothesis that site-specific modifications of PP2Ac may drive cytoskeletal reorganization by vimentin dephosphorylation through nitric oxide signaling. We speculate that nitric oxide determines protein nitration under stress conditions. Our results demonstrate that PP2A and vimentin are modulated by nitric oxide as a key element involved in cytoskeletal signaling. The current study suggests that external stress enhances nitric oxide to regulate PP2Ac and vimentin phosphorylation, thereby stabilizing or destabilizing vimentin. Phosphorylation may result in depolymerization of vimentin, leading to nonfilamentous particle formation. We propose that a stabilized vimentin might act as an anti-apoptotic molecule when cells are under oxidative stress.


Biological membranes in EV biogenesis, stability, uptake, and cargo transfer: an ISEV position paper arising from the ISEV membranes and EVs workshop.
Paracrine and endocrine roles have increasingly been ascribed to extracellular vesicles (EVs) generated by multicellular organisms. Central to the biogenesis, content, and function of EVs are their delimiting lipid bilayer membranes. To evaluate research progress on membranes and EVs, the International Society for Extracellular Vesicles (ISEV) conducted a workshop in March 2018 in Baltimore, Maryland, USA, bringing together key opinion leaders and hands-on researchers who were selected on the basis of submitted applications. The workshop was accompanied by two scientific surveys and covered four broad topics: EV biogenesis and release; EV uptake and fusion; technologies and strategies used to study EV membranes; and EV transfer and functional assays. In this ISEV position paper, we synthesize the results of the workshop and the related surveys to outline important outstanding questions about EV membranes and describe areas of consensus. The workshop discussions and survey responses reveal that while much progress has been made in the field, there are still several concepts that divide opinion. Good consensus exists in some areas, including particular aspects of EV biogenesis, uptake and downstream signalling. Areas with little to no consensus include EV storage and stability, as well as whether and how EVs fuse with target cells. Further research is needed in these key areas, as a better understanding of membrane biology will contribute substantially towards advancing the field of extracellular vesicles.


Selective neutralization of APP-C99 with monoclonal antibodies reduces the production of Alzheimer's Aβ peptides.
The toxic amyloid-β (Aβ) peptides involved in Alzheimer's disease (AD) are produced after processing of the amyloid precursor protein-C-terminal fragment APP-C99 by γ-secretase. Thus, major therapeutic efforts have been focused on inhibiting the activity of this enzyme. However, preclinical and clinical trials testing γ-secretase inhibitors revealed adverse side effects most likely attributed to impaired processing of the Notch-1 receptor, a γ-secretase substrate critically involved in cell fate decisions. Here we report an innovative approach to selectively target the γ-secretase-mediated processing of APP-C99 with monoclonal antibodies neutralizing this substrate. Generated by immunizing mice with natively folded APP-C99, these antibodies bound N- or C-terminal accessible epitopes of this substrate, and decorated extracellular amyloid deposits in AD brain tissues. In cell-based assays, the same antibodies impaired APP-C99 processing by γ-secretase, and reduced Aβ production. Furthermore, they significantly decreased brain Aβ levels in the APPPS1 mouse model of AD after intracerebroventricular injection. Together, our findings support APP-C99 substrate-targeting antibodies as new immunotherapeutic and Notch-sparing agents to lower the levels of Aβ peptides implicated in AD.


Side chain modifications in lankacidin group antibiotics.
Novel N-acyl analogs of lankacidin may be prepared from 3-isocyanatolankone diformate [7,13-bis(formyloxy)-2-isocyanato-1,4,10,19-tetramethyl-16- oxabicyclo[13.2.2.]nonadeca-3,5,9,11-tetraen-17,18-dione]. Of seven such analogs evaluated in vitro only homolankacidin diformate showed significant activity. However, in a cell-free system two of the inactive analogs inhibited polypeptide synthesis as well as did lankacidin itself or erythromycin. Antibacterial activity, therefore, is a function of the ability of a congener to penetrate the bacterial cell membrane in addition to its intrinsic activity. Similarly, lankacidinol is as potent as lankacidin or erythromycin as an inhibitor of bacterial polypeptide synthesis in a cell-free system. This intrinsic activity is expressed as potent antibacterial activity against growing gram-positive cultures in O(2')-acyl derivatives with the proper lipophilicity.


Immunoelectron microscopic studies of the intracellular transport of the membrane glycoprotein (G) of vesicular stomatitis virus in infected Chinese hamster ovary cells.
An immunoelectron microscopic study was undertaken to survey the intracellular pathway taken by the integral membrane protein (G-protein) of vesicular stomatitis virus from its site of synthesis in the rough endoplasmic reticulum to the plasma membrane of virus-infected Chinese hamster ovary cells. Intracellular transport of the G-protein was synchronized by using a temperature-sensitive mutant of the virus (0-45). At the nonpermissive temperature (39.8 degrees C), the G-protein is synthesized in the cell infected with 0-45, but does not leave the rough endoplasmic reticulum. Upon shifting the temperature to 32 degrees C, the G-protein moves by stages to the plasma membrane. Ultrathin frozen sections of 0-45-infected cells were prepared and indirectly immunolabeled for the G-protein at different times after the temperature shift. By 3 min, the G-protein was seen at high density in saccules at one face of the Golgi apparatus. No large accumulation of G-protein-containing vesicles were observed near this entry face, but a few 50-70-mm electron-dense vesicular structures labeled for G-protein were observed that might be transfer vesicles between the rough endoplasmic reticulum and the Golgi complex. At blebbed sites on the nuclear envelope at these early times there was a suggestion that the G-protein was concentrated, these sites perhaps serving as some of the transitional elements for subsequent transfer of the G-protein from the rough endoplasmic reticulum to the Golgi complex. By 3 min after its initial asymmetric entry into the Golgi complex, the G-protein was uniformly distributed throughout all the saccules of the complex. At later times, after the G-protein left the Golgi complex and was on its way to the plasma membrane, a new class of G-protein-containing vesicles of approximately 200-nm diameter was observed that are probably involved in this stage of the transport process. These data are discussed, and the further prospects of this experimental approach are assessed.


Mental rotation of body parts and non-corporeal objects in patients with idiopathic cervical dystonia.
Mental rotation of body parts is performed through inner simulation of actual movements, and is likely to rely upon cortical and subcortical systems (e.g. motor and premotor areas and basal ganglia) involved in motor planning and execution. Studies indicate that sensory and motor deficits, such as for example pain, limb amputation or focal hand dystonia, bring about a specific impairment in mental rotation of the affected body parts. Here we explored the ability of patients affected by idiopathic cervical dystonia (CD) to mentally rotate affected (neck) and unaffected (hands and feet) body districts. The experimental stimuli consisted of realistic photos of left or right hands or feet and the head of a young men with a black patch on the left or the right eye. As non-corporeal stimulus the front view of a car with a black patch on the left or the right headlight was used. The stimuli were presented at six different degrees of orientations. Twelve CD patients and 12 healthy participants were asked to verbally report whether the hands or feet were left or right, or whether the patch was on the left or the right eye or headlight. Reaction times and accuracy in performing the laterality tasks on the four stimuli were collected. Results showed that CD patients are slow in mental rotation of stimuli representing body parts, namely hand, foot and head. This abnormality was not due to a general impairment in mental rotation per se, since patients' ability to rotate a non-corporeal object (a car) was not significantly different from that of healthy participants. We posit that the deficit in mental rotation of body parts in CD patients may derive from a defective integration of body- and world-related knowledge, a process that is likely to allow a general representation of "me in the external world".


Interventions to reduce fear of falling in community-living older people: a systematic review.
The objective was to assess which interventions effectively reduce fear of falling in community-living older people. An extensive search for relevant literature comprised a database search of PubMed, EMBASE, PsycINFO, and the Cochrane Central Register of Controlled Trials; expert consultation; and manually searching reference lists from potentially relevant papers. Randomized, controlled trials that assessed fear of falling in community-living older people were included. Two independent reviewers extracted data from full papers on study characteristics, methodological quality, outcomes, and process characteristics of the intervention. The search identified 599 abstracts, and 19 papers met the inclusion criteria. Seven of those papers were identified using expert consultation. Fifty-five percent of all validity items and 39% of process characteristic items were fulfilled across the 19 trials. Twelve of the 19 papers were of higher methodological quality. In 11 of these trials, fear of falling was lower in the intervention group than in the control group. Interventions that showed effectiveness were fall-related multifactorial programs (n=5), tai chi interventions (n=3), exercise interventions (n=2), and a hip protector intervention (n=1). Three of these interventions explicitly aimed to reduce fear of falling. Several interventions, including interventions not explicitly aimed at fear of falling, resulted in a reduction of fear of falling in community-living older people. Limited but fairly consistent findings in trials of higher methodological quality showed that home-based exercise and fall-related multifactorial programs and community-based tai chi delivered in group format have been effective in reducing fear of falling in community-living older people.


Comparative physiology and fermentation performance of Saaz and Frohberg lager yeast strains and the parental species Saccharomyces eubayanus.
Two distinct genetic groups (Saaz and Frohberg) exist within the hybrid Saccharomyces pastorianus (S. cerevisiae × S. eubayanus) taxon. However, physiological/technological differences that exist between the two groups are not known. Fermentative capability of the parental S. eubayanus has likewise never been studied. Here, 58 lager strains were screened to determine which hybrid group they belonged to, and selected strains were characterized to determine salient characteristics. In 15 °P all-malt wort fermentations at 22 °C, Frohberg strains showed greater growth and superior fermentation (80% apparent attenuation, 6.5% alcohol by volume in 3-4 days) compared to all other strains and maintained highest viability values (>93%). Fermentation with S. eubayanus was poor at the same temperature (33% apparent attenuation, 2.7% alcohol by volume at 6 days and viability reduced to 75%). Saaz strains and S. eubayanus were the least sensitive to cold (10 °C), though this did not translate to greater fermentation performance. Fermentation with S. eubayanus was poor at 10 °C but equal to or greater than that of the Saaz strains. Performance of Saaz yeast/S. eubayanus was limited by an inability to use wort maltotriose. [(14)C]-Maltotriose transport assays also showed negligible activity in these strains (≤0.5 µmol min(-1) g(-1) dry yeast). Beers from Saaz fermentations were characterized by two- to sixfold lower production of the flavour compounds methyl butanol, ethyl acetate and 3-methylbutyl acetate compared to Frohberg strains. Higher alcohol and ester production by S. eubayanus was similar to that of Frohberg strains.


Accumbens dopamine D2 receptors increase motivation by decreasing inhibitory transmission to the ventral pallidum.
Dopamine D2 receptors (D2Rs) in the nucleus accumbens (NAc) regulate motivated behavior, but the underlying neurobiological mechanisms remain unresolved. Here, we show that selective upregulation of D2Rs in the indirect pathway of the adult NAc enhances the willingness to work for food. Mechanistic studies in brain slices reveal that D2R upregulation attenuates inhibitory transmission at two main output projections of the indirect pathway, the classical long-range projections to the ventral pallidum (VP), as well as local collaterals to direct pathway medium spiny neurons. In vivo physiology confirms the reduction in indirect pathway inhibitory transmission to the VP, and inhibition of indirect pathway terminals to VP is sufficient to enhance motivation. In contrast, D2R upregulation in the indirect pathway does not disinhibit neuronal activity of the direct pathway in vivo. These data suggest that D2Rs in ventral striatal projection neurons promote motivation by weakening the canonical output to the ventral pallidum.


Sharpened and Mechanically Durable Carbon Fiber Electrode Arrays for Neural Recording.
Bioelectric medicine treatments target disorders of the nervous system unresponsive to pharmacological methods. While current stimulation paradigms effectively treat many disorders, the underlying mechanisms are relatively unknown, and current neuroscience recording electrodes are often limited in their specificity to gross averages across many neurons or axons. Here, we develop a novel, durable carbon fiber electrode array adaptable to many neural structures for precise neural recording. Carbon fibers ( [Formula: see text] diameter) were sharpened using a reproducible blowtorchmethod that uses the reflection of fibers against the surface of a water bath. The arrays were developed by partially embedding carbon fibers in medical-grade silicone to improve durability. We recorded acute spontaneous electrophysiology from the rat cervical vagus nerve (CVN), feline dorsal root ganglia (DRG), and rat brain. Blowtorching resulted in fibers of 72.3 ± 33.5-degree tip angle with [Formula: see text] exposed carbon. Observable neural clusters were recorded using sharpened carbon fiber electrodes fromrat CVN ( [Formula: see text]), feline DRG ( [Formula: see text]), and rat brain ( [Formula: see text]). Recordings from the feline DRG included physiologically relevant signals from increased bladder pressure and cutaneous brushing. These results suggest that this carbon fiber array is a uniquely durable and adaptable neural recordingdevice. In the future, this device may be useful as a bioelectric medicine tool for diagnosis and closed-loop neural control of therapeutic treatments and monitoring systems.


The dark side of cosmology: dark matter and dark energy.
A simple model with only six parameters (the age of the universe, the density of atoms, the density of matter, the amplitude of the initial fluctuations, the scale dependence of this amplitude, and the epoch of first star formation) fits all of our cosmological data . Although simple, this standard model is strange. The model implies that most of the matter in our Galaxy is in the form of "dark matter," a new type of particle not yet detected in the laboratory, and most of the energy in the universe is in the form of "dark energy," energy associated with empty space. Both dark matter and dark energy require extensions to our current understanding of particle physics or point toward a breakdown of general relativity on cosmological scales.


Moving Forward with Dysphagia Care: Implementing Strategies during the COVID-19 Pandemic and Beyond.
Growing numbers of SARS-CoV-2 cases coupled with limited understanding of transmissibility and virulence, have challenged the current workflow and clinical care pathways for the dysphagia provider. At the same time, the need for non-COVID-19-related dysphagia care persists. Increased awareness of asymptomatic virus carriers and variable expression of the disease have also focused attention to appropriate patient care in the context of protection for the healthcare workforce. The objective of this review was to create a clinical algorithm and reference for dysphagia clinicians across clinical settings to minimize spread of COVID-19 cases while providing optimal care to patients suffering from swallowing disorders. Every practitioner and healthcare system will likely have different constraints or preferences leading to the utilization of one technique over another. Knowledge about this pandemic increases every day, but the algorithms provided here will help in considering the best options for proceeding with safe and effective dysphagia care in this new era.


Mechanistic mathematical model of polarity in yeast.
The establishment of cell polarity involves positive-feedback mechanisms that concentrate polarity regulators, including the conserved GTPase Cdc42p, at the "front" of the polarized cell. Previous studies in yeast suggested the presence of two parallel positive-feedback loops, one operating as a diffusion-based system, and the other involving actin-directed trafficking of Cdc42p on vesicles. F-actin (and hence directed vesicle traffic) speeds fluorescence recovery of Cdc42p after photobleaching, suggesting that vesicle traffic of Cdc42p contributes to polarization. We present a mathematical modeling framework that combines previously developed mechanistic reaction-diffusion and vesicle-trafficking models. Surprisingly, the combined model recapitulated the observed effect of vesicle traffic on Cdc42p dynamics even when the vesicles did not carry significant amounts of Cdc42p. Vesicle traffic reduced the concentration of Cdc42p at the front, so that fluorescence recovery mediated by Cdc42p flux from the cytoplasm took less time to replenish the bleached pool. Simulations in which Cdc42p was concentrated into vesicles or depleted from vesicles yielded almost identical predictions, because Cdc42p flux from the cytoplasm was dominant. These findings indicate that vesicle-mediated delivery of Cdc42p is not required to explain the observed Cdc42p dynamics, and raise the question of whether such Cdc42p traffic actually contributes to polarity establishment.


Minority Primary Care Patients With Depression: Outcome Disparities Improve With Collaborative Care Management.
Racial and ethnic disparities in depression incidence, prevalence, treatment, and outcomes still persist. The hypothesis of this study was that use of collaborative care management (CCM) in treating depressed primary care patients would decrease racial disparities in 6-month clinical outcomes compared with those patients treated with usual primary care (UC). In a retrospective chart review analysis, 3588 (51.2%) patients received UC and 3422 (48.8%) patients were enrolled in CCM. Logistic regression analyses were used to examine disparities in 6-month outcomes. Minority patients enrolled in CCM were more likely to be participating in depression care at 6 months than minority patients in UC (61.8% vs. 14.4%; P≤0.001). After adjustment for demographic and clinical covariates, this difference remained statistically significant (odds ratio=9.929; 95% CI, 6.539-15.077, P≤0.001).The 568 minority UC patients with 6-month follow-up PHQ-9 data demonstrated a much lower odds ratio of a PHQ-9 score of <5 (0.220; 95% CI, 0.085-0.570; P=0.002) and a much higher odds ratio of PHQ-9 score of ≥10 (3.068; 95% CI, 1.622-5.804; P<0.001) when compared with the white, non-Hispanic patients. In contrast, the 2329 patients treated with CCM, the odds ratio for a PHQ-9 score of <5 or ≥10 after 6 months, demonstrated no significance of minority status. Utilization of CCM for depression was associated with a significant reduction of the disparities for outcomes of compliance, remission, or persistence of depressive symptoms for minority patients with depression versus those treated with UC.


In vitro pharmacodynamics of 1-beta-D-arabinofuranosylcytosine: synergy of antitumor activity with cis-diamminedichloroplatinum(II).
1-beta-D-Arabinofuranosylcytosine (ara-C) was tested at a concentration of 10 micrograms/ml in the human tumor colony-forming assay against 55 human tumors of various histological types. Using the criterion for sensitivity of at least 70% inhibition of colony formation, 12 tumors (22%) were sensitive to ara-C. ara-C was most active against lung tumors (3 of 8 tumors were sensitive), and melanomas (6 of 8 sensitive). However, ara-C was not active against breast cancer (0 of 7) or colon cancer (0 of 3), and only 1 of 13 ovarian cancers was sensitive to ara-C. The activity of ara-C against melanoma and other solid tumors was confirmed using a thymidine incorporation assay. The time (t) and concentration (C) dependency of the cytotoxicity of ara-C and other chemotherapeutic agents was determined. Most agents such as Adriamycin, cis-diamminedichloroplatinum(II) (cis-platinum), and bleomycin were found to follow the C x t rule. That is, as the drug concentration was doubled, an equivalent amount of cell kill was achieved in half the time. However, the activity of ara-C was more concentration dependent than time dependent. ara-C was more effective when cells were exposed to high concentrations for short time periods. Synergy of activity between ara-C and cis-platinum was demonstrated in the breast 231 and melanoma M19 cell lines. No synergy of interaction between these two drugs was observed in the colon HT29 and lung P3 cell lines. When fresh biopsy specimens were tested with the combination, there was evidence of a synergistic interaction in 9 of 36 (25%). Maximum cytotoxicity was obtained when cells were exposed to ara-C 2 h before the addition of cis-platinum. The addition of cis-platinum before ara-C decreased the synergism.


Resin-modified glass ionomer containing calcium glycerophosphate: physico-mechanical properties and enamel demineralization.
Sources of calcium and phosphate have been added to dental restorative materials to improve their anticaries effect. This study evaluated the effect of adding calcium glycerophosphate (CaGP) to resin-modified glass ionomer cement (RMGIC) on the physico-mechanical properties, ion release, and enamel demineralization. Material and Methods: Specimens were fabricated for each experimental group: RMGIC without CaGP (Control), RMGIC with 1, 3 and 9% CaGP. To determine the release of fluoride (F), calcium (Ca) and phosphorus (P), six specimens were immersed in demineralization and remineralization solutions for 15 days. In another experimental trial, the following physico-mechanical properties were evaluated at time intervals of 1 and 7 days after fabrication: compressive strength (n=12), diametral tensile strength (n=12), surface hardness of material (n=6) and the degree of conversion of monomers (n=8). To study enamel demineralization, specimens (n=12) were attached to enamel blocks and submitted to pH-cycling. Subsequently, surface and cross-sectional hardness and the concentration of F, Ca and P in enamel were determined. The addition of CaGP to RMGIC led to higher mean release of F, Ca and P when compared with control (p<0.001). Mechanical properties were within the range of those of the ionomer cements after addition of 1% and 3% CaGP. The degree of conversion did not differ between groups at the 1st and the 7th day (p>0.439). The addition of 3% and 9% CaGP reduced mineral loss and increased F, Ca and P in the enamel when compared with control (p<0.05). The addition of 3% CaGP in RMGIC increased the release of F, P and Ca, reduced enamel demineralization, and maintained the physico-mechanical properties within the parameters for this material.


Increasing sexual risk behaviour among Dutch men who have sex with men: mathematical models versus prospective cohort data.
Changes in risk behaviour among men who have sex with men (MSM) in the Netherlands were estimated by fitting a mathematical model to annual HIV and AIDS diagnoses in the period 1980-2009 and, independently, from rates of unprotected anal intercourse in a prospective cohort study in Amsterdam. The agreement between the two approaches was very good, confirming that in terms of incidence, increasing risk behaviour between MSM is offsetting benefits offered by enhanced testing and treatment.


Nuss bar procedure: past, present and future.
Repair of pectus excavatum began at the beginning of the 20th century before endotracheal intubation was standard practice. Surgeons therefore developed techniques that corrected the deformity using an open procedure via the anterior chest wall. Initial techniques were unsatisfactory, but by the 1930s the partial rib resection and sternal osteotomy technique had been developed and was used in combination with external traction post-operatively to prevent the sternum from sinking back into the chest. In 1949, Ravitch recommended complete resection of the costal cartilages and complete mobilization of the sternum without external traction, and in 1961 Adkins and Blades introduced the concept of a substernal strut for sternal support. The wide resection resulted in a very rigid anterior chest wall, and in some instances, the development of asphyxiating chondrodystrophy. The primary care physicians therefore became reluctant to refer the patients for repair. In 1987, Nuss developed a minimally invasive technique that required no cartilage or sternal resection and relied only on internal bracing by means of a sub-sternal bar, which is inserted into the chest through two lateral thoracic incisions and guided across the mediastinum with the help of thoracoscopy. After publication of the procedure in 1998, it became widely accepted and a flood of new patients suddenly started to appear, which allowed for rapid improvements and modifications of the technique. New instruments were developed specifically for the procedure, complications were recognized, and the steps taken to prevent them included the development of a stabilizer and the use of pericostal sutures to prevent bar displacement. Various options were developed for sternal elevation prior to mediastinal dissection to prevent injury to the mediastinal structures, allergy testing was implemented, and pain management improved. The increased number of patients coming for repair permitted studies of cardiopulmonary function, which showed that patients with a severe degree of pectus excavatum have right- sided cardiac compression, decreased filling, and decreased stroke volume. The degree of pulmonary restriction and obstruction is related to the degree of deformity and degree of cardiac displacement into the left chest. The indications for surgical repair have been clearly outlined, the procedure has been standardized, and post-operative management protocols are now available. A review of our prospective database showed that 98% of patients have a good to excellent outcome. This review of the "Past" outlines the progression of the surgical techniques during the 20th century, the review of the "Present" outlines the important modifications and results of the closed technique, and the review of the "Future" outlines the various new options that are becoming available for the treatment of pectus excavatum.


Direct analysis of polyols using 3-nitrophenylboronic acid in capillary electrophoresis: thermodynamic and electrokinetic principles of molecular recognition.
The design of boronic acid sensors for photometric detection of carbohydrates has relied on exploiting differences in the thermodynamic stability of complex formation for molecular recognition. Herein, we introduce a direct method for analysis of sugar alcohols using 3-nitrophenylboronic acid (NPBA) as an electrokinetic probe in capillary electrophoresis (CE). Dynamic complexation of neutral polyols by NPBA during electromigration allows for their simultaneous resolution and UV detection based on formation of an anionic ternary boronate ester complex in phosphate buffer. Unlike conventional boronic acid sensors, thermodynamic and electrokinetic processes in CE allow for improved selectivity for the resolution of sugar alcohol stereoisomers having different vicinal polyol chain lengths even in cases when binding affinity is similar due to differences in their complex mobility. Three complementary approaches were investigated to compare the thermodynamics of polyol chelation with NPBA, namely direct binding assays by CE, UV absorbance spectroscopy and an indirect pK (a) depression method. Overall, CE offers a convenient platform for characterization of reversible arylboronic acid interactions in free solution while allowing for direct analysis of complex mixtures of neutral/UV-transparent polyols without complicated sample handling.


c-fos regulates neuronal excitability and survival.
Excitotoxicity is a process in which glutamate or other excitatory amino acids induce neuronal cell death. Accumulating evidence suggests that excitotoxicity may contribute to human neuronal cell loss caused by acute insults and chronic degeneration in the central nervous system. The immediate early gene (IEG) c-fos encodes a transcription factor. The c-Fos proteins form heterodimers with Jun family proteins, and the resulting AP-1 complexes regulate transcription by binding to the AP-1 sequence found in many cellular genes. Emerging evidence suggests that c-fos is essential in regulating neuronal cell survival versus death. Although c-fos is induced by neuronal activity, including kainic acid-induced seizures, whether and how c-fos is involved in excitotoxicity is still unknown. To address this issue, we generated a mouse in which c-fos expression is largely eliminated in the hippocampus. We found that these mutant mice have more severe kainic acid-induced seizures, increased neuronal excitability and neuronal cell death, compared with control mice. Moreover, c-Fos regulates the expression of the kainic acid receptor GluR6 and brain-derived neurotrophic factor (BDNF), both in vivo and in vitro. Our results suggest that c-fos is a genetic regulator for cellular mechanisms mediating neuronal excitability and survival.


3D periodic human motion reconstruction from 2D motion sequences.
We present and evaluate a method of reconstructing three-dimensional (3D) periodic human motion from two-dimensional (2D) motion sequences. Using Fourier decomposition, we construct a compact representation for periodic human motion. A low-dimensional linear motion model is learned from a training set of 3D Fourier representations by means of principal components analysis. Two-dimensional test data are projected onto this model with two approaches: least-square minimization and calculation of a maximum a posteriori probability using the Bayes' rule. We present two different experiments in which both approaches are applied to 2D data obtained from 3D walking sequences projected onto a plane. In the first experiment, we assume the viewpoint is known. In the second experiment, the horizontal viewpoint is unknown and is recovered from the 2D motion data. The results demonstrate that by using the linear model, not only can missing motion data be reconstructed, but unknown view angles for 2D test data can also be retrieved.


Changes in Composition and Diversity of Epiphytic Microorganisms on Field Pea Seeds, Partial Crop Peas, and Whole Crop Peas during Maturation and Ensiling with or without Lactic Acid Bacteria Inoculant.
The present study was conducted under the hypothesis that, in field peas, type of plant material, stage of maturity, ensiling, silage additive, and aerobic stress affect the composition and diversity of epiphytic microbial communities. Epiphytic microbial composition and diversity of pea seeds, partial crop peas, and whole crop peas was analyzed at different stages of late maturity, before and after ensiling, and with or without the use of lactic acid bacteria (LAB) as inoculant. Suitable combinations among pea crop variants, maturity stages, and inoculant use for the production of stable silages with sufficient aerobic stability after opening and during feed-out were identified. Genomic DNA was extracted, and 16S and 18S rRNA gene amplicons were sequenced. To assess the quality of the various silages, nutrient concentration, pH value, concentration of lactic acid, short chain fatty acids, and alcohols, and aerobic stability were determined. Pea seeds were barely colonized by epiphytic microorganisms. In partial and whole crop peas, composition and α-diversity (Shannon index) of bacterial communities did not differ between crop variants but differed among maturity stages. Epiphytic eukaryotes were rarely found on partial and whole crop peas. Bacterial composition and α-diversity were affected by ensiling and subsequent aerobic storage. In partial and whole crop peas, plant maturation caused an increase of the relative abundance of naturally occurring LAB (Weissella, Pediococcus, and Lactobacillus spp.). As a possible result, natural LAB support stable ensiling conditions even without the use of inoculants beginning with a maturity of 78 on the BBCH scale. This corresponded with a dry matter (DM) concentration of 341 and 363 g/kg in partial and whole crop peas, respectively. Addition of LAB inoculants, however, reduced ammonia, acetic acid, and butanol concentrations, and supported aerobic stability. Earlier stages of plant maturity (BBCH 76 and 77, 300 g DM/kg or less) were more prone to microbial spoilage. Stable pea seed silages can be produced at a maturity between BBCH 78 (427 g DM/kg) and 79 (549 g DM/kg), but they undoubtedly require LAB inoculation or application of other ensiling agents. IMPORTANCE Field peas are important protein suppliers for human and animal nutrition. They can be grown in many areas of the world, which may reduce imports of protein plants and has beneficial economic and ecological effects. Ensiling is a method of preserving feed that can be implemented easily and cost-effectively at the farm. Peas harvested as seeds, partial crop, or whole crop at different maturities enable a wide range of applications. The study characterized epiphytic microbial communities on peas in terms of composition and diversity depending on the maturity of the plants and feed conservation by ensiling as they play an essential role for the production of silages. Even if this study did not consider year, site, or cultivar effects, the results would show which part of the plant is probably well suited for the production of stable and high-quality silages and at which stage of maturity.


Clinical holistic medicine: holistic adolescent medicine.
The holistic medical approach seems to be efficient and can also be used in adolescent medicine. Supporting the teenager to grow and develop is extremely important in order to prevent many of the problems they can carry into adulthood. The simple consciousness-based, holistic medicine--giving love, winning trust, giving holding, and getting permission to help the patient feel, understand, and let go of negative beliefs--is easy for the physician interested in this kind of practice and it requires little previous training for the physician to be able to care for his/her patient. A deeper insight into the principles of holistic treatment and a thorough understanding of our fellow human beings are making it work even better. Holistic medicine is not a miracle cure, but rather a means by which the empathic physician can support the patient in improving his/her future life in respect to quality of life, health, and functional capacity--through coaching the patient to work on him/herself in a hard and disciplined manner. When the patient is young, this work is so much easier. During our lifetime, we have several emotional traumas arranged in the subconscious mind with the smallest at the top, and it is normal for the person to work on a large number of traumatic events that have been processed to varying degrees. Some traumas have been acknowledged, some are still being explored by the person, and yet others are still preconscious, which can be seen for example in the form of muscle tension. Sometimes the young dysfunctional patient carries severe traumas of a violent or sexual nature, but the physician skilled in the holistic medical toolbox can help the patient on his/her way to an excellent quality of life, full self-expression, a love and sex life, and a realization of his/her talents--all that a young patient is typically dreaming about. Biomedicine is not necessary or even recommended when the physical or mental symptoms are caused by disturbances in the personal development that can be corrected with love and understanding. If possible, biomedicine must be avoided, even if this means suffering for the young person, who needs to confront the tough realities of life in order to grow into an able and sound adult.


Evaluation of genotoxic potential of neurotoxin anatoxin-a with the use of umuC test.
The aim of this study was to evaluate genotoxicity of anatoxin-a, cyanotoxin of neurotoxic activity. Additionally, other frequently detected cyanotoxin of previously described genotoxic potential, microcystin-LR, was used at the same concentrations, as well as the mixture of both toxins, anatoxin-a and microcystin-LR. Genotoxicity of the toxins was determined with the use of the umuC assay, in which the induction and expression of the umuC - lacZ reporter gene was assessed. The test was conducted on Salmonella typhimurium TA 1535/pSK1002 strain, with and without metabolic transformation. The toxin concentrations were 0.25, 0.5, 1 and 2 µg/ml. The exposure time was 2 h. The highest inefficient concentration of anatoxin-a without metabolic transformation was 0.25 µg/ml, of microcystin-LR was 0.5 µg/ml and in case of the toxin mixture all used concentrations induced the umuC gene. When S9 fraction was added to the samples, no effects were detected. To our knowledge, this is the first report on genotoxic effects of anatoxin-a. Although the study is preliminary and needs further research, however, indicates the new potential activity of the toxin, as well as the possible increase of genotoxicity of other cyanotoxins, more stable in the environment, e.g. microcystin-LR.


The α-tocopherol transfer protein is essential for vertebrate embryogenesis.
The hepatic α-tocopherol transfer protein (TTP) is required for optimal α-tocopherol bioavailability in humans; mutations in the human TTPA gene result in the heritable disorder ataxia with vitamin E deficiency (AVED, OMIM #277460). TTP is also expressed in mammalian uterine and placental cells and in the human embryonic yolk-sac, underscoring TTP's significance during fetal development. TTP and vitamin E are essential for productive pregnancy in rodents, but their precise physiological role in embryogenesis is unknown. We hypothesize that TTP is required to regulate delivery of α-tocopherol to critical target sites in the developing embryo. We tested to find if TTP is essential for proper vertebrate development, utilizing the zebrafish as a non-placental model. We verify that TTP is expressed in the adult zebrafish and its amino acid sequence is homologous to the human ortholog. We show that embryonic transcription of TTP mRNA increases >7-fold during the first 24 hours following fertilization. In situ hybridization demonstrates that Ttpa transcripts are localized in the developing brain, eyes and tail bud at 1-day post fertilization. Inhibiting TTP expression using oligonucleotide morpholinos results in severe malformations of the head and eyes in nearly all morpholino-injected embryos (88% compared with 5.6% in those injected with control morpholinos or 1.7% in non-injected embryos). We conclude that TTP is essential for early development of the vertebrate central nervous system.


Ibudilast (MN-166) in amyotrophic lateral sclerosis- an open label, safety and pharmacodynamic trial.
Ibudilast (MN-166) is an inhibitor of macrophage migration inhibitory factor (MIF) and phosphodiesterases 3,4,10 and 11 (Gibson et al., 2006; Cho et al., 2010). Ibudilast attenuates CNS microglial activation and secretion of pro-inflammatory cytokines (Fujimoto et al., 1999; Cho et al., 2010). In vitro evidence suggests that ibudilast is neuroprotective by suppressing neuronal cell death induced by microglial activation. People with ALS have increased microglial activation measured by [11C]PBR28-PET in the motor cortices. The primary objective is to determine the impact of ibudilast on reducing glial activation and neuroaxonal loss in ALS, measured by PBR28-PET and serum Neurofilament light (NfL). The secondary objectives included determining safety and tolerability of ibudilast high dosage (up to 100 mg/day) over 36 weeks. In this open label trial, 35 eligible ALS participants underwent ibudilast treatment up to 100 mg/day for 36 weeks. Of these, 30 participants were enrolled in the main study cohort and were included in biomarker, safety and tolerability analyses. Five additional participants were enrolled in the expanded access arm, who did not meet imaging eligibility criteria and were included in the safety and tolerability analyses. The primary endpoints were median change from baseline in (a) PBR28-PET uptake in primary motor cortices, measured by standard uptake value ratio (SUVR) over 12-24 weeks and (b) serum NfL over 36-40 weeks. The secondary safety and tolerability endpoints were collected through Week 40. The baseline median (range) of PBR28-PET SUVR was 1.033 (0.847, 1.170) and NfL was 60.3 (33.1, 219.3) pg/ml. Participants who completed both pre and post-treatment scans had PBR28-PET SUVR median(range) change from baseline of 0.002 (-0.184, 0.156) , P = 0.5 (n = 22). The median(range) NfL change from baseline was 0.4 pg/ml (-1.8, 17.5), P = 0.2 (n = 10 participants). 30(86%) participants experienced at least one, possibly study drug related adverse event. 13(37%) participants could not tolerate 100 mg/day and underwent dose reduction to 60-80 mg/day and 11(31%) participants discontinued study drug early due to drug related adverse events. The study concludes that following treatment with ibudilast up to 100 mg/day in ALS participants, there were no significant reductions in (a) motor cortical glial activation measured by PBR28-PET SUVR over 12-24 weeks or (b) CNS neuroaxonal loss, measured by serum NfL over 36-40 weeks. Dose reductions and discontinuations due to treatment emergent adverse events were common at this dosage in ALS participants. Future pharmacokinetic and dose-finding studies of ibudilast would help better understand tolerability and target engagement in ALS.


Long-term results after treatment of humeral neck fractures using modified Hackethal bundle nailing.
This study reports the long-term surgical outcomes of elderly patients who underwent surgery using the modified Hackethal bundle nailing method on the basis of an approximately 10-year follow-up study. We treated 34 patients (7 males, 27 females) with 2- and 3-fragment fractures of the proximal humeral neck. Their ages at the time of operation ranged from 65 to 75 years (mean age, 69.5 years). They were classified as Neer group I (G-I, 8.8%), III (G-III, 79.4%) or IV (G-IV 11.8%). The duration of follow-up in patients averaged 130.6 months (range: 125.0 - 156.0 months). Patients were graded according to the Constant-Murley (CM) scoring system. Pre-operative and postoperative X-rays were also assessed. All the fractures united within 6- 9 weeks, with an average of 7.4 weeks. The mean overall Constant score was 80.0 points (G-I: 83.3; G-III: 80.5; G-IV 75.6). Among the 34 patients, 30 (88.2%) obtained excellent results and 4 (11.8%) obtained good results. Mal-union in the coronal plane was observed in two patients (6.28%) who had 160 degrees angulation in three part fracture. Mal-union of the greater tuberosity occurred in one patient (3.14%) leading to limitation of abduction to 90 degrees. There were no cases of avascular necrosis, neurovascular complications or deep infections. This study suggests that the modified H-technique is simple, less invasive, and a reliable and effective procedure for elderly patients.


Gaze Entropy Measures Reveal Alcohol-Induced Visual Scanning Impairment During Ascending and Descending Phases of Intoxication.
Visuospatial awareness is critical for everyday activities like driving. Higher order processes, such as visuospatial working memory (VSWM) and top-down modulation of gaze control, enable goal-driven visual scanning. Although available evidence suggests that alcohol differentially affects VSWM during the ascending and descending phases of the blood alcohol concentration (BAC) curve, it remains unclear whether such impact extends to a systemic disruption of visual scanning behavior. In a placebo-controlled and repeated-measures design, the present study investigated the influence of moderate alcohol intake (0.6 g/kg) on VSWM and gaze behavior by using gaze entropy measures to quantify visual scanning efficiency. Thirty-eight (18 female, 20 male) healthy participants completed a VSWM task across three consecutive sessions (baseline, ascending, descending) while their eye movements were simultaneously recorded. Performance in VSWM was affected during the descending session, where response accuracy declined significantly. Stationary gaze entropy (SGE) and gaze transition entropy (GTE) measures significantly reduced during both ascending and descending sessions. Fixation rate and duration were also affected by alcohol, but only during the ascending session. Reduction in SGE suggests a less explorative distribution of gaze, whereas low GTE is indicative of reduced visual scanning efficiency. These findings reflect the detrimental effects of alcohol on top-down control of gaze behavior, which may limit visual scanning efficiency. Deficits in visual scanning efficiency across the blood alcohol concentration curve may reduce visuospatial awareness and contribute to unintentional injuries during periods of intoxication.


The Prevalence of Problem Gambling and Gambling Disorder Among Homeless People: A Systematic Review And Meta-Analysis.
Gambling problems are often associated with homelessness and linked to elevated psychiatric morbidity and homelessness chronicity. We performed a systematic review and meta-analysis on prevalence rates of problem gambling (PG) and gambling disorder (GD) in homeless people. Following PRISMA guidelines, we searched databases Medline, Embase and PsycINFO from inception of databases to 4th may 2021. We included studies reporting prevalence estimates on clinical gambling problems in representative samples of homeless people based on standardized diagnostics. Risk of bias was assessed. A random effects meta-analysis was performed, and subgroup analyses based on methodological characteristics of primary studies were conducted. We identified eight studies from five countries, reporting information on 1938 participants. Prevalence rates of clinically significant PG and GD ranged from 11.3 to 31.3%. There was evidence for substantial heterogeneity with I2 = 86% (95% CI 63-97%). A subgroup of four low risk of bias studies displayed a significantly lower results ranging from 11.3 to 23.6%. Additionally, high rates of subclinical problem gambling were reported (11.6-56.4%). At least one in ten homeless persons experiences clinically significant PG or GD. Social support and health care services for the homeless should address this problem by implementing models for early detection and treatment.


ARMC5 Alterations in Primary Macronodular Adrenal Hyperplasia (PMAH) and the Clinical State of Variant Carriers.
Primary macronodular adrenal hyperplasia (PMAH) is a rare type of Cushing or subclinical Cushing syndrome and is associated with bilateral multinodular formation. ARMC5 is one of the responsible genes for PMAH. This study was performed to identify the genotype-phenotype correlation of ARMC5 in a cohort of Japanese patients. Fourteen patients with clinically diagnosed PMAH and family members of selected patients were studied for ARMC5 gene alteration and clinical phenotype. The associated nonadrenal tumor tissues were also studied. Of fourteen patients with PMAH, 10 had pathogenic or likely pathogenic variants of ARMC5. We found two variants. Five unrelated patients had identical variants (p.R619*). In two patients, the variant was found in offspring with the asymptomatic or presymptomatic state. Six of ten patients who tested positive for the ARMC5 pathogenic or likely pathogenic variant carried nonadrenal tumors; however, no loss of heterozygosity (LOH) or second hit of the ARMC5 gene was evident. The ARMC5 variant-positive group showed a significantly higher basal cortisol level. Furthermore, age-dependent cortisol hypersecretion was seen in the ARMC5 variant-positive group. ARMC5 pathogenic variants are common (71%) in Japanese patients with PMAH. p.R619* might be a hot spot in Japanese patients with PMAH. Asymptomatic or presymptomatic pathogenic variant carriers were found among the family members of the patients. Although 50% of ARMC5 variant carriers had nonadrenal neoplastic lesions, no LOH or second hit of ARMC5 in the tumor tissues was evident. The ARMC5 variant-positive mutant group showed a higher basal cortisol level than the negative group.


Cranberry extract standardized for proanthocyanidins promotes the immune response of Caenorhabditis elegans to Vibrio cholerae through the p38 MAPK pathway and HSF-1.
Botanicals are rich in bioactive compounds, and some offer numerous beneficial effects to animal and human health when consumed. It is well known that phytochemicals in cranberries have anti-oxidative and antimicrobial activities. Recently, an increasing body of evidence has demonstrated that cranberry phytochemicals may have potential benefits that promote healthy aging. Here, we use Caenorhabditis elegans as a model to show that water-soluble cranberry extract standardized to 4.0% proanthocyanidins (WCESP), a major component of cranberries, can enhance host innate immunity to resist against Vibrio cholerae (V. cholerae; wild type C6706 (O1 El Tor biotype)) infection. Supplementation of WCESP did not significantly alter the intestinal colonization of V. cholerae, but upregulated the expression of C. elegans innate immune genes, such as clec-46, clec-71, fmo-2, pqn-5 and C23G10.1. Additionally, WCESP treatment did not affect the growth of V. cholerae and expression of the major bacterial virulence genes, and only slightly reduced bacterial colonization within C. elegans intestine. These findings indicate that the major components of WCESP, including proanthocyanidins (PACs), may play an important role in enhancing the host innate immunity. Moreover, we engaged C. elegans mutants and identified that the p38 MAPK signaling, insulin/IGF-1 signaling (IIS), and HSF-1 play pivotal roles in the WCESP-mediated host immune response. Considering the level of conservation between the innate immune pathways of C. elegans and humans, the results of this study suggest that WCESP may also play an immunity-promoting role in higher order organisms.


Feedback inhibition of steroidogenic acute regulatory protein expression in vitro and in vivo by androgens.
Müllerian-inhibiting substance (MIS) reduces testosterone synthesis in Leydig cells by inhibiting cytochrome P450C17 hydroxylase/C17-20 lyase expression. However, in mouse Leydig MA-10 cells, MIS also enhances the cAMP-induced expression of mRNA for steroidogenic acute regulatory protein (StAR), which transports cholesterol to the inner mitochondrial membrane for conversion to pregnenolone. We hypothesized that the MIS-induced StAR expression is the indirect result of reduced testosterone synthesis in Leydig cells caused by MIS. We show that, in addition to MIS, flutamide, an androgen receptor antagonist, enhanced StAR mRNA expression when added to cAMP-treated MA-10 cells, whereas dihydrotestosterone, a potent androgen receptor agonist, attenuated these responses. Progesterone, dexamethasone, and estradiol also inhibited StAR mRNA expression. Addition of MIS to cAMP-treated MA-10 cells transfected with a StAR-promoter luciferase reporter resulted in increased StAR promoter activity over cAMP alone; this effect was inhibited by dihydrotestosterone, suggesting that androgens inhibit StAR mRNA expression at the transcriptional level. Androgen-mediated inhibition of StAR expression was also observed in primary Leydig cell culture and in vivo using both hypophysectomized mice and mice treated with the GnRH antagonist, acyline. These results suggest that the induction of StAR expression by MIS occurs secondary to the MIS-mediated reduction in testosterone synthesis by relieving a hitherto uncharacterized androgen-dependent feedback inhibition on StAR expression. These findings may impact future treatment strategies aimed at reducing androgen; for example, in the treatment of prostatic cancer, antiandrogen treatment might benefit from adjuvant therapy to inhibit StAR expression.