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Patients with obsessive-compulsive disorder (OCD) display disrupted performance and abnormal lateral orbitofrontal cortex (LOFC) activity during reversal learning tasks. However, it is unknown whether compulsions and reversal learning deficits share a common neural substrate. To answer this question, we measured neural activity with in vivo calcium imaging in LOFC during compulsive grooming and reversal learning before and after fluoxetine treatment. Sapap3 knockout (KO) mice were used as a model for OCD-relevant behaviors. Sapap3 KOs and control littermates were injected with a virus encoding GCaMP6f and implanted with gradient-index lenses to visualize LOFC activity using miniature microscopes. Grooming, reversal learning, and neural activity were measured pre- and post-fluoxetine treatment (18 mg/kg, 4 weeks). Baseline compulsive grooming and reversal learning impairments in KOs improved after fluoxetine treatment. In addition, KOs displayed distinct patterns of abnormal LOFC activity during grooming and reversal learning, both of which normalized after fluoxetine. Finally, reversal learning–associated neurons were distributed randomly among grooming-associated neurons (i.e., overlap is what would be expected by chance). In OCD, LOFC is disrupted during both compulsive behaviors and reversal learning, but whether these behaviors share common neural underpinnings is unknown. We found that LOFC plays distinct roles in compulsive grooming and impaired reversal learning and their improvement with fluoxetine. These findings suggest that LOFC plays separate roles in pathophysiology and treatment of different perseverative behaviors in OCD. [ABSTRACT FROM AUTHOR]

To assess the comparative safety and effectiveness of 2 prostate cancer treatment ablation modalities: irreversible electroporation (IRE) and high-intensity focused ultrasound (HIFU). Two systematic literature reviews (SLRs) and meta-analyses (MAs) on IRE and HIFU were conducted in accordance with PRISMA guidelines. Searches were conducted in PubMed and EMBASE. Independent reviewers assessed literature eligibility and abstracted safety and effectiveness data. Oncological, safety, functional, and quality of life (QOL) outcomes were examined for each technology. MAs were conducted where data quality and availability allowed, using normal methods and a random/mixed effects model, and quality assessments performed. Fifty-five publications (n = 22 IRE; n = 33 HIFU) were included in the SLRs, and MAs were conducted on negative in-field post-procedure biopsy, prostate-specific antigen (PSA) level reduction, potency, urinary continence, and AE rate outcomes. MAs revealed that IRE patients had lower mean percent PSA level reductions, higher mean rates of in-field negative post-treatment biopsy, and higher rates of potency maintenance than HIFU patients. Most adverse events (AEs) reported were comparable and minor (Grades I, II), with urinary tract infection, dysuria, hematuria, and incontinence or urgency most frequently reported. The proportion of patients experiencing a severe AE (≥Grade III) ranged from 0 to 8% after IRE and HIFU. Both modalities were associated with positive functional outcomes as well as maintenance of QOL after treatment. Both IRE and HIFU were found to produce favorable effectiveness outcomes and have low complication rates while minimally impacting patient urinary and erectile function and maintaining overall QOL. These real-world findings can help guide clinical decision making and improve disease management for patients with prostate cancer. [ABSTRACT FROM AUTHOR]

Obsessive compulsive disorder (OCD) is associated with disruption of sensorimotor gating, which may contribute to difficulties inhibiting intrusive thoughts and compulsive rituals. Neural mechanisms underlying these disturbances are unclear; however, striatal dopamine is implicated in regulation of sensorimotor gating and OCD pathophysiology. The goal of this study was to examine the relationships between sensorimotor gating, compulsive behavior, and striatal dopamine receptor levels in Sapap3 knockout mice (KOs), a widely used preclinical model system for OCD research. We found a trend for disruption of sensorimotor gating in Sapap3-KOs using the translational measure prepulse inhibition (PPI); however, there was significant heterogeneity in both PPI and compulsive grooming in KOs. Disruption of PPI was significantly correlated with a more severe compulsive phenotype. In addition, PPI disruption and compulsive grooming severity were associated with reduced dopamine D1 and D2/3 receptor density in the nucleus accumbens core (NAcC). Compulsive grooming progressively worsened in Sapap3-KOs tested longitudinally, but PPI disruption was first detected in high-grooming KOs at 7 months of age. Through detailed characterization of individual differences in OCD-relevant behavioral and neurochemical measures, our findings suggest that NAcC dopamine receptor changes may be involved in disruption of sensorimotor gating and compulsive behavior relevant to OCD. [ABSTRACT FROM AUTHOR]

• Changing associations between events in the environment cause behavioural conflict. • The prefrontal cortex and amygdala contribute to adaptive behaviour during conflict. • Conflict exists in popular extinction, reversal learning and active avoidance tasks. • Deconstructing behaviour and neural control reveals common features of conflict. In complex environments, organisms must respond adaptively to situations despite conflicting information. Under natural (i.e. non-laboratory) circumstances, it is rare that cues or responses are consistently paired with a single outcome. Inconsistent pairings are more common, as are situations where cues and responses are associated with multiple outcomes. Such inconsistency creates conflict, and a response that is adaptive in one scenario may not be adaptive in another. Learning to adjust responses accordingly is important for species to survive and prosper. Here we review the behavioural and brain mechanisms of responding under conflict by focusing on three popular behavioural procedures: extinction, reversal learning, and active avoidance. Extinction involves adapting from reinforcement to non-reinforcement, reversal learning involves swapping the reinforcement of cues or responses, and active avoidance involves performing a response to avoid an aversive outcome, which may conflict with other defensive strategies. We note that each of these phenomena relies on somewhat overlapping neural circuits, suggesting that such circuits may be critical for the general ability to respond appropriately under conflict. [ABSTRACT FROM AUTHOR]

This study evaluated the role of bulk and substrate physics on hydrolysis rates and biogas yields in anaerobic digestion (AD) pretreated by thermal hydrolysis (THP). Although THP decreases sludge viscosity, no evidence was found that bulk viscosity impacted the biogas yield or hydrolysis kinetics. In addition, no significant difference between the biogas yields for different total solids concentrations nor floc sizes was detected. However, increased mixing speeds did increase biogas yields. As a result of thermal treatment, the model protein, bovine serum albumin, was harder to degrade in terms of both overall biodegradability and hydrolysis rates when their macrostructures were changed from liquid to gel and to solid structures; the opposite was true for the model polysaccharide, amylopectin. These results demonstrated that hydrolysis in THP‐AD systems was impacted mostly by the physical properties of the substrate (gelation) rather than the bulk physical properties within the digester. Practitioner points: Bulk viscosity does not significantly impact hydrolysis efficiency (biogas yield). However, mixing speed impacts hydrolysis beyond biogas holdup effect.Increasing the amount of substrate–microbe collisions through increasing biomass concentration does not have an impact on hydrolysis efficiency or biogas yield.Proteins are harder to degrade when macrostructure changes from liquid to gel/solid as a result of heat treatment.Polysaccharides are easier to degrade when macrostructure changes from liquid to gel/solid as a result of heat treatment.The time required for digesters to reach peak biogas production rates increased with decreasing specific surface available on gel and solid structures. [ABSTRACT FROM AUTHOR]

The membrane (M) glycoprotein of coronaviruses (CoVs) serves as the nidus for virion assembly. Using a yeast two-hybrid screen, we identified the interaction of the cytosolic tail of Murine Hepatitis Virus (MHV-CoV) M protein with Myosin Vb (MYO5B), specifically with the alternative splice variant of cellular MYO5B including exon D (MYO5B+D), which mediates interaction with Rab10. When co-expressed in human lung epithelial A549 and canine kidney epithelial MDCK cells, MYO5B+D co-localized with the MHV-CoV M protein, as well as with the M proteins from Porcine Epidemic Diarrhea Virus (PEDV-CoV), Middle East Respiratory Syndrome (MERS-CoV) and Severe Acute Respiratory Syndrome 2 (SARS-CoV-2). Co-expressed M proteins and MYO5B+D co-localized with endogenous Rab10 and Rab11a. We identified point mutations in MHV-CoV M that blocked the interaction with MYO5B+D in yeast 2-hybrid assays. One of these point mutations (E121K) was previously shown to block MHV-CoV virion assembly and its interaction with MYO5B+D. The E to K mutation at homologous positions in PEDV-CoV, MERS-CoV and SARS-CoV-2 M proteins also blocked colocalization with MYO5B+D. The knockdown of Rab10 blocked the co-localization of M proteins with MYO5B+D and was rescued by re-expression of CFP-Rab10. Our results suggest that CoV M proteins traffic through Rab10-containing systems, in association with MYO5B+D. [ABSTRACT FROM AUTHOR]

Hyperactivity in striatum is associated with compulsive behaviors in obsessive-compulsive disorder (OCD) and related illnesses, but it is unclear whether this hyperactivity is due to intrinsic striatal dysfunction or abnormalities in corticostriatal inputs. Understanding the cellular and circuit properties underlying striatal hyperactivity could help inform the optimization of targeted stimulation treatments for compulsive behavior disorders. To investigate the cellular and synaptic abnormalities that may underlie corticostriatal dysfunction relevant to OCD, we used the Sapap3 knock-out (Sapap3-KO) mouse model of compulsive behaviors, which also exhibits hyperactivity in central striatum. Ex vivo electrophysiology in double-transgenic mice was used to assess intrinsic excitability and functional synaptic input in spiny projection neurons (SPNs) and fast-spiking interneurons (FSIs) in central striatum of Sapap3-KOs and wild-type (WT) littermates. While we found no differences in intrinsic excitability of SPNs or FSIs between Sapap3-KOs and WTs, excitatory drive to FSIs was significantly increased in KOs. Contrary to predictions, lateral orbitofrontal cortex-striatal synapses were not responsible for this increased drive; optogenetic stimulation revealed that lateral orbitofrontal cortex input to SPNs was reduced in KOs (--3-fold) and unchanged in FSIs. However, secondary motor area (M2) postsynaptic responses in central striatum were significantly increased (~6-fold) in strength and reliability in KOs relative to WTs. These results suggest that increased M2-striatal drive may contribute to both in vivo striatal hyperactivity and compulsive behaviors, and support a potential role for presupplementary/supplementary motor cortical regions in the pathology and treatment of compulsive behavior disorders. [ABSTRACT FROM AUTHOR]

A widespread rule of sex work is that payment occurs before service provision. Drawing on a subset of data collected as part of an ethnographic study conducted in metro Vancouver, Canada, this paper explores the temporal and gendered connections between payment and financial violence in a semi-criminalised indoor sex industry. A detailed examination of the timing of payment with 51 independent indoor sex workers reveals the gendered nature of the violence and its direct connection to anti-violence strategies indoor sex workers employ. We found that women (including transgender women) (n= 26) and men (n= 25) use payment schedules to minimise potential violence, but in divergent ways. Sex workers adhere to, negotiate and reject the golden rule of payment in advance based on different experiences of gendered violence. Through a gendered relational analysis, we show the contextual relationship between men and women as they negotiate payment schedules in their sex work interactions. These findings offer insight into the significance that the timing of payment has in sex workers’ anti-violence practices. [ABSTRACT FROM PUBLISHER]

This paper presents the continued development of a novel non-destructive testing method termed tube-jack testing. The goal of the tube-jack system is to provide an enhanced and less destructive method than traditional flat-jack testing for determination of mechanical characteristics and local stress states in irregular masonry walls. Single tube-jack tests were performed, using previously developed rubber tube-jacks, in regular masonry walls of granite and cement-lime mortar. A traditional flat-jack test was also performed in the same masonry wall. Conclusions suggest that tube-jacks are successful in applying pressure to the masonry at low stress states. [ABSTRACT FROM AUTHOR]

Growing clinical evidence suggests that persistent psychosis which occurs in methamphetamine users is closely related to schizophrenia. However, preclinical studies in animal models have focussed on psychosis-related behaviours following methamphetamine, and less work has been done to assess endophenotypes relevant to other deficits observed in schizophrenia. Altered social behaviour is a feature of both the negative symptoms and cognitive deficits in schizophrenia, and significantly impacts patient functioning. We recently found that brain-derived neurotrophic factor (BDNF) heterozygous mice show disrupted sensitization to methamphetamine, supporting other work suggesting an important role of this neurotrophin in the pathophysiology of psychosis and the neuronal response to stimulant drugs. In the current study, we assessed social and cognitive behaviours in methamphetamine-treated BDNF heterozygous mice and wildtype littermate controls. Following chronic methamphetamine exposure male wildtype mice showed a 50% reduction in social novelty preference. Vehicle-treated male BDNF heterozygous mice showed a similar impairment in social novelty preference, with a trend for no further disruption by methamphetamine exposure. Female mice were unaffected in this task, and no groups showed any changes in sociability or short-term spatial memory. These findings suggest that chronic methamphetamine alters behaviour relevant to disruption of social cognition in schizophrenia, supporting other studies which demonstrate a close resemblance between persistent methamphetamine psychosis and schizophrenia. Together these findings suggest that dynamic regulation of BDNF signalling is necessary to mediate the effects of methamphetamine on behaviours relevant to schizophrenia. [ABSTRACT FROM AUTHOR]

Protein-coding mutations in the transcription factor-encoding gene ARX cause various forms of intellectual disability (ID) and epilepsy. In contrast, variations in surrounding non-coding sequences are correlated with milder forms of non-syndromic ID and autism and had suggested the importance of ARX gene regulation in the etiology of these disorders. We compile data on several novel and some already identified patients with or without ID that carry duplications of ARX genomic region and consider likely genetic mechanisms underlying the neurodevelopmental defects. We establish the long-range regulatory domain of ARX and identify its brain region-specific autoregulation. We conclude that neurodevelopmental disturbances in the patients may not simply arise from increased dosage due to ARX duplication. This is further exemplified by a small duplication involving a non-functional ARX copy, but with duplicated enhancers. ARX enhancers are located within a 504-kb region and regulate expression specifically in the forebrain in developing and adult zebrafish. Transgenic enhancer-reporter lines were used as in vivo tools to delineate a brain region-specific negative and positive autoregulation of ARX. We find autorepression of ARX in the telencephalon and autoactivation in the ventral thalamus. Fluorescently labeled brain regions in the transgenic lines facilitated the identification of neuronal outgrowth and pathfinding disturbances in the ventral thalamus and telencephalon that occur when arxa dosage is diminished. In summary, we have established a model for how breakpoints in long-range gene regulation alter the expression levels of a target gene brain region-specifically, and how this can cause subtle neuronal phenotypes relating to the etiology of associated neuropsychiatric disease. [ABSTRACT FROM AUTHOR]

Stress has a strong influence on mental health around the world. Decades of research has sought to identify mechanisms through which stress contributes to psychiatric disorders such as depression, to potentially guide the development of therapeutics targeting stress systems. The hypothalamic pituitary adrenal (HPA) axis is the key endocrine system that is responsible for coordinating body‐wide changes that are necessary for survival under stress, and much of the research aimed at understanding the mechanisms by which stress contributes to depression has focussed on HPA axis dysfunction. Corticotrophin releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) sit at the apex of the HPA axis, integrating signals relevant to stress and external threats, to ensure HPA axis activity is appropriate for the given context. In addition to this, emerging research has demonstrated that neural activity in PVNCRH neurons regulates stress related behaviours via modulation of downstream synaptic targets. This review will summarize convergent evidence from preclinical studies on chronic stress and clinical research in mood disorders demonstrating changes in PVNCRH neural function, consider how this may influence synaptic targets of PVNCRH neurons, and discuss the potential role of these PVNCRH synaptic pathways in the development of maladaptive behaviours following chronic stress that are relevant to depression. We will also highlight important questions for future research aimed at precisely dissecting endocrine and synaptic roles of PVNCRH neurons in chronic stress, their potential interactions, and therapeutic opportunities for the treatment of stress related disorders. [ABSTRACT FROM AUTHOR]

Abstract: This paper presents the development and initial testing of tube-jack prototypes for the enhanced non-destructive testing method called tube-jack testing. The tube-jack system is being developed to provide a less destructive method than traditional flat-jack testing for determination of mechanical characteristics and stress states in irregular masonry walls. PVC, rubber, and latex tube-jack prototypes were constructed and tested using various methods. Rubber and latex prototypes were improved with fabric socks added to the design. Final conclusions suggest further tube-jack prototype testing with the modified prototypes in larger masonry specimens and investigation into the effects of horizontal stresses induced by the pressurization. [Copyright &y& Elsevier]

Abstract: To assess the strengthening ability of a strain hardening cementitious composite (SHCC), a layer of SHCC was applied to masonry beams subjected to bending. When compared to the strengthening performance of steel fibre reinforced self-compacting concrete (SFRSCC) layer for this type of brittle beams, the SHCC presented better workability in fresh state, and provided a higher load carrying capacity and deflection ductility even with a smaller layer thickness. By using the data derived from the experimental tests with the constituent materials of the strengthened masonry beams, the behaviour of the tested strengthened masonry beams was numerically simulated with good accuracy. [Copyright &y& Elsevier]

The article presents a study exploring the relation between the use of illicit drugs like cannabis and methamphetamine in the increased risk of schizophrenia and psychosis. Methods of the study included available evidence such as clinical, animal model, and molecular studies focusing on neurotransmitter systems and the brain region. Further studies are needed to learn more about the mechanisms that intervene in the neurodevelopment and long-term effects of these drugs.

An editorial is presented on the radical transformation of clinical research and service resourcing and organization in Australia by way of strengthened collaboration between consumers, careers, clinical services. It outlines the reasons for delays to diagnosis and treatment include factors relating to patients. An overview of the clinical service associated with obsessive-compulsive disorder (OCD) is presented.

Schizophrenia is a devastating psychiatric illness with a complex pathophysiology. We have recently documented schizophrenia-like endophenotypes in phospholipase C-β1 knockout (PLC-β1−/−) mice, including deficits in prepulse inhibition, hyperlocomotion, and cognitive impairments. PLC-β1 signals via multiple G-protein coupled receptor pathways implicated in neural cellular plasticity; however, adult neurogenesis has yet to be explored in this knockout model. In this study, weemployed PLC-β1−/− mice to elucidate possible correlates between aberrant adult hippocampal neurogenesis (AHN) and schizophrenia-like behaviors. Using stereology and bromodeoxyuridine (BrdU) immunohistochemistry we demonstrated a significant increase in the density of adult-generated cells in the granule cell layer (GCL) of adult PLC-β1−/− mice compared with wild-type littermates. Cellular phenotype analysis using confocal microscopy revealed these cells to be mature granule neurons expressing NeuN and calbindin. Increased neuronal survival occurred concomitant with reduced caspase-3(+) cells in the GCL of PLC-β1−/− mice. Stereological analysis of Ki67(+) cells in the subgranular zone suggested that neural precursor proliferation is unchanged in PLC-β1−/− mice. We further showed aberrant migration of mature granule neurons within the GCL of adult PLC-β1−/− mice with excessive adult-generated mature neurons residing in the middle and outer GCL. PLC-β1−/− mice exhibited specific behavioral deficits in location recognition, a measure of hippocampal-dependent memory, but not novel object recognition. Overall, we have shown that PLC-β1−/− mice have a threefold increase in net AHN, and have provided further evidence to suggest a specific deficit in hippocampal-dependent cognition. We propose that abnormal cellular plasticity in these mice may contribute to their schizophrenia-like behavioral endophenotypes. © 2010 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Objectives: Mycobacterium avium subspecies paratuberculosis (MAP) has been targeted for treatment with clarithromycin and rifamycin derivatives in numerous cases of Crohn's disease (CD). 6-Mercaptopurine and its pro-drug azathioprine are widely used as immunomodulators in the treatment of CD and have recently been shown to have anti-MAP activity in vitro. The objectives of the study were to evaluate the in vitro effects on MAP of (i) 6-mercaptopurine when combined with each of eight conventional antibacterial agents with in vitro anti-MAP activity and (ii) antibacterial combinations consisting of two drugs (clarithromycin combined with amikacin, rifampicin, ciprofloxacin or ethambutol) and three drugs (clarithromycin, rifabutin and clofazimine). [ABSTRACT FROM PUBLISHER]

In this article, the author discusses the practices of sexual health assessments that has been plagued by sexual and gender politics in the U.S. She explains that the policy is influenced by the homonormative agenda put forward by lesbian, gay, bisexual, and transgender (LGBT) organizations that produce their own sexual health practices. She informs that sexual health risk assessments helps the health care professionals to access the risk posed to patients due to engagement in sexual activities.

• Chronic methamphetamine (METH) has long-term effects on the serotonin system. • METH decreased dorsal raphe nucleus (DRN) 5-HT 1A receptor binding. • METH reduced tryptophan hydroxylase-positive cell numbers in subregions of DRN. • Brain-Derived Neurotrophic Factor (BDNF) heterozygosity enhanced METH vulnerability. • Findings could be relevant for psychosis-like symptoms associated with METH abuse. To assess the long-term effects of chronic adolescent methamphetamine (METH) treatment on the serotonin system in the brain, we used serotonin-1A receptor (5-HT 1A) and serotonin transporter (SERT) autoradiography, and quantitative tryptophan-hydroxylase 2 (TPH2) immunohistochemistry in the raphe nuclei of mice. Because of the modulatory role of brain-derived neurotrophic factor (BDNF) on the serotonin system and the effects of METH, we included both BDNF heterozygous (HET) mice and wildtype (WT) controls. Male and female mice of both genotypes were treated with an escalating METH dose regimen from the age of 6–9 weeks. At least two weeks later, acute locomotor hyperactivity induced by a 5 mg/kg D-amphetamine challenge was significantly enhanced in METH-pretreated mice, showing long-term sensitisation. METH pretreatment caused a small, but significant decrease of 5-HT 1A receptor binding in the dorsal raphe nucleus (DRN) of males independent of genotype, but there were no changes in the median raphe nucleus (MRN) or in SERT binding density. METH treatment reduced the number of TPH2 positive cells in ventral subregions of the rostral and medial DRN independent of genotype. METH treatment selectively reduced DRN cell counts in BDNF HET mice compared to wildtype mice in medial and caudal ventrolateral subregions previously associated with panic-like behaviour. The data increase our understanding of the long-term and selective effects of METH on brain serotonin systems. These findings could be relevant for some of the psychosis-like symptoms associated with long-term METH use. [ABSTRACT FROM AUTHOR]

Abstract: The present study used inbred, histocompatible Fischer 344 (FIS) and Lewis (LEW) rats to begin to explore the role of the hypothalamic–pituitary–adrenal (HPA) axis in the immune processes and pain behavior associated with the carrageenan model of acute hindpaw inflammation. Because the HPA axis contributes in part to morphine’s analgesic and immunomodulatory properties, the present study also assessed the effects of morphine in carrageenan-inflamed LEW and FIS rats. The results showed that carrageenan-induced hindpaw swelling and pain behavior were greater in FIS than in LEW rats. The enhanced hindpaw swelling in FIS rats correlated with an increase in myeloperoxidase (MPO; a measure of neutrophils) in the inflamed hindpaw. FIS rats showed lower circulating levels of TNFα, higher IL-6 levels, and similar IL-1β and nitric oxide levels, when compared to LEW rats. Morphine produced a significant decrease in carrageenan-induced hindpaw swelling and MPO in both strains, but morphine did not significantly alter circulating cytokine/mediator levels. Morphine’s analgesic effects were greater in the inflamed than the noninflamed hindpaw, and they did not correlate with morphine’s anti-inflammatory effects. In fact, low doses of morphine produced a mechanical allodynia and hyperalgesia in the noninflamed hindpaw of FIS, but not LEW, rats. These results suggest a positive relationship between HPA axis activity and acute inflammation and inflammatory pain. In contrast, little evidence is provided for HPA axis involvement in morphine’s anti-inflammatory or analgesic effects. [Copyright &y& Elsevier]

Surveys for Mycobacterium avium subsp. paratuberculosis infection in free-ranging mammals and birds were conducted on nine dairy and beef cattle farms in Wisconsin and Georgia. Specimens were collected from 774 animals representing 25 mammalian and 22 avian species. Specimens of ileum, liver, intestinal lymph nodes, and feces were harvested from the larger mammals; a liver specimen and the gastrointestinal tract were harvested from birds and small mammals. Cultures were performed by using radiometric culture and acid-fast isolates were identified by 16S/IS900/IS1311 PCR and mycobactin dependency characteristics. M. avium subsp. paratuberculosis was cultured from tissues and feces from 39 samples from 30 animals representing nine mammalian and three avian species. The prevalence of infected wild animals by premises ranged from 2.7 to 8.3% in Wisconsin and from 0 to 6.0% in Georgia. Shedding was documented in seven (0.9%) animals: three raccoons, two armadillos, one opossum, and one feral cat. The use of two highly polymorphic short sequence repeat loci for analysis of 29 of the 39 strains identified 10 alleles. One allelic pattern broadly shared in domestic ruminants ("7,5") appeared in approximately one-third of the wildlife M. avium subsp. paratuberculosis isolates studied. Given the few cases of shedding by free-ranging animals compared to the volume of contaminated manure produced by infected domestic ruminant livestock, contamination of the farm environment by infected wildlife was negligible. Wildlife may, however, have epidemiological significance for farms where M. avium subsp. paratuberculosis recently has been eliminated or on farms free of M. avium subsp. paratuberculosis but located in the geographic vicinity of farms with infected livestock. [ABSTRACT FROM AUTHOR]

Discusses the use of the green fluorescent protein (GFP) in cell research. GFP being responsible for a jellyfish's glimmer; The advantages of GFP above other tagging methods; The initial discovery by Martin Chalfie at Columbia University; The highly unusual structure of GFP; Other luciferin.

Discussion The differential diagnoses for this patient included comedonal/follicular variant of DDD or familial dyskeratotic comedones. We present the case of a 71-year-old woman with widespread comedones since adolescence. [Colour figure can be viewed at wileyonlinelibrary.com] gl Histopathological findings A 5-mm punch biopsy was taken from the left antecubital fossa incorporating a comedo-like macule. [Extracted from the article]

Diffuse midline glioma (DMG), including tumors diagnosed in the brainstem (diffuse intrinsic pontine glioma; DIPG), are uniformly fatal brain tumors that lack effective treatment. Analysis of CRISPR/Cas9 loss-of-function gene deletion screens identified PIK3CA and MTOR as targetable molecular dependencies across patient derived models of DIPG, highlighting the therapeutic potential of the blood-brain barrier-penetrant PI3K/Akt/mTOR inhibitor, paxalisib. At the human-equivalent maximum tolerated dose, mice treated with paxalisib experienced systemic glucose feedback and increased insulin levels commensurate with patients using PI3K inhibitors. To exploit genetic dependence and overcome resistance while maintaining compliance and therapeutic benefit, we combined paxalisib with the antihyperglycemic drug metformin. Metformin restored glucose homeostasis and decreased phosphorylation of the insulin receptor in vivo, a common mechanism of PI3K-inhibitor resistance, extending survival of orthotopic models. DIPG models treated with paxalisib increased calciumactivated PKC signaling. The brain penetrant PKC inhibitor enzastaurin, in combination with paxalisib, synergistically extended the survival of multiple orthotopic patient-derived and immunocompetent syngeneic allograft models; benefits potentiated in combination with metformin and standard-of-care radiotherapy. Therapeutic adaptation was assessed using spatial transcriptomics and ATAC-Seq, identifying changes in myelination and tumor immune microenvironment crosstalk. Collectively, this study has identified what we believe to be a clinically relevant DIPG therapeutic combinational strategy. [ABSTRACT FROM AUTHOR]

Recent work shows that the developmental potential of progenitor cells in the HH10 chick brain changes rapidly, accompanied by subtle changes in morphology. This demands increased temporal resolution for studies of the brain at this stage, necessitating precise and unbiased staging. Here, we investigated whether we could train a deep convolutional neural network to sub-stage HH10 chick brains using a small dataset of 151 expertly labelled images. By augmenting our images with biologically informed transformations and datadriven preprocessing steps, we successfully trained a classifier to sub-stage HH10 brains to 87.1% test accuracy. To determine whether our classifier could be generally applied, we re-trained it using images (269) of randomised control and experimental chick wings, and obtained similarly high test accuracy (86.1%). Saliency analyses revealed that biologically relevant features are used for classification. Our strategy enables training of image classifiers for various applications in developmental biology with limited microscopy data. [ABSTRACT FROM AUTHOR]

In the spinal cord, the central canal forms through a poorly understood process termed dorsal collapse that involves attrition and remodelling of pseudostratified ventricular layer (VL) cells. Here, we use mouse and chick models to show that dorsal ventricular layer (dVL) cells adjacent to dorsal midline Nestin(+) radial glia (dmNes+RG) down-regulate apical polarity proteins, including Crumbs2 (CRB2) and delaminate in a stepwise manner; live imaging shows that as one cell delaminates, the next cell ratchets up, the dmNes+RG endfoot ratchets down, and the process repeats. We show that dmNes+RG secrete a factor that promotes loss of cell polarity and delamination. This activity is mimicked by a secreted variant of Crumbs2 (CRB2S) which is specifically expressed by dmNes+RG. In cultured MDCK cells, CRB2S associates with apical membranes and decreases cell cohesion. Analysis of Crb2F/F/Nestin-Cre+/− mice, and targeted reduction of Crb2/CRB2S in slice cultures reveal essential roles for transmembrane CRB2 (CRB2TM) and CRB2S on VL cells and dmNes+RG, respectively. We propose a model in which a CRB2S–CRB2TM interaction promotes the progressive attrition of the dVL without loss of overall VL integrity. This novel mechanism may operate more widely to promote orderly progenitor delamination. During prenatal development, the lumen of the vertebrate spinal cord is remodelled into the central canal when progenitor cells progressively delaminate. Imaging studies in the mouse provide novel insights into how roof plate–derived dorsal midline glia secrete a factor that regulates local delamination and ratcheting. Gain- and loss-of-function approaches show that the apical polarity protein, Crumbs2, mediates these events, and highlight the role of a secreted variant of Crumbs2. [ABSTRACT FROM AUTHOR]

The article discusses the highlights of a special panel presentation hosted by the Robert Wood Johnson Foundation (RWJF) for the American Medical Writers Association (AMWA) Delaware Valley Chapter (DVC). This meeting entitled "A Conversation with Leaders in Public Health and Health Care" centered on the role of RWJF in the areas of health care, insurance coverage and other public health issues.