Wittjones6716

Temperature affects the conductances and kinetics of the ionic channels that underlie neuronal activity. Each membrane conductance has a different characteristic temperature sensitivity, which raises the question of how neurons and neuronal circuits can operate robustly over wide temperature ranges. To address this, we employed computational models of the pyloric network of crabs and lobsters. We produced multiple different models that exhibit a triphasic pyloric rhythm over a range of temperatures and explored the dynamics of their currents and how they change with temperature. Temperature can produce smooth changes in the relative contributions of the currents to neural activity so that neurons and networks undergo graceful transitions in the mechanisms that give rise to their activity patterns. Moreover, responses of the models to deletions of a current can be different at high and low temperatures, indicating that even a well-defined genetic or pharmacological manipulation may produce qualitatively distinct effects depending on the temperature.MCL1 has critical antiapoptotic functions and its levels are tightly regulated by ubiquitylation and degradation, but mechanisms that drive this degradation, particularly in solid tumors, remain to be established. We show here in prostate cancer cells that increased NOXA, mediated by kinase inhibitor activation of an integrated stress response, drives the degradation of MCL1, and identify the mitochondria-associated ubiquitin ligase MARCH5 as the primary mediator of this NOXA-dependent MCL1 degradation. Therapies that enhance MARCH5-mediated MCL1 degradation markedly enhance apoptosis in response to a BH3 mimetic agent targeting BCLXL, which may provide for a broadly effective therapy in solid tumors. Conversely, increased MCL1 in response to MARCH5 loss does not strongly sensitize to BH3 mimetic drugs targeting MCL1, but instead also sensitizes to BCLXL inhibition, revealing a codependence between MARCH5 and MCL1 that may also be exploited in tumors with MARCH5 genomic loss.Despite the introduction of biologics, topical dithranol (anthralin) has remained one of the most effective anti-psoriatic agents. Serial biopsies from human psoriatic lesions and both the c-Jun/JunB and imiquimod psoriasis mouse model allowed us to study the therapeutic mechanism of this drug. Top differentially expressed genes in the early response to dithranol belonged to keratinocyte and epidermal differentiation pathways and IL-1 family members (i.e. IL36RN) but not elements of the IL-17/IL-23 axis. In human psoriatic response to dithranol, rapid decrease in expression of keratinocyte differentiation regulators (e.g. involucrin, SERPINB7 and SERPINB13), antimicrobial peptides (e.g. ß-defensins like DEFB4A, DEFB4B, DEFB103A, S100 proteins like S100A7, S100A12), chemotactic factors for neutrophils (e.g. CXCL5, CXCL8) and neutrophilic infiltration was followed with much delay by reduction in T cell infiltration. Targeting keratinocytes rather than immune cells may be an alternative approach in particular for topical anti-psoriatic treatment, an area with high need for new drugs.The fusion of gamete membranes during fertilization is an essential process for sexual reproduction. Despite its importance, only three proteins are known to be indispensable for sperm-egg membrane fusion the sperm proteins IZUMO1 and SPACA6, and the egg protein JUNO. Here we demonstrate that another sperm protein, TMEM95, is necessary for sperm-egg interaction. TMEM95 ablation in mice caused complete male-specific infertility. Sperm lacking this protein were morphologically normal exhibited normal motility, and could penetrate the zona pellucida and bind to the oolemma. However, once bound to the oolemma, TMEM95-deficient sperm were unable to fuse with the egg membrane or penetrate into the ooplasm, and fertilization could only be achieved by mechanical injection of one sperm into the ooplasm, thereby bypassing membrane fusion. These data demonstrate that TMEM95 is essential for mammalian fertilization.Background Most people who are dying want to be cared for at home, but only half of them achieve this. The likelihood of a home death often depends on the availability of able and willing lay carers. When people who are dying are unable to take oral medication, injectable medication is used. When top-up medication is required, a health-care professional travels to the dying person's home, which may delay symptom relief. selleck chemical The administration of subcutaneous medication by lay carers, although not widespread UK practice, has proven to be key in achieving better symptom control for those dying at home in other countries. Objectives To determine if carer administration of as-needed subcutaneous medication for common breakthrough symptoms in people dying at home is feasible and acceptable in the UK, and if it would be feasible to test this intervention in a future definitive randomised controlled trial. Design We conducted a two-arm, parallel-group, individually randomised, open pilot trial of the intervention versusIHR Journals Library website for further project information.Objectives Gonorrhoea continues to be a public health concern in Belgium with pharyngeal and rectal infections increasing in persons with high-risk sexual behaviour. Belgian health care practitioners rely on international guidance when managing gonorrhoea resulting in non-adapted suboptimal care for the Belgian patient. This guideline will rectify this situation. Methods This guideline was developed following an evidence-based approach and involving a guideline development group (GDG). Research questions were prioritised by the GDG and researchers conducted a systematic review of the evidence that was assessed using GRADE approach. Results The guideline offers recommendations for gonorrhoea diagnosis, treatment and management for primary care professionals in Belgium and applies a risk group approach. This approach aims for improved identification of at-risk persons and targeted testing of at-risk groups; it includes behavioural questioning when deciding on diagnostic sampling and provides clear advice on treatment.