Sarcopenic obesity is associated with increased visceral fat and decreased muscle mass, resulting in decreased insulin sensitivity, increased production of inflammatory cytokines, and oxidative stress. In this study, we first evaluated the effects of herbal medicines on the transcriptional activity of the Sirtuin 1 (sirt1) promoter in vitro as an indicator of their therapeutic effect. Our data suggested that hot water Saikokeishikankyoto (SKK) extracts increased sirt1 transcriptional activity in vitro, identifying it as a candidate therapeutic for evaluation in the KKAy type 2 diabetic obesity mouse model. These in vivo evaluations revealed that SKK treatment increased the wet weight and muscle fiber content in cross sections of the gastrocnemius muscle (GA) and restored motor function in these animals. In addition, SKK treatment reduced tumor necrosis factor-α (TNFα) expression in the sera and suppressed Atrogin1 and MuRF1 transcription in the GA samples. This treatment also increased sirt1 expression in these tissues. These results suggest that SKK inhibits skeletal muscle atrophy and improves motor function in KKAy mice by suppressing inflammation. In actual clinical practice, SKK is expected to inhibit muscle atrophy and improve motor dysfunction in sarcopenic obesity.Gene-knockout pigs have important applications in agriculture and medicine. Compared with CRISPR/Cas9, Adenine base editor (ABE) convert single A·T pairs to G·C pairs in the genome without generating DNA double-strand breaks, and this method has higher accuracy and biosafety in pig genetic modification. However, the application of ABE in pig gene knockout is limited by protospacer-adjacent motif sequences and the base-editing window. Alternative mRNA splicing is an important mechanism underlying the formation of proteins with diverse functions in eukaryotes. Spliceosome recognizes the conservative sequences of splice donors and acceptors in a precursor mRNA. Mutations in these conservative sequences induce exon skipping, leading to proteins with novel functions or to gene inactivation due to frameshift mutations. In this study, adenine base-editing-mediated exon skipping was used to expand the application of ABE in the generation of gene knockout pigs. We first constructed a modified „all-in-one” ABE vector s This is the first proof-of-concept study of adenine base-editing-mediated exon skipping for gene regulation in pigs, and this work provides a new strategy for accurate and safe genetic modification of pigs for agricultural and medical applications.

To report a case of Vogt-Koyanagi-Harada (VKH) syndrome-like posterior uveitis after nivolumab administration to treat an ovarian cancer with an electrophysiological finding. A 61-year-old woman with ovarian cancer (stage 3A) and salpingo-oophorectomy surgery history visited the clinic complaining of blurred vision in both eyes. She had been enrolled a clinical trial using nivolumab in patients with ovarian cancer. She received four cycles of nivolumab administration and experienced blurred vision one week before the initial visit. There was no remarkable finding in the anterior segment and the vitreous body. Multiple subretinal fluid accumulations and serous retinal detachment were identified on the posterior pole. Subretinal fluid with choroidal folding was noted in optical coherence tomography, and multiple leakage points were also observed in wide-field fundus fluorescein angiography. Therefore, intravenous high-dose steroid pulse therapy was applied under the diagnosis of VKH syndrome-like posterior uvnhibitor. It is associated with the upregulation of T-cell activity by interfering with the interaction between the programmed death-1 (PD-1) receptor and the PD-ligand. Targeted therapy using immunotherapy agents has been widely used for malignant melanoma, lung cancer, renal cell carcinoma, and other cancers. However, immunotherapy agents such as nivolumab can induce autoimmune-related adverse events including uveitis. This report suggests that VKH syndrome-like posterior uveitis could be induced by nivolumab administration for an ovarian cancer treatment, which was resolved by steroid pulse therapy.Human hemodynamic responses during exposure to multi-axial acceleration was a relatively new topic in the fields of acceleration physiology. This study aimed to focus on these responses, especially variations of blood perfusion to brain and eyes, through mathematical modeling. A mathematical model was established using lumped parameter methods, containing compartments of four heart chambers, systemic arteries and veins, circulation of typical systemic organs, and some compartments for pulmonary circulation, together with autonomic regulation considered. This model was firstly validated by using experimental data from experiment of posture change and centrifuge tests of +Gz accelerations, and then applied to analyze human hemodynamic responses to typical multi-axial accelerations. Validation results demonstrated the mathematical model could generate reasonable responses of human cardiovascular system during posture change and exposure to +Gz accelerations. Simulation results of hemodynamic responses to multi-ations.Hypoxia plays an important regulatory role in the vasculature to adjust blood flow to meet metabolic requirements. At the level of gene transcription, the responses are mediated by hypoxia-inducible factor (HIF) the stability of which is controlled by the HIF prolyl 4-hydroxylase-2 (PHD2). In the lungs hypoxia results in vasoconstriction, however, the pathophysiological relevance of PHD2 in the major arterial cell types; endothelial cells (ECs) and arterial smooth muscle cells (aSMCs) in the adult vasculature is incompletely characterized. Here, we investigated PHD2-dependent vascular homeostasis utilizing inducible deletions of PHD2 either in ECs (Phd2∆ECi) or in aSMCs (Phd2∆aSMC). Cardiovascular function and lung pathologies were studied using echocardiography, Doppler ultrasonography, intraventricular pressure measurement, histological, ultrastructural, and transcriptional methods. Cell intrinsic responses were investigated in hypoxia and in conditions mimicking hypertension-induced hemodynamic stress. Phd2∆ECi resulted in progressive pulmonary disease characterized by a thickened respiratory basement membrane (BM), alveolar fibrosis, increased pulmonary artery pressure, and adaptive hypertrophy of the right ventricle (RV). A low oxygen environment resulted in alterations in cultured ECs similar to those in Phd2∆ECi mice, involving BM components and vascular tone regulators favoring the contraction of SMCs. In contrast, Phd2∆aSMC resulted in elevated RV pressure without alterations in vascular tone regulators. Mechanistically, PHD2 inhibition in aSMCs involved actin polymerization -related tension development via activated cofilin. The results also indicated that hemodynamic stress, rather than PHD2-dependent hypoxia response alone, potentiates structural remodeling of the extracellular matrix in the pulmonary microvasculature and respiratory failure.Socio-demographic risks are associated with higher child screen time and higher screen time is associated with poor socioemotional and developmental health. Existing studies have not examined children’s screen time as a mechanism through which distal risks may be associated with child outcomes. In the current study, we examined whether two proximal factors, screen time and parenting quality, mediate the relation between distal cumulative risk and child outcomes. Participants (N = 1992) were drawn from a birth cohort of mothers and their children (81% white; 46% female). Mothers reported on cumulative risk factors (maternal income, education, depression, stress, marital status, housing instability, unemployment, and maternal history of childhood adversity) during the prenatal period. Parenting quality (ineffective/hostile, positive interactions) and children’s screen time (hours/week) were assessed when children were three years of age. Child socioemotional (internalizing and externalizing problems) and developmental (achievement of developmental milestones) outcomes were measured at five years of age. Path analysis revealed indirect effects from cumulative risk to internalizing symptoms and achievement of developmental milestones via screen time. Indirect effects were observed from cumulative risk to internalizing and externalizing behavior via hostile parenting behavior. Over and above the effects of parenting, screen time may be a factor that links structural forms of social disadvantage during the prenatal period to child socioemotional and developmental outcomes. Due to modest effect sizes of screen time, it remains the case that child socioemotional and developmental health should be conceptualized within the context of distal cumulative risk factors such as caregiver psychological and material resources.It is well established that anxiety can contribute to social functioning difficulties during childhood and adolescence. It is less clear which anxious youth are most likely to struggle socially, and what types of difficulties they are likely to experience, limiting the extent of identification and intervention efforts. In this study, we aim to improve specification of the linkages between youth anxiety severity and social functioning by examining several potential moderators of these associations. Specifically, we examine whether family accommodation of youth anxiety, in addition to youth age, sex, and the presence of a social anxiety disorder diagnosis, influence associations between anxiety severity and social functioning among youth with anxiety disorders. Youth (N = 158, Mage = 9.99 years, SD = 2.74) and their mothers completed diagnostic interviews and questionnaires assessing anxiety and depression symptoms, family accommodation, and a range of social functioning variables. In a series of hierarchical linear regressions, we found that youth anxiety severity was most strongly associated with social impairment at high levels of family accommodation for adolescents and for youth without social anxiety disorder (mother-report). We also found several direct effects of anxiety severity, family accommodation, and youth age, sex, and diagnosis on different facets of youth social functioning (youth- and/or mother-report). We discuss clinical implications and future research directions focused on specifying the nature of associations between youth anxiety and their social functioning.With the rise in popularity of media pieces depicting alternative sexual/relationship preferences, there has been a rise in interest in kink and BDSM (Sprott & Berkey, 2015), which corresponds with research suggesting that approximately 20% of Americans have been in a consensually non-monogamous relationship (Haupert et al., 2016). Despite this growing popularity, these populations are often stigmatized and misunderstood (Bettinger, 2002). The present study examined the self-reported experiences of individuals who have participated in kink, BDSM, non-monogamy, and/or polyamory. Specifically, the study used qualitative methodology to examine narratives of discrimination, harassment, coming out, being outed, consent violations, and/or sexual assault in a BDSM or non-monogamous encounter. Participants consisted of 67 adults who completed an online survey conducted by the National Coalition for Sexual Freedom and were asked to provide narratives of their experience. Data were analyzed using a modified consensual qualitative research methodology (CQR-M; Spangler et al.