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This short-term longitudinal study investigates whether maternal educational attainment, maternal employment status, and family income affect African American children's behavioral and cognitive functioning over time through their impacts on mothers' psychological functioning and parenting efficacy in a sample of 100 poor and near-poor single Black mothers and their 3- and 4-year-old focal children. Results indicate that education, working status, and earnings display statistically significant, negative, indirect relations with behavior problems and, with the exception of earnings, statistically significant, positive, indirect relationships with teacher-rated adaptive language skills over time. Findings suggest further that parenting efficacy may mediate the link between poor and near-poor single Black mothers' depressive symptoms and their preschoolers' subsequent school adjustment. Implications of these findings for policy and program interventions are discussed. [ABSTRACT FROM AUTHOR]

The present study sought to investigate the effects of employment on low-income single black mothers and their preschool children. The sample included 90 mothers from New York City communities who were welfare recipients in 1996, and followed two years later. At follow-up, 53 of the 90 mothers were employed. The findings indicated that lower levels of depressive affect or financial strain were not predictive of entry into the work force. However, once employed, mothers reported less depressive symptoms than those not working. Attaining more education predicted better outcomes for mothers and their children, and provided more of an opportunity to be successful in the job market. For example, having more education was associated with gaining employment, exiting welfare, having stable employment, earning higher wages, and better reading abilities in children. Maternal employment was beneficial to children, as mothers who entered the work force had children who performed better in math achievement at follow-up, after controlling for maternal socioeconomic characteristics and school readiness at baseline. Implications of the findings will be discussed. [ABSTRACT FROM AUTHOR]

Using data from a sample of 178 single black mothers and their young children who were ages three to five at time 1 and ages five to eight at time 2, this study examined the links between and among low-wage employment, mothers' self-efficacy beliefs, depressive symptoms, and a constellation of parenting behaviors in the preschool years to children's cognitive and behavioral functioning in early elementary school years. In general, the results supported a model in which the influence of mothers' employment on maternal parenting and child outcomes was largely indirect and mediated by perceived self-efficacy. Employment was related directly to higher self-efficacy, which in turn was associated with decreased depressive symptoms. Depressive symptoms were associated with the quality of the mother-nonresident father relationship and the latter with the frequency of nonresident fathers' contacts with their children. More contact between nonresident fathers and their children predicted more adequate maternal parenting, which in turn was associated directly with the children's subsequent behavioral and cognitive functioning in early elementary school. The results are discussed in the context of social cognitive theory and the Personal Responsibility and Work Opportunity Reconciliation Act of 1996. [ABSTRACT FROM AUTHOR]

Using a sample of 188 low-income single black mothers (93 employed and 95 nonemployed), this study investigated financial strain, maternal depressive affect, and parenting stress among former welfare recipients who are now working, and current welfare recipients who are not employed. The findings suggested that being employed did not reduce financial strain, as the two groups reported similar levels of strain. However, regression analyses indicated that not being employed was associated with reporting higher levels of stress. Parenting stress was also associated with attaining less education, having boys, reporting more financial strain and depressive affect. Correlates of maternal depressive affect were mother's education and financial strain. Interaction effects were found for employment by financial strain, indicating that higher levels of depressive affect were related to more financial strain among nonemployed mothers. The findings suggest that although employment is associated with better mental health for poor mothers, entry into the workforce is associated with stronger links between financial strain, parenting stress and depressive affect for mothers leaving welfare. [ABSTRACT FROM AUTHOR]

ABSTRACT It was evaluated the possibility to produce two seedlings per avocado seed, through the separation of cotyledons. Two seed lots from two different ungrafted trees were evaluated. From the first tree were obtained 60 seeds, and 50 from the second. Half the seeds of each lot had their cotyledons separated and then whole seeds and half-seeds were sown in river sand. At 90 days after sowing, percentage of germinated seeds, shoot height, main root length, fresh and dry mass of shoots, roots and cotyledons were evaluated. From the first lot of seeds, there was 100% germination, both for the whole seeds and for the half-seeds. For all traits evaluated, higher mean values were observed for seedlings formed from whole seeds. In the second lot of seeds, 88% of germination was observed for whole seeds and 82% of germination for half-seeds. In this second lot, there were no significant differences between the seedlings formed from whole seeds and half-seeds for any of the characteristics evaluated, except for fresh and dry mass of cotyledons. Thus, it is possible to produce two seedlings or rootstocks with a single avocado seed, although this may slightly delay the development of the seedlings

Phosphosphingolipids (PSL) are essential components of eukaryotic membranes. The major PSL in fungi and protists is inositol phosphorylceramide (IPC), while sphingomyelin (SM), and to a lesser extent ethanolamine phosphorylceramide (EPC) predominate in mammals. Most kinetoplastid protozoa have a syntenic locus that encodes a single sphingolipid synthase (SLS) gene. Uniquely, among the kinetoplastids, the salivarian (African) trypanosomes have expanded this locus from a single gene in Trypanosoma vivax (TvSLS) to four genes in T. brucei (TbSLS1-4). We have previously shown that one of these is an IPC synthase, while the others are SM/EPC synthases, and that specificity is controlled by a single signature residue (IPC, serine; SM/EPC, phenylalanine). This residue is serine in T. cruzi and Leishmania major SLSs, both of which are demonstrated IPC synthases. However, T. vivax has a tyrosine at this residue raising the issue of specificity. Using a liposome-supplemented in vitro translation system we now show that T. vivax SLS is an SM/EPC synthase, and that the basal kinetoplastid Bodo saltans SLS is an IPC synthase (serine). We use these data, and a multiple alignment of available sequences, to discuss the evolution of kinetoplastid SLSs and their unique expansion in T. brucei and related salivarian trypanosomes., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Recent studies suggest a need for reliable biomarkers enhancing prognosis prediction and treatment strategies in cancer. Here, we performed a data analysis bearing on the expression of SCN3B, voltage-gated sodium channel (VGSC) β3 subunit, as a possible candidate for the development of a glioma biomarker for the first time. This extends our previous review article that mentioned the potential of SCN3B as a prognostic biomarker for glioma survival, further examining its association with existing indicators and immune responses. We utilized clinical and genomic data from multiple glioma cohorts. These include the Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA). We employed analytical techniques including time-dependent receiver operating characteristic (ROC) analysis, decision curves analysis (DCA), and correlation studies with immune checkpoint markers. Our findings indicate a differential SCN3B expression between glioma grades, and that this significantly correlates with patient survival, particularly in oligodendroglioma subtypes. The DCA curves suggested that the inclusion of SCN3B in the prognostic model would improve decision-making in these subtypes. Moreover, SCN3B expression positively correlated with the presence of key immune cells and negatively correlated with several immune checkpoint inhibitors. This suggests potential roles in modulating immune responses in glioma. Thus, SCN3B emerges as a promising potential prognostic biomarker for glioma, especially for oligodendroglioma. Its dual correlations with prognosis and immune regulation present a compelling case for further experimental and clinical investigations to establish its utility in enhancing glioma management strategies. These findings underscore the importance of integrating novel biomarkers with traditional prognostic models to refine treatment paradigms and improve patient outcomes., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Solid tumours have abnormally high intracellular [Na + ]. The activity of various Na + channels may underlie this Na + accumulation. Voltage-gated Na + channels (VGSCs) have been shown to be functionally active in cancer cell lines, where they promote invasion. However, the mechanisms involved, and clinical relevance, are incompletely understood. Here, we show that protein expression of the Na v 1.5 VGSC subtype strongly correlates with increased metastasis and shortened cancer-specific survival in breast cancer patients. In addition, VGSCs are functionally active in patient-derived breast tumour cells, cell lines, and cancer-associated fibroblasts. Knockdown of Na v 1.5 in a mouse model of breast cancer suppresses expression of invasion-regulating genes. Na v 1.5 activity increases ATP demand and glycolysis in breast cancer cells, likely by upregulating activity of the Na + /K + ATPase, thus promoting H + production and extracellular acidification. The pH of murine xenograft tumours is lower at the periphery than in the core, in regions of higher proliferation and lower apoptosis. In turn, acidic extracellular pH elevates persistent Na + influx through Na v 1.5 into breast cancer cells. Together, these findings show positive feedback between extracellular acidification and the movement of Na + into cancer cells which can facilitate invasion. These results highlight the clinical significance of Na v 1.5 activity as a potentiator of breast cancer metastasis and provide further evidence supporting the use of VGSC inhibitors in cancer treatment., (© 2024. The Author(s).)

Voltage-gated sodium channels (VGSCs) initiate action potentials in electrically excitable cells and tissues. Surprisingly, some VGSC genes are aberrantly expressed in a variety of cancers, derived from "non-excitable" tissues that do not generate classic action potentials, showing potential as a promising pharmacological target for cancer. Most of the previous review articles on this topic are limited in scope, and largely unable to provide researchers with a comprehensive understanding of the role of VGSC in cancers. Here, we review the expression patterns of all nine VGSC α-subunit genes (SCN1A-11A) and their four regulatory β-subunit genes (SCN1B-4B). We reviewed data from the Cancer Genome Atlas (TCGA) database, complemented by an extensive search of the published papers. We summarized and reviewed previous independent studies and analyzed the VGSC genes in the TCGA database regarding the potential impact of VGSC on cancers. A comparison between evidence gathered from independent studies and data review was performed to scrutinize potential biases in prior research and provide insights into future research directions. The review supports the view that VGSCs play an important role in diagnostics as well as therapeutics of some cancer types, such as breast, colon, prostate, and lung cancer. This paper provides an overview of the current knowledge on voltage-gated sodium channels in cancer, as well as potential avenues for further research. While further research is required to fully understand the role of VGSCs in cancer, the potential of VGSCs for clinical diagnosis and treatment is promising., (© 2024. The Author(s).)

Flue Gas Desulfurization (FGD) gypsum is a byproduct of the coal-fired power plant process commonly used to remove sulfur dioxide emissions from the flue gas. FGD gypsum has numerous industrial, agricultural, and environmental applications. This study aimed to explore a novel approach involving the use of FGD gypsum combined with different litter treatments as bedding for broiler production. It focused on performance metrics, including adjusted feed conversion ratio (AFCR) and average body weight (BW), foot pad dermatitis (FPD), and fear response over 5 consecutive flocks. A total of 1,800 one-day-old Ross 708 chicks were randomly assigned to 24 pens (75 birds/pen), divided into 6 treatment groups (4 pens/treatment), with 5 replications and raised until 42 d old (d). Treatments were gypsum that was decaked (D), rotovated (E), and rotovated then windrowed (F) between flocks. Control treatments using pine shavings were decaked (A), rotovated (B), and windrowed postrotovating (C). AFCR, average BW, and mortality were used as a measure of production. Foot pad dermatitis scores were taken on d42 using a scale of 0 (absence), 1 (mild), and 2 (severe). Response to observer and human approach test were used to measure fear response. Data were analyzed as a 2-way ANOVA (Proc Glimmix) for the main effects of bedding type and litter treatment. Means were identified using Tukey's HSD. No effect of bedding type or litter treatment was found for AFCR, BW, or mortality. FPD scores 2 and 1, were higher with pine shavings than gypsum (P = 0.01 and P = 0.01, respectively). While FPD scores 0 were higher for gypsum than the pine shaving (P = 0.01). No difference in fear response was found among birds raised on any of the gypsum litter treatments and any of the pine shaving litter treatments. Overall, the use of gypsum as bedding results in equivalent production and fear response to pine shavings, while increasing FPD quality when compared to pine shaving., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

This study examined the roles of neighborhood social cohesion, adverse childhood experiences (ACEs), and parenting stress in early childhood on child behavioral outcomes in middle childhood and adolescence among socioeconomically disadvantaged Black families. To test a model linking perceptions of neighborhood social cohesion, single mothers' parenting stress, ACEs, and behavior problems in middle childhood and adolescence. We used four waves of longitudinal data from a subsample of 800 unmarried Black mothers and their children (at child birth and ages 3, 5, 9, and 15) from the Future of Families and Child Wellbeing Study, a nationally representative data set. Structural equation modeling with latent variables was used to measure direct and indirect effects. Mothers' perceptions of neighborhood social cohesion were significantly and negatively associated parenting stress (β = -0.34, p < 0.05); parenting stress was significantly and positively related to adverse childhood experiences (β = 0.40, p < 0.05) and behavior problems (β = 0.32, p < 0.05); Adverse childhood experiences were significantly and positively related to behavior problems (β = 0.26, p < 0.05); and behavior problems were indirectly influenced by neighborhood social cohesion through adverse childhood experiences (β = -0.14, p < 0.05) and parenting stress (β = 0.10, p < 0.05). Neighborhood factors may play a significant role in parenting stress, adverse childhood experiences in early childhood, and children's behavior problems in middle childhood and adolescence among some single mothers and children in economically and socially disadvantaged Black families. Interventions that enhance neighborhood social cohesion and foster supportive interactions among community members and organizations are recommended., (© 2024 Wiley Periodicals LLC.)

Cardiac arrhythmias cause significant morbidity and mortality and pose a major public health problem. They arise from disruptions in the normally orderly propagation of cardiac electrophysiological activation and recovery through successive cardiomyocytes in the heart. They reflect abnormalities in automaticity, initiation, conduction, or recovery in cardiomyocyte excitation. The latter properties are dependent on surface membrane electrophysiological mechanisms underlying the cardiac action potential. Their disruption results from spatial or temporal instabilities and heterogeneities in the generation and propagation of cellular excitation. These arise from abnormal function in their underlying surface membrane, ion channels, and transporters, as well as the interactions between them. The latter, in turn, form common regulatory targets for the hierarchical network of diverse signaling mechanisms reviewed here. In addition to direct molecular-level pharmacological or physiological actions on these surface membrane biomolecules, accessory, adhesion, signal transduction, and cytoskeletal anchoring proteins modify both their properties and localization. At the cellular level of excitation-contraction coupling processes, Ca 2+ homeostatic and phosphorylation processes affect channel activity and membrane excitability directly or through intermediate signaling. Systems -level autonomic cellular signaling exerts both acute channel and longer-term actions on channel expression. Further upstream intermediaries from metabolic changes modulate the channels both themselves and through modifying Ca 2+ homeostasis. Finally, longer-term organ -level inflammatory and structural changes, such as fibrotic and hypertrophic remodeling, similarly can influence all these physiological processes with potential pro-arrhythmic consequences. These normal physiological processes may target either individual or groups of ionic channel species and alter with particular pathological conditions. They are also potentially alterable by direct pharmacological action, or effects on longer-term targets modifying protein or cofactor structure, expression, or localization. Their participating specific biomolecules, often clarified in experimental genetically modified models, thus constitute potential therapeutic targets. The insights clarified by the physiological and pharmacological framework outlined here provide a basis for a recent modernized drug classification. Together, they offer a translational framework for current drug understanding. This would facilitate future mechanistically directed therapeutic advances, for which a number of examples are considered here. The latter are potentially useful for treating cardiac, in particular arrhythmic, disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lei, Salvage, Jackson and Huang.)

Introduction: In addition to gap junction conduction, recent reports implicate possible ephaptic coupling contributions to action potential (AP) propagation between successive adjacent cardiomyocytes. Here, AP generation in an active cell, withdraws Na + from, creating a negative potential within, ephaptic spaces between the participating membranes, activating the initially quiescent neighbouring cardiomyocyte. However, sustainable ephaptic transmission requires subsequent complete recovery of the ephaptic charge difference. We explore physical contributions of passive electrodiffusive ion exchange with the remaining extracellular space to this recovery for the first time. Materials and Methods: Computational, finite element, analysis examined limiting, temporal and spatial, ephaptic [Na + ], [Cl - ], and the consequent Gaussian charge differences and membrane potential recovery patterns following a Δ V ∼130 mV AP upstroke at physiological (37°C) temperatures. This incorporated Nernst-Planck formalisms into equations for the time-dependent spatial concentration gradient profiles. Results: Mammalian atrial, ventricular and purkinje cardiomyocyte ephaptic junctions were modelled by closely apposed circularly symmetric membranes, specific capacitance 1 μF cm -2 , experimentally reported radii a = 8,000, 12,000 and 40,000 nm respectively and ephaptic axial distance w = 20 nm. This enclosed an ephaptic space containing principal ions initially at normal extracellular [Na + ] = 153.1 mM and [Cl - ] = 145.8 mM, respective diffusion coefficients D Na = 1.3 × 10 9 and D Cl = 2 × 10 9 nm 2 s -1 . Stable, concordant computational solutions were confirmed exploring ≤1,600 nm mesh sizes and Δ t ≤0.08 ms stepsize intervals. The corresponding membrane voltage profile changes across the initially quiescent membrane were obtainable from computed, graphically represented a and w -dependent ionic concentration differences adapting Gauss's flux theorem. Further simulations explored biological variations in ephaptic dimensions, membrane anatomy, and diffusion restrictions within the ephaptic space. Atrial, ventricular and Purkinje cardiomyocytes gave 40, 180 and 2000 ms 99.9% recovery times, with 720 or 360 ms high limits from doubling ventricular radius or halving diffusion coefficient. Varying a , and D Na and D Cl markedly affected recovery time-courses with logarithmic and double-logarithmic relationships, Varying w exerted minimal effects. Conclusion: We thereby characterise the properties of, and through comparing atrial, ventricular and purkinje recovery times with interspecies in vivo background cardiac cycle duration data, (blue whale ∼2000, human∼90, Etruscan shrew, ∼40 ms) can determine physical limits to, electrodiffusive contributions to ephaptic recovery., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Morris, Bardsley, Salvage, Jackson, Matthews and Huang.)

Salmonella and Campylobacter are two of the most common foodborne pathogens associated with poultry meat. Regulatory restrictions and consumer concerns have increased the interest for plant-derived antimicrobials and emerging novel technologies. The objective of this study was to determine the antimicrobial activity of photoactive compounds curcumin (CUR) and chlorophyllin (CH) followed by activating light exposure for the reduction of Salmonella and Campylobacter. Peroxyacetic acid (PAA) was also evaluated as a poultry industry standard antimicrobial processing aid. CUR and CH were evaluated in 96-well plates at concentrations of 100, 500, and 1,000 ppm, along with PAA at 100, 200, and 300 ppm, or distilled water (DW). Each well was inoculated with 10 5  CFU/mL of Salmonella Typhimurium or Campylobacter jejuni, and plates were exposed to activating light (430 nm) for 0 or 5 min. No detectable reductions were observed for Salmonella or Campylobacter when treated with CUR, CH, or 100 ppm PAA. However, when Salmonella was treated with 200 ppm PAA, counts were reduced from 4.57 to 2.52 log 10  CFU/mL. When Salmonella was treated with 300 ppm PAA, counts were reduced to below detectable levels (5 CFU/mL). Campylobacter was reduced from 4.67 to 2.82 log 10  CFU/mL when treated with 200 ppm PAA. However, no further reductions were observed when Campylobacter was treated with 300 ppm PAA (2.50 log 10  CFU/mL). These results indicate that CUR and CH were not effective as antimicrobials under the evaluated conditions, particularly in comparison to the commonly used antimicrobial, PAA., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

CDC45-MCM2-7-GINS (CMG) helicase assembly is the central event in eukaryotic replication initiation. In yeast, a multi-subunit "pre-loading complex" (pre-LC) accompanies GINS to chromatin-bound MCM2-7, leading to CMG formation. Here, we report that DONSON, a metazoan protein mutated in microcephalic primordial dwarfism, is required for CMG assembly in vertebrates. Using AlphaFold to screen for protein-protein interactions followed by experimental validation, we show that DONSON scaffolds a vertebrate pre-LC containing GINS, TOPBP1, and DNA pol ε. Our evidence suggests that DONSON docks the pre-LC onto MCM2-7, delivering GINS to its binding site in CMG. A patient-derived DONSON mutation compromises CMG assembly and recapitulates microcephalic dwarfism in mice. These results unify our understanding of eukaryotic replication initiation, implicate defective CMG assembly in microcephalic dwarfism, and illustrate how in silico protein-protein interaction screening accelerates mechanistic discovery.

The RGD motif on the SARS-CoV-2 spike protein has been suggested to interact with RGD-binding integrins αVβ3 and α5β1 to enhance viral cell entry and alter downstream signaling cascades. The D405N mutation on the Omicron subvariant spike proteins, resulting in an RGN motif, has recently been shown to inhibit binding to integrin αVβ3. Deamidation of asparagines in protein ligand RGN motifs has been demonstrated to generate RGD and RGisoD motifs that permit binding to RGD-binding integrins. Two asparagines, N481 and N501, on the Wild-type spike receptor-binding domain have been previously shown to have deamidation half-lives of 16.5 and 123 days, respectively, which may occur during the viral life cycle. Deamidation of Omicron subvariant N405 may recover the ability to interact with RGD-binding integrins. Thus, herein, all-atom molecular dynamics simulations of the Wild-type and Omicron subvariant spike protein receptor-binding domains were conducted to investigate the potential for asparagines, the Omicron subvariant N405 in particular, to assume the optimized geometry for deamidation to occur. In summary, the Omicron subvariant N405 was primarily found to be stabilized in a state unfavourable for deamidation after hydrogen bonding with downstream E406. Nevertheless, a small number of RGD or RGisoD motifs on the Omicron subvariant spike proteins may restore the ability to interact with RGD-binding integrins. The simulations also provided structural clarification regarding the deamidation rates of Wild-type N481 and N501 and highlighted the utility of tertiary structure dynamics information in predicting asparagine deamidation. Further work is needed to characterize the effects of deamidation on spike-integrin interactions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Blastocystis is the most prevalent microbial eukaryote in the human and animal gut, yet its role as commensal or parasite is still under debate. Blastocystis has clearly undergone evolutionary adaptation to the gut environment and possesses minimal cellular compartmentalization, reduced anaerobic mitochondria, no flagella, and no reported peroxisomes. To address this poorly understood evolutionary transition, we have taken a multi-disciplinary approach to characterize Proteromonas lacertae, the closest canonical stramenopile relative of Blastocystis. Genomic data reveal an abundance of unique genes in P. lacertae but also reductive evolution of the genomic complement in Blastocystis. Comparative genomic analysis sheds light on flagellar evolution, including 37 new candidate components implicated with mastigonemes, the stramenopile morphological hallmark. The P. lacertae membrane-trafficking system (MTS) complement is only slightly more canonical than that of Blastocystis, but notably, we identified that both organisms encode the complete enigmatic endocytic TSET complex, a first for the entire stramenopile lineage. Investigation also details the modulation of mitochondrial composition and metabolism in both P. lacertae and Blastocystis. Unexpectedly, we identify in P. lacertae the most reduced peroxisome-derived organelle reported to date, which leads us to speculate on a mechanism of constraint guiding the dynamics of peroxisome-mitochondrion reductive evolution on the path to anaerobiosis. Overall, these analyses provide a launching point to investigate organellar evolution and reveal in detail the evolutionary path that Blastocystis has taken from a canonical flagellated protist to the hyper-divergent and hyper-prevalent animal and human gut microbe., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Skeletal and cardiac muscle excitation-contraction coupling commences with Na v 1.4/Na v 1.5-mediated, surface and transverse (T-) tubular, action potential generation. This initiates feedforward , allosteric or Ca 2+ -mediated, T-sarcoplasmic reticular (SR) junctional, voltage sensor-Cav1.1/Cav1.2 and ryanodine receptor-RyR1/RyR2 interaction. We review recent structural, physiological and translational studies on possible feedback actions of the resulting SR Ca 2+ release on Na v 1.4/Na v 1.5 function in native muscle. Finite-element modelling predicted potentially regulatory T-SR junctional [Ca 2+ ] TSR domains. Na v 1.4/Na v 1.5, III-IV linker and C-terminal domain structures included Ca 2+ and/or calmodulin-binding sites whose mutations corresponded to specific clinical conditions. Loose-patch-clamped native murine skeletal muscle fibres and cardiomyocytes showed reduced Na + currents ( I Na ) following SR Ca 2+ release induced by the Epac and direct RyR1/RyR2 activators, 8-(4-chlorophenylthio)adenosine-3',5'-cyclic monophosphate and caffeine, abrogated by the RyR inhibitor dantrolene. Conversely, dantrolene and the Ca 2+ -ATPase inhibitor cyclopiazonic acid increased I Na . Experimental, catecholaminergic polymorphic ventricular tachycardic RyR2-P2328S and metabolically deficient Pgc1β -/- abnormalities rescued by dantrolene- and flecainide-mediated RyR block. Finally, hydroxychloroquine challenge implicated action potential (AP) prolongation in slowing AP conduction through modifying Ca I transients. The corresponding tissue/organ preparations each showed pro-arrhythmic, slowed AP upstrokes and conduction velocities. We finally extend discussion of possible Ca Na accompanying [Ca 2+ ] i abnormalities rescued by dantrolene- and flecainide-mediated RyR block. Finally, hydroxychloroquine challenge implicated action potential (AP) prolongation in slowing AP conduction through modifying Ca 2+ transients. The corresponding tissue/organ preparations each showed pro-arrhythmic, slowed AP upstrokes and conduction velocities. We finally extend discussion of possible Ca 2+ -mediated effects to further, Ca 2+ , K + and Cl - , channel types. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.

The voltage-gated sodium channel Na V 1.7 is involved in various pain phenotypes and is physiologically regulated by the Na V -β3-subunit. Venom toxins ProTx-II and OD1 modulate Na V 1.7 channel function and may be useful as therapeutic agents and/or research tools. Here, we use patch-clamp recordings to investigate how the β3-subunit can influence and modulate the toxin-mediated effects on Na V 1.7 function, and we propose a putative binding mode of OD1 on Na V 1.7 to rationalise its activating effects. The inhibitor ProTx-II slowed the rate of Na V 1.7 activation, whilst the activator OD1 reduced the rate of fast inactivation and accelerated recovery from inactivation. The β3-subunit partially abrogated these effects. OD1 induced a hyperpolarising shift in the V 1/2 of steady-state activation, which was not observed in the presence of β3. Consequently, OD1-treated Na V 1.7 exhibited an enhanced window current compared with OD1-treated Na V 1.7-β3 complex. We identify candidate OD1 residues that are likely to prevent the upward movement of the DIV S4 helix and thus impede fast inactivation. The binding sites for each of the toxins and the predicted location of the β3-subunit on the Na V 1.7 channel are distinct. Therefore, we infer that the β3-subunit influences the interaction of toxins with Na V 1.7 via indirect allosteric mechanisms. The enhanced window current shown by OD1-treated Na V 1.7 compared with OD1-treated Na V 1.7-β3 is discussed in the context of differing cellular expressions of Na V 1.7 and the β3-subunit in dorsal root ganglion (DRG) neurons. We propose that β3, as the native binding partner for Na V 1.7 in DRG neurons, should be included during screening of molecules against Na V 1.7 in relevant analgesic discovery campaigns., (© 2023 The Authors. Journal of Cellular Physiology published by Wiley Periodicals LLC.)

In cardiac myocytes, the voltage-gated sodium channel Na V 1.5 opens in response to membrane depolarisation and initiates the action potential. The Na V 1.5 channel is typically associated with regulatory β-subunits that modify gating and trafficking behaviour. These β-subunits contain a single extracellular immunoglobulin (Ig) domain, a single transmembrane α-helix and an intracellular region. Here we focus on the role of the β1 and β3 subunits in regulating Na V 1.5. We catalogue β1 and β3 domain specific mutations that have been associated with inherited cardiac arrhythmia, including Brugada syndrome, long QT syndrome, atrial fibrillation and sudden death. We discuss how new structural insights into these proteins raises new questions about physiological function., (© 2022 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

This report describes the recruitment of a sample of older African American women to test the effectiveness of an educational HIV prevention intervention that sought to reduce depressive symptoms and thereby HIV risks in this population. The outreach venue is the Black church. A framework for maximizing response is suggested. Of 62 women who participated in two arms of the intervention, 29 were assigned randomly to a four-session discussion group (experimental condition) and 33 were assigned to a one-session informational group (control condition) focused on HIV prevention education. Between-within subjects analyses of variance showed that participation in the study was associated with a significant improvement in the women's psychological status, i.e., decreased depressive symptoms. This change in depressive symptoms was due in part to the experimental condition assignment. Implications for future HIV prevention interventions, research, and methods used to maximize the probability of response among older African American women are discussed., Competing Interests: Both authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer NH declared a shared affiliation with the author AJ to the handling editor at the time of review., (© 2023 Ebor and Jackson.)

The interstellar objects 1I/'Oumuamua and 2I/Borisov confirm the long-held expectation that bodies from one stellar system will be carried to another, allowing, in principle, interstellar panspermia. Life might be transferred between stellar systems, depending on the nature of the bodies and how they escaped their systems. 2I/Borisov appears to be a comet, with no more likelihood of carrying life than Solar System comets. In contrast, the nature of 1I/'Oumuamua has been difficult to determine. We review various hypotheses for its origin, including ejection of N 2 ice from the surface of an exo-Pluto, formation in a molecular cloud by freezing of H 2 , and a derelict solar sail of alien construction. Of these, the N 2 ice fragment hypothesis is uniquely falsifiable, plausible, and completely consistent with all observations. The possibility of interstellar panspermia would be made more probable if 'Oumuamua originated on a dwarf planet rather than a comet, although substantial challenges to transfer of life would remain. Of proposed mechanisms for interstellar panspermia, transfer of life via rocky meteoroids is perhaps less improbable.

Embryonic development is dictated by tight regulation of DNA replication, cell division and differentiation. Mutations in DNA repair and replication genes disrupt this equilibrium, giving rise to neurodevelopmental disease characterized by microcephaly, short stature and chromosomal breakage. Here, we identify biallelic variants in two components of the RAD18-SLF1/2-SMC5/6 genome stability pathway, SLF2 and SMC5, in 11 patients with microcephaly, short stature, cardiac abnormalities and anemia. Patient-derived cells exhibit a unique chromosomal instability phenotype consisting of segmented and dicentric chromosomes with mosaic variegated hyperploidy. To signify the importance of these segmented chromosomes, we have named this disorder Atelís (meaning - incomplete) Syndrome. Analysis of Atelís Syndrome cells reveals elevated levels of replication stress, partly due to a reduced ability to replicate through G-quadruplex DNA structures, and also loss of sister chromatid cohesion. Together, these data strengthen the functional link between SLF2 and the SMC5/6 complex, highlighting a distinct role for this pathway in maintaining genome stability., (© 2022. The Author(s).)

Trypanosoma vivax is a unicellular hemoparasite, and a principal cause of animal African trypanosomiasis (AAT), a vector-borne and potentially fatal livestock disease across sub-Saharan Africa. Previously, we identified diverse T. vivax-specific genes that were predicted to encode cell surface proteins. Here, we examine the immune responses of naturally and experimentally infected hosts to these unique parasite antigens, to identify immunogens that could become vaccine candidates. Immunoprofiling of host serum shows that one particular family (Fam34) elicits a consistent IgG antibody response. This gene family, which we now call Vivaxin, encodes at least 124 transmembrane glycoproteins that display quite distinct expression profiles and patterns of genetic variation. We focused on one gene (viv-β8) that encodes one particularly immunogenic vivaxin protein and which is highly expressed during infections but displays minimal polymorphism across the parasite population. Vaccination of mice with VIVβ8 adjuvanted with Quil-A elicits a strong, balanced immune response and delays parasite proliferation in some animals but, ultimately, it does not prevent disease. Although VIVβ8 is localized across the cell body and flagellar membrane, live immunostaining indicates that VIVβ8 is largely inaccessible to antibody in vivo. However, our phylogenetic analysis shows that vivaxin includes other antigens shown recently to induce immunity against T. vivax. Thus, the introduction of vivaxin represents an important advance in our understanding of the T. vivax cell surface. Besides being a source of proven and promising vaccine antigens, the gene family is clearly an important component of the parasite glycocalyx, with potential to influence host-parasite interactions., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: DA and GJW are named inventors on patents relating to the use of IFX and V31 as animal trypanosomiasis vaccines.

Cleavage of the severe respiratory syndrome coronavirus-2 (SARS-CoV-2) spike protein has been demonstrated to contribute to viral-cell fusion and syncytia formation. Studies have shown that variants of concern (VOC) and variants of interest (VOI) show differing membrane fusion capacity. Mutations near cleavage motifs, such as the S1/S2 and S2' sites, may alter interactions with host proteases and, thus, the potential for fusion. The biochemical basis for the differences in interactions with host proteases for the VOC/VOI spike proteins has not yet been explored. Using sequence and structure-based bioinformatics, mutations near the VOC/VOI spike protein cleavage sites were inspected for their structural effects. All mutations found at the S1/S2 sites were predicted to increase affinity to the furin protease but not TMPRSS2. Mutations at the spike residue P681 in several strains, such P681R in the Delta strain, resulted in the disruption of a proline-directed kinase phosphorylation motif at the S1/S2 site, which may lessen the impact of phosphorylation for these variants. However, the unique N679K mutation in the Omicron strain was found to increase the propensity for O-linked glycosylation at the S1/S2 cleavage site, which may prevent recognition by proteases. Such glycosylation in the Omicron strain may hinder entry at the cell surface and, thus, decrease syncytia formation and induce cell entry through the endocytic pathway as has been shown in previous studies. Further experimental work is needed to confirm the effect of mutations and posttranslational modifications on SARS-CoV-2 spike protein cleavage sites., (© 2022 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

In 2017, a mortality event affected Humboldt penguins at Chester Zoo (UK), which coincided with the diagnosis of avian malaria (AM) in some birds. AM is found worldwide wherever a competent mosquito vector is present, but the disease is particularly severe in penguins and other species that originate from non-endemic regions. To better understand the role of AM and manage its threat to penguin collections, Plasmodium was surveyed through PCR at Chester Zoo in mosquitoes, penguins, and dead free-living wild birds during and around the mortality event. Additional sequences were obtained from penguin fatalities from four other UK zoological collections. All sequences were integrated into phylogenetic analyses to determine parasite species and lineages. In total, 753/6459 positive mosquitoes were recorded (11.7% prevalence), reaching a weekly peak of 30% prevalence in mid-summer. Among penguin fatalities at Chester Zoo, several penguins presented signs and lesions compatible with AM; nevertheless, exoerythrocytic meronts were identified in only one case and Plasmodium spp. was identified in 5/22 birds. Phylogenetic analysis revealed at least five parasite cytb lineages of three Plasmodium species ( P. matutinum, P. relictum and P. vaughani ) circulating in mosquitoes at Chester Zoo; however, infections in free-living wild birds and penguins were only from P. matutinum . Plasmodium matutinum was confirmed as the cause of death of one penguin and was highly suspected to be the cause of death of another three. The lineage LINN1 was associated with 4/5 penguin infections. AM had a key role in the penguin multicausal mortality event. Understanding the risk of AM to penguin collections at Chester Zoo and elsewhere requires long-term surveillance to examine the association between Plasmodium infection and penguin mortality and the variability in parasite virulence. Surveillance of Plasmodium spp. in mosquitoes and local birds provides information about the parasite's transmission cycle locally, and could warn about infection risks to species of interest, which is essential for efficient disease control and prevention., Competing Interests: None., (© 2022 The Authors.)

The ability of the cellular immune system to discriminate self from foreign antigens depends on the appropriate calibration of the T cell receptor (TCR) signalling threshold. The lymphocyte homeostatic cytokine interleukin 7 (IL-7) is known to affect TCR thresholding, but the molecular mechanism is not fully elucidated. A better understanding of this process is highly relevant in the context of autoimmune disease therapy and cancer immunotherapy. We sought to characterise the early signalling events attributable to IL-7 priming; in particular, the altered phosphorylation of signal transduction proteins and their molecular localisation to the TCR. By integrating high-resolution proximity- phospho-proteomic and imaging approaches using primary T cells, rather than engineered cell lines or an in vitro expanded T cell population, we uncovered transduction events previously not linked to IL-7. We show that IL-7 leads to dephosphorylation of cytohesin interacting protein (CYTIP) at a hitherto undescribed phosphorylation site (pThr280) and alters the co-localisation of cytohesin-1 with the TCR and LFA-1 integrin. These results show that IL-7, acting via CYTIP and cytohesin-1, may impact TCR activation thresholds by enhancing the co-clustering of TCR and LFA-1 integrin., (© 2022 The Author(s).)