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Background: The COVID-19 pandemic exacerbated disparities in mental healthcare and substance use disorder (SUD) treatment access, especially in under-resourced communities. This study aimed to comprehend the experiences of under-resourced women with SUD during the pandemic, their knowledge and attitudes toward it, and its impact on substance use and treatment access., Methods: A cross-sectional study included 66 under-resourced women receiving medically managed withdrawal treatment at a community residential SUD center. Data collection occurred between November 2021 and August 2022, utilizing a 75-item instrument covering COVID-19 exposure and its impact on health, substance use, treatment access, vaccination status, beliefs, and knowledge. Descriptive analyses summarized the data., Results: Participants faced various challenges during the pandemic. Many reported increased substance use, especially alcohol, opioids, benzodiazepines, and nicotine. Mental health stability was negatively affected, exacerbating existing disorders and limiting mental healthcare access. A majority (56.1%) reported that their chronic mental health disorder was less stable during the pandemic. Twenty (30.3%) participants reported that they had been diagnosed with a new mental health disorder since the pandemic, and 28.8% reported that it was harder for them to access mental healthcare during the pandemic. Job loss, housing instability, and financial strain were prevalent. Half (n=33, 50%) received a COVID-19 vaccine dose, while 27.3% (n=18) declined vaccination due to knowledge gaps and religious beliefs. The majority (n=41, 62.1%) worried about securing basic needs such as groceries and medication, with 64.6% (n=42) expressing a desire to cope using alcohol or drugs., Conclusions: This study expands upon previous research by examining the effect of the COVID-19 pandemic on mental health in the context of substance use disorder treatment. Unlike previous data, which focused solely on substance use behaviors, our study delves into the impact of the pandemic on co-occurring mental health disorders. Findings underscore the need for gender-responsive and culturally appropriate SUD treatment. Vaccine hesitancy, as reflected in the study, necessitates more effective, tailored evidence-based informational campaigns. Efforts must focus on enhancing mental healthcare access, reducing stigma, and supporting individuals with co-occurring conditions amidst this evolving COVID-19 health crisis., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. The Institutional Review Board of Baylor College of Medicine issued approval H-50771. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Mejia et al.)

EB1 is a key cellular protein that delivers regulatory molecules throughout the cell via the tip-tracking of growing microtubule plus-ends. Thus, it is important to understand the mechanism for how EB1 efficiently tracks growing microtubule plus-ends. It is widely accepted that EB1 binds with higher affinity to GTP-tubulin subunits at the growing microtubule tip, relative to GDP-tubulin along the microtubule length. However, it is unclear whether this difference in affinity alone is sufficient to explain the tip-tracking of EB1 at growing microtubule tips. Previously, we found that EB1 binds to exposed microtubule protofilament-edge sites at a ~70 fold faster rate than to closed-lattice sites, due to diffusional steric hindrance to binding. Thus, we asked whether rapid protofilament-edge binding could contribute to efficient EB1 tip tracking. A computational simulation with differential EB1 on-rates based on closed-lattice or protofilament-edge binding, and with EB1 off-rates that were dependent on the tubulin hydrolysis state, robustly recapitulated experimental EB1 tip tracking. To test this model, we used cell-free biophysical assays, as well as live-cell imaging, in combination with a Designed Ankyrin Repeat Protein (DARPin) that binds exclusively to protofilament-edge sites, and whose binding site partially overlaps with the EB1 binding site. We found that DARPin blocked EB1 protofilament-edge binding, which led to a decrease in EB1 tip tracking on dynamic microtubules. We conclude that rapid EB1 binding to microtubule protofilament-edge sites contributes to robust EB1 tip tracking at the growing microtubule plus-end., Competing Interests: SG, JH, RG, TR, MM, MG No competing interests declared, (© 2024, Gonzalez et al.)

Early life adversity predicts shorter adult lifespan in several animal taxa. Yet, work on long-lived primate populations suggests the evolution of mechanisms that contribute to resiliency and long lives despite early life insults. Here, we tested associations between individual and cumulative early life adversity and lifespan on rhesus macaques at the Cayo Santiago Biological Field Station using 50 years of demographic data. We performed sex-specific survival analyses at different life stages to contrast short-term effects of adversity (i.e., infant survival) with long-term effects (i.e., adult survival). Female infants showed vulnerability to multiple adversities at birth, but affected females who survived to adulthood experienced a reduced risk later in life. In contrast, male infants showed vulnerability to a lower number of adversities at birth, but those who survived to adulthood were negatively affected by both early life individual and cumulative adversity. Our study shows profound immediate effects of insults  on female infant cohorts and suggests that affected female adults are more robust. In contrast, adult males who experienced harsh conditions early in life showed an increased mortality risk at older ages as expected from hypotheses within the life course perspective. Our analysis suggests sex-specific selection pressures on life histories and highlights the need for studies addressing the effects of early life adversity across multiple life stages., Competing Interests: We declare no conflict of interest., (© 2023 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

During mitosis, sister chromatids are stretched apart at their centromeres via their attachment to oppositely oriented kinetochore microtubules. This stretching generates inwardly directed tension across the separated sister centromeres. The cell leverages this tension signal to detect and then correct potential errors in chromosome segregation, via a mechanical tension signaling pathway that detaches improperly attached kinetochores from their microtubules. However, the sequence of events leading up to these detachment events remains unknown. In this study, we used microfluidics to sustain and observe low-tension budding yeast metaphase spindles over multiple hours, allowing us to elucidate the tension history prior to a detachment event. We found that, under conditions in which kinetochore phosphorylation weakens low-tension kinetochore-microtubule connections, the mechanical forces produced via the dynamic growth and shortening of microtubules is required to efficiently facilitate detachment events. Our findings underscore the critical role of robust kinetochore microtubule dynamics in ensuring the fidelity of chromosome segregation during mitosis., (© 2023 Parmar et al.)

Anxiety disorders are the most common psychiatric conditions in children and adolescents, affecting nearly 1 in 12 children and 1 in 4 adolescents. Anxiety disorders include specific phobias, social anxiety disorder, separation anxiety disorder, agoraphobia, panic disorder, and generalized anxiety disorder. Risk factors include parental history of anxiety disorders, socioeconomic stressors, exposure to violence, and trauma. The U.S. Preventive Services Task Force recommends screening for anxiety disorders in children eight years and older; there is insufficient evidence to support screening in children younger than eight years. Symptoms of anxiety disorders in children and adolescents are similar to those in adults and can include physical and behavioral symptoms such as diaphoresis, palpitations, and tantrums. Care should be taken to distinguish symptoms of a disorder from normal developmental fears and behaviors, such as separation anxiety in infants and toddlers. Several validated screening measures are useful for initial assessment and ongoing monitoring. Cognitive behavior therapy and selective serotonin reuptake inhibitors are the mainstay of treatment and may be used as monotherapies or in combination. Prognosis is improved with early intervention, caretaker support, and professional collaboration.

Kinesin-14 molecular motors represent an essential class of proteins that bind microtubules and walk toward their minus-ends. Previous studies have described important roles for Kinesin-14 motors at microtubule minus-ends, but their role in regulating plus-end dynamics remains controversial. Kinesin-14 motors have been shown to bind the EB family of microtubule plus-end binding proteins, suggesting that these minus-end-directed motors could interact with growing microtubule plus-ends. In this work, we explored the role of minus-end-directed Kinesin-14 motor forces in controlling plus-end microtubule dynamics. In cells, a Kinesin-14 mutant with reduced affinity to EB proteins led to increased microtubule lengths. Cell-free biophysical microscopy assays were performed using Kinesin-14 motors and an EB family marker of growing microtubule plus-ends, Mal3, which revealed that when Kinesin-14 motors bound to Mal3 at growing microtubule plus-ends, the motors subsequently walked toward the minus-end, and Mal3 was pulled away from the growing microtubule tip. Strikingly, these interactions resulted in an approximately twofold decrease in the expected postinteraction microtubule lifetime. Furthermore, generic minus-end-directed tension forces, generated by tethering growing plus-ends to the coverslip using λ-DNA, led to an approximately sevenfold decrease in the expected postinteraction microtubule growth length. In contrast, the inhibition of Kinesin-14 minus-end-directed motility led to extended tip interactions and to an increase in the expected postinteraction microtubule lifetime, indicating that plus-ends were stabilized by nonmotile Kinesin-14 motors. Together, we find that Kinesin-14 motors participate in a force balance at microtubule plus-ends to regulate microtubule lengths in cells., Competing Interests: The authors declare no competing interest.

Adversity early in life can shape the reproductive potential of individuals through negative effects on health and life span. However, long-lived populations with multiple reproductive events may present alternative life history strategies to optimize reproductive schedules and compensate for shorter life spans. Here, we quantify the effects of major hurricanes and density dependence as sources of early-life ecological adversity on Cayo Santiago rhesus macaque female reproduction and decompose their effects onto the mean age-specific fertility, reproductive pace, and lifetime reproductive success (LRS). Females experiencing major hurricanes exhibit a delayed reproductive debut but maintain the pace of reproduction past debut and show a higher mean fertility during prime reproductive ages, relative to unaffected females. Increasing density at birth is associated to a decrease in mean fertility and reproductive pace, but such association is absent at intermediate densities. When combined, our study reveals that hurricanes early in life predict a delay-overshoot pattern in mean age-specific fertility that supports the maintenance of LRS. In contrast to predictive adaptive response models of accelerated reproduction, this long-lived population presents a novel reproductive strategy where females who experience major natural disasters early in life ultimately overcome their initial reproductive penalty with no major negative fitness outcomes. Density presents a more complex relation with reproduction that suggests females experiencing a population regulated at intermediate densities early in life will escape density dependence and show optimized reproductive schedules. Our results support hypotheses about life history trade-offs in which adversity-affected females ensure their future reproductive potential by allocating more energy to growth or maintenance processes at younger adult ages., Competing Interests: We declare no conflict of interest., (© 2022 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

In the failing heart, the cardiac myocyte microtubule network is remodeled, which contributes to cellular contractile failure and patient death. However, the origins of this deleterious cytoskeletal reorganization are unknown. We now find that oxidative stress, a condition characteristic of heart failure, leads to cysteine oxidation of microtubules. Our electron and fluorescence microscopy experiments revealed regions of structural damage within the microtubule lattice that occurred at locations of oxidized tubulin. The incorporation of GTP-tubulin into these damaged, oxidized regions led to stabilized "hot spots" within the microtubule lattice, which suppressed the shortening of dynamic microtubules. Thus, oxidative stress may act inside of cardiac myocytes to facilitate a pathogenic shift from a sparse microtubule network into a dense, aligned network. Our results demonstrate how a disease condition characterized by oxidative stress can trigger a molecular oxidation event, which likely contributes to a toxic cellular-scale transformation of the cardiac myocyte microtubule network., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Giardia duodenalis is a gastrointestinal protozoan causing 184 million cases of giardiasis worldwide annually. Detection is by microscopy or coproantigen assays, although sensitivity is often compromised by intermittent shedding of cysts or trophozoites, or operator expertise. Therefore, for enhanced surveillance field-applicable, point-of-care (POC), molecular assays are needed. Our aims were to: (i) optimise the recombinase polymerase amplification (RPA) assay for the isothermal amplification of the G. duodenalis β-giardin gene from trophozoites and cysts, using published primer and probes; and (ii) perform a pilot field validation of RPA at a field station in a resource-poor setting, on DNA extracted from stool samples from schoolchildren in villages around Lake Albert, Uganda. Results were compared to an established laboratory small subunit ribosomal RNA (SSU rDNA) qPCR assay with additional testing using a qPCR targeting the triose phosphate isomerase (tpi) DNA regions that can distinguish G. duodenalis of two different assemblages (A and B), which are human-specific., Results: Initial optimisation resulted in the successful amplification of predicted RPA products from G. duodenalis-purified gDNA, producing a double-labelled amplicon detected using lateral flow strips. In the field setting, of 129 stool samples, 49 (37.9%) were positive using the Giardia/Cryptosporidium QuikChek coproantigen test; however, the RPA assay when conducted in the field was positive for a single stool sample. Subsequent molecular screening in the laboratory on a subset (n = 73) of the samples demonstrated better results with 21 (28.8%) RPA positive. The SSU rDNA qPCR assay resulted in 30/129 (23.3%) positive samples; 18 out of 73 (24.7%) were assemblage typed (9 assemblage A; 5 assemblage B; and 4 mixed A+B). Compared with the SSU rDNA qPCR, QuikChek was more sensitive than RPA (85.7 vs 61.9%), but with similar specificities (80.8 vs 84.6%). In comparison to QuikChek, RPA had 46.4% sensitivity and 82.2% specificity., Conclusions: To the best of our knowledge, this is the first in-field and comparative laboratory validation of RPA for giardiasis in low resource settings. Further refinement and technology transfer, specifically in relation to stool sample preparation, will be needed to implement this assay in the field, which could assist better detection of asymptomatic Giardia infections.

Background: Since 1979, mortality from hepatocellular cancer (HCC) has doubled in the United States (US). Lifesaving drugs, prohibitively expensive for some, were approved and marketed to treat hepatitis C virus (HCV), a major risk factor for HCC, beginning in 1997. After the prior introduction of other lifesaving innovations, including active retroviral drug therapy for human immunodeficiency virus and surfactant for respiratory distress syndrome of the newborn, racial inequalities in their mortalities increased in the US. In this descriptive study, we explored racial inequalities in mortality from HCC before and after licensure of HCV drugs in the US., Methods: The US Centers for Disease Control and Prevention Wide-ranging ONline Data for Epidemiologic Research (WONDER) were used to describe HCC mortality rates from 1979 to 2016 in those 55 years of age and older, because they suffer the largest disease burden. Joinpoint regression was used to analyze trends. To estimate excess deaths, we applied White age-sex-specific rates to corresponding Black populations., Findings: From 1979 to 1998, racial inequalities in mortality from HCC in the US were declining but from 1998 to 2016 racial inequalities steadily increased. From 1998 to 2016, of the 16,770 deaths from HCC among Blacks, the excess relative to Whites increased from 27.8% to 45.4%, and the trends were more prominent in men. Concurrently, racial inequalities in mortality decreased for major risk factors for HCC, including alcohol, obesity and diabetes., Interpretation: These descriptive data, useful to formulate but not test hypotheses, demonstrate decreasing racial inequalities in mortality from HCC which were followed by increases after introduction of lifesaving drugs for HCV in the US. Among many plausible hypotheses generated are social side effects, including unequal accessibility, acceptability and/or utilization. Analytic epidemiological studies designed a priori to do so are necessary to test these and other hypotheses., Competing Interests: RSL, MCM, JLS, SJG, MHA, BAH, RJZ report no conflicts., (© 2020 The Author(s).)

Objective: To examine high school youths' perceptions of health risks, and personal and parental attitudes toward cigarette, cigar, and marijuana use among youth who use or modify cigars., Participants: The 2013 Cuyahoga County Youth Risk Behavior Survey used a two-stage cluster sample design to randomly sample public high schools and classrooms. Students in selected classrooms were eligible; 16,855 students completed the survey., Main Outcome Measures: This study examines the association between risk perceptions of and youths' personal and parental attitudes toward smoking cigarettes, cigars, and marijuana with current use of cigars, cigarillos or little cigars (CCLCs) or modified CCLCs (ie, freaking or blunting)., Results: 23.5% of youth reported current use of CCLCs in some way; 11.0% reported current freaking and 18.5% reported current blunt use. CCLC users tended to be male and Black. Perceiving all smoking behaviors as risky, wrong, or wrong by parents reduced odds of using CCLCs. After multivariate analysis, Blacks had increased odds of using CCLCs if they perceived smoking cigarettes as harmful, which was not found among other race/ethnicity categories. Having parents who believed that smoking CCLCs is wrong increased the odds of youth freaking or blunting among all CCLC users. Odds of blunting was greater for those who believed CCLCs were more risky among all CCLC users., Conclusions: Findings suggest that CCLC users may think cigars are safer than cigarettes, and that modifiers may think their use is safer and more in line with their parents' views than non-modified CCLCs., Competing Interests: Competing Interests: None declared.

Malignant pleural mesothelioma is a highly aggressive tumor. Alternative treatment strategies such as oncolytic viral therapy may offer promising treatment options in the future. In this study, the oncolytic efficacy and induction of tumor remission by a genetically engineered Newcastle disease virus [NDV; NDV(F3aa)-GFP; GFP, green fluorescent protein] in malignant pleural mesothelioma is tested and monitored by bioluminescent tumor imaging. The efficacy of NDV(F3aa)-GFP was tested against several mesothelioma cell lines in vitro. Firefly luciferase-transduced MSTO-211H* orthotopic pleural mesothelioma tumor-bearing animals were treated with either single or multiple doses of NDV(F3aa)-GFP at different time points (days 1 and 10) after tumor implantation. Tumor burden was assessed by bioluminescence imaging. Mesothelioma cell lines exhibited dose-dependent susceptibility to NDV lysis in the following order of sensitivity: MSTO-211H > MSTO-211H* > H-2452 > VAMT > JMN. In vivo studies with MSTO-211H* cells showed complete response to viral therapy in 65% of the animals within 14 days after treatment initiation. Long-term survival in all of these animals was >50 days after tumor installation (control animals, <23 d). Multiple treatment compared with single treatment showed a significantly better response (P = 0.005). NDV seems to be an efficient viral oncolytic agent in the therapy of malignant pleural mesothelioma in an orthotopic pleural mesothelioma tumor model.