Mimicking functional elements of the natural flow regime promotes native fish recovery in a regulated river.

Streamflow regimes that maintain vital functions and processes of aquatic ecosystems are critical to sustaining ecosystem health. In rivers with altered flow regimes, restoring components of the natural flow regime is predicted to conserve freshwater biodiversity by supporting ecological functions and geomorphological processes to which native communities are adapted. However, the effectiveness of environmental flow restoration is poorly understood because of inadequate monitoring and uncertainty in ecological responses to managed changes in specific, quantifiable aspects of the annual streamflow regime. Here, we used time series models to analyze 25 years of fish assemblage data collected before and after environmental flow implementation in a dammed river in California, USA. We examined the response of the fish community to changes in individual components of the flow regime known to support ecosystem functions. We found that as functional flow components shifted toward their predicted natural range, the quasi-extinction risk (likelihood of population declines of >80%) decreased for the native fish assemblage. Following environmental flow implementation, observed changes toward natural ranges of dry season duration, fall pulse flow magnitude, and wet season timing each reduced quasi-extinction risk by at least 40% for the native assemblage. However, functional flow components that shifted away from their predicted natural range, including lower spring recession flows and higher dry season baseflow, resulted in greater quasi-extinction risk for native species. In contrast, non-native species decreased in abundance when flow components shifted toward predicted natural ranges and increased when components shifted away from their natural range. Although most functional flow components remained outside of their natural range following environmental flow implementation, our results indicate that even moderate shifts toward a natural flow regime can benefit native and suppress non-native fish species. Overall, this study provides the most compelling evidence to date of the effectiveness of functional environmental flows in supporting native fish recovery in a highly regulated river.

COVID-19 and friendships: Agreeableness and neuroticism are associated with more concern about COVID-19 and friends' risky behaviors.

Given the importance of friendships during challenging times and the mixed associations between personality traits and disease-related behaviors, we investigated the correlations between personality traits and perceptions of friendships during the COVID-19 pandemic. Data were collected as part of a longitudinal investigation of the correlations between the pandemic and various cooperative relationships. In this investigation, we found that agreeableness and neuroticism predicted participants being more concerned about COVID-19 and bothered by friends' risky behavior, and extraversion predicted enjoying helping friends during the pandemic. Our results suggest that personality differences are associated with how individuals cope with friends' risky behaviors during the COVID-19 pandemic.

A Novel Dual Incretin Agent, Tirzepatide (LY3298176), for the Treatment of Type 2 Diabetes Mellitus and Cardiometabolic Health.

ABSTRACT: The incretin hormone system is the target of multiple type 2 diabetes mellitus (T2DM) treatments because defects in this system play major roles in the pathogenesis of diabetes. Currently, the glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are recommended for patients with atherosclerotic cardiovascular (CV) disease and those at high risk for atherosclerotic CV disease. In addition to the favorable CV effects, GLP-1 RAs also provide robust lowering of hemoglobin A1c and weight. Although these factors make GLP-1 RAs attractive options for T2DM, the currently available agents have no effect on glucose-dependent insulinotropic polypeptide (GIP). Patients with T2DM are known to have GIP defect which is significant due to its profound insulinotropic effects. Tirzepatide is a novel incretin agent currently recently approved by the Food and Drug Administration for the treatment of T2DM. This first-in-class agent serves as a coagonist for both the GLP-1 and GIP receptors. In this review, we report on the pharmacologic mechanism of GLP-1, GIP, and coagonist effects on the cardiometabolic system. In addition, we review the glycemic lowering, weight loss effects, and other cardiometabolic outcomes of tirzepatide based on phase 2 and 3 data. The safety profile of tirzepatide is consistent across all phase 3 trials. The most common adverse effects are gastrointestinal symptoms, but they generally have a low risk for discontinuation. Overall, preliminary data suggest that tirzepatide is an efficacious and safe agent for the treatment of T2DM.

Do Smartphones Create a Coordination Problem for Face-to-Face Interaction? Leveraging Game Theory to Understand and Solve the Smartphone Dilemma.

Smartphone use changes the landscape of social interactions, including introducing new social dilemmas to daily life. The challenge of putting down one's smartphone is an example of a classic coordination problem from game theory: the stag hunt game. In a stag hunt game, there are two possible coordination points, one that involves big payoffs for both partners (e.g., working together to hunt large game like stag) and one that involves smaller payoffs for both partners (e.g., individually hunting small game like rabbits) but is safer because it does not require that your partner choose that option as well. This is similar to the challenges of putting down smartphones to have a face-to-face interaction: you and your interaction partner might both prefer the higher payoff option of having a face-to-face interaction, but neither of you wants to put down your phone and risk not having anything to do in the meantime. It is also discussed how new technological innovations are changing the payoffs of face-to-face conversation versus side-by-side smartphone scrolling. Insights that come from applying game theory to this "social media dilemma" are discussed here and potential solutions that come out of a game theoretic analysis are offered. Also see the video abstract here https://youtu.be/9esL578zM-E.

Younger people and people with higher subjective SES experienced more negative effects of the pandemic on their friendships.

Friendships provide social support and mental health benefits, yet the COVID-19 pandemic has limited interactions with friends. In August 2020, we asked participants (N = 634) about their friendships during the pandemic as part of a larger study. We found that younger people and people with higher subjective SES reported more negative effects on their friendships, including feeling more isolated and lonelier. We also found that stress, isolation, and guilt were associated with greater COVID-related social risk-taking, such as making and visiting new friends in person. Our results suggest the pandemic is affecting friendships differently across demographic groups and these negative effects might motivate social risk-taking.

Subtypes of Barrett's oesophagus and oesophageal adenocarcinoma based on genome-wide methylation analysis.

OBJECTIVE: To identify and characterise DNA methylation subtypes in oesophageal adenocarcinoma (EAC) and its precursor Barrett's oesophagus (BE). DESIGN: We performed genome-wide DNA methylation profiling on samples of non-dysplastic BE from cancer-free patients (n=59), EAC (n=23), normal squamous oesophagus (n=33) and normal fundus (n=9), and identified methylation subtypes using a recursively partitioned mixture model. We assessed genomic alterations for 9 BE and 22 EAC samples with massively parallel sequencing of 243 EAC-associated genes, and we conducted integrative analyses with transcriptome data to identify epigenetically repressed genes. We also carried out in vitro experiments treating EAC cell lines with 5-Aza-2'-Deoxycytidine (5-Aza-dC), short hairpin RNA knockdown and anticancer therapies. RESULTS: We identified and validated four methylation subtypes of EAC and BE. The high methylator subtype (HM) of EAC had the greatest number of activating events in ERBB2 (p<0.05, Student's t-test) and the highest global mutation load (p<0.05, Fisher's exact test). PTPN13 was silenced by aberrant methylation in the HM subtype preferentially and in 57% of EACs overall. In EAC cell lines, 5-Aza-dC treatment restored PTPN13 expression and significantly decreased its promoter methylation in HM cell lines (p<0.05, Welch's t-test). Inhibition of PTPN13 expression in the SK-GT-4 EAC cell line promoted proliferation, colony formation and migration, and increased phosphorylation in ERBB2/EGFR/Src kinase pathways. Finally, EAC cell lines showed subtype-specific responses to topotecan, SN-38 and palbociclib treatment. CONCLUSIONS: We identified and characterised methylator subtypes in BE and EAC. We further demonstrated the biological and clinical relevance of EAC methylator subtypes, which may ultimately help guide clinical management of patients with EAC.

Recent Developments in the Role of Coenzyme Q10 for Coronary Heart Disease: a Systematic Review.

PURPOSE OF REVIEW: This review examines recent randomized clinical trials evaluating the role of coenzyme Q10 (CoQ10) in the management of coronary heart disease. RECENT FINDINGS: CoQ10 is one of the most commonly used dietary supplements in the USA. Due to its antioxidant and anti-inflammatory effects, CoQ10 has been studied extensively for possible use in managing coronary heart disease. One of the most common applications of CoQ10 is to mitigate statin-associated muscle symptoms (SAMS) based on the theory that SAMS are caused by statin depletion of CoQ10 in the muscle. Although previous studies of CoQ10 for SAMS have produced mixed results, CoQ10 appears to be safe. Because CoQ10 is a cofactor in the generation of adenosine triphosphate, supplementation has also recently been studied in patients with heart failure, which is inherently an energy deprived state. The Q-SYMBIO trial found that CoQ10 supplementation in patients with heart failure not only improved functional capacity, but also significantly reduced cardiovascular events and mortality. Despite these positive findings, a larger prospective trial is warranted to support routine use of CoQ10. Less impressive are the effects of CoQ10 on specific cardiovascular risk factors such as blood pressure, dyslipidemia, and glycemic control. Current evidence does not support routine use of CoQ10 in patients with coronary heart disease. Additional studies are warranted to fully determine the benefit of CoQ10 in patients with heart failure before including it in guideline-directed medical therapy.

Evaluation of pigtail macaques as a model for the effects of copper intrauterine devices on HIV infection.

BACKGROUND: Long-acting, hormonal contraception may increase HIV risk. Copper intrauterine devices (IUDs) could serve as non-hormonal alternatives. We pilot a pigtail macaque model for evaluating HIV susceptibility factors during copper IUD use. METHODS: Frameless and flexible GyneFix(®) copper IUDs were surgically implanted into three SHIVSF 162p3 -positive macaques via hysterotomy and monitored for up to 4 months. Four macaques served as non-IUD controls. RESULTS: All animals retained the devices without complications. No consistent change in vaginal viral RNA or inflammatory cytokines was seen. Two animals had altered menstrual cycles and experienced marked thinning of vaginal epithelium after IUD insertion. Histological examination of uterine tissue at necropsy revealed endometrial ulceration and lymphocytic inflammation with glandular loss at sites of direct IUD contact. CONCLUSIONS: Although the need for insertion surgery could limit its usefulness, this model will allow studies on copper IUDs and SHIV shedding, disease progression, and HIV susceptibility factors.

How Genetic-Conflict Theory Can Inform Studies of Human Nature.

Understanding how genetics influences human psychology is something that the evolutionary sciences emphasize. However, the functions of complex genetic influences on behavior have been overlooked in favor of perspectives that posit unitary influences of genes on behavior. One such example is the belief that human growth, development, and behavior are influenced uniformly by their genes even though previous research has highlighted the genetic conflict endemic in these domains. Although much psychological research has robustly documented areas in which we see the footprints of genetic conflict in human behavior, these areas are referred to by different names that prevent researchers from making connections under a unifying framework. In this article, I outline what genetic conflict is and how genetic conflict can provide a unifying framework for psychological investigations of social relationships. I also discuss avenues for future research on genetic conflict in humans and the importance of considering cultural, ecological, and other developmental factors when researching the genetic influences on human behavior.

Genetic Tools for Cell Lineage Tracing and Profiling Developmental Trajectories in the Skin.

The epidermis is the body's first line of protection against dehydration and pathogens, continually regenerating the outermost protective skin layers throughout life. During both embryonic development and wound healing, epidermal stem and progenitor cells must respond to external stimuli and insults to build, maintain, and repair the cutaneous barrier. Recent advances in CRISPR-based methods for cell lineage tracing have remarkably expanded the potential for experiments that track stem and progenitor cell proliferation and differentiation over the course of tissue and even organismal development. Additional tools for DNA-based recording of cellular signaling cues promise to deepen our understanding of the mechanisms driving normal skin morphogenesis and response to stressors as well as the dysregulation of cell proliferation and differentiation in skin diseases and cancer. In this review, we highlight cutting-edge methods for cell lineage tracing, including in organoids and model organisms, and explore how cutaneous biology researchers might leverage these techniques to elucidate the developmental programs that support the regenerative capacity and plasticity of the skin.

Mapping the core senescence phenotype of primary human colon fibroblasts.

Advanced age is the largest risk factor for many diseases and several types of cancer, including colorectal cancer (CRC). Senescent cells are known to accumulate with age in various tissues, where they can modulate the surrounding tissue microenvironment through their senescence associated secretory phenotype (SASP). Recently, we showed that there is an increased number of senescent cells in the colons of CRC patients and demonstrated that senescent fibroblasts and their SASP create microniches in the colon that are conducive to CRC onset and progression. However, the composition of the SASP is heterogenous and cell-specific, and the precise senescence profile of colon fibroblasts has not been well-defined. To generate a SASP atlas of human colon fibroblasts, we induced senescence in primary human colon fibroblasts using various in vitro methods and assessed the resulting transcriptome. Using RNASequencing and further validation by quantitative RT-PCR and Luminex assays, we define and validate a 'core senescent profile' that might play a significant role in shaping the colon microenvironment. We also performed KEGG analysis and GO analyses to identify key pathways and biological processes that are differentially regulated in colon fibroblast senescence. These studies provide insights into potential driver proteins involved in senescence-associated diseases, like CRC, which may lead to therapies to improve overall health in the elderly and to prevent CRC.

Alterations of biaxial viscoelastic properties of the right ventricle in pulmonary hypertension development in rest and acute stress conditions.

Introduction: The right ventricle (RV) mechanical property is an important determinant of its function. However, compared to its elasticity, RV viscoelasticity is much less studied, and it remains unclear how pulmonary hypertension (PH) alters RV viscoelasticity. Our goal was to characterize the changes in RV free wall (RVFW) anisotropic viscoelastic properties with PH development and at varied heart rates. Methods: PH was induced in rats by monocrotaline treatment, and the RV function was quantified by echocardiography. After euthanasia, equibiaxial stress relaxation tests were performed on RVFWs from healthy and PH rats at various strain-rates and strain levels, which recapitulate physiological deformations at varied heart rates (at rest and under acute stress) and diastole phases (at early and late filling), respectively. Results and Discussion: We observed that PH increased RVFW viscoelasticity in both longitudinal (outflow tract) and circumferential directions. The tissue anisotropy was pronounced for the diseased RVs, not healthy RVs. We also examined the relative change of viscosity to elasticity by the damping capacity (ratio of dissipated energy to total energy), and we found that PH decreased RVFW damping capacity in both directions. The RV viscoelasticity was also differently altered from resting to acute stress conditions between the groups-the damping capacity was decreased only in the circumferential direction for healthy RVs, but it was reduced in both directions for diseased RVs. Lastly, we found some correlations between the damping capacity and RV function indices and there was no correlation between elasticity or viscosity and RV function. Thus, the RV damping capacity may be a better indicator of RV function than elasticity or viscosity alone. These novel findings on RV dynamic mechanical properties offer deeper insights into the role of RV biomechanics in the adaptation of RV to chronic pressure overload and acute stress.

Descriptive norms caused increases in mask wearing during the COVID-19 pandemic.

Human sociality is governed by two types of social norms: injunctive norms, which prescribe what people ought to do, and descriptive norms, which reflect what people actually do. The process by which these norms emerge and their causal influences on cooperative behavior over time are not well understood. Here, we study these questions through social norms influencing mask wearing during the COVID-19 pandemic. Leveraging 2 years of data from the United States (18 time points; n = 915), we tracked mask wearing and perceived injunctive and descriptive mask wearing norms as the pandemic unfolded. Longitudinal trends suggested that norms and behavior were tightly coupled, changing quickly in response to public health recommendations. In addition, longitudinal modeling revealed that descriptive norms caused future increases in mask wearing across multiple waves of data collection. These cross-lagged causal effects of descriptive norms were large, even after controlling for non-social beliefs and demographic variables. Injunctive norms, by contrast, had less frequent and generally weaker causal effects on future mask wearing. During uncertain times, cooperative behavior is more strongly driven by what others are actually doing, rather than what others think ought to be done.

Development of statistical models for estimating daily nitrate load in Iowa.

There is an ongoing need to increase our understanding of the sources and timing of stream nitrate loads across agricultural watersheds in Iowa as water quality improvement strategies are implemented. The goal of this study was to model the relationship between nitrate load and the two components of streamflow (i.e., baseflow and stormflow) to quantify in-stream nitrate patterns and develop a new method for estimating loads on days when monitoring data are not available. We analyzed eight watersheds in Iowa that had long-term water quality data where grab samples have been collected from 1987 to 2019. Four regression models were developed that related daily nitrate load to daily baseflow, stormflow, and streamflow discharge. The first model considered baseflow as a predictor, the second model used stormflow, the third model included both baseflow and stormflow as two different covariates, and the final model used total streamflow (unseparated). For all eight watersheds, the baseflowstormflow models had the highest correlation coefficients, which indicates that both components are necessary and together improve nitrate load estimates. While baseflow models estimated lower nitrate loads better, stormflow models captured the variability associated with larger loads. In addition, streamflow models tended to overestimate large nitrate loads. This simple modeling framework can be used to calculate daily, monthly and annual nitrate loads. Delineating nitrate loads between stormflow and baseflow can help identify differences in nitrate sources for nutrient reduction and remediation.

Associations Between Change Over Time in Pandemic-Related Stress and Change in Physical Activity.

BACKGROUND: Physical activity (PA) mitigated psychological distress during the initial weeks of the COVID-19 pandemic, yet not much is known about whether PA had effects on stress in subsequent months. We examined the relationship between change over time in COVID-related stress and self-reported change in PA between March and July 2020. METHODS: Latent growth modeling was used to examine trajectories of change in pandemic-related stress and test their association with self-reported changes in PA in an international sample (n = 679). RESULTS: The participants reported a reduction in pandemic-related stress between April and July of 2020. Significant linear (factor mean = -0.22) and quadratic (factor mean = 0.02) changes (Ps < .001) were observed, indicating a deceleration in stress reduction over time. Linear change was related to change in PA such that individuals who became less active during the pandemic reported less stress reduction over time compared with those who maintained or increased their PA during the pandemic. CONCLUSIONS: Individuals who experienced the greatest reduction in stress over time during the pandemic were those who maintained their activity levels or became more active. Our study cannot establish a causal relationship between these variables, but the findings are consistent with other work showing that PA reduces stress.

Loss of MGA repression mediated by an atypical polycomb complex promotes tumor progression and invasiveness.

MGA, a transcription factor and member of the MYC network, is mutated or deleted in a broad spectrum of malignancies. As a critical test of a tumor suppressive role, we inactivated Mga in two mouse models of non-small cell lung cancer using a CRISPR-based approach. MGA loss significantly accelerated tumor growth in both models and led to de-repression of non-canonical Polycomb ncPRC1.6 targets, including genes involved in metastasis and meiosis. Moreover, MGA deletion in human lung adenocarcinoma lines augmented invasive capabilities. We further show that MGA-MAX, E2F6, and L3MBTL2 co-occupy thousands of promoters and that MGA stabilizes these ncPRC1.6 subunits. Lastly, we report that MGA loss also induces a pro-growth effect in human colon organoids. Our studies establish MGA as a bona fide tumor suppressor in vivo and suggest a tumor suppressive mechanism in adenocarcinomas resulting from widespread transcriptional attenuation of MYC and E2F target genes mediated by MGA-MAX associated with a non-canonical Polycomb complex.

Hematologic Values of Jamaican Fruit Bats (Artibeus jamaicensis) and the Effects of Isoflurane Anesthesia.

Jamaican fruit bats (Artibeus jamaicensis) are used as an animal model for several viruses, including Middle East respiratory syndrome virus, dengue virus, Zika virus, and Tacaribe virus. However, despite ongoing studies regarding these pathogens, little is known regarding the bats' normal physiology. In this study, phlebotomy of the propetagial (cephalic) vein was performed to establish baseline hematologic parameters in an apparently healthy, captive population of Jamaican fruit bats. Furthermore, we compared results from physically restrained and isoflurane-anesthetized bats. Our findings indicate significant increases in WBC count, lymphocytes, and monocytes in the anesthetized bats. However, RBC and platelet parameters were not different between the 2 groups. This information on the normal hematologic parameters of Jamaican fruit bats, adds to our overall understanding of the normal physiology of this species, and expands our knowledge on bat species in general.

The value of linking mitigation and adaptation: a case study of Bangladesh.

There are two principal strategies for managing climate change risks: mitigation and adaptation. Until recently, mitigation and adaptation have been considered separately in both climate change science and policy. Mitigation has been treated as an issue for developed countries, which hold the greatest responsibility for climate change, while adaptation is seen as a priority for the South, where mitigative capacity is low and vulnerability is high. This conceptual divide has hindered progress against the achievement of the fundamental sustainable development challenges of climate change. Recent attention to exploring the synergies between mitigation and adaptation suggests that an integrated approach could go some way to bridging the gap between the development and adaptation priorities of the South and the need to achieve global engagement in mitigation. These issues are explored through a case study analysis of climate change policy and practice in Bangladesh. Using the example of waste-to-compost projects, a mitigation-adaptation-development nexus is demonstrated, as projects contribute to mitigation through reducing methane emissions; adaptation through soil improvement in drought-prone areas; and sustainable development, because poverty is exacerbated when climate change reduces the flows of ecosystem services. Further, linking adaptation to mitigation makes mitigation action more relevant to policymakers in Bangladesh, increasing engagement in the international climate change agenda in preparation for a post-Kyoto global strategy. This case study strengthens the argument that while combining mitigation and adaptation is not a magic bullet for climate policy, synergies, particularly at the project level, can contribute to the sustainable development goals of climate change and are worth exploring.

Senescence-associated tissue microenvironment promotes colon cancer formation through the secretory factor GDF15.

The risk of colorectal cancer (CRC) varies between people, and the cellular mechanisms mediating the differences in risk are largely unknown. Senescence has been implicated as a causative cellular mechanism for many diseases, including cancer, and may affect the risk for CRC. Senescent fibroblasts that accumulate in tissues secondary to aging and oxidative stress have been shown to promote cancer formation via a senescence-associated secretory phenotype (SASP). In this study, we assessed the role of senescence and the SASP in CRC formation. Using primary human colon tissue, we found an accumulation of senescent fibroblasts in normal tissues from individuals with advanced adenomas or carcinomas in comparison with individuals with no polyps or CRC. In in vitro and ex vivo model systems, we induced senescence using oxidative stress in colon fibroblasts and demonstrated that the senescent fibroblasts secrete GDF15 as an essential SASP factor that promotes cell proliferation, migration, and invasion in colon adenoma and CRC cell lines as well as primary colon organoids via the MAPK and PI3K signaling pathways. In addition, we observed increased mRNA expression of GDF15 in primary normal colon tissue from people at increased risk for CRC in comparison with average risk individuals. These findings implicate the importance of a senescence-associated tissue microenvironment and the secretory factor GDF15 in promoting CRC formation.

Analgesia during Monkeypox Virus Experimental Challenge Studies in Prairie Dogs (Cynomys ludovicianus).

Because human patients with monkeypox virus (MPXV) infection report painful symptoms, it is reasonable to assume that animals infected with MPXV experience some degree of pain. Understanding whether and how analgesics affect MPXV disease progression is crucial when planning in vivo challenge experiments. In the current study, we challenged prairie dogs with a low dose (4 ×10³ pfu) of MPXV and treated with meloxicam (NSAID) or buprenorphine (opioid); control animals did not receive analgesia or received analgesia without MPXV challenge. Subsets of animals from each group were serially euthanized during the course of the study. Disease progression and viral kinetics were similar between groups, but MXPVinfected, meloxicam-treated animals showed increasing trends of morbidity and mortality compared with other groups. Differences between no-analgesia MPXV-infected control animals and MPXV-infected animals treated with buprenorphine were minimal. The findings in the current study allow more informed decisions concerning the use of analgesics during experimental MPXV challenge studies, thereby improving animal welfare. In light of these findings, we have modified our pain scale for this animal model to include the use of buprenorphine for pain relief when warranted after MPXV challenge.