Marine heatwaves disrupt ecosystem structure and function via altered food webs and energy flux.

The prevalence and intensity of marine heatwaves is increasing globally, disrupting local environmental conditions. The individual and population-level impacts of prolonged heatwaves on marine species have recently been demonstrated, yet whole-ecosystem consequences remain unexplored. We leveraged time series abundance data of 361 taxa, grouped into 86 functional groups, from six long-term surveys, diet information from a new diet database, and previous modeling efforts, to build two food web networks using an extension of the popular Ecopath ecosystem modeling framework, Ecotran. We compare ecosystem models parameterized before and after the onset of recent marine heatwaves to evaluate the cascading effects on ecosystem structure and function in the Northeast Pacific Ocean. While the ecosystem-level contribution (prey) and demand (predators) of most functional groups changed following the heatwaves, gelatinous taxa experienced the largest transformations, underscored by the arrival of northward-expanding pyrosomes. We show altered trophic relationships and energy flux have potentially profound consequences for ecosystem structure and function, and raise concerns for populations of threatened and harvested species.

Comparative population genomics of manta rays has global implications for management.

Understanding population connectivity and genetic diversity is of fundamental importance to conservation. However, in globally threatened marine megafauna, challenges remain due to their elusive nature and wide-ranging distributions. As overexploitation continues to threaten biodiversity across the globe, such knowledge gaps compromise both the suitability and effectiveness of management actions. Here, we use a comparative framework to investigate genetic differentiation and diversity of manta rays, one of the most iconic yet vulnerable groups of elasmobranchs on the planet. Despite their recent divergence, we show how oceanic manta rays (Mobula birostris) display significantly higher heterozygosity than reef manta rays (Mobula alfredi) and that M. birostris populations display higher connectivity worldwide. Through inferring modes of colonization, we reveal how both contemporary and historical forces have likely influenced these patterns, with important implications for population management. Our findings highlight the potential for fisheries to disrupt population dynamics at both local and global scales and therefore have direct relevance for international conservation of marine species.

Boom-bust cycles in gray whales associated with dynamic and changing Arctic conditions.

Climate change is affecting a wide range of global systems, with polar ecosystems experiencing the most rapid change. Although climate impacts affect lower-trophic-level and short-lived species most directly, it is less clear how long-lived and mobile species will respond to rapid polar warming because they may have the short-term ability to accommodate ecological disruptions while adapting to new conditions. We found that the population dynamics of an iconic and highly mobile polar-associated species are tightly coupled to Arctic prey availability and access to feeding areas. When low prey biomass coincided with high ice cover, gray whales experienced major mortality events, each reducing the population by 15 to 25%. This suggests that even mobile, long-lived species are sensitive to dynamic and changing conditions as the Arctic warms.

The induction of p53 correlates with defects in the production, but not the levels, of the small ribosomal subunit and stalled large ribosomal subunit biogenesis.

Ribosome biogenesis is one of the biggest consumers of cellular energy. More than 20 genetic diseases (ribosomopathies) and multiple cancers arise from defects in the production of the 40S (SSU) and 60S (LSU) ribosomal subunits. Defects in the production of either the SSU or LSU result in p53 induction through the accumulation of the 5S RNP, an LSU assembly intermediate. While the mechanism is understood for the LSU, it is still unclear how SSU production defects induce p53 through the 5S RNP since the production of the two subunits is believed to be uncoupled. Here, we examined the response to SSU production defects to understand how this leads to the activation of p53 via the 5S RNP. We found that p53 activation occurs rapidly after SSU production is blocked, prior to changes in mature ribosomal RNA (rRNA) levels but correlated with early, middle and late SSU pre-rRNA processing defects. Furthermore, both nucleolar/nuclear LSU maturation, in particular late stages in 5.8S rRNA processing, and pre-LSU export were affected by SSU production defects. We have therefore uncovered a novel connection between the SSU and LSU production pathways in human cells, which explains how p53 is induced in response to SSU production defects.

Human theca arises from ovarian stroma and is comprised of three discrete subtypes.

Theca cells serve multiple essential functions during the growth and maturation of ovarian follicles, providing structural, metabolic, and steroidogenic support. While the function of theca during folliculogenesis is well established, their cellular origins and the differentiation hierarchy that generates distinct theca sub-types, remain unknown. Here, we performed single cell multi-omics analysis of primary cell populations purified from human antral stage follicles (1-3 mm) to define the differentiation trajectory of theca/stroma cells. We then corroborated the temporal emergence and growth kinetics of defined theca/stroma subpopulations using human ovarian tissue samples and xenografts of cryopreserved/thawed ovarian cortex, respectively. We identified three lineage specific derivatives termed structural, androgenic, and perifollicular theca cells, as well as their putative lineage-negative progenitor. These findings provide a framework for understanding the differentiation process that occurs in each primordial follicle and identifies specific cellular/molecular phenotypes that may be relevant to either diagnosis or treatment of ovarian pathologies.

Design principles of microparticle size and immunomodulatory factor formulation dictate antigen-specific amelioration of multiple sclerosis in a mouse model.

Antigen-specific therapies allow for modulation of the immune system in a disease relevant context without systemic immune suppression. These therapies are especially valuable in autoimmune diseases such as multiple sclerosis (MS), where autoreactive T cells destroy myelin sheath. This work shows that an antigen-specific dual-sized microparticle (dMP) system can effectively halt and reverse disease progression in a mouse model of MS. Current MS treatments leave patients immunocompromised, but the dMP formulation spares the immune system as mice can successfully clear a Listeria Monocytogenes infection. Furthermore, we highlight design principles for particle based immunotherapies including the importance of delivering factors specific for immune cell recruitment (GM-CSF or SDF-1), differentiation (GM-CSF or FLT3L) and suppression (TGF-ß or VD3) in conjunction with disease relevant antigen, as the entire formulation is required for maximum efficacy. Lastly, the dMP scheme relies on formulating phagocytosable and non-phagocytosable MP sizes to direct payload to target either cell surface receptors or intracellular targets, as the reverse sized dMP formulation failed to reverse paralysis. We also challenge the design principles of the dMP system showing that the size of the MPs impact efficacy and that GM-CSF plays two distinct roles and that both of these must be replaced to match the primary effect of the dMP system. Overall, this work shows the versatile nature of the dMP system and expands the knowledge in particle science by emphasizing design tenets to guide the next generation of particle based immunotherapies.

The use of fertility preservation services for cancer patients: a single institution experience.

Objective: To analyze the use of services regarding fertility preservation (FP) in cancer patients at a single institution. Design: A retrospective cohort study. Setting: Academic medical center. Patients: A total of 208 FP referrals. Interventions: None. Main Outcome Measures: Method of FP; time from referral to FP intervention. Results: A total of 553 patients were referred to a reproductive specialist for FP in the setting of a medical diagnosis from 2011 to 2016. Of these, 208 patients satisfied the inclusion criteria and met with a reproductive specialist. Ninety patients underwent FP services. The average age at referral was 30.9 ± 7.9 years. Breast cancer (n=94, 45%) and leukemia/lymphoma (n=62, 30%) were the most prevalent cancer diagnoses. A 68.9% of patients underwent oocyte cryopreservation (n=62), 26.7% underwent embryo cryopreservation (n=24) and 4.4% underwent ovarian tissue preservation (n=4). The time interval from the referral to the FP intervention ranged from 1 to 810 days, with a median of 17 days. Conclusions: In the setting of a cancer diagnosis, most patients undergoing FP intervention underwent oocyte cryopreservation, were <35 years old, and underwent FP intervention in <30 days from referral. Whereas FP should ideally be initiated at the time of cancer diagnosis, all patients with a cancer diagnosis should be referred to a reproductive specialist and counseled on options for FP to preserve the optionality for the reproductive future they desire.

Treatment with an antigen-specific dual microparticle system reverses advanced multiple sclerosis in mice.

Antigen-specific therapies hold promise for treating autoimmune diseases such as multiple sclerosis while avoiding the deleterious side effects of systemic immune suppression due to delivering the disease-specific antigen as part of the treatment. In this study, an antigen-specific dual-sized microparticle (dMP) treatment reversed hind limb paralysis when administered in mice with advanced experimental autoimmune encephalomyelitis (EAE). Treatment reduced central nervous system (CNS) immune cell infiltration, demyelination, and inflammatory cytokine levels. Mechanistic insights using single-cell RNA sequencing showed that treatment impacted the MHC II antigen presentation pathway in dendritic cells, macrophages, B cells, and microglia, not only in the draining lymph nodes but also strikingly in the spinal cord. CD74 and cathepsin S were among the common genes down-regulated in most antigen presenting cell (APC) clusters, with B cells also having numerous MHC II genes reduced. Efficacy of the treatment diminished when B cells were absent, suggesting their impact in this therapy, in concert with other immune populations. Activation and inflammation were reduced in both APCs and T cells. This promising antigen-specific therapeutic approach advantageously engaged essential components of both innate and adaptive autoimmune responses and capably reversed paralysis in advanced EAE without the use of a broad immunosuppressant.

The distribution of manta rays in the western North Atlantic Ocean off the eastern United States.

In 2018, the giant manta ray was listed as threatened under the U.S. Endangered Species Act. We integrated decades of sightings and survey effort data from multiple sources in a comprehensive species distribution modeling (SDM) framework to evaluate the distribution of giant manta rays off the eastern United States, including the Gulf of Mexico. Manta rays were most commonly detected at productive nearshore and shelf-edge upwelling zones at surface thermal frontal boundaries within a temperature range of approximately 20-30 °C. SDMs predicted highest nearshore occurrence off northeastern Florida during April, with the distribution extending northward along the shelf-edge as temperatures warm, leading to higher occurrences north of Cape Hatteras, North Carolina from June to October, and then south of Savannah, Georgia from November to March as temperatures cool. In the Gulf of Mexico, the highest nearshore occurrence was predicted around the Mississippi River delta from April to June and again from October to November. SDM predictions will allow resource managers to more effectively protect manta rays from fisheries bycatch, boat strikes, oil and gas activities, contaminants and pollutants, and other threats.

Beliefs, Understanding, and Barriers Related to Dementia Research Participation Among Older African Americans.

BACKGROUND: United States Census Bureau projects African Americans (AAs) will be one of the fastest growing populations over the next 30 years. Research suggests they are at higher risk for developing dementia. It is important to know about AA adults' beliefs about, and knowledge of, dementia; and how these beliefs and knowledge impact participation in dementia research. METHODS: Four focus groups were completed with 51 older AA adults (76.5% female; mean age=68) in Baton Rouge, Louisiana to examine understanding of dementia and barriers influencing willingness to participate in a clinical trial on dementia risk reduction. FINDINGS: Participants exhibited awareness of several risk and protective factors related to dementia, including family history of dementia, lack of cognitive engagement, and sedentary lifestyles. They were willing to participate in interventions to lower the risk of developing dementia. Barriers to participation included invasive procedures, pharmaceutical interventions, mistrust of investigators, inadequate compensation, and long study duration. DISCUSSION: Given the high relevance of dementia research to older AAs, their knowledge of dementia, and their willingness to participate in dementia research once barriers are addressed, it is imperative to continue to identify and remediate factors contributing to the poor representation of AAs in dementia research.

High bycatch rates of manta and devil rays in the "small-scale" artisanal fisheries of Sri Lanka.

BACKGROUND: Expanding fisheries in developing nations like Sri Lanka have a significant impact on threatened marine species such as elasmobranchs. Manta and devil (mobulid) rays have some of the most conservative life history strategies of any elasmobranch, and even low to moderate levels of bycatch from gillnet fisheries may lead to significant population declines. A lack of information on life history, demographics, population trends, and fisheries impacts hinders effective management measures for these species. METHOD: We report on mobulid fishery landings over nine years between 2011 and 2020 across 38 landing sites in Sri Lanka. We collected data on catch numbers, body sizes, sex, and maturity status for five mobulid species. We used a Bayesian state-space model to estimate monthly country-wide catch rates and total annual landings of mobulid rays. We used catch curve analyses to estimate total mortality for Mobula mobular, and evaluated trends in recorded body sizes across the study period for M. mobular, M. birostris, M. tarapacana and M. thurstoni. RESULTS: We find that catch rates have declined an order of magnitude for all species across the study period, and that total annual captures of mobulid rays by the Sri Lankan artisanal fishing fleet exceed the estimated annual captures of mobulids in all global, industrial purse seine fisheries combined. Catch curve analyses suggest that M. mobular is being fished at rates far above the species' intrinsic population growth rate, and the average sizes of all mobulids in the fishery except for M. birostris are declining. Collectively, these findings suggest overfishing of mobulid ray populations in the northern Indian Ocean by Sri Lankan artisanal fisheries. We recommend strengthening the management of these species through improved implementation of CITES, CMS, and regional fisheries management actions. In addition, we report on the demographic characteristics of mobulids landed in Sri Lanka and provide the first record of M. eregoodoo in the country.

Incidence of first trimester pregnancy loss in the infertile population during the first wave of the coronavirus disease 2019 pandemic in New York City.

OBJECTIVE: To describe the incidence of first trimester clinical pregnancy loss in the infertile population during the first wave of the COVID-19 pandemic in New York City. DESIGN: Web-based cross-sectional survey. SETTING: New York City-based academic reproductive medicine practice. PATIENTS: A total of 305 infertile patients with a confirmed intrauterine pregnancy in their first trimester between December 1, 2019, and April 1, 2020, were matched by age and treatment type to pregnant patients from the year prior. INTERVENTIONS: None. MAIN OUTCOME MEASURES: First trimester clinical pregnancy loss rate. RESULTS: In total, the first trimester pregnancy loss rate was lower in the COVID-19 era cohort compared with that in the pre-COVID-19 era cohort (11.9% vs. 20.1%). There was no difference between cohorts in the pregnancy loss rate of women conceiving via fresh embryo transfer (19.6% vs. 24.4%) or via frozen embryo transfer with preimplantation genetic testing (5.4% vs. 9.5%,). In women conceiving via frozen embryo transfer without preimplantation genetic testing, the pregnancy loss rate was statistically lower in the COVID-19 group (12.5% vs. 24.5%). There was no difference in the pregnancy loss rate by treatment type when stratifying by COVID-19 testing or symptom status. Of the 40 (13.1%) patients with a pregnancy loss, there was no difference in self-reported COVID-19 symptoms or symptom type compared with results in those who did not experience a pregnancy loss. CONCLUSION: Despite patients expressing significant worry about COVID-19 and pregnancy, our data provides reassuring information that the first trimester pregnancy loss rate is not elevated for women conceiving via assisted reproductive technology during the global COVID-19 pandemic.

Decreasing body lengths in North Atlantic right whales.

Whales are now largely protected from direct harvest, leading to partial recoveries in many previously depleted species.1 However, most populations remain far below their historical abundances and incidental human impacts, especially vessel strikes and entanglement in fishing gear, are increasingly recognized as key threats.2 In addition, climate-driven changes to prey dynamics are impacting the seasonal foraging grounds of many baleen whales.2 In many cases these impacts result directly in mortality. But it is less clear how widespread and increasing sub-lethal impacts are affecting life history, individual fitness, and population viability. We evaluated changes in body lengths of North Atlantic right whales (NARW) using aerial photogrammetry measurements collected from crewed aircraft and remotely operated drones over a 20-year period (Figure 1). NARW have been monitored consistently since the 1980s and have been declining in abundance since 2011 due primarily to deaths associated with entanglements in active fishing gear and vessel strikes.3 High rates of sub-lethal injuries and individual-level information on age, size and observed entanglements make this an ideal population to evaluate the effects that these widespread stressors may have on individual fitness. We find that entanglements in fishing gear are associated with shorter whales, and that body lengths have been decreasing since 1981. Arrested growth may lead to reduced reproductive success4,5 and increased probability of lethal gear entanglements.6 These results show that sub-lethal stressors threaten the recoveries of vulnerable whale populations even in the absence of direct harvest.

The impact of injury on apparent survival of whale sharks (Rhincodon typus) in South Ari Atoll Marine Protected Area, Maldives.

The whale shark (Rhincodon typus) is an endangered species with a declining global population. The South Ari Atoll Marine Protected Area (SAMPA), Maldives, is one of few locations globally where year-long residency of individuals occurs. This SAMPA aggregation appears to consist almost exclusively of immature males. Due to its year-round residency, this local aggregation is subjected to a high degree of tourism pressure. This ecotourism contributes to the high level of interest and protection offered to whale sharks by the local community. Unfortunately, if regulations are not followed or enforced, tourism can bring with it major stressors, such as accidental injuries. We used POPAN capture-mark-recapture models and lagged identification rate analysis to assess the effect of major injuries on whale shark residency within SAMPA. Injuries may be obtained outside SAMPA. We found individuals with major injuries had a higher apparent survival in the area than those without. Lagged identification rates also demonstrated that sharks with major injuries are more likely to return to the area. We suggest that major injuries result in sharks prolonging their time in the developmental habitat. These findings have implications for individual fitness and the population viability of this endangered species. We propose targeted conservation strategies be considered to protect sharks from further injury. Based on the presented spatio-temporal distributions of sharks, and current local knowledge of sighting patterns, speed limit zones and propeller-exclusion zones should be implemented and enforced. If carried out alongside tourist education, these measures will contribute to the protection of whale sharks within SAMPA and beyond. Furthermore, our results can aid research direction, alongside regulation and enforcement development, at similar sites worldwide.

SM04755, a small-molecule inhibitor of the Wnt pathway, as a potential topical treatment for tendinopathy.

The Wnt pathway is upregulated in tendinopathy, affecting inflammation and tenocyte differentiation. Given its potential role in tendinopathy, this signaling pathway may be a relevant target for treatment. The current study examined the therapeutic potential of SM04755, a topical, small-molecule Wnt pathway inhibitor, for the treatment of tendinopathy using in vitro assays and animal models. In vitro, SM04755 decreased Wnt pathway activity, induced tenocyte differentiation, and inhibited catabolic enzymes and pro-inflammatory cytokines in human mesenchymal stem cells, rat tendon-derived stem cells, and human peripheral blood mononuclear cells. Evaluation of the mechanism of action of SM04755 by biochemical profiling and computational modeling identified CDC-like kinase 2 (CLK2) and dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) as molecular targets. CLK and DYRK1A inhibition by siRNA knockdown or pharmacological inhibition induced tenocyte differentiation and reduced tenocyte catabolism. In vivo, topically applied SM04755 showed therapeutically relevant exposure in tendons with low systemic exposure and no detectable toxicity in rats. Moreover, SM04755 showed reduced tendon inflammation and evidence of tendon regeneration, decreased pain, and improved weight-bearing function in rat collagenase-induced tendinopathy models compared with vehicle control. Together, these data demonstrate that CLK2 and DYRK1A inhibition by SM04755 resulted in Wnt pathway inhibition, enhanced tenocyte differentiation and protection, and reduced inflammation. SM04755 has the potential to benefit symptoms and modify disease processes in tendinopathy.

Thoughts on the popularity of ICSI.

PURPOSE: Intracytoplasmic sperm injection (ICSI) is the most widely utilized assisted reproductive technique (ART) worldwide. In this feature, we review the early assisted fertilization attempts that eventually led to the development of ICSI, and discuss its current utilization in cases of male and non-male factor infertility. METHODS: We researched the literature related to the development, indications, and current use of ICSI, such as sperm structural abnormalities, male genetic indications, surgically retrieved sperm, high sperm chromatin fragmentation, oocyte dysmorphism, and preimplantation genetic testing (PGT). We also describe the potential future applications of ICSI. RESULTS: This review summarizes the early micromanipulation techniques that led to the inception of ICSI. We also explore its current indications, including non-male factor infertility, where its use is more controversial. Finally, we consider the benefits of future advancements in reproductive biology that may incorporate ICSI, such as in vitro spermatogenesis, neogametogenesis, and heritable genome editing. CONCLUSION: The versatility, consistency, and reliability of ICSI have made it the most prevalently utilized ART procedure worldwide.

Immunomodulatory Dual-Sized Microparticle System Conditions Human Antigen Presenting Cells Into a Tolerogenic Phenotype In Vitro and Inhibits Type 1 Diabetes-Specific Autoreactive T Cell Responses.

Current monotherapeutic agents fail to restore tolerance to self-antigens in autoimmune individuals without systemic immunosuppression. We hypothesized that a combinatorial drug formulation delivered by a poly-lactic-co-glycolic acid (PLGA) dual-sized microparticle (dMP) system would facilitate tunable drug delivery to elicit immune tolerance. Specifically, we utilized 30 µm MPs to provide local sustained release of granulocyte-macrophage colony-stimulating factor (GM-CSF) and transforming growth factor ß1 (TGF-ß1) along with 1 µm MPs to facilitate phagocytic uptake of encapsulated antigen and 1α,25(OH)2 Vitamin D3 (VD3) followed by tolerogenic antigen presentation. We previously demonstrated the dMP system ameliorated type 1 diabetes (T1D) and experimental autoimmune encephalomyelitis (EAE) in murine models. Here, we investigated the system's capacity to impact human cell activity in vitro to advance clinical translation. dMP treatment directly reduced T cell proliferation and inflammatory cytokine production. dMP delivery to monocytes and monocyte-derived dendritic cells (DCs) increased their expression of surface and intracellular anti-inflammatory mediators. In co-culture, dMP-treated DCs (dMP-DCs) reduced allogeneic T cell receptor (TCR) signaling and proliferation, while increasing PD-1 expression, IL-10 production, and regulatory T cell (Treg) frequency. To model antigen-specific activation and downstream function, we co-cultured TCR-engineered autoreactive T cell "avatars," with dMP-DCs or control DCs followed by ß-cell line (ßlox5) target cells. For G6PC2-specific CD8+ avatars (clone 32), dMP-DC exposure reduced Granzyme B and dampened cytotoxicity. GAD65-reactive CD4+ avatars (clone 4.13) exhibited an anergic/exhausted phenotype with dMP-DC presence. Collectively, these data suggest this dMP formulation conditions human antigen presenting cells toward a tolerogenic phenotype, inducing regulatory and suppressive T cell responses.

Phylogenomics and species delimitation for effective conservation of manta and devil rays.

Practical biodiversity conservation relies on delineation of biologically meaningful units. Manta and devil rays (Mobulidae) are threatened worldwide, yet morphological similarities and a succession of recent taxonomic changes impede the development of an effective conservation strategy. Here, we generate genome-wide single nucleotide polymorphism (SNP) data from a geographically and taxonomically representative set of manta and devil ray samples to reconstruct phylogenetic relationships and evaluate species boundaries under the general lineage concept. We show that nominal species units supported by alternative data sources constitute independently evolving lineages, and find robust evidence for a putative new species of manta ray in the Gulf of Mexico. Additionally, we uncover substantial incomplete lineage sorting indicating that rapid speciation together with standing variation in ancestral populations has driven phylogenetic uncertainty within Mobulidae. Finally, we detect cryptic diversity in geographically distinct populations, demonstrating that management below the species level may be warranted in certain species. Overall, our study provides a framework for molecular genetic species delimitation that is relevant to wide-ranging taxa of conservation concern, and highlights the potential for genomic data to support effective management, conservation and law enforcement strategies.

Nano and Microparticle Emerging Strategies for Treatment of Autoimmune Diseases: Multiple Sclerosis and Type 1 Diabetes.

Autoimmune diseases affect 10% of the world's population, and 1 in 200 people worldwide suffer from either multiple sclerosis (MS) or type 1 diabetes (T1D). While the targeted organ systems are different, MS and T1D share similarities in terms of autoreactive immune cells playing a critical role in pathogenesis. Both diseases can be managed only symptomatically without curative remission, and treatment options are limited and non-specific. Most current therapies cause some degree of systemic immune suppression, leaving the patients susceptible to opportunistic infections and other complications. Thus, there is considerable interest in the development of immunotherapies not associated with generalized immune suppression for these diseases. This review presents current and preclinical strategies for MS and T1D treatment, emphasizing those aimed to modulate the immune response, including the most recent strategies for tolerance induction. A central focus is on the emerging approaches using nano- and microparticle platforms, their evolution as immunotherapeutic carriers, including those incorporating specific antigens to induce tolerance and reduce unwanted generalized immune suppression.