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.

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.

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.

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.

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.

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.

Contemporary Management of Unexplained Infertility.

Infertility is estimated to affect about 10% to 15% of couples. Most cases of infertility have etiologies that can be attributed to tubal factors, ovulatory dysfunction, endometriosis, uterine factor, male factor, or diminished ovarian reserve, while the remainder often do not have a known attributable cause, that is, unexplained infertility. The current manuscript summarizes the contemporary management of unexplained infertility.

A treatment approach for couples with disrupted sperm DNA integrity and recurrent ART failure.

OBJECTIVE: To test a novel method to select spermatozoa with high chromatin integrity. DESIGN: Specimens with high sperm chromatin fragmentation (SCF) were selected by density gradient selection (DGS) and microfluidic sperm sorting (MSS). SETTING: Academic medical center. PATIENT(S): Ejaculates from consenting men were processed by DGS/MSS. Couples underwent ICSI cycles with spermatozoa processed by DGS/MSS. Clinical outcomes were evaluated after embryo transfer. INTERVENTION(S): SCF was measured by TUNEL. ICSI with spermatozoa selected by DGS and MSS was performed. MAIN OUTCOME MEASURE(S): Fertilization, embryo implantation, and pregnancy outcomes were compared between DGS and MSS. RESULT(S): A total of 23 men had an average SCF of 20.7 ± 10%. After DGS and MSS, the SCF was 12.5 ± 5% and 1.8 ± 1%, respectively. In couples who underwent ICSI, the average SCF was 28.8 ± 9%, which fell to 21.0 ± 9% after DGS and 1.3 ± 0.7% after MSS. Four couples underwent 11 ICSI cycles with DGS and achieved one (25%) pregnancy that resulted in pregnancy loss. In four subsequent ICSI cycles with MSS, an ongoing clinical pregnancy rate of 50% was achieved. Five additional couples underwent 12 cycles of ICSI with DGS. After preimplantation genetic testing for aneuploidy, 30.3% of the embryos were euploid. One pregnancy was achieved, resulting in pregnancy loss. With MSS, 31.5% of the embryos were euploid and 4 couples obtained a pregnancy. Finally, sixteen couples underwent 20 ICSI cycles solely with MSS at our center. Of these couples, 8 had failed 13 ICSI cycles with DGS elsewhere. These couples achieved an overall implantation of 34.5% (10/29) and a pregnancy rate of 58.8% (10/17). CONCLUSION(S): Microfluidic selection yielded spermatozoa with optimal genomic integrity and improved chances of obtaining a euploid conceptus.

CGG repeat length and AGG interruptions as indicators of fragile X-associated diminished ovarian reserve.

PURPOSE: Fragile X premutation (PM) carriers may experience difficulties conceiving a child probably due to fragile X-associated diminished ovarian reserve (FXDOR). We investigated which subgroups of carriers with a PM are at higher risk of FXDOR, and whether the number of AGG interruptions within the repeat sequence further ameliorates the risk. METHODS: We compared markers of ovarian reserve, including anti-Müllerian hormone, antral follicle count, and number of oocytes retrieved between different subgroups of patients with a PM. RESULTS: We found that carriers with midrange repeats size (70-90 CGG) demonstrate significantly lower ovarian reserve. Additionally, the number of AGG interruptions directly correlated with parameters of ovarian reserve. Patients with longer uninterrupted CGG repeats post-AGG interruptions had the lowest ovarian reserve. CONCLUSION: This study connects AGG interruptions and certain CGG repeat length to reduced ovarian reserve in carriers with a PM. A possible explanation for our findings is the proposed gonadotoxicity of the FMR1 transcripts. Reduction of AGG interruptions could increase the likelihood that secondary RNA structures in the FMR1 messenger RNA are formed, which could cause cell dysfunction within the ovaries. These findings may provide women with guidance regarding their fertility potential and accordingly assist with their family planning.

The prevalence of false confessions in experimental laboratory simulations: A meta-analysis.

We assessed experimental false confession studies using a meta-analysis to evaluate the prevalence of false confessions across methodologies and several moderator variables. False confessions were more likely in typing task studies than in collaborative or individual cheating studies. In typing studies, speed of typing did not affect false confession rates, but placement of the forbidden key in locations that rendered errors less plausible lowered the false confession rates. False-evidence ploys increased the likelihood of false confessions. We explore implications for courts, expert witnesses, scholars, and police interrogators.

Placental malperfusion as a possible mechanism of preterm birth in patients with Müllerian anomalies.

OBJECTIVE: Müllerian anomalies are associated with increased risk of miscarriage, intrauterine growth restriction (IUGR) and preterm birth. While a commonly implicated cause is restricted expansion of endometrial cavity, alternatively it could be due to abnormal placentation. We sought to examine clinical and histopathologic factors associated with preterm delivery in women with Müllerian anomalies. STUDY DESIGN: One hundred and eleven singleton pregnancies in 85 women were analyzed retrospectively. There were 42 pregnancies with bicornaute, 24 with unicornuate, 24 with septate, 19 with didelphys and one each with arcuate and T-shaped uterus. Primary outcomes included gestational age at delivery, placental histopathology, placenta previa and accreta. RESULTS: Twenty-eight (25.2%) of pregnancies were delivered prior to term. Of those, only 14 (50%) were due to preterm labor or preterm premature rupture of membranes (PPROM). Histological evidence of placental malperfusion was present in 22% of all pregnancies and those delivered at an earlier median gestational age [34 (IQR 31-37) vs. 37 weeks (IQR 34-39); P=0.001]. Malperfusion was more common in preterm than in full term births (46% vs. 14%; P=0.04). Conversely, inflammation was not more common in preterm compared to term deliveries (17.9% vs. 16.9%; P=0.89). Five pregnancies had placenta previa, three of which were complicated by accreta. CONCLUSION: Placental malperfusion, rather than inflammation, was more commonly associated with preterm births in women with uterine anomalies.

Female patients with lymphoma demonstrate diminished ovarian reserve even before initiation of chemotherapy when compared with healthy controls and patients with other malignancies.

PURPOSE: The purpose of this study is to investigate if female patients with lymphoma demonstrate diminished ovarian reserve prior to initiation of the lymphoma treatment. METHODS: Sixty-four patients with newly diagnosed lymphoma undergoing controlled ovarian hyperstimulation for fertility preservation were compared with 365 healthy controls undergoing elective oocyte cryopreservation (controlled ovarian hyperstimulation (COH)) and 128 patients with other types of malignancy prompting fertility preservation. The data of all lymphoma patients, all elective, and all the patients with other types of malignancy who met the inclusion criteria and underwent COH for fertility preservation during the study period were retrospectively analyzed. Primary outcomes included serum anti-Müllerian hormone (AMH) levels (ng/mL) and antral follicle count (AFC). RESULTS: Patients in the lymphoma group demonstrated significantly lower AMH levels and AFC and had less oocytes harvested and cryopreserved when compared to healthy controls as well as patients with other malignancies. CONCLUSION: Patients with lymphoma demonstrate diminished ovarian reserve when compared with healthy controls and patients with other malignancies. This should be taken into consideration when deciding on the dose for COH.

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.

Surface orientation affects the direction of cone growth by Leptolyngbya sp. strain C1, a likely architect of coniform structures Octopus Spring (Yellowstone National Park).

Laminated, microbially produced stromatolites within the rock record provide some of the earliest evidence for life on Earth. The chemical, physical, and biological factors that lead to the initiation of these organosedimentary structures and shape their morphology are unclear. Modern coniform structures with morphological features similar to stromatolites are found on the surface of cyanobacterial/microbial mats. They display a vertical element of growth, can have lamination, can be lithified, and observably grow with time. To begin to understand the microbial processes and interactions required for cone formation, we determined the phylogenetic composition of the microbial community of a coniform structure from a cyanobacterial mat at Octopus Spring, Yellowstone National Park, and reconstituted coniform structures in vitro. The 16S rRNA clone library from the coniform structure was dominated by Leptolyngbya sp. Other cyanobacteria and heterotrophic bacteria were present in much lower abundance. The same Leptolyngbya sp. identified in the clone library was also enriched in the laboratory and could produce cones in vitro. When coniform structures were cultivated in the laboratory, the initial incubation conditions were found to influence coniform morphology. In addition, both the angle of illumination and the orientation of the surface affected the angle of cone formation demonstrating how external factors can influence coniform, and likely, stromatolite morphology.

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.

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.

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 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.