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Thermosensation, the ability to detect and estimate temperature, is an evolutionarily conserved process that is essential for survival. Thermosensing is impaired in various pain syndromes, resulting in thermal allodynia, the perception of an innocuous temperature as painful, or thermal hyperalgesia, an exacerbated perception of a painful thermal stimulus. Several behavioral assays exist to study thermosensation and thermal pain in rodents, however, most rely on reflexive withdrawal responses or the subjective quantification of spontaneous nocifensive behaviors. Here, we created a new apparatus, the thermal escape box, which can be attached to temperature-controlled plates and used to assess temperature-dependent effort-based decision-making. The apparatus consists of a light chamber with an opening that fits around temperature-controlled plates, and a small entryway into a dark chamber. A mouse must choose to stay in a brightly lit aversive area or traverse the plates to escape to the enclosed dark chamber. We quantified escape latencies of adult C57Bl/6 mice at different plate temperatures from video recordings and found they were significantly longer at 5 °C, 18 °C, and 52 °C, compared to 30 °C, a mouses preferred ambient temperature. Differences in escape latencies were abolished in male Trpm8-/- mice and in male Trpv1-/- animals. Finally, we show that chronic constriction injury procedures or oxaliplatin treatement significantly increased escape latencies at cold temperatures compared to controls, the later of which was prevented by the analgesic meloxicam. This demonstrates the utility of this assay in detecting cold pain. Collectively, our study has identified a new and effective tool that uses cost-benefit valuations to study thermosensation and thermal pain.

Despite rapid evolution across eutherian mammals, the X-linked MIR-506 family miRNAs are located in a region flanked by two highly conserved protein-coding genes (SLITRK2 and FMR1) on the X chromosome. Intriguingly, these miRNAs are predominantly expressed in the testis, suggesting a potential role in spermatogenesis and male fertility. Here, we report that the X-linked MIR-506 family miRNAs were derived from the MER91C DNA transposons. Selective inactivation of individual miRNAs or clusters caused no discernible defects, but simultaneous ablation of five clusters containing 19 members of the MIR-506 family led to reduced male fertility in mice. Despite normal sperm counts, motility, and morphology, the KO sperm were less competitive than wild-type sperm when subjected to a polyandrous mating scheme. Transcriptomic and bioinformatic analyses revealed that these X-linked MIR-506 family miRNAs, in addition to targeting a set of conserved genes, have more targets that are critical for spermatogenesis and embryonic development during evolution. Our data suggest that the MIR-506 family miRNAs function to enhance sperm competitiveness and reproductive fitness of the male by finetuning gene expression during spermatogenesis.

Abstract Historically, most insect chronoecological research has used direct observations, cameras or infrared beam‐based monitors to quantify movement across timed intervals. Although some alternative DIY systems are cheaper than the current standard locomotor activity monitor, these options remain complicated to build and/or computationally intensive. We developed the imaging Locomotor Activity Monitor (iLAM), an affordable (~$75 USD/unit) system for activity quantification. The iLAM utilizes a Raspberry Pi Zero W computer and night‐vision camera inside a flight cage to photograph a population of insects at user‐defined intervals. Open‐source, modular R‐scripts process the images and output a file containing the number, size, coordinate location and timestamp of all movements (blobs) identified between consecutive images. Output can be analysed directly or converted into the standard TriKinetics DAM format. We demonstrated the flexibility and power of the iLAM system by comparing diel and circadian activity of different insect species (fireflies: Photinus marginellus, P. greeni, P. obscurellus), ecotypes (moths: Ostrinia nubilalis) and sexes (moths: O. nubilalis). Data captured by only six iLAMs ($450) identified that peak activity of O. nubilalis females (AZT: 19.2 h) occurs significantly earlier than males (22.0 h). Additionally, male moths from a univoltine population exhibited a significantly shorter endogenous period length (AZT: 21.3 h) than males from a bivoltine genetic background (22.7 h). The iLAM will serve as a valuable tool for researchers seeking to measure locomotor activity across diverse species, sexes and populations in constant and changing environments.

We examined factors that lead to the attrition and retention of special education teachers (SETs) based on gender, race, and geographical location. Factors leading to SETs intent to stay or leave teaching is commonly overlooked in research, particularly when controlling for gender and race. Thus, we reviewed survey data of 778 SETs, controlling for gender and race in different settings (urban, suburban, and rural). We found differences between men and women SETs, including significant differences in supports for men and women identifying within the same race/ethnicity demographics in urban settings. We propose research and practice directions for attracting, supporting, and retaining SETs across multiply marginalized groups.

Virtual community-based programming for people with disabilities has become a popular method for advocating for health promotion, specifically exercise, for people with disabilities (PWD). Using theoretical frameworks to better understand the perspective of PWD who participate in virtual exercise programs allows strategies of implementation following completion of virtual exercise programs. The objective of this study was to examine the effect adherence had on perceptions, experiences, and post-program exercise maintenance in participants with disabilities. Eight qualitative interviews were conducted in highly adherent participants using the Social Cognitive Theory (SCT). Interviews were recorded on Zoom, transcribed using Microsoft 365, and analyzed using NVivo software. Data were analyzed by the primary author and an independent coder to increase rigor and reduce bias. Thirty-five unique codes were generated from transcribed interviews. Member-checking was employed to increase internal validity; 100% of participants agreed with the findings. Results demonstrate an overall positive experience in the virtual exercise program, noting specific facilitators (i.e., knowledgeable instructor, program provided equipment, etc.) and barriers (i.e., limited physical space at home to exercise, other participant's attitudes, etc.) of participating. Impressionably, 100% of participants maintained exercise following their time within the virtual exercise program.

Reports that mouse sperm gain small RNAs from the epididymosomes secreted by epididymal epithelial cells and that these "foreign" small RNAs act as an epigenetic information carrier mediating the transmission of acquired paternal traits have drawn great attention because the findings suggest that heritable information can flow from soma to germ line, thus invalidating the long-standing Weismann's barrier theory on heritable information flow. Using small RNA sequencing (sRNA-seq), northern blots, sRNA in situ hybridization, and immunofluorescence, we detected substantial changes in the small RNA profile in murine caput epididymal sperm (sperm in the head of the epididymis), and we further determined that the changes resulted from sperm exchanging small RNAs, mainly tsRNAs and rsRNAs, with cytoplasmic droplets rather than the epididymosomes. Moreover, the murine sperm-borne small RNAs were mainly derived from the nuclear small RNAs in late spermatids. Thus, caution is needed regarding sperm gaining foreign small RNAs as an underlying mechanism of epigenetic inheritance.

Neurons require large amounts of energy, but whether they can perform glycolysis or require glycolysis to maintain energy remains unclear. Using metabolomics, we show that human neurons do metabolize glucose through glycolysis and can rely on glycolysis to supply tricarboxylic acid (TCA) cycle metabolites. To investigate the requirement for glycolysis, we generated mice with postnatal deletion of either the dominant neuronal glucose transporter (GLUT3cKO) or the neuronal-enriched pyruvate kinase isoform (PKM1cKO) in CA1 and other hippocampal neurons. GLUT3cKO and PKM1cKO mice show age-dependent learning and memory deficits. Hyperpolarized magnetic resonance spectroscopic (MRS) imaging shows that female PKM1cKO mice have increased pyruvate-to-lactate conversion, whereas female GLUT3cKO mice have decreased conversion, body weight, and brain volume. GLUT3KO neurons also have decreased cytosolic glucose and ATP at nerve terminals, with spatial genomics and metabolomics revealing compensatory changes in mitochondrial bioenergetics and galactose metabolism. Therefore, neurons metabolize glucose through glycolysis in vivo and require glycolysis for normal function.

Loss of quadriceps strength after total knee arthroplasty (TKA) is most pronounced acutely but persists long-term, negatively impacting physical function in daily activities. Neuromuscular electrical stimulation (NMES) early after surgery is an effective adjuvant to standard of care rehabilitation (SOC) for attenuating strength loss following TKA, but the mechanisms whereby NMES maintains strength are unclear. This work aimed to determine the effects of early NMES on quadriceps strength and skeletal muscle fiber size 2 weeks after TKA compared to SOC. Patients scheduled for primary, unilateral TKA were enrolled and randomized into SOC (n = 9) or NMES plus SOC (n = 10) groups. NMES was started within 48 h of TKA, with 45-min sessions twice a day for 2 weeks. Isometric quadriceps strength was assessed preoperatively and 2 weeks following TKA. Vastus lateralis muscle biopsies of the involved leg were performed at the same time points and immunohistochemistry conducted to assess muscle fiber cross-sectional area and distinguish fiber types. Groups did not differ in age, body mass index, sex distribution, or preoperative strength. Both groups got weaker postoperatively, but the NMES group had higher normalized strength. After 2 weeks, the group receiving NMES and SOC had significantly greater MHC IIA and MHC IIA/IIX fiber size compared to SOC alone, with no group differences in MHC I fiber size. These results suggest that NMES mitigates early muscle weakness following TKA, in part, via effects on fast-twitch, type II muscle fiber size. This investigation advances our understanding of how adjuvant, early postoperative NMES aids muscle strength recovery.

Background: Many pregnant individuals with opioid use disorder (OUD) spend time in jail, yet access to standard of care medications for OUD (MOUD) in jail is limited. Though qualitative studies of non-incarcerated pregnant and non-pregnant incarcerated individuals with OUD demonstrate complexities that must be considered in delivering effective care, studies with pregnant, incarcerated patients with OUD are lacking. Methods: We conducted semi-structured qualitative interviews from October 2020–November 2021 with pregnant and postpartum people with OUD who were currently or previously in jail in Florida, Maryland, Ohio, and Virginia. Interview guides incorporated understandings of the power dynamics of incarceration and gendered expectations of motherhood. We analyzed transcripts using descriptive phenomenology to identify themes around experiences of treatment or withdrawal in jail and upon release. Results: We interviewed 32 women, 23 pregnant and nine postpartum. Some received MOUD in jail and others endured withdrawal. All participants expressed concern for their babies. Five themes emerged: 1)lack of counseling or accurate information about MOUD in pregnancy; 2)absent, delayed, or coercive care in jail; 3)experiences of stigma and discrimination from staff and caregivers; 4)structural barriers to safe transitions and continuing MOUD; and 5)the destructive presence of child protective services for care continuity. These factors all influenced their ability to recover. Conclusions: Jails must provide OUD care that is attentive to pregnancy physiology, pregnancy-stigma, reentry needs, and patients’ fetal-newborn concerns. Tailoring care specific to pregnancy and postpartum context can improve recovery success, reduce overdose, and promote intergenerational equity.

Fragile X (FMR1) premutation is a common mutation that affects about 1 in 200 females and 1 in 450 males and can lead to the development of fragile-X-associated tremor/ataxia syndrome (FXTAS). Although there is no targeted, proven treatment for FXTAS, research suggests that sulforaphane, an antioxidant present in cruciferous vegetables, can enhance mitochondrial function and maintain redox balance in the dermal fibroblasts of individuals with FXTAS, potentially leading to improved cognitive function. In a 24-week open-label trial involving 15 adults aged 60-88 with FXTAS, 11 participants successfully completed the study, demonstrating the safety and tolerability of sulforaphane. Clinical outcomes and biomarkers were measured to elucidate the effects of sulforaphane. While there were nominal improvements in multiple clinical measures, they were not significantly different after correction for multiple comparisons. PBMC energetic measures showed that the level of citrate synthase was higher after sulforaphane treatment, resulting in lower ATP production. The ratio of complex I to complex II showed positive correlations with the MoCA and BDS scores. Several mitochondrial biomarkers showed increased activity and quantity and were correlated with clinical improvements.

Special education teachers of color are underrepresented in research about attrition and retention, despite evidence of their role in the academic, social, and emotional success of students of color. We used critical quantitative methods and structural equation modeling to investigate the attrition and retention variability between special education teachers (SETs) of color and White SETs. We sampled 778 SETs and found SETs of color reported higher rates of intent to remain in the profession than White SETs. SETs of color in urban schools also rated supports higher than White SETs, based on school geographical location, suggesting higher retention of SETs of color in urban schools. We offer implications for ensuring SETs of color are reflected in research, and policy and practice recommendations to move the discussion of race and teacher shortage forward in the field.

Abstract The 2021 La Palma eruption (Tajogaite) was unprecedented in magnitude, duration, and degree of monitoring compared to historical volcanism on La Palma. Here, we provide data on melt inclusions in samples from the beginning and end of the eruption to compare the utility of both melt and fluid inclusions as recorders of magma storage. We also investigated compositional heterogeneities within the magmatic plumbing system. We found two populations of olivine crystals: a low Mg# (78–82) population present at the beginning and end of eruption, recording the maximum volatile contents (2.5 wt % H2O, 1,800 ppm F, 700 ppm Cl, 3,800 ppm S) and a higher Mg# (83–86) population sampled toward the end of the eruption, with lower volatile contents. Despite their host composition, melt inclusions share the same maximum range of CO2 concentrations (1.2–1.4 wt %), indicating olivine growth and inclusion capture at similar depths. Overall, both melt and fluid inclusions record similar pressures (450–850 MPa, ∼15–30 km), and when hosted in the same olivine crystal pressures are indistinguishable within error. At these mantle pressures, CO2 is expected to be an exsolved phase explaining the similar range of CO2 between the two samples, but other volatile species (F, Cl, S) behave incompatibly, and thus, the increase between the two olivine populations can be explained by fractional crystallization prior to eruption. Finally, based on our new data, we provide estimates on the total volatile emission of the eruption.

Abstract Background Germline cancer genetic testing has become a standard evidence-based practice, with established risk reduction and screening guidelines for genetic carriers. Access to genetic services is limited in many places, which leaves many genetic carriers unidentified and at risk for late diagnosis of cancers and poor outcomes. This poses a problem for childhood cancer survivors, as this is a population with an increased risk for subsequent malignant neoplasms (SMN) due to cancer therapy or inherited cancer predisposition. The ENGaging and Activating cancer survivors in Genetic services (ENGAGE) study evaluates the effectiveness of an in-home, collaborative PCP model of remote telegenetic services to increase uptake of cancer genetic testing in childhood cancer survivors compared to usual care options for genetic testing. Methods The ENGAGE study is a 3-arm randomized hybrid type 1 effectiveness and implementation study within the Childhood Cancer Survivor Study population which tests a clinical intervention while gathering information on its delivery during the effectiveness trial and its potential for future implementation among 360 participants. Participants are randomized into three arms. Those randomized to Arm A receive genetic services via videoconferencing, those in Arm B receive these services by phone, and those randomized to Arm C will receive usual care services. Discussion With many barriers to accessing genetic services, innovative delivery models are needed to address this gap and increase uptake of genetic services. The ENGAGE study evaluates the effectiveness of an adapted model of remote delivery of genetic services to increase the uptake of recommended genetic testing in childhood cancer survivors. This study assesses the uptake in remote genetic services and identify barriers to uptake to inform future recommendations and a theoretically-informed process evaluation which can inform modifications to enhance dissemination beyond this study population and to realize the benefits of precision medicine. Trial registration This protocol was registered at clinicaltrials.gov (NCT04455698) on July 2, 2020.

Abstract Necroptosis, a type of lytic cell death executed by the pseudokinase Mixed Lineage Kinase Domain-Like (MLKL) has been implicated in the detrimental inflammation caused by SARS-CoV-2 infection. We minimally and extensively passaged a single clinical SARS-CoV-2 isolate to create models of mild and severe disease in mice allowing us to dissect the role of necroptosis in SARS-CoV-2 disease pathogenesis. We infected wild-type and MLKL-deficient mice and found no significant differences in viral loads or lung pathology. In our model of severe COVID-19, MLKL-deficiency did not alter the host response, ameliorate weight loss, diminish systemic pro-inflammatory cytokines levels, or prevent lethality in aged animals. Our in vivo models indicate that necroptosis is dispensable in the pathogenesis of mild and severe COVID-19.

It is easy to believe, after decades of research and ever-increasing awareness, that gender bias issues in our classrooms have subsided. Our current students, both undergraduate and many graduate, comprise what is arguably one of the most equity-aware generations in history. Equality, fair treatment, and unbiased interactions should be the norm among our business students. This simple but remarkably effective exercise suggests otherwise. For instructors using mixed-gender student teams for classroom projects, this exercise will provide a powerful opening to meaningful discussions about gender-based perceptions while supporting equity, inclusion, and improved team performance.

At the St. Louis College of Pharmacy, a teaching group has been working on the development of student metacognitive skills through using 'Two-Stage Cooperative Testing' in the Physiology course sequence. A research group has been administering the Metacognitive Awareness Inventory (MAI) and tracking students through the curriculum to see what relationship between MAI scores and success in the program might exist. In the fall of 2017 the two groups found a natural point of connection and began comparing course grade information with MAI results. The result was a demonstration of both a slight positive correlation between the MAI and overall semester GPA (r = 0.313, p < 0.001) and a slightly stronger correlation between the Knowledge of Cognition sub-score and course grades specifically in Medical Physiology (r = 0.377, p < 0.001). The relationship between the Regulation of Cognition sub-score and Medical Physiology course grades was also significant but less robust (r = 0.273, p < 0.001). Future collaboration will continue investigating how metacognition in students might be more systematically fostered.

Limited research exists on special education teachers (SETs) of students with intellectual disability (ID), developmental delay (DD), and/or autism spectrum disorder (ASD), their intent to leave or stay in the teaching profession, and the working conditions impacting those decisions. Through an online survey, we investigated working conditions of SETs who teach students with ID, DD, and ASD and their career intent, with attention to teacher demographic characteristics. Our investigation (n = 564) found Black/African American, Asian, Hawaiian/Pacific Islander SETs of students with ID, DD, or ASD reported higher intent to leave, as well as male SETs, compared to White SETs. Other differences are reported between groups. Results emphasize a need to focus on ways to retain SETs from underrepresented groups. Implications for practice and research related to working conditions are discussed.

Despite rapid evolution across eutherian mammals, the X-linked MIR-506 family miRNAs are located in a region flanked by two highly conserved protein-coding genes (SLITRK2 and FMR1) on the X chromosome. Intriguingly, these miRNAs are predominantly expressed in the testis, suggesting a potential role in spermatogenesis and male fertility. Here, we report that the X-linked MIR-506 family miRNAs were derived from the MER91C DNA transposons. Selective inactivation of individual miRNAs or clusters caused no discernible defects, but simultaneous ablation of five clusters containing 19 members of the MIR-506 family led to reduced male fertility in mice. Despite normal sperm counts, motility, and morphology, the KO sperm were less competitive than wild-type sperm when subjected to a polyandrous mating scheme. Transcriptomic and bioinformatic analyses revealed that these X-linked MIR-506 family miRNAs, in addition to targeting a set of conserved genes, have more targets that are critical for spermatogenesis and embryonic development during evolution. Our data suggest that the MIR-506 family miRNAs function to enhance sperm competitiveness and reproductive fitness of the male by finetuning gene expression during spermatogenesis.

BackgroundSafe and potent antiretroviral medications in child-friendly formulations are needed to treat young children living with HIV-1. We aimed to select dosing for a dispersible tablet formulation of dolutegravir that achieved pharmacokinetic exposures similar to those in adults, and was safe and well tolerated in young children.MethodsInternational Maternal Pediatric Adolescent AIDS Clinical Trial (IMPAACT) P1093 is a phase 1-2 ongoing multicentre, open-label, non-comparative study of dolutegravir. A 5 mg dispersible tablet formulation of dolutegravir was studied in children aged 4 weeks to less than 6 years old, weighing at least 3 kg, with HIV RNA of greater than 1000 copies per mL and no previous treatment with integrase strand transfer inhibitor recruited from IMPAACT clinical research sites in Africa, the Americas, and Asia. Doses were selected on the basis of intensive pharmacokinetic evaluation on days 5-10, with safety and tolerability assessed up to 48 weeks. The primary objectives of this study are to evaluate the pharmacokinetics of dolutegravir in combination with optimised background therapy and to establish the dose of dolutegravir that achieves the targeted 24-h trough concentration and 24-h area under the curve for infants, children, and adolescents with HIV-1, to establish the safety and tolerability of dolutegravir at 24 and 48 weeks, and to select a dose that achieves similar exposure to the dolutegravir 50 mg once daily dose in adults. This analysis included participants treated with the proposed dose of dolutegravir dispersible tablets in two stages for each of three age cohorts. This trial is registered at ClinicalTrials.gov (NCT01302847) and is ongoing.FindingsWe recruited 181 participants from April 20, 2011, to Feb 19, 2020; of these, 96 received dolutegravir dispersible tablets. This analysis included 73 (35, 48% female) participants who received the final proposed dose with median (range) age of 1 year (0·1 to 6·0), weight (minimum-maximum) of 8·5 kg (3·7 to 18·5), plasma HIV-1 RNA concentration of 4·2 log10 copies per mL (2·1 to 7·0), and CD4% of 24·0% (0·3 to 49·0); 64 (87·7%) were treatment-experienced. The selected dose within each age cohort (≥2 years to

Abstract Background Using the World Health Organization Classification 5th edition (beta version online; WHO-HAEM5bv) in emerging economies is key to global healthcare equity. Although there may be ongoing updates, hesitancy in accepting and reporting these diagnoses in publication conflicts with the WHO’s commitment to global accessibility. Aggressive NK cell leukemia (ANKL) and systemic EBV-positive T-cell lymphoma of childhood (SEBVTCL) with CD4-positive immunophenotype are both rare entities, are most described in Asians and East Asians, are associated with prior systemic chronic active EBV disease (CAEBV), and presentation with Hemophagocytic Lymphohistiocytosis (HLH). Recognizing and diagnosing any one of these entities requires not only training and experience in hematopathology, but good cooperation between clinical physicians and all areas of the laboratory. We describe a 30-year-old woman who presented to a Vietnam hospital and was rapidly diagnosed with ANKL, SEBVTCL, and HLH using WHO-HAEM5bv essential criteria, aided by expert consultation from a United States (US) board certified hematopathologist in real-time using video conferencing software. Methods Zoom™ videoconferencing software; Immunohistochemistry; flow cytometric immunophenotyping; polymerase chain reaction (PCR), Next Generation Sequencing (NGS). Results At the time of hospital admission, automated complete blood count (CBC) with differential count showed slight anemia, slight lymphocytosis, and moderate thrombocytopenia. HIV serology was negative. Whole blood PCR for EBV was positive showing 98,000 copies/ml. A lymph node biopsy revealed histology and immunohistochemistry consistent with the online beta version WHO-HAEM5 classification of SEBVTCL arising in CAEBV. Blood and bone marrow studies performed for staging revealed no histologic or immunohistochemical evidence of T-cell lymphoma in the bone marrow core, however, atypical blood smear lymphocyte morphology and blood immunophenotyping by flow cytometry were consistent with WHO-HAEM5 classification of ANKL. NGS revealed no evidence of genetic variant(s) associated with HLH in Vietnam. All laboratory studies were performed at Blood Transfusion Hematology Hospital (BTHH) in Ho Chi Minh City Vietnam. Conclusion Although Vietnam, an emerging economy, currently lacks the laboratory infrastructure to more rigorously confirm a rare synchronous presentation of two distinct EBV-driven T/NK cell neoplasms, these two concomitant diagnoses were made using only laboratory techniques available in Vietnam with the help of WHO-HAEM5bv and real-time video consultation by a US hematopathologist.

Abstract Volcanic ash emissions impact atmospheric processes, depositional ecosystems, human health, and global climate. These effects are sensitive to the size and composition of the ash; however, datasets describing the constituent phases over size ranges relevant for atmospheric transport and widely distributed impacts are practically nonexistent. Here, we present results of X-ray diffraction measurements on size-separated fractions of 40 ash samples from VEI 2–6 eruptions. We characterize changes in phase fractions with grainsize, tectonic setting, and whole-rock SiO2. For grainsizes