A WC/WO star exploding within an expanding carbon-oxygen-neon nebula.

The final fate of massive stars, and the nature of the compact remnants they leave behind (black holes and neutron stars), are open questions in astrophysics. Many massive stars are stripped of their outer hydrogen envelopes as they evolve. Such Wolf-Rayet stars1 emit strong and rapidly expanding winds with speeds greater than 1,000 kilometres per second. A fraction of this population is also helium-depleted, with spectra dominated by highly ionized emission lines of carbon and oxygen (types WC/WO). Evidence indicates that the most commonly observed supernova explosions that lack hydrogen and helium (types Ib/Ic) cannot result from massive WC/WO stars2,3, leading some to suggest that most such stars collapse directly into black holes without a visible supernova explosion4. Here we report observations of SN 2019hgp, beginning about a day after the explosion. Its short rise time and rapid decline place it among an emerging population of rapidly evolving transients5-8. Spectroscopy reveals a rich set of emission lines indicating that the explosion occurred within a nebula composed of carbon, oxygen and neon. Narrow absorption features show that this material is expanding at high velocities (greater than 1,500 kilometres per second), requiring a compact progenitor. Our observations are consistent with an explosion of a massive WC/WO star, and suggest that massive Wolf-Rayet stars may be the progenitors of some rapidly evolving transients.

Compression of curium pyrrolidine-dithiocarbamate enhances covalency.

Curium is unique in the actinide series because its half-filled 5f 7 shell has lower energy than other 5f n configurations, rendering it both redox-inactive and resistant to forming chemical bonds that engage the 5f shell1-3. This is even more pronounced in gadolinium, curium's lanthanide analogue, owing to the contraction of the 4f orbitals with respect to the 5f orbitals4. However, at high pressures metallic curium undergoes a transition from localized to itinerant 5f electrons5. This transition is accompanied by a crystal structure dictated by the magnetic interactions between curium atoms5,6. Therefore, the question arises of whether the frontier metal orbitals in curium(III)-ligand interactions can also be modified by applying pressure, and thus be induced to form metal-ligand bonds with a degree of covalency. Here we report experimental and computational evidence for changes in the relative roles of the 5f/6d orbitals in curium-sulfur bonds in [Cm(pydtc)4]- (pydtc, pyrrolidinedithiocarbamate) at high pressures (up to 11 gigapascals). We compare these results to the spectra of [Nd(pydtc)4]- and of a Cm(III) mellitate that possesses only curium-oxygen bonds. Compared with the changes observed in the [Cm(pydtc)4]- spectra, we observe smaller changes in the f-f transitions in the [Nd(pydtc)4]- absorption spectrum and in the f-f emission spectrum of the Cm(III) mellitate upon pressurization, which are related to the smaller perturbation of the nature of their bonds. These results reveal that the metal orbital contributions to the curium-sulfur bonds are considerably enhanced at high pressures and that the 5f orbital involvement doubles between 0 and 11 gigapascal. Our work implies that covalency in actinides is complex even when dealing with the same ion, but it could guide the selection of ligands to study the effect of pressure on actinide compounds.

Application of Laser-Induced Acoustic Desorption for Molecular Rotational Resonance Spectroscopy.

Molecular Rotational Resonance (MRR) spectroscopy is a uniquely precise tool for the determination of molecular structures of volatile compounds in mixtures, as the characteristic rotational transition frequencies of a molecule are extremely sensitive to its 3D structure through the moments of inertia in a three-dimensional coordinate system. This enables identification of the compounds based on just a few parameters that can be calculated, as opposed to, for example, mass spectrometric data, which often require expert analysis of 10-20 different signals and the use of many standards/model compounds. This paper introduces a new sampling technique for MRR, laser-induced acoustic desorption (LIAD), to allow the vaporization of nonvolatile and thermally labile analytes without the need for excessive heating or derivatization. In this proof-of-concept study, LIAD was successfully coupled to an MRR instrument to conduct measurements on seven compounds with differing polarities, molecular weights, and melting and boiling points. Identification of three isomers in a mixture was also successfully performed using LIAD/MRR. Based on these results, LIAD/MRR is demonstrated to provide a powerful approach for the identification of nonvolatile and/or thermally labile analytes with molecular weights up to 600 Da in simple mixtures, which does not require the use of reference compounds. In the future, applications to more complex mixtures, such as those relevant to pharmaceutical research, and quantitative aspects of LIAD/MRR will be reported.

Changes in Countermovement Vertical Jump Force-Time Metrics During a Game in Professional Male Basketball Players.

ABSTRACT: Cabarkapa, D, Johnson, QR, Cabarkapa, DV, Philipp, NM, Eserhaut, DA, and Fry, AC. Changes in countermovement vertical jump force-time metrics during a game in professional male basketball players. J Strength Cond Res 38(7): 1326-1329, 2024-As technology within elite basketball advances and is more available to sporting organizations, novel approaches for assessing and addressing athletic performance during practice or competition are being continuously explored. The aim of this investigation was to examine changes in neuromuscular performance during live basketball play. Eight professional male basketball players volunteered to participate in this study. The testing procedures were conducted during a pre-tournament camp over a span of 2 days. During the first day, the athletes were familiarized with the testing procedures, and baseline measurements were obtained. Using a uni-axial force plate system sampling at 1,000 Hz, each athlete performed 3 countermovement vertical jumps (CVJ) without an arm swing before proceeding with their regular training activities. During the second day of the pre-tournament camp, the athletes repeated identical CVJ testing procedures before the start of the first quarter and post-first, second, third, and fourth quarter of a simulated 5-on-5 basketball game. Repeated-measures testing design was used to examine statistically significant differences in various force-time metrics of interest in comparison to the baseline levels (p < 0.05). Besides a trivial decrease in eccentric mean force, the findings of this study revealed no statistically significant changes in any force-time metrics of interest within both eccentric and concentric phases of the CVJ (i.e., mean and peak force and power, jump height, impulse, velocity, and contraction time). Thus, we can conclude that these variables were not sensitive to acute fatigue, suggesting that the neuromuscular performances of professional male basketball players tend to remain unchanged throughout a 5-on-5 simulated game.

METTL7A (TMT1A) and METTL7B (TMT1B) Are Responsible for Alkyl S-Thiol Methyl Transferase Activity in Liver.

S-methylation of drugs containing thiol-moieties often alters their activity and results in detoxification. Historically, scientists attributed methylation of exogenous aliphatic and phenolic thiols to a putative S-adenosyl-L-methionine (SAM)-dependent membrane-associated enzyme referred to as thiol methyltransferase (TMT). This putative TMT appeared to have a broad substrate specificity and methylated the thiol metabolite of spironolactone, mertansine, ziprasidone, captopril, and the active metabolites of the thienopyridine prodrugs, clopidogrel, and prasugrel. Despite TMT's role in the S-methylation of clinically relevant drugs, the enzyme(s) responsible for this activity remained unknown. We recently identified methyltransferase-like protein 7B (METTL7B) as an alkyl thiol methyltransferase. METTL7B is an endoplasmic reticulum-associated protein with similar biochemical properties and substrate specificity to the putative TMT. Yet, the historic TMT inhibitor 2,3-dichloro-α-methylbenzylamine (DCMB) did not inhibit METTL7B, indicating that multiple enzymes contribute to TMT activity. Here we report that methyltransferase-like protein 7A (METTL7A), an uncharacterized member of the METTL7 family, is also a SAM-dependent thiol methyltransferase. METTL7A exhibits similar biochemical properties to METTL7B and putative TMT, including inhibition by DCMB (IC50 = 1.17 µM). Applying quantitative proteomics to human liver microsomes and gene modulation experiments in HepG2 and HeLa cells, we determined that TMT activity correlates closely with METTL7A and METTL7B protein levels. Furthermore, purification of a novel His-GST-tagged recombinant protein and subsequent activity experiments prove that METTL7A can selectively methylate exogenous thiol-containing substrates, including 7α-thiospironolactone, dithiothreitol, 4-chlorothiophenol, and mertansine. We conclude that the METTL7 family encodes for two enzymes, METTL7A and METTL7B, which are now renamed thiol methyltransferase 1A (TMT1A) and thiol methyltransferase 1B (TMT1B), respectively, that are responsible for thiol methylation activity in human liver microsomes. SIGNIFICANCE STATEMENT: We identified methyltransferase-like protein 7A (thiol methyltransferase 1A) and methyltransferase-like protein 7B (thiol methyltransferase 1B) as the enzymes responsible for the microsomal alkyl thiol methyltransferase (TMT) activity. These are the first two enzymes directly associated with microsomal TMT activity. S-methylation of commonly prescribed thiol-containing drugs alters their pharmacological activity and/or toxicity, and identifying the enzymes responsible for this activity will improve our understanding of the drug metabolism and pharmacokinetic (DMPK) properties of alkyl- or phenolic thiol-containing therapeutics.

Salivary Testosterone and Cortisol Changes During a Game in Professional Male Basketball Players.

ABSTRACT: Cabarkapa, D, Eserhaut, DA, Cabarkapa, DV, Philipp, NM, and Fry, AC. Salivary testosterone and cortisol changes during a game in professional male basketball players. J Strength Cond Res 37(8): 1687-1691, 2023-The purpose of this study was to examine acute changes in salivary testosterone (T), cortisol (C), and testosterone-to-cortisol ratio (T/C) during a simulated 5-on-5 basketball game. Seven professional male basketball players volunteered to participate in this study. Repeated-measures analysis design was used to examine changes in hormonal concentrations across 8 testing time points: immediately upon arrival to the gymnasium-baseline (BS); post-warm-up (PW); post-first (P1Q), second (P2Q), third (P3Q), and fourth quarter (P4Q); and 30 (P30) and 60 minutes (P60) postgame. The findings of this study indicate that a simulated 5-on-5 basketball game provoked significant changes in salivary T, C, and T/C. When compared to the BS levels (x̄ ± SD [nmol·L-1]; 6.72 ± 2.53), salivary C concentration experienced a notable increase P3Q (16.20 ± 7.70) and remained elevated throughout the rest of the sampling periods, with values failing to return to BS levels P60 (11.88 ± 5.58). Conversely, a significant increase in salivary T occurred P1Q (0.76 ± 0.21) when compared to the BS levels (0.58 ± 0.12) and remained elevated up to P30 (0.75 ± 0.20), with values returning to BS levels P60 (0.63 ± 0.14). In addition, despite no significant intragame alterations, T/C exhibited a notable decrease P30 (0.06 ± 0.02) and P60 (0.07 ± 0.04), when compared to BS values (0.10 ± 0.04). Overall, these findings provide additional insight into the physiological stress that basketball players are exposed to during 5-on-5 competitive play and can be used to appropriately adjust and monitor training loads to optimize recovery and on-court basketball performance.

High-Precision Triple Oxygen Isotope Analysis of Carbon Dioxide by Tunable Infrared Laser Absorption Spectroscopy.

Precision measurements of the stable isotope ratios of oxygen (18O/16O and 17O/16O) in CO2 are critical to atmospheric monitoring and terrestrial climate research. High-precision 17O measurements by isotope ratio mass spectrometry (IRMS) are challenging because they require complicated sample preparation procedures, long measurement times, and relatively large samples sizes. Recently, tunable infrared laser direct absorption spectroscopy (TILDAS) has shown significant potential as an alternative technique for triple oxygen isotope analysis of CO2, although the ultimate level of reproducibility is unknown, partly because it is unclear how to relate TILDAS measurements to an internationally accepted isotope abundance scale (e.g., VSMOW2-SLAP2). Here, we present a method for high-precision triple oxygen isotope analysis of CO2 by TILDAS, requiring ∼8-9 µmol of CO2 (or 0.9 mg carbonate) in 50 min, plus ∼1.5 h for sample preparation and dilution of CO2 in N2 to a nominal 400 µmol mol-1. Overall reproducibility of Δ'17O (CO2) was 0.004‰ (4 per meg) for IAEA603 (SE, n = 6) and 10 per meg for NBS18 (SE, n = 4). Values corrected to the VSMOW2-SLAP2 scale are in good agreement with established techniques of high-precision IRMS, with the exception of Δ'17O measured by platinum-catalyzed exchange of CO2 with O2. Compared to high-precision IRMS, TILDAS offers the advantage of ∼10 times less sample, and greater throughput, without loss of reproducibility. The flexibility of the technique should allow for many important applications to global biogeochemical monitoring and investigation of 17O anomalies in a range of geological materials.

Contributions of side effects to contraceptive discontinuation and method switch among Kenyan women: a prospective cohort study.

OBJECTIVE: To determine the contribution of specific contraceptive side effects to method switch and modern-method discontinuation among Kenyan women. DESIGN: A prospective cohort study. SETTING: Five counties in Western Kenya. PARTICIPANTS: Women aged ≥18 years old and emancipated female minors ≥14 years old using modern, reversible contraception were recruited while attending 10 public health facilities. METHODS: Patient-reported adverse effect symptoms, method switch and discontinuation were reported through weekly text message-based surveys for 24 weeks. MAIN OUTCOME MEASUREMENTS: Prevalence, hazards ratio (HR). RESULTS: Among 825 women, 44% were using implants, 43% injectables, 7% an intrauterine device and 6% oral contraceptive pills at enrolment. Most (61%) women were continuing a method used in the previous month. During the 24-week follow up, incidence of contraceptive switch was 61.3 per 100 person-years (95% confidence interval [CI] 52.4-71.8) and incidence of discontinuation was 38.5 per 100 person-years (95% CI 31.6-47.0). On average, one-quarter (prevalence [Pr] 0.24, 95% CI 0.22-0.26) of participants reported side effects or method problems weekly, with sexual side effects the most prevalent symptom (Pr 0.15, 95% CI 0.13-0.16). Lack of expected bleeding was associated with higher risk of method switch (adjusted hazard ratio [aHR] 2.36, 95% CI 1.22-4.57). Risk of all-modern method discontinuation was higher among women experiencing irregular bleeding (aHR 2.39, 95% CI 1.20-4.77), weight changes (aHR 2.72, 95% CI 1.47-4.68) and sexual side effects (aHR 2.42, 95% CI 1.40-4.20). CONCLUSIONS: Addressing irregular bleeding, weight changes and sexual side effects through development of new products that minimise these specific side effects and anticipatory counseling may reduce method-related discontinuation. TWEETABLE ABSTRACT: Bleeding, weight changes, sexual problems associated with discontinuation of #contraception, but many continue despite side effects.

Cervical cytomegalovirus reactivation, cytokines and spontaneous preterm birth in Kenyan women.

Genital cytomegalovirus (CMV) reactivation is common during the third trimester of pregnancy. We hypothesized that cervical CMV shedding may increase risk of spontaneous preterm birth (sPTB) through the release of inflammatory cytokines in the cervix. We conducted a nested case-control analysis to determine the relationship between CMV shedding and sPTB using data and samples from a prospective cohort study in western Kenya. Women who delivered between 28 + 0 and 33 + 6 weeks gestation were matched by gestational age at sample collection to controls who delivered ≥ 37 + 0 weeks. Levels of CMV DNA and interleukin (IL)-1 beta (ß), IL-6, IL-8 and tumor necrosis factor (TNF)-α were measured in cervical swabs. We used conditional logistic regression to assess relationships between CMV shedding, cervical cytokine levels and sPTB. Among 86 cases and 86 matched controls, cervical CMV levels were not significantly associated with sPTB [odds ratio (OR) = 1·23, 95% confidence interval (CI) = 0·59-2·56], but were significantly associated with higher levels of cervical IL-6 (ß = 0·15, 95% CI = 0·02-0·29) and TNF-α (ß = 0·14, 95% CI = 0·01-0·27). In univariate analysis, higher odds of sPTB was associated with higher cervical IL-6 levels (OR = 1·54, 95% CI = 1·00-2·38), but not with other cervical cytokines. In this cohort of Kenyan women, we did not find a significant association between cervical CMV shedding and sPTB before 34 weeks.

Candidate Electromagnetic Counterpart to the Binary Black Hole Merger Gravitational-Wave Event S190521g.

We report the first plausible optical electromagnetic counterpart to a (candidate) binary black hole merger. Detected by the Zwicky Transient Facility, the electromagnetic flare is consistent with expectations for a kicked binary black hole merger in the accretion disk of an active galactic nucleus [B. McKernan, K. E. S. Ford, I. Bartos et al., Astrophys. J. Lett. 884, L50 (2019)AJLEEY2041-821310.3847/2041-8213/ab4886] and is unlikely [

Maternal antenatal daytime sleepiness and child neuropsychiatric and neurocognitive development.

BACKGROUND: The prevalence of sleep problems among pregnant women is over 50%, and daytime sleepiness is among the most common sleep problems. Previous studies have associated antenatal sleep problems with adverse maternal health and neonatal outcomes, but the consequences of antenatal sleep problems and particularly daytime sleepiness on child psychological development have not been assessed prospectively. METHODS: In this prospective cohort study including 111 mother-child dyads, we examined the associations of maternal daytime sleepiness during pregnancy, assessed at 17 and 28 weeks of gestation using the Epworth Sleepiness Scale, with child neuropsychiatric problems and neuropsychological development, assessed with mother-rated questionnaires and individually administered neuropsychological tests, at child age 2.6-5.7 years (mean = 4.3 years). RESULTS: Independently of sociodemographic and perinatal covariates and maternal depressive and anxiety symptoms during and/or after pregnancy, maternal antenatal daytime sleepiness was associated with increased total [unstandardized regression coefficient (B) = 0.25 standard deviation (s.d.) units; 95% confidence interval (CI) 0.01-0.48] and internalizing (B = 0.25 s.d.s: 95% CI 0.01-0.49) psychiatric problems and ADHD symptoms (B = 0.27 s.d.s: 95% CI 0.04-0.50) in children, and with poorer executive function, particularly in the areas of attention, working memory and inhibitory control (B = -0.39 s.d.s: 95% CI -0.69 to -0.10). CONCLUSIONS: Maternal antenatal daytime sleepiness carries adverse consequences for offspring psychological development. The assessment of sleep problems may be an important addition to standard antenatal care.

Short message service communication improves exclusive breastfeeding and early postpartum contraception in a low- to middle-income country setting: a randomised trial.

OBJECTIVE: To assess the effect of short message service (SMS) communication on facility delivery, exclusive breastfeeding (EBF), and contraceptive use. DESIGN: Mobile WACh was a three-arm unblinded individually randomised controlled trial. SETTING: A public sector maternal child health (MCH) clinic in Nairobi, Kenya. POPULATION: Three hundred women attending antenatal care were randomised, 100 to each arm, and followed for 24 weeks postpartum. Pregnant women, at least 14 years old with access to a mobile phone and able to read SMS were eligible for participation. METHODS: Women were randomised (1:1:1) to receive one-way SMS versus two-way SMS with a nurse versus control. Weekly SMS content was tailored for maternal characteristics and pregnancy or postpartum timing. MAIN OUTCOME MEASURES: Facility delivery, EBF, and contraceptive use were compared separately between each intervention arm and the control arm by Kaplan-Meier analysis and chi-square tests using intent-to-treat analyses. RESULTS: The overall facility delivery rate was high (98%) and did not differ by arm. Compared with controls, probability of EBF was higher in the one-way SMS arm at 10 and 16 weeks, and in the two-way SMS arm at 10, 16, and 24 weeks (P < 0.005 for all). Contraceptive use was significantly higher in both intervention arms by 16 weeks (one-way SMS: 72% and two-way SMS: 73%; P = 0.03 and P = 0.02 versus 57% control, respectively); however, this difference was not significant when correcting for multiple comparisons. CONCLUSION: One-way and two-way SMS improved EBF practices and early contraceptive use. Two-way SMS had an added benefit on sustained EBF, providing evidence that SMS messaging influences uptake of interventions that improve maternal and neonatal health. SOURCE OF FUNDING: Funding was provided by the National Institutes of Health (K12HD001264 to JAU, R01HD080460, K24HD054314 to GJS, and K01AI116298 to ALD), the National Science Foundation (Graduate Research Fellowship to TP and BD), as well as the University of Washington Global Center for Integrated Health of Women Adolescents and Children (Global WACh). TWEETABLE ABSTRACT: The Mobile WACh RCT demonstrates that SMS improved practice of exclusive breastfeeding and early postpartum contraception.

Prenatal exposure to very severe maternal obesity is associated with adverse neuropsychiatric outcomes in children.

BACKGROUND: Prenatal maternal obesity has been linked to adverse childhood neuropsychiatric outcomes, including increased symptoms of attention deficit hyperactivity disorder (ADHD), internalizing and externalizing problems, affective disorders and neurodevelopmental problems but few studies have studied neuropsychiatric outcomes among offspring born to very severely obese women or assessed potential familial confounding by maternal psychological distress. METHOD: We evaluated neuropsychiatric symptoms in 112 children aged 3-5 years whose mothers had participated in a longitudinal study of obesity in pregnancy (50 very severe obesity, BMI ⩾40 kg/m2, obese class III and 62 lean, BMI 18.5-25 kg/m2). The mothers completed the Conners' Hyperactivity Scale, Early Symptomatic Syndrome Eliciting Neurodevelopmental Clinical Examination Questionnaire (ESSENCE-Q), Child's Sleep Habits Questionnaire (CSHQ), Strengths and Difficulties Questionnaire (SDQ), and Child Behavior Checklist (CBCL) to assess child neuropsychiatric symptoms. Covariates included child's sex, age, birthweight, gestational age, socioeconomic deprivation levels, maternal age, parity, smoking status during pregnancy, gestational diabetes and maternal concurrent symptoms of anxiety and depression assessed using State Anxiety of Spielberger State-Trait Anxiety Index (STAI) and General Health Questionnaire (GHQ), respectively. RESULTS: Children exposed to prenatal maternal very severe obesity had significantly higher scores in the Conners' Hyperactivity Scale; ESSENCE-Q; total sleep problems in CSHQ; hyperactivity, conduct problems and total difficulties scales of the SDQ; higher externalizing and total problems, anxious/depressed, aggressive behaviour and other problem syndrome scores and higher DSM-oriented affective, anxiety and ADHD problems in CBCL. Prenatal maternal very severe obesity remained a significant predictor of child neuropsychiatric problems across multiple scales independent of demographic factors, prenatal factors and maternal concurrent symptoms of anxiety and depression. CONCLUSIONS: Prenatal maternal very severe obesity is a strong predictor of increased neuropsychiatric problems in early childhood.

Estrogens protect male mice from obesity complications and influence glucocorticoid metabolism.

BACKGROUND: Although the prevalence of obesity is higher among women than men, they are somewhat protected from the associated cardiometabolic consequences. The increase in cardiovascular disease risk seen after the menopause suggests a role for estrogens. There is also growing evidence for the importance of estrogen on body fat and metabolism in males. We hypothesized that that estrogen administration would ameliorate the adverse effects of obesity on metabolic parameters in males. METHODS: Male and female C57Bl/6 mice were fed control or obesogenic (DIO) diets from 5 weeks of age until adulthood. Glucose tolerance testing was performed at 13 weeks of age. Mice were killed at 15 weeks of age and liver and adipose tissue were collected for analysis of gene expression. A second cohort of male mice underwent the same experimental design with the addition of estradiol pellet implantation or sham surgery at 6 weeks. RESULTS: DIO males had greater mesenteric adipose deposition and more severe increases in plasma glucose, insulin and lipids than females. Treatment of males with estradiol from 6 weeks of age prevented DIO-induced increases in adipose tissue mass and alterations in glucose-insulin homeostasis. We also identified sex differences in the transcript levels and activity of hepatic and adipose glucocorticoid metabolizing enzymes. Estrogen treatment feminized the pattern of DIO-induced changes in glucocorticoid metabolism, rendering males similar to females. CONCLUSIONS: Thus, DIO induces sex-specific changes in glucose-insulin homeostasis, which are ameliorated in males treated with estrogen, highlighting the importance of sex steroids in metabolism. Given that altered peripheral glucocorticoid metabolism has been observed in rodent and human obesity, our results also suggest that sexually dimorphic expression and activity of glucocorticoid metabolizing enzymes may have a role in the differential metabolic responses to obesity in males and females.

Supernova 2007bi as a pair-instability explosion.

Stars with initial masses such that 10M[symbol: see text] or= 140M[symbol: see text] (if such exist) develop oxygen cores with masses, M(core), that exceed 50M[symbol: see text], where high temperatures are reached at relatively low densities. Conversion of energetic, pressure-supporting photons into electron-positron pairs occurs before oxygen ignition and leads to a violent contraction which triggers a nuclear explosion that unbinds the star in a pair-instability supernova. Transitional objects with 100M[symbol: see text] < M(initial) < 140M[symbol: see text] may end up as iron-core-collapse supernovae following violent mass ejections, perhaps as a result of brief episodes of pair instability, and may already have been identified. Here we report observations of supernova SN 2007bi, a luminous, slowly evolving object located within a dwarf galaxy. We estimate the exploding core mass to be M(core) approximately 100M[symbol: see text], in which case theory unambiguously predicts a pair-instability supernova. We show that >3M[symbol: see text] of radioactive (56)Ni was synthesized during the explosion and that our observations are well fitted by models of pair-instability supernovae. This indicates that nearby dwarf galaxies probably host extremely massive stars, above the apparent Galactic stellar mass limit, which perhaps result from processes similar to those that created the first stars in the Universe.

Technical characteristics of elite junior men and women race walkers.

AIM: Successful coaching in race walking requires a thorough understanding of the biomechanical principles underlying this unique form of gait. The purpose of this study was to analyze elite male and female junior race walkers and identify key kinematic variables. METHODS: Twenty junior men and 20 junior women were videoed as they competed over 10 km in the 8th European Cup Race Walking. Three-dimensional kinematic data were obtained using motion analysis software (SIMI, Munich). RESULTS: Step length and cadence were correlated with speed in both sexes, and greater step lengths were the kinematic reason for junior men's faster walking speeds. While cadence did not differ between junior men and junior women, there was a difference in proportion of step time spent in contact. There were some differences between genders for upper body joint angles (e.g., elbow) but there were few differences within lower limb joint angles. CONCLUSION: Although some technical aspects (e.g., pelvic and shoulder girdle rotation) appeared undeveloped, it was noteworthy that most athletes achieved full knee extension at initial contact in accordance with the rules. However, in many athletes flight times were evident that might present problems during the transition to the higher standards of senior competition. There was a large range of ability among both sexes and coaches are advised to ensure that technical development continues during the transition to senior competition.

Associations between insulin resistance indices and subclinical atherosclerosis: A contemporary review.

Even in the absence of hyperglycemia or hyperlipidemia, it has been demonstrated that insulin resistance is an independent risk factor for atherosclerosis. Finding markers of insulin resistance that are associated with markers of atherosclerosis could help identify patients early in their disease course and allow for earlier initiation of preventative treatments. We reviewed available evidence regarding associations between known markers of insulin resistance and known markers of atherosclerosis. Serum triglycerides (TG), triglyceride-glucose index (TyG), and homeostasis model assessment (HOMA) were the insulin resistance markers reviewed. The coronary artery calcium score (CAC), carotid intimal medium thickness (cIMT), and pulse wave velocity (PWV) were reviewed as markers of atherosclerosis. TyG showed the most consistent association with CAC across broad demographic groups, though HOMA showed potential in obese individuals and those without diabetes. The data regarding cIMT and the reviewed insulin resistance markers did not yield any consistent associations, though very elevated TyG did appear to be associated with cIMT among normal weight individuals. Serum triglycerides showed a strong and consistent association with PWV across numerous studies and populations, though TyG index also demonstrated a strong association with PWV in a large systematic review. Of the insulin resistance markers reviewed, the TyG index appears to be most consistently associated with markers of atherosclerosis. TyG can be easily calculated with routine labwork and has the potential to inform decisions regarding early initiation of therapies in patients who would otherwise not be treated. Targeting insulin sensitivity prior to the development of T2DM has the potential to reduce development and progression of atherosclerosis, and patients without T2DM but who have elevated TyG index should be the topic of further research.

Development of ISB 1442, a CD38 and CD47 bispecific biparatopic antibody innate cell modulator for the treatment of multiple myeloma.

Antibody engineering can tailor the design and activities of therapeutic antibodies for better efficiency or other advantageous clinical properties. Here we report the development of ISB 1442, a fully human bispecific antibody designed to re-establish synthetic immunity in CD38+ hematological malignancies. ISB 1442 consists of two anti-CD38 arms targeting two distinct epitopes that preferentially drive binding to tumor cells and enable avidity-induced blocking of proximal CD47 receptors on the same cell while preventing on-target off-tumor binding on healthy cells. The Fc portion of ISB 1442 is engineered to enhance complement dependent cytotoxicity, antibody dependent cell cytotoxicity and antibody dependent cell phagocytosis. ISB 1442 thus represents a CD47-BsAb combining biparatopic targeting of a tumor associated antigen with engineered enhancement of antibody effector function to overcome potential resistance mechanisms that hamper treatment of myeloma with monospecific anti-CD38 antibodies. ISB 1442 is currently in a Phase I clinical trial in relapsed refractory multiple myeloma.

The Methyltransferases METTL7A and METTL7B Confer Resistance to Thiol-Based Histone Deacetylase Inhibitors.

Histone deacetylase inhibitors (HDACi) are part of a growing class of epigenetic therapies used for the treatment of cancer. Although HDACis are effective in the treatment of T-cell lymphomas, treatment of solid tumors with this class of drugs has not been successful. Overexpression of the multidrug resistance protein P-glycoprotein (P-gp), encoded by ABCB1, is known to confer resistance to the HDACi romidepsin in vitro, yet increased ABCB1 expression has not been associated with resistance in patients, suggesting that other mechanisms of resistance arise in the clinic. To identify alternative mechanisms of resistance to romidepsin, we selected MCF-7 breast cancer cells with romidepsin in the presence of the P-gp inhibitor verapamil to reduce the likelihood of P-gp-mediated resistance. The resulting cell line, MCF-7 DpVp300, does not express P-gp and was found to be selectively resistant to romidepsin but not to other HDACis such as belinostat, panobinostat, or vorinostat. RNA-sequencing analysis revealed upregulation of the mRNA coding for the putative methyltransferase, METTL7A, whose paralog, METTL7B, was previously shown to methylate thiol groups on hydrogen sulfide and captopril. As romidepsin has a thiol as the zinc-binding moiety, we hypothesized that METTL7A could inactivate romidepsin and other thiol-based HDACis via methylation of the thiol group. We demonstrate that expression of METTL7A or METTL7B confers resistance to thiol-based HDACis and that both enzymes are capable of methylating thiol-containing HDACis. We thus propose that METTL7A and METTL7B confer resistance to thiol-based HDACis by methylating and inactivating the zinc-binding thiol.

Clinical care in craniofacial microsomia: a review of current management recommendations and opportunities to advance research.

Craniofacial microsomia (CFM) is a complex condition associated with microtia, mandibular hypoplasia, and preauricular tags. It is the second most common congenital facial condition treated in many craniofacial centers and requires longitudinal multidisciplinary patient care. The purpose of this article is to summarize current recommendations for clinical management and discuss opportunities to advance clinical research in CFM.