An Individual vs Parent Supported Physical Activity Intervention in Adolescents with Intellectual Disabilities.

INTRODUCTION: Moderate-to-vigorous physical activity (MVPA) is inadequate in adolescents with intellectual and developmental disabilities (IDD). This report describes the results of an 18-mo. clinical trial in adolescents with IDD which compared changes in accelerometer assessed daily MVPA, gross motor quotient and leg press strength between participants randomized to an exercise intervention delivered to adolescents only (AO) or to the adolescent and a parent (A + P). METHODS: The 18-mo. trial included a 6-mo. active intervention, 6-mo. maintenance interventions, and a 6-mo. no-contact follow-up. Adolescents in both arms were asked to attend 40 min. remotely delivered group video exercise sessions (0-6 mos. =3 sessions·wk-1., 7-12 mos. =1 session·wk-1). In the A + P arm, one parent/guardian was asked to attend all group remote video exercise sessions and a monthly remotely delivered 30-min. educations/support session with their adolescent across the 12-mo. intervention. RESULTS: Adolescents (n = 116) with IDD (age ~ 16 yrs., 52% female) were randomized to the AO (n = 59) or A + P (n = 57) arms. Mixed modeling, controlling for baseline MVPA and season, indicated minimal but statistically significant changes in MVPA across 6 (p = 0.006), 12 (p < 0.001), and 18 mos. (p < 0.001). However, the change in MVPA in the two intervention arms did not differ significantly at any time point (all p > 0.05). Similarly, gross motor quotient and leg press strength improved significantly over time (p < 0.001) and these changes did not differ between intervention arms (all p > 0.05). CONCLUSIONS: Parental involvement had no impact on changes in daily MVPA, gross motor quotient or leg press strength in response to a remotely delivered exercise intervention in adolescents with IDD.

Chronic electrical stimulation with a peripheral suprachoroidal retinal implant: a preclinical safety study of neuroprotective stimulation.

Purpose: Extraocular electrical stimulation is known to provide neuroprotection for retinal cells in retinal and optic nerve diseases. Currently, the treatment approach requires patients to set up extraocular electrodes and stimulate potentially weekly due to the lack of an implantable stimulation device. Hence, a minimally-invasive implant was developed to provide chronic electrical stimulation to the retina, potentially improving patient compliance for long-term use. The aim of the present study was to determine the surgical and stimulation safety of this novel device designed for neuroprotective stimulation. Methods: Eight normally sighted adult feline subjects were monocularly implanted in the suprachoroidal space in the peripheral retina for 9-39 weeks. Charge balanced, biphasic, current pulses (100 µA, 500 µs pulse width and 50 pulses/s) were delivered continuously to platinum electrodes for 3-34 weeks. Electrode impedances were measured hourly. Retinal structure and function were assessed at 1-, 2-, 4-, 6- and 8-month using electroretinography, optical coherence tomography and fundus photography. Retina and fibrotic thickness were measured from histological sections. Randomized, blinded histopathological assessments of stimulated and non-stimulated retina were performed. Results: All subjects tolerated the surgical and stimulation procedure with no evidence of discomfort or unexpected adverse outcomes. The device position was stable after a post-surgery settling period. Median electrode impedance remained within a consistent range (5-10 kΩ) over time. There was no change in retinal thickness or function relative to baseline and fellow eyes. Fibrotic capsule thickness was equivalent between stimulated and non-stimulated tissue and helps to hold the device in place. There was no scarring, insertion trauma, necrosis, retinal damage or fibroblastic response in any retinal samples from implanted eyes, whilst 19% had a minimal histiocytic response, 19% had minimal to mild acute inflammation and 28% had minimal to mild chronic inflammation. Conclusion: Chronic suprathreshold electrical stimulation of the retina using a minimally invasive device evoked a mild tissue response and no adverse clinical findings. Peripheral suprachoroidal electrical stimulation with an implanted device could potentially be an alternative approach to transcorneal electrical stimulation for delivering neuroprotective stimulation.

Four decades of data indicate that planted mangroves stored up to 75% of the carbon stocks found in intact mature stands.

Mangroves' ability to store carbon (C) has long been recognized, but little is known about whether planted mangroves can store C as efficiently as naturally established (i.e., intact) stands and in which time frame. Through Bayesian logistic models compiled from 40 years of data and built from 684 planted mangrove stands worldwide, we found that biomass C stock culminated at 71 to 73% to that of intact stands ~20 years after planting. Furthermore, prioritizing mixed-species planting including Rhizophora spp. would maximize C accumulation within the biomass compared to monospecific planting. Despite a 25% increase in the first 5 years following planting, no notable change was observed in the soil C stocks thereafter, which remains at a constant value of 75% to that of intact soil C stock, suggesting that planting effectively prevents further C losses due to land use change. These results have strong implications for mangrove restoration planning and serve as a baseline for future C buildup assessments.

AL amyloidosis manifesting as a vertebral amyloidoma secondary to an unrecognized plasmacytoma expressing cyclin D1 case report.

INTRODUCTION: Immunoglobin-related (AL) amyloidosis is the production of amyloidogenic immunoglobulin light chains from clonal plasma cells or, rarely, B-cell lymphomas with plasmacytic differentiation. Amyloid deposition causes progressive end organ destruction with profound morbidity. PRESENTATION OF CASE: We present a rare case of a lambda light chain AL amyloidoma localized to a thoracic vertebra of an 87-year-old woman who had a remote history of an unspecified non-Hodgkin B-cell lymphoma (NHL). Our patient presented with upper extremity neuropathy and was found by MRI to have a malignant-appearing lesion throughout the T1 vertebra. Initial biopsy showed amyloid deposition and staging evaluation found localized disease. Prior to planned surgery and radiation the following year, she had worsening neuropathy including multiple falls. Repeat MRI confirmed lesion progression with concern for cord compression. Urgent surgical resection was performed. Histology showed numerous plasma cells with abundant amyloid deposition that was found by amyloid typing to be lambda light chain. An incidental B-cell rich lymphoid aggregate was also seen in a bone marrow fragment that required additional immunohistochemical evaluation, showing the aggregate to be benign while revealing the plasma cells to be positive for cyclin D1. She received localized radiation and has been asymptomatic. DISCUSSION: Amyloidosis and plasma cell neoplasms require appropriate staging evaluation. The cyclin D1-positive plasma cells raises the possibility of the t(11;14)/IGH::CCND1 translocation that portends better prognosis and therapeutic response with venetoclax. CONCLUSION: Amyloidomas are uncommon and may present in nearly any site, requiring a high index of clinical suspicion for proper diagnosis.

Microsecond time-resolved X-ray scattering by utilizing MHz repetition rate at second-generation XFELs.

Detecting microsecond structural perturbations in biomolecules has wide relevance in biology, chemistry and medicine. Here we show how MHz repetition rates at X-ray free-electron lasers can be used to produce microsecond time-series of protein scattering with exceptionally low noise levels of 0.001%. We demonstrate the approach by examining Jɑ helix unfolding of a light-oxygen-voltage photosensory domain. This time-resolved acquisition strategy is easy to implement and widely applicable for direct observation of structural dynamics of many biochemical processes.

Observing isolated synaptic vesicle association and fusion ex vivo.

Here, we present a protocol for isolating functionally intact glutamatergic synaptic vesicles from whole-mouse brain tissue and using them in a single-vesicle assay to examine their association and fusion with plasma membrane mimic vesicles. This is a Protocol Extension, building on our previous protocol, which used a purely synthetic system comprised of reconstituted proteins in liposomes. We also describe the generation of a peptide based on the vesicular glutamate transporter, which is essential in the isolation process of glutamatergic synaptic vesicles. This method uses easily accessible reagents to generate fusion-competent glutamatergic synaptic vesicles through immunoisolation. The generation of the vGlut peptide can be accomplished in 6 d, while the isolation of the synaptic vesicles by using the peptide can be accomplished in 2 d, with an additional day to fluorescently label the synaptic vesicles for use in a single-vesicle hybrid fusion assay. The single-vesicle fusion assay can be accomplished in 1 d and can unambiguously delineate synaptic vesicle association, dissociation, Ca2+-independent and Ca2+-dependent fusion modalities. This assay grants control of the synaptic vesicle environment while retaining the complexity of the synaptic vesicles themselves. This protocol can be adapted to studies of other types of synaptic vesicles or, more generally, different secretory or transport vesicles. The workflow described here requires expertise in biochemistry techniques, in particular, protein purification and fluorescence imaging. We assume that the laboratory has protein-purification equipment, including chromatography systems.

Parsing Dynamics of Protein Backbone NH and Side-Chain Methyl Groups using Molecular Dynamics Simulations.

Experimental NMR spectroscopy and theoretical molecular dynamics (MD) simulations provide complementary insights into protein conformational dynamics and hence into biological function. The present work describes an extensive set of backbone NH and side-chain methyl group generalized order parameters for the Escherichia coli ribonuclease HI (RNH) enzyme derived from 2-µs microsecond MD simulations using the OPLS4 and AMBER-FF19SB force fields. The simulated generalized order parameters are compared with values derived from NMR 15N and 13CH2D spin relaxation measurements. The squares of the generalized order parameters, S2 for the N-H bond vector and Saxis2 for the methyl group symmetry axis, characterize the equilibrium distribution of vector orientations in a molecular frame of reference. Optimal agreement between simulated and experimental results was obtained by averaging S2 or Saxis2 calculated by dividing the simulated trajectories into 50 ns blocks (∼five times the rotational diffusion correlation time for RNH). With this procedure, the median absolute deviations (MAD) between experimental and simulated values of S2 and Saxis2 are 0.030 (NH) and 0.061 (CH3) for OPLS4 and 0.041 (NH) and 0.078 (CH3) for AMBER-FF19SB. The MAD between OPLS4 and AMBER-FF19SB are 0.021 (NH) and 0.072 (CH3). The generalized order parameters for the methyl group symmetry axis can be decomposed into contributions from backbone fluctuations, between-rotamer dihedral angle transitions, and within-rotamer dihedral angle fluctuations. Analysis of the simulation trajectories shows that (i) backbone and side chain conformational fluctuations exhibit little correlation and that (ii) fluctuations within rotamers are limited and highly uniform with values that depend on the number of dihedral angles considered. Low values of Saxis2, indicative of enhanced side-chain flexibility, result from between-rotamer transitions that can be enhanced by increased local backbone flexibility.

Validation of the Center for Neurologic Study Bulbar Function Scale-Chinese version in a population with amyotrophic lateral sclerosis.

OBJECTIVE: The Center for Neurologic Study Bulbar Function Scale (CNS-BFS) was specifically designed as a self-reported measure of bulbar function. The purpose of this research was to validate the Chinese translation of the CNS-BFSC as an effective measurement for the Chinese population with ALS. METHODS: A total of 111 ALS patients were included in this study. The CNS-BFSC score, three bulbar function items from the ALSFRS-R, and visual analog scale (VAS) score for speech, swallowing and salivation were assessed in the present study. Forty-six ALS patients were retested on the same scale 5-10 days after the first evaluation. RESULTS: The CNS-BFSC sialorrhea, speech and swallowing subscores were separately correlated with the VAS subscores (p < 0.001). The CNS-BFSC total score and sialorrhea and speech scores were significantly correlated with the ALSFRS-R bulbar subscore (p < 0.001). The CNS-BFSC total score and ALSFRS-R bulbar subscale score were highly predictive of a clinician diagnosis of impaired bulbar function (area under the receiver operating characteristic curve, 0.947 and 0.911, respectively; p < 0.001). A cutoff value for the CNS-BFSC total score was selected by maximizing Youden's index; this cutoff score was 33, with 86.4% sensitivity and 93.3% specificity. The CNS-BFSC total score and the sialorrhea, speech and swallowing subscores had good-retest reliability (p > 0.05). The Cronbach's α of the CNS-BFSC was 0.972. CONCLUSION: The Chinese version of the CNS-BFSC has acceptable efficacy and reliability for the assessment of bulbar dysfunction in ALS patients.

Recombinant H77C gpE1/gpE2 heterodimer elicits superior HCV cross-neutralisation than H77C gpE2 alone.

BACKGROUND & AIMS: An optimal HCV vaccine requires the induction of antibodies that neutralise the infectivity of many heterogenous viral isolates. In this study, we have focused on determining the optimal recombinant envelope glycoprotein component to elicit cross-neutralising antibodies against global HCV genotypes. We compared the immunoreactivity and antigenicity of the recombinant HCV genotype 1a strain H77C envelope glycoprotein heterodimer gpE1/gpE2 with that of recombinant gpE2 alone derived from an infectious molecular clone (H77C). METHODS: Characterization of the envelope glycoproteins was accomplished by determining their ability to bind to a panel of broadly cross-neutralising monoclonal antibodies (bNAbs). Immunogenicity was determined by testing the ability of vaccine antisera to neutralise the infectivity in vitro of a panel of pseudotyped HCV particles in which gpE1/gpE2 derived from representative isolates of the major global HCV genotypes were displayed. RESULTS: gpE1/gpE2 binds to more diverse bNabs than gpE2 alone and elicits a broader profile of cross-neutralising antibodies in animals, especially against more heterologous, non-1a genotypes. While not all heterologous HCV strains can be potently inhibited in vitro by gpE1/gpE2 antisera derived from a single HCV strain, the breadth of heterologous cross-neutralisation is shown to be substantial. CONCLUSIONS: Our work supports the inclusion of gpE1/gpE2 in an HCV vaccine in order to maximise the cross-neutralisation of heterogenous HCV isolates. Our data also offers future directions in formulating a cocktail of gpE1/gpE2 antigens from a small selection of HCV genotypes to further enhance cross-neutralisation of global HCV strains and hopefully, achieving global protection. IMPACT AND IMPLICATIONS: An HCV vaccine is urgently required to prevent the high global incidence of HCV infection and disease. Since HCV is a highly heterogeneous virus, it is desirable for a vaccine to elicit antibodies that neutralise the infectivity of most global strains. To this end, we have compared the immunoreactivity and antigenicity of recombinant H77C E1E2 heterodimer with that of H77C E2 alone and show that the former exhibits more cross-neutralising epitopes and demonstrates a broader cross-neutralisation profile in vitro. In addition, our data suggests a way to further broaden cross-neutralisation using a combination of E1E2 antigens derived from a few different HCV clades. Our work provides encouragement for the development of an effective global HCV vaccine.

The nature of the last universal common ancestor and its impact on the early Earth system.

The nature of the last universal common ancestor (LUCA), its age and its impact on the Earth system have been the subject of vigorous debate across diverse disciplines, often based on disparate data and methods. Age estimates for LUCA are usually based on the fossil record, varying with every reinterpretation. The nature of LUCA's metabolism has proven equally contentious, with some attributing all core metabolisms to LUCA, whereas others reconstruct a simpler life form dependent on geochemistry. Here we infer that LUCA lived ~4.2 Ga (4.09-4.33 Ga) through divergence time analysis of pre-LUCA gene duplicates, calibrated using microbial fossils and isotope records under a new cross-bracing implementation. Phylogenetic reconciliation suggests that LUCA had a genome of at least 2.5 Mb (2.49-2.99 Mb), encoding around 2,600 proteins, comparable to modern prokaryotes. Our results suggest LUCA was a prokaryote-grade anaerobic acetogen that possessed an early immune system. Although LUCA is sometimes perceived as living in isolation, we infer LUCA to have been part of an established ecological system. The metabolism of LUCA would have provided a niche for other microbial community members and hydrogen recycling by atmospheric photochemistry could have supported a modestly productive early ecosystem.

Utilization and outcomes of transcranial magnetic stimulation and usual care for MDD in a large group psychiatric practice.

BACKGROUND: General psychiatrists' practice standards vary regarding when to implement transcranial magnetic stimulation (TMS) for care of patients with major depressive disorder (MDD). Furthermore, few studies have examined real-world utilization and clinical outcomes of TMS. This study analyzed data from a large, multi-site psychiatric practice to evaluate utilization and outcomes of TMS as well as usual care (UC) for patients with MDD. METHODS: Depression outcomes for TMS and UC among adult patients at a multi-site psychiatric group practice were examined in this retrospective cohort analysis. Patients with a primary diagnosis of MDD, PHQ-9 ≥ 10, and a visit in November 2020 with 6-month follow-up were included and categorized into the TMS or UC cohorts. RESULTS: Of 1,011 patients with qualifying PHQ-9 at the baseline visit, 9% (89) received a full course of TMS, and 583 patients receiving UC met study inclusion criteria (339 patients were excluded due to lacking a 6-month follow-up visit or receiving esketamine during the study period). The TMS cohort had higher baseline PHQ-9 than UC (17.9 vs. 15.5, p < .001) and had failed more medication trials (≥ 4 vs. 3.1, p < .001). Mean PHQ-9 decreased by 5.7 points (SD = 6.7, p < .001) in the TMS cohort and by 4.2 points (SD = 6.4, p < .001) in the UC cohort over the study period. Among patients who had failed four or more antidepressant medications, PHQ-9 decreased by 5.8 points in the TMS cohort (SD = 6.7, p < .001) and by 3.2 points in the UC cohort (SD = 6.3, p < .001). CONCLUSIONS: TMS utilization was low, despite TMS showing significant real-world clinical benefits. Future research should examine and address barriers to wider adoption of TMS into routine patient care for patients with treatment-resistant MDD. Wider adoption including routine use of TMS in less treatment-resistant patients will allow statistical comparisons of outcomes between TMS and UC populations that are difficult to do when TMS is underutilized.

The use of insect cell line Sf21 for ecotoxicity testing.

Insect cell lines are finding utility in many areas of biology, but their application as an in vitro tool for ecotoxicity testing has been given less attention. Our study aimed to demonstrate the utility and sensitivity of Sf21 cells to commonly used fungicides: Propiconazole and CuSO4, as well as dimethyl sulphoxide (DMSO) an industrial solvent. Sf21 cells were readily cultured from frozen stocks in 3-4 days and showed utility as an invertebrate in vitro acute toxicity test. The data showed the threshold levels of cell survivability against propiconazole and CuSO4. The EC50 values were 135.1 µM and 3.31 mM respectively. The LOAEL (lowest observed adverse effect level) was ≈ 1 µM for propiconazole and ≈ 10 µM for CuSO4. Culturing of Sf21 cells in media containing the solvent DMSO showed that 0.5% DMSO concentration did not effect cell viability. Sf21 cells are sensitive and useful as a robust ecologically relevant screening tool for acute toxicity testing.

Frequency of pharmacogenomic variation and medication exposures among All of Us Participants.

Pharmacogenomics promises improved outcomes through individualized prescribing. However, the lack of diversity in studies impedes clinical translation and equitable application of precision medicine. We evaluated the frequencies of PGx variants, predicted phenotypes, and medication exposures using whole genome sequencing and EHR data from nearly 100k diverse All of Us Research Program participants. We report 100% of participants carried at least one pharmacogenomics variant and nearly all (99.13%) had a predicted phenotype with prescribing recommendations. Clinical impact was high with over 20% having both an actionable phenotype and a prior exposure to an impacted medication with pharmacogenomic prescribing guidance. Importantly, we also report hundreds of alleles and predicted phenotypes that deviate from known frequencies and/or were previously unreported, including within admixed American and African ancestry groups.

Paths of least resistance: Unconventional effector secretion by fungal and oomycete plant pathogens.

Effector secretion by different routes mediates the molecular interplay between host plant and pathogen, but mechanistic details in eukaryotes are sparse. This may limit the discovery of new effectors that could be utilized for improving host plant disease resistance. In fungi and oomycetes, apoplastic effectors are secreted via the conventional ER-Golgi pathway while cytoplasmic effectors are packaged into vesicles that bypass Golgi in an unconventional protein secretion (UPS) pathway. In Magnaporthe oryzae, the Golgi bypass UPS pathway incorporates components of the exocyst complex and a t-SNARE, presumably to fuse Golgi bypass vesicles to the fungal plasma membrane. Upstream, cytoplasmic effector mRNA translation in M. oryzae requires the efficient decoding of AA-ending codons. This involves the modification of wobble uridines in the anticodon loop of cognate tRNAs and fine-tunes cytoplasmic effector translation and secretion rates to maintain biotrophic interfacial complex integrity and permit host infection. Thus, plant-fungal interface integrity is intimately tied to effector codon usage, a surprising constraint on pathogenicity. Here, we discuss these findings within the context of fungal and oomycete effector discovery, delivery, and function in host cells. We show how cracking the codon code for unconventional cytoplasmic effector secretion in M. oryzae has revealed AA-ending codon usage bias in cytoplasmic effector mRNAs across kingdoms, including within the RxLR-dEER motif-encoding sequence of a bona fide Phytophthora infestans cytoplasmic effector, suggesting its subjection to translational speed control. By focusing on recent developments in understanding unconventional effector secretion, we draw attention to this important but understudied area of host-pathogen interactions.

Dolutegravir Resistance in African Programmatic Settings Among Patients With Failure of Dolutegravir-based ART.

Dolutegravir resistance is emerging in routine clinical contexts in southern Africa, primarily in patients with prior treatment experience failing dolutegravir-based antiretroviral therapy (ART). This potential issue was raised by The Nucleosides and Darunavir/Dolutegravir in Africa trial that compared dolutegravir and boosted protease inhibitor-based therapy as second-line ART, in which new dolutegravir resistance was observed at failure. However, recent data suggest that also at risk are patients who were transitioned to dolutegravir from non-nucleoside reverse transcriptase inhibitor-based ART while viremic. Identifying patients experiencing failure of dolutegravir with resistance will be difficult given current gaps in viral load monitoring and limited capacity for genotypic resistance testing. As a result, in the short term, most patients affected will go unrecognized, with particularly important implications for patients affected who have advanced HIV or who are pregnant/breastfeeding. Prospective research is needed to understand the scope of the problem, identify additional risk factors, and determine best management. In the short term, for most patients with dolutegravir resistance and prior non-nucleoside reverse transcriptase inhibitor exposure, the best option will be a timely switch to a regimen anchored by a boosted protease inhibitor, with a high genetic barrier to resistance.

Do aversive well-being comparisons mediate the effects of childhood adversity on anxiety and depression?

BACKGROUND: Childhood adversity (CA) is strongly associated with depression and anxiety in later life. Many adults with a history of CA may have internalized an insecure self-concept, which may contribute to negative evaluations of one's current well-being relative to different standards. Yet, there is lack of research on well-being comparisons in adults with a history of CA. OBJECTIVE: We examined aversive well-being comparisons (i.e., comparisons threatening the comparer's motives) in the context of CA and their predictive value in depression and anxiety beyond self-esteem, emotion regulation, and external control beliefs. Further, we investigated whether well-being comparison processes mediate the relationship between CA and depression and anxiety. PARTICIPANTS AND SETTING: We conducted a two-wave longitudinal study with 942 adult participants (mean age: 31.56 years, SD = 10.49, 18-75 years). METHODS: Participants completed measures of CA, aversive well-being comparisons (social, temporal, counterfactual, and criteria-based comparisons), self-esteem, emotion regulation, and locus of control at two time points, three months apart. RESULTS: CA was significantly linked to more frequent aversive well-being comparisons. These comparisons were associated with greater discrepancies relative to the comparison standard and a more negative affective impact, ultimately contributing to higher levels of subsequent anxiety and depression symptoms. Comparison frequency emerged as key mediator, highlighting potential pathways through which CA affects adult mental health. These associations emerged despite controlling for established variables in this context, namely self-esteem, emotion regulation, and external locus of control. CONCLUSION: Our findings underscore the unique importance of aversive well-being comparisons in individuals with a history of CA.

Scalable Ab Initio Electronic Structure Methods with Near Chemical Accuracy for Main Group Chemistry.

This study evaluates the precision of widely recognized quantum chemical methodologies, CCSD(T), DLPNO-CCSD(T), and localized ph-AFQMC, for determining the thermochemistry of main group elements. DLPNO-CCSD(T) and localized ph-AFQMC, which offer greater scalability compared to canonical CCSD(T), have emerged over the past decade as pivotal in producing precise benchmark chemical data. Our investigation includes closed-shell, neutral molecules, focusing on their heat of formation and atomization energy sourced from four specific small molecule data sets. First, we selected molecules from the G2 and G3 data sets, noted for their reliable experimental heat of formation data. Additionally, we incorporate molecules from the W4-11 and W4-17 sets, which provide high-level theoretical reference values for atomization energy at 0 K. Our findings reveal that both DLPNO-CCSD(T) and ph-AFQMC methods are capable of achieving a root-mean-square deviation of less than 1 kcal/mol across the combined data set, aligning with the threshold for chemical accuracy. Moreover, we make efforts to confine the maximum deviations within 2 kcal/mol, a degree of precision that significantly broadens the applicability of these methods in fields such as biology and materials science.