Making Sense of Censored Covariates: Statistical Methods for Studies of Huntington's Disease.

The landscape of survival analysis is constantly being revolutionized to answer biomedical challenges, most recently the statistical challenge of censored covariates rather than outcomes. There are many promising strategies to tackle censored covariates, including weighting, imputation, maximum likelihood, and Bayesian methods. Still, this is a relatively fresh area of research, different from the areas of censored outcomes (i.e., survival analysis) or missing covariates. In this review, we discuss the unique statistical challenges encountered when handling censored covariates and provide an in-depth review of existing methods designed to address those challenges. We emphasize each method's relative strengths and weaknesses, providing recommendations to help investigators pinpoint the best approach to handling censored covariates in their data.

The genome sequences of the marine diatom Epithemia pelagica strain UHM3201 (Schvarcz, Stancheva & Steward, 2022) and its nitrogen-fixing, endosymbiotic cyanobacterium.

We present the genome assembly of the pennate diatom Epithemia pelagica strain UHM3201 (Ochrophyta; Bacillariophyceae; Rhopalodiales; Rhopalodiaceae) and that of its cyanobacterial endosymbiont (Chroococcales: Aphanothecaceae). The genome sequence of the diatom is 60.3 megabases in span, and the cyanobacterial genome has a length of 2.48 megabases. Most of the diatom nuclear genome assembly is scaffolded into 15 chromosomal pseudomolecules. The organelle genomes have also been assembled, with the mitochondrial genome 40.08 kilobases and the plastid genome 130.75 kilobases in length. A number of other prokaryote MAGs were also assembled.

SAK3 confers neuroprotection in the neurodegeneration model of X-linked Dystonia-Parkinsonism.

Background X-linked Dystonia-Parkinsonism(XDP) is an adult-onset neurodegenerative disorder that results in the loss of striatal medium spiny neurons (MSNs). XDP is associated with disease-specific mutations in and around the TAF1 gene. This study highlights the utility of directly reprogrammed MSNs from fibroblasts of affected XDP individuals as a platform that captures cellular and epigenetic phenotypes associated with XDP-related neurodegeneration. In addition, the current study demonstrates the neuroprotective effect of SAK3 currently tested in other neurodegenerative diseases. Methods XDP fibroblasts from three independent patients as well as age- and sex-matched control fibroblasts were used to generate MSNs by direct neuronal reprogramming using miRNA-9/9*-124 and thetranscription factors CTIP2 , DLX1 -P2A- DLX2 , and MYT1L . Neuronal death, DNA damage, and mitochondrial health assays were carried out to assess the neurodegenerative state of directly reprogrammed MSNs from XDP patients (XDP-MSNs). RNA sequencing and ATAC sequencing were performed to infer changes in the transcriptomic and chromatin landscapesof XDP-MSNs compared to those of control MSNs (Ctrl-MSNs). Results Our results show that XDP patient fibroblasts can be successfully reprogrammed into MSNs and XDP-MSNs display several degenerative phenotypes, including neuronal death, DNA damage, and mitochondrial dysfunction, compared to Ctrl-MSNs reprogrammed from age- and sex-matched control individuals' fibroblasts. In addition, XDP-MSNs showed increased vulnerability to TNFα -toxicity compared to Ctrl-MSNs. To dissect the altered cellular state in XDP-MSNs, we conducted transcriptomic and chromatin accessibility analyses using RNA- and ATAC-seq. Our results indicate that pathways related to neuronal function, calcium signaling, and genes related to other neurodegenerative diseases are commonly altered in XDP-MSNs from multiple patients. Interestingly, we found that SAK3, a T-type calcium channel activator, that may have therapeutic values in other neurodegenerative disorders, protected XDP-MSNs from neuronal death. Notably, we found that SAK3-mediated alleviation of neurodegeneration in XDP-MSNs was accompanied by gene expression changes toward Ctrl-MSNs.

Strategies for phase matching control in a multidimensional Floquet state spectroscopy.

Floquet state spectroscopy is an optical analogue of multiple quantum coherence nuclear magnetic resonance (MQC-NMR). Tunable ultrafast excitation pulses resonantly excite multiple states in a sample to form the Floquet state. The Floquet state emits multiple coherent beams at frequencies and in directions that conserve energy and momenta. The different output beams differ in the time ordering and coherences created by the excitation beams. They correspond to the different methodologies in the NMR family. Isolating a specific beam and monitoring the output intensity as a function of excitation frequencies creates multidimensional spectra containing cross-peaks between coupled states. The frequency range of the multidimensional spectra is limited by phase matching constraints. This paper presents a new, to the best of our knowledge, active phase matching strategy that increases the versatility of multidimensional Floquet state spectroscopy through both longer sample path lengths and larger spectral ranges.

The dimensionality of infection networks among viruses infecting microbial eukaryotes and bacteria.

Diverse viruses and their hosts are interconnected through complex networks of infection, which are thought to influence ecological and evolutionary processes, but the principles underlying infection network structure are not well understood. Here we focus on network dimensionality and how it varies across 37 networks of viruses infecting eukaryotic phytoplankton and bacteria. We find that dimensionality is often strikingly low, with most networks being one- or two-dimensional, although dimensionality increases with network richness, suggesting that the true dimensionality of natural systems is higher. Low-dimensional networks generally exhibit a mixture of host partitioning among viruses and nestededness of host ranges. Networks of bacteria-infecting and eukaryote-infecting viruses possess comparable distributions of dimensionality and prevalence of nestedness, indicating that fundamentals of network structure are similar among domains of life and different viral lineages. The relative simplicity of many infection networks suggests that coevolutionary dynamics are often driven by a modest number of underlying mechanisms.

Notch Inhibition Enhances Morphological Reprogramming of microRNA-Induced Human Neurons.

Although the importance of Notch signaling in brain development is well-known, its specific contribution to cellular reprogramming remains less defined. Here, we use microRNA-induced neurons that are directly reprogrammed from human fibroblasts to determine how Notch signaling contributes to neuronal identity. We found that inhibiting Notch signaling led to an increase in neurite extension, while activating Notch signaling had the opposite effect. Surprisingly, Notch inhibition during the first week of reprogramming was both necessary and sufficient to enhance neurite outgrowth at a later timepoint. This timeframe is when the reprogramming miRNAs, miR-9/9* and miR-124, primarily induce a post-mitotic state and erase fibroblast identity. Accordingly, transcriptomic analysis showed that the effect of Notch inhibition was likely due to improvements in fibroblast fate erasure and silencing of anti-neuronal genes. To this effect, we identify MYLIP , whose downregulation in response to Notch inhibition significantly promoted neurite outgrowth. Moreover, Notch inhibition resulted in cells with neuronal transcriptome signature defined by expressing long genes at a faster rate than the control, demonstrating the effect of accelerated fate erasure on neuronal fate acquisition. Our results demonstrate the critical role of Notch signaling in mediating morphological changes in miRNA-based neuronal reprogramming of human adult fibroblasts.

The yaq project: Standardized software enabling flexible instrumentation.

Modern instrumentation development often involves the incorporation of many dissimilar hardware peripherals into a single unified instrument. The increasing availability of modular hardware has brought greater instrument complexity to small research groups. This complexity stretches the capability of traditional, monolithic orchestration software. In many cases, a lack of software flexibility leads creative researchers to feel frustrated, unable to perform experiments they envision. Herein, we describe Yet Another acQuisition (yaq), a software project defining a new standardized way of communicating with diverse hardware peripherals. yaq encourages a highly modular approach to experimental software development that is well suited to address the experimental flexibility needs of complex instruments. yaq is designed to overcome hardware communication barriers that challenge typical experimental software. A large number of hardware peripherals are already supported, with tooling available to expand support. The yaq standard enables collaboration among multiple research groups, increasing code quality while lowering development effort.

Decarboxylative halogenation of indoles by vanadium haloperoxidases.

Halogenated heteroarenes are key building blocks across numerous chemical industries. Here, we report that vanadium haloperoxidases are capable of producing 3-haloindoles through decarboxylative halogenation of 3-carboxyindoles. This biocatalytic method is applicable to decarboxylative chlorination, bromination, and iodination in moderate to high yields and with excellent chemoselectivity.

Advancing a grounded theory of parental support in competitive girls' golf.

Parental support in youth sport has been associated with positive athlete outcomes, such as sport enjoyment and continued participation. Although research has demonstrated the significant and influential role parents fulfil in the youth sport context, there remains a dearth of theoretical frameworks detailing parental support in youth sport and an absence of empirical research examining parental support across athlete development stages and sports. The present study sought to examine athletes' perceptions of parental support, with a view to advancing a grounded theory of parental support in youth golf. Fourteen online synchronous focus groups were conducted with an international sample (Australia, Canada, England, Finland, Ireland, New Zealand, Scotland) of 61 girls, in the specialising (n = 27) and investment stages (n = 34) of athlete development. Data were analysed in three phases: open-coding, axial coding, and theoretical integration. The substantive grounded theory is constructed on the core category of 'Individual Parental Support Preferences'. This core category is underpinned by four sub-categories of parental support which were evident across development stages: instrumental, informational, emotional, and autonomy support, and is influenced by a host of athlete (e.g., athletes' performance), parent (e.g., parents' knowledge), and contextual characteristics (e.g., location). Unconditional parental support is an important aspect of emotional support, however the concept of adopting a person-first approach to sport parenting is novel. These results provide a rich and novel insight of parental support in girls' golf, advancing a grounded theoretical understanding of parental support mechanisms in a youth sport context.

Physical activity in childhood and adolescence and future depressive symptoms: an 11-year prospective cohort study.

BACKGROUND: Physical activity (PA) can reduce young peoples' risk of depressive symptoms. Associations between PA and depressive symptoms are often investigated over timeframes spanning minutes to weeks. Less is known about whether childhood/adolescent PA can predict depressive symptoms in early adulthood. METHODS: Using a nationally representative sample from Ireland, latent growth mixture modelling was performed to investigate the extent to which different PA trajectories existed from ages 9-17, whether gender, weight status, and socio-economic deprivation at age 9, predicted PA trajectories from ages 9-17, and whether trajectory class membership predicted depressive symptoms at age 20. RESULTS: A 4-class solution was the best fit to the data (AIC = 52 175.69; BIC = 52 302.69; ssaBIC = 52 245.49; entropy = 1.00). Classes were labelled according to their baseline PA and slope of their trajectory: 'High-Decreasers'; 'Moderate-Decreasers'; 'Moderate-Stable'; and 'Low-Increasers'. A negative linear association existed between activity trajectory and the likelihood class members were female, overweight or socioeconomically deprived at age 9. The most active class (High-Decreasers) were significantly less likely to report depressive symptoms at age 20 than other classes. CONCLUSIONS: Multiple PA trajectories exist throughout childhood and adolescence although differences in PA levels reduced over time. The most/least active children continued to be the most/least active throughout adolescence. Those most active were least at risk of depressive symptoms in early adulthood. Being female, overweight or experiencing deprivation at age 9 were all risk factors for inactivity throughout adolescence. Findings have implications for public health and PA promotion in young people.

Evaluation of Field Sobriety Tests for Identifying Drivers Under the Influence of Cannabis: A Randomized Clinical Trial.

Importance: With increasing medicinal and recreational cannabis legalization, there is a public health need for effective and unbiased evaluations for determining whether a driver is impaired due to Δ9-tetrahydrocannabinol (THC) exposure. Field sobriety tests (FSTs) are a key component of the gold standard law enforcement officer-based evaluations, yet controlled studies are inconclusive regarding their efficacy in detecting whether a person is under the influence of THC. Objective: To examine the classification accuracy of FSTs with respect to cannabis exposure and driving impairment (as determined via a driving simulation). Design, Setting, and Participants: This double-blind, placebo-controlled parallel randomized clinical trial was conducted from February 2017 to June 2019 at the Center for Medicinal Cannabis Research, University of California, San Diego. Participants were aged 21 to 55 years and had used cannabis in the past month. Data were analyzed from August 2021 to April 2023. Intervention: Participants were randomized 1:1:1 to placebo (0.02% THC), 5.9% THC cannabis, or 13.4% THC cannabis smoked ad libitum. Main Outcome and Measures: The primary end point was law enforcement officer determination of FST impairment at 4 time points after smoking. Additional measures included officer estimation as to whether participants were in the THC or placebo group as well as driving simulator data. Officers did not observe driving performance. Results: The study included 184 participants (117 [63.6%] male; mean [SD] age, 30 [8.3] years) who had used cannabis a mean (SD) of 16.7 (9.8) days in the past 30 days; 121 received THC and 63, placebo. Officers classified 98 participants (81.0%) in the THC group and 31 (49.2%) in the placebo group as FST impaired (difference, 31.8 percentage points; 95% CI, 16.4-47.2 percentage points; P < .001) at 70 minutes after smoking. The THC group performed significantly worse than the placebo group on 8 of 27 individual FST components (29.6%) and all FST summary scores. However, the placebo group did not complete a median of 8 (IQR, 5-11) FST components as instructed. Of 128 participants classified as FST impaired, officers suspected 127 (99.2%) as having received THC. Driving simulator performance was significantly associated with results of select FSTs (eg, ≥2 clues on One Leg Stand was associated with impairment on the simulator: odds ratio, 3.09; 95% CI, 1.63-5.88; P < .001). Conclusions and Relevance: This randomized clinical trial found that when administered by highly trained officers, FSTs differentiated between individuals receiving THC vs placebo and driving abilities were associated with results of some FSTs. However, the high rate at which the participants receiving placebo failed to adequately perform FSTs and the high frequency that poor FST performance was suspected to be due to THC-related impairment suggest that FSTs, absent other indicators, may be insufficient to denote THC-specific impairment in drivers. Trial Registration: ClinicalTrials.gov Identifier: NCT02849587.

Comparing tryptophan:lysine ratios in dried distillers grains with solubles-based diets with and without a dried distillers grains with solubles withdrawal strategy on growth, carcass characteristics, and carcass fat iodine value of growing-finishing pigs.

A total of 6,240 finishing pigs (DNA 600 × PIC 1050; initially 22.5 ±â€…1.00 kg), divided into two groups, were used in a 119 or 120 d study comparing increasing Trp:Lys ratio in diets containing dried distillers grains with solubles (DDGS) or a DDGS withdrawal strategy (removing all DDGS from the last phase before marketing) on growth performance and carcass fat iodine value (IV). Pigs were randomly allotted to one of seven dietary treatments with 30 to 36 pigs per pen and 26 replications per treatment. Diets were fed in four phases, approximately 23 to 44, 44 to 71, 71 to 100, and 100 kg to market. Diets included a control corn-soybean meal-based diet (no DDGS) formulated to a 19% standardized ileal digestibility (SID) Trp:Lys ratio, four diets with 30% DDGS fed in all four phases and formulated to provide SID Trp:Lys ratios of 16%, 19%, 22%, or 25%, and two DDGS withdrawal strategy diets: 19% SID Trp:Lys with 30% DDGS in phases 1 through 3 and then 0% DDGS in phase 4 with either a 19% or 25% Trp:Lys ratio. Overall, body weight (BW), average daily gain (ADG), average daily feed intake (ADFI), and gain:feed ratio (G:F) increased (linear, P < 0.05) as SID Trp:Lys ratio increased in diets with 30% DDGS fed in all phases. Simultaneously, hot carcass weight (quadratic, P = 0.014), carcass yield (quadratic, P = 0.012), and backfat depth (linear, P = 0.040) increased with increasing Trp:Lys ratio. Pigs fed the 19% SID Trp:Lys ratio withdrawal strategy diet had similar ADG and ADFI as those fed the control diet, the 25% Trp:Lys withdrawal diet, or the 30% DDGS diets with 25% Trp:Lys ratio throughout the study. Pigs fed the control diet had decreased (P < 0.05) carcass fat IV compared to pigs fed the DDGS diets throughout the study, with pigs fed the two DDGS withdrawal strategy diets intermediate. In summary, increasing the SID Trp:Lys ratio in diets with 30% DDGS resulted in a linear increase in ADG, ADFI, G:F, and BW but did not influence carcass fat IV, with most of the benefits observed as diets increased from 16% to 19% Trp:Lys. Removing DDGS from the diet in the last period reduced carcass fat IV and increased growth rate during the withdrawal period compared to pigs fed with 30% DDGS throughout, indicating value in a withdrawal strategy.

Feeding high levels of dried distillers grains with solubles (DDGS) up to marketing has been found to have negative impacts on growth performance and carcass characteristics of finishing pigs, specifically carcass yield. High inclusion of DDGS has also been shown to increase iodine value (IV), a measurement of fat quality, due to increased deposition of unsaturated fatty acids. However, recent data suggested that when feeding finishing pigs diets containing DDGS, increasing the standardized ileal digestible Trp:Lys ratio well above the NRC requirement estimates can prevent or lessen some of these negative effects. This study compared removing DDGS from the final dietary phase with two levels of Trp:Lys ratio, commonly referred to as a withdrawal strategy, to increasing levels of Trp:Lys in diets containing 30% DDGS. The results of this study indicate that increasing the Trp:Lys ratio in diets containing DDGS to a 25% Trp:Lys ratio resulted in growth performance similar to the control diet and the withdrawal strategy, with most of the benefits observed when Trp:Lys is increased from a deficient to adequate status. However, feeding diets with DDGS up to market resulted in increased IV.

Perspectives on the pharmacological management of complex regional pain syndrome.

INTRODUCTION: Complex regional pain syndrome (CRPS) is a chronic pain condition that is notoriously difficult to treat. Therapies for CRPS include cognitive behavioral, physical, and occupational therapy, single or multidrug pharmacotherapy, and a variety of interventional techniques. Unfortunately, randomized clinical trials of these therapies are limited. The large number of potential pharmacologic options can be overwhelming for providers in their attempts to develop a treatment plan. AREAS COVERED: This article will review the literature on the pharmacologic management of CRPS. It is based on a systematic search of PubMed using keywords, followed by evaluation of the bibliographies for relevant articles. EXPERT OPINION: No single drug has amassed enough evidence to suggest clear efficacy, but a handful of agents with at least modest evidence are commonly used, including gabapentinoids, bisphosphonates, ketamine, and pulsed dose steroids. Meanwhile, other agents that lack significant evidence specifically in CRPS but have evidence in other neuropathic conditions are commonly prescribed, including tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SNRIs). In our opinion, careful selection and prompt initiation of appropriate pharmacotherapy may optimize pain relief and improve functionality in patients burdened with this debilitating condition.

Effect of different sow lactation feeder types and drip cooling on sow bodyweight, litter performance, and feeder cleaning criteria.

A total of 600 sows (line 3; PIC, Hendersonville, TN) were used to evaluate the effect of different lactation feeder types and drip cooling on sow farrowing performance and litter growth performance during the summer. For the feeder evaluation, the trial was conducted in two sequential groups with 300 sows per group. Five 60-farrowing-stall rooms with tunnel ventilation were used for each group. On approximately days 110 to 112 of gestation, sows were blocked by body condition score (BCS), parity, and offspring sire (lines 2 or 3 sires; PIC), then randomly allotted to one of three feeder types: 1) PVC tube feeder, 2) Rotecna feeder (Rotecna), or 3) SowMax feeder (Hog Slat). The three feeder types were placed in one of three stalls with the same sequence from the front to the end of all rooms to balance for environmental effects. For drip cooling evaluation, the trial was conducted during the 2nd group of 300 sows. Drippers were blocked in three of every six farrowing stalls to balance feeder type and environmental effects. After farrowing, sows had ad libitum access to feed. For litter performance data, only pigs from sows bred to line 2 sires were recorded. Line 3 sire pigs were not included in litter performance data, but sows of these pigs were included in sow body weight (BW) and feed disappearance data. After weaning, feeder cleaning time was recorded on a subsample of 67 feeders (19, 23, and 25 for PVC tube, Rotecna, and SowMax, respectively). There was no evidence of difference (P > 0.05) in sow entry BW, exit BW, BW change, and litter performance among the different feeder types. However, sows using the SowMax feeders had decreased (P < 0.05) total feed disappearance, average daily feed disappearance, and total feed cost compared to those fed with the PVC tube feeders. There was a marginal difference (P < 0.10) between feeder types in cleaning time, with PVC tube feeders requiring less time than the Rotecna feeders; however, cleaning time varied greatly between the personnel doing the cleaning. Sows with drip cooling had greater (P < 0.05) feed disappearance, litter growth performance, and subsequent total born, and reduced (P < 0.05) BW change. In conclusion, using a SowMax feeder reduced feed disappearance with no effects on sow and litter performance compared to a PVC tube feeder, and drip cooling improved sow and litter performance during summer.

Chemoenzymatic Catalysis: Cooperativity Enables Opportunity.

The application of enzymes in synthetic organic chemistry has emerged as a powerful means to generate molecular complexity in a highly selective, efficient, and sustainable manner. While enzymes have increasingly been incorporated into synthetic sequences for numerous academic and industrial applications on their own and in sequential processes, their utility in cooperative catalysis with small molecule catalytic platforms has recently drawn increased attention across the field of organic synthesis. In this review, we present a selection of notable accomplishments in cooperative chemoenzymatic catalysis and provide a perspective on its future directions.

Trophic strategies explain the ocean niches of small eukaryotic phytoplankton.

A large fraction of marine primary production is performed by diverse small protists, and many of these phytoplankton are phagotrophic mixotrophs that vary widely in their capacity to consume bacterial prey. Prior analyses suggest that mixotrophic protists as a group vary in importance across ocean environments, but the mechanisms leading to broad functional diversity among mixotrophs, and the biogeochemical consequences of this, are less clear. Here we use isolates from seven major taxa to demonstrate a tradeoff between phototrophic performance (growth in the absence of prey) and phagotrophic performance (clearance rate when consuming Prochlorococcus). We then show that trophic strategy along the autotrophy-mixotrophy spectrum correlates strongly with global niche differences, across depths and across gradients of stratification and chlorophyll a. A model of competition shows that community shifts can be explained by greater fitness of faster-grazing mixotrophs when nutrients are scarce and light is plentiful. Our results illustrate how basic physiological constraints and principles of resource competition can organize complexity in the surface ocean ecosystem.

Validity of a Smartphone Application in Calculating Measures of Heart Rate Variability.

The purpose of the current study was to determine the concurrent validity of the Elite HRV smartphone application when calculating heart rate variability (HRV) metrics in reference to an independent software criterion. A total of 5 minutes of R−R interval and natural log of root mean square of the successive differences (lnRMSSD) resting HRV data were simultaneously collected using two Polar H10 heart rate monitors (HRMs) in both the seated and supine positions from 22 participants (14 males, 8 females). One H10 HRM was paired with a Polar V800 watch and one with the Elite HRV application. When no artifact correction was applied, significant, but small, differences in the lnRMSSD data were observed between the software in the seated position (p = 0.022), and trivial and nonstatistically significant differences were observed in the supine position (p = 0.087). However, significant differences (p > 0.05) in the lnRMSSD data were no longer identifiable in either the seated or the supine positions when applying Very Low, Low, or Automatic artifact-correction filters. Additionally, excellent agreements (ICC3,1 = 0.938 − 0.998) and very strong to near-perfect (r = 0.889 − 0.997) relationships were observed throughout all correction levels. The Elite HRV smartphone application is a valid tool for calculating resting lnRMSSD HRV metrics.