Human Studies Research Articles

Growth-phase-dependent control of rRNA synthesis in Saccharomyces cerevisiae.

Saccharomyces cerevisiae is one of the most well-studied model organisms used in the scientific community. Its ease of manipulation, accessible growth conditions, short life cycle, and conserved eukaryotic metabolic pathways make it a useful model organism. Consequently, yeast has been used to investigate a myriad of phenomena, from microbial to human studies. Most of the research performed using this model organism utilizes yeast cell populations when they are growing exponentially, a growth phase aptly termed exponential or log phase. However, log phase encompasses several yeast generations and ranges several hours of yeast growth, meaning that there is a potential for variability during this "homogenous" growth phase. Cells in log phase require robust ribosome biogenesis to support their rapid growth and cell division. Interestingly, during log phase, ribosomal RNA (rRNA) synthesis (which is the first and rate limiting step in ribosome biosynthesis) has been shown to decrease prior to growth rate decline in stationary phase. In this study, we utilized several genomic and biochemical methods to elucidate the relationship between subphases of log phase and rRNA synthesis. Our results indicate that as yeast cells progress through subphases of log growth, both polymerase I transcription and rRNA processing are repressed. Overall, this study establishes a growth-phase-dependent control of rRNA synthesis that unexpectedly begins prior to the switch to stationary phase (i.e., pre-diauxic shift) as a putative mechanism of anticipating nutrient starvation.IMPORTANCESaccharomyces cerevisiae is a ubiquitously used model organism in a wide range of scientific research fields. The conventional practice when performing yeast studies is to investigate its properties during logarithmic growth phase. This growth phase is defined as the period during which the cell population doubles at regular intervals, and nutrients are not limiting. However, this growth phase lasts hours and encompasses several yeast cell generations which consequently introduce heterogeneity to log growth phase depending on their time of harvest. This study reveals significant changes in the transcriptomic landscape even in early stages of exponential growth. The overall significance of this work is the revelation that even the seemingly homogenous log growth phase is far more diverse than was previously believed.

A-079 Investigation of gut microbial flavonoid catabolites in metabolic diseases

Abstract Background Flavonoids, a secondary metabolite found in plant-based diets, have gained attention in the last decade for their antioxidative properties in high-fat diet induced obesity animal models and human studies. Previous work showed that certain gut microbiota members can metabolize flavonoids into monophenolic acids (MPAs), and some of these MPAs have similar effects to insulin when administered orally. Our objective is to explore the microbiome connection between flavonoid-rich diets and improved metabolic parameters in obesity. We hypothesize that flavonoid-supplemented diets are most effective in the presence of gut microbiota capable of MPA formation and that these bacterial metabolites are the main bioactive compounds responsible for the improved metabolic parameters Methods To investigate our hypothesis, we fed male and female C57BL/6 mice a high-fat control diet (HFD) or the same diet supplemented with 1% MPA or 1% berry extract for 12 weeks. Each group was further divided into subgroups that received regular drinking water (RW) or antibiotic water (ABW) to suppress gut microbial communities. A range of metabolic parameters, such as body weight, lean and fat mass, glucose and insulin tolerance, histological assessment of liver cells, quantification of liver injury biomarkers, transcriptional changes in metabolically active tissues, and glucose and lipid metabolism pathways, were monitored. Additionally, 16s sequencing was performed on the cecal microbial composition of each group. Results Mice on HFD control with RW or ABW showed prominent hepatic steatosis and an increase in liver lipids accumulation demonstrated by a significant decrease in the activation of lipid metabolism pathways. Similarly, mice on HFD with 1% MPA and RW or ABW exhibited a significant reduction in hepatic steatosis and an increase in the activation of the lipid metabolism pathways, regardless of gut microbiota presence. In line with our hypothesis, mice on HFD with 1% berry extract and RW showed a similar reduction in hepatic steatosis to both 1% MPA groups. However, mice on HFD with 1% berry extract and ABW displayed noticeable hepatic steatosis, indicating the loss of the positive effect provided by berry extract metabolites once gut microbiota was depleted by antibiotics. Insulin tolerance test revealed a gut microbial effect as well in the HFD with 1% berry extract, illustrated by a significant reduction in glucose levels after insulin injection and an increase in insulin sensitivity. In contrast, the HFD control mice experienced an increase in glucose levels after insulin injection and insulin resistance. Although there were notable decreases in fasting blood glucose, there were no significant effects on fat and lean mass, insulin, glucagon, or liver injury marker levels. Finally, the mice on HFD with 1% berry extract had significantly more diverse cecal microbial communities than those fed HFD or HFD with 1% MPA. Conclusions Feeding mice a flavonoid-rich diet in the presence of intact gut microbiome can improve metabolic parameters associated with metabolic diseases, potentially preventing, or reversing these diseases. Our findings suggest promising avenues for treatment, such as dietary flavonoid supplementation with concurrent gut microbial probiotic therapy.

Inducing ipsilateral motor-evoked potentials in the biceps brachii muscle in healthy humans.

To assess reticulospinal tract excitability, high-intensity transcranial magnetic stimulation (TMS) has been used to elicit ipsilateral motor-evoked potentials (iMEPs). However, there is no consensus on robust and valid methods for use in human studies. The present study proposes a standardized method for eliciting and analysing iMEPs in the biceps brachii. Twenty-four healthy young adults participated in this study. Electromyography (EMG) electrodes recorded contralateral MEPs (cMEPs) from the right and iMEPs from the left biceps brachii. A dynamic preacher curl task was used with ~15% of the subject's one-repetition maximum load. The protocol included maximal compound action potential (M-max) determination of the right biceps brachii muscle, TMS hotspot determination, and four sets of five repetitions where 100% stimulator output was delivered at an elbow angle of 110° of flexion. We normalized cMEP amplitude by M-max (% M-max) and iMEP by cMEP amplitude ratio (ICAR). Clear iMEPs above background EMG were observed in 21 subjects (88%, ICAR = .31 ± .19). Good-to-excellent agreement (intraclass correlation coefficient [ICC] = .795-1.000) and low bias (.01-.08 mV and .60-1.11 ms) were demonstrated when comparing two different analysis methods (i.e. fixed time-window vs. manual onset detection) to determine the cMEP and iMEP amplitude and latency, respectively. Most subjects demonstrated clear iMEPs above background EMG triggered at a pre-determined joint angle during a light-load dynamic preacher curl exercise. Similar results were obtained when comparing a single-trial manual identification of iMEP and a semi-automated time-window data analysis approach.

The causal relationship between gut microbiota and lower extremity deep vein thrombosis combined with pulmonary embolism.

Over the years, numerous studies have explored the relationship between gut microbiota and lower extremity deep vein thrombosis (LEDVT) and pulmonary embolism (PE). The present study utilized Mendelian randomization (MR) to assess the causal link between gut microbiota and LEDVT combined with PE. Human gut microbiota genome-wide association study (GWAS) summary data from the MiBioGen consortium (n = 18,340) were utilized. Summary-level data on LEDVT (2,116 cases and 359,078 controls) and LEDVT combined with PE (4,319 cases and 356,875 controls) were obtained from the IEU Open GWAS project. MR analysis was conducted using the inverse variance weighted (IVW) method as the primary analysis. Additionally, MR-Egger, weighted median, weighted mode, and simple mode were employed as supplementary methods. Sensitivity analyses, including tests for heterogeneity and horizontal pleiotropy, were performed. Lastly, reverse MR analysis was performed. The IVW analyses revealed seven causal relationships between genetic liability in the gut microbiota and LEDVT and five causal relationships between genetic liability in the gut microbiota and LEDVT combined with PE. The intersection of these outcomes identified that the genus Butyricicoccus reduced the risk of both LEDVT and LEDVT combined with PE, while the genus Clostridium innocuum increased the risk for both conditions. This study demonstrates that the gut microbiota is causally associated with LEDVT and LEDVT combined with PE. Our findings provide valuable insights into the underlying mechanisms and suggest potential avenues for further clinical investigations of these conditions.

Chronobiological Spatial Clusters of Cortical Regions in the Human Brain.

We demonstrate that different regions of the cerebral cortex have different diurnal rhythms of spontaneously occurring high-frequency oscillations (HFOs). High-frequency oscillations were assessed with standard-of-care stereotactic electroencephalography in patients with drug-resistant epilepsy. To ensure generalizability of our findings beyond patients with drug-resistant epilepsy, we excluded stereotactic electroencephalography electrode contacts lying within seizure-onset zones, epileptogenic lesions, having frequent epileptiform activity, and excessive artifact. For each patient, we evaluated twenty-four 5-minute stereotactic electroencephalography epochs, sampled hourly throughout the day, and obtained the HFO rate (number of HFOs/minute) in every stereotactic electroencephalography channel. We analyzed diurnal rhythms of the HFO rates with the cosinor model and clustered neuroanatomic parcels in a standard brain space based on similarity of their cosinor parameters. Finally, we compared overlap among resting-state networks, described in the neuroimaging literature, and chronobiological spatial clusters discovered by us. We found five clusters that localized predominantly or exclusively to the left perisylvian, left perirolandic and left temporal, right perisylvian and right parietal, right frontal, and right insular-opercular cortices, respectively. These clusters were characterized by similarity of the HFO rates according to the time of the day. Also, these chronobiological spatial clusters preferentially overlapped with specific resting-state networks, particularly default mode network (clusters 1 and 3), frontoparietal network (cluster 1), visual network (cluster 1), and mesial temporal network (cluster 2). This is probably the first human study to report clusters of cortical regions with similar diurnal rhythms of electrographic activity. Overlap with resting-state networks attests to their functional significance and has implications for understanding cognitive functions and epilepsy-related mortality.

Preterm Birth and Kidney Health: From the Womb to the Rest of Life.

Chronic kidney disease (CKD) is a widespread condition often resulting from multiple factors, including maternal influences. These risk factors not only heighten the likelihood of developing CKD but increase the risk of a preterm birth. Adverse events during nephrogenesis can disrupt kidney development, leading to a reduced number of nephrons. As survival rates for preterm infants improve, more individuals are living into adulthood, thereby elevating their risk of CKD later in life. This review aims to explore the connections between preterm birth, kidney development, and the increased risk of CKD, while proposing practical solutions for the future through a multidisciplinary approach. We examine human studies linking preterm birth to negative kidney outcomes, summarize animal models demonstrating kidney programming and reduced nephron numbers, and consolidate knowledge on common mechanisms driving kidney programming. Additionally, we discuss factors in the postnatal care environment that may act as secondary insults contributing to CKD risk, such as acute kidney injury (AKI), the use of nephrotoxic drugs, preterm nutrition, and catch-up growth. Finally, we outline recommendations for action, emphasizing the importance of avoiding modifiable risk factors and implementing early CKD screening for children born preterm. Together, we can ensure that advancements in kidney health keep pace with improvements in preterm care.

The gut-brain axis in appetite, satiety, food intake, and eating behavior: Insights from animal models and human studies.

The gut-brain axis plays a pivotal role in the finely tuned orchestration of food intake, where both homeostatic and hedonic processes collaboratively control our dietary decisions. This interplay involves the transmission of mechanical and chemical signals from the gastrointestinal tract to the appetite centers in the brain, conveying information on meal arrival, quantity, and chemical composition. These signals are processed in the brain eventually leading to the sensation of satiety and the termination of a meal. However, the regulation of food intake and appetite extends beyond the realms of pure physiological need. Hedonic mechanisms, including sensory perception (i.e., through sight, smell, and taste), habitual behaviors, and psychological factors, exert profound influences on food intake. Drawing from studies in animal models and human research, this comprehensive review summarizes the physiological mechanisms that underlie the gut-brain axis and its interplay with the reward network in the regulation of appetite and satiety. The recent advancements in neuroimaging techniques, with a focus on human studies that enable investigation of the neural mechanisms underpinning appetite regulation are discussed. Furthermore, this review explores therapeutic/pharmacological strategies that hold the potential for controlling food intake.

High Protein Diets and Glomerular Hyperfiltration in Athletes and Bodybuilders: Is Chronic Kidney Disease the Real Finish Line?

Several observational and experimental studies in humans have suggested that high protein intake (PI) causes intraglomerular hypertension leading to hyperfiltration. This phenomenon results in progressive loss of renal function with long-term exposure to high-protein diets (HPDs), even in healthy people. The recommended daily allowance for PI is 0.83g/kg per day, which meets the protein requirement for approximately 98% of the population. A HPD is defined as a protein consumption > 1.5g/kg per day. Athletes and bodybuilders are encouraged to follow HPDs to optimize muscle protein balance, increase lean body mass, and enhance performance. A series of studies in resistance-trained athletes looking at HPD has been published concluding that there are no harmful effects of HPD on renal health. However, the aim of these studies was to evaluate body composition changes and they were not designed to assess safety or kidney outcomes. Here we review the effects of HPD on kidney health in athletes and healthy individuals with normal kidney function.

Magnetization transfer MRI of intragastric milk digestion: A feasibility study in humans

Gastric milk protein coagulation has been extensively studied using in vitro and animal models. Yet, verifying these results in humans remains essential. In this study, we assessed the feasibility of using MT MRI for monitoring milk protein coagulation in vivo in humans. Twelve adults underwent MRI scans before and after ingesting 300 g of milk with low- or high-protein denaturation (LPD or HPD, respectively). We assessed coagulation and gastric emptying dynamics by deriving the MT ratio (MTR), total gastric content (TGC), semi-solid, and liquid volumes. The MTR values increased during digestion for both milk products, indicating an increase in the degree of coagulation. Prolonged heating of milk did not affect the MTR (MD = 16 %, 95 % CI [10–21], p = 0.15), but resulted in higher TGC volumes (MD 40.3 mL, 95 % CI [25.5–55.1], p = 0.044), indicating slower gastric emptying. We thus showed that by combining MT with conventional anatomical MRI both milk protein coagulation and gastric emptying dynamics, and thereby the impact of heating on gastric milk digestion, can be assessed in vivo in humans. Our work underpins the feasibility of using MRI as a non-invasive imaging tool for studying the effects of food processing and composition on gastric digestion.

Current Overview of the Biology and Pharmacology in Sugen/Hypoxia-Induced Pulmonary Hypertension in Rats.

The Sugen 5416/hypoxia (Su/Hx) rat model of pulmonary arterial hypertension (PAH) demonstrates most of the distinguishing features of PAH in humans, including increased wall thickness and obstruction of the small pulmonary arteries along with plexiform lesion formation. Recently, significant advancement has been made describing the epidemiology, genomics, biochemistry, physiology, and pharmacology in Su/Hx challenge in rats. For example, there are differences in the overall reactivity to Su/Hx challenge in different rat strains and only female rats respond to estrogen treatments. These conditions are also encountered in human subjects with PAH. Also, there is a good translation in both the biochemical and metabolic pathways in the pulmonary vasculature and right heart between Su/Hx rats and humans, particularly during the transition from the adaptive to the nonadaptive phase of right heart failure. Noninvasive techniques such as echocardiography and magnetic resonance imaging have recently been used to evaluate the progression of the pulmonary vascular and cardiac hemodynamics, which are important parameters to monitor the efficacy of drug treatment over time. From a pharmacological perspective, most of the compounds approved clinically for the treatment of PAH are efficacious in Su/Hx rats. Several compounds that show efficacy in Su/Hx rats have advanced into phase II/phase III studies in humans with positive results. Results from these drug trials, if successful, will provide additional treatment options for patients with PAH and will also further validate the excellent translation that currently exists between Su/Hx rats and the human PAH condition.

T-wave Peak-to-End Changes Quantified by Time-Warping Predicts Ventricular Fibrillation in a Porcine Myocardial Infarction Model.

The T-peak-to-T-end ( Tpe) interval has shown potential in predicting ventricular arrhythmic risk. It is an appealing index to be measured during ischemia since it is less influenced by ST-segment changes than the early part of the T wave. A time-warping-based index, derived from a spatially transformed PCA lead, [Formula: see text], quantifying changes in the Tpe morphology, has previously demonstrated utility in tracking repolarization changes induced by a 5-minute ischemia model in humans. The value of [Formula: see text] as a predictor of ventricular fibrillation (VF) episodes is assessed in a porcine model of myocardial ischemia with ischemia maintained for 40 minutes. From 32 pigs undergoing a coronary occlusion, pre-occlusion and occlusion ECG recordings from 10 pigs suffering a VF episode after 10 min of occlusion (Delayed VF) and 16 that did not had any episode during the recording were analyzed. The [Formula: see text] series was measured by comparing Tpe morphologies at different stages of the occlusion relative to the peak-to-end morphology of a baseline T-wave. During baseline, [Formula: see text] remained stationary with an intra-recording median [IQR] value of 1.60 [1.33] ms. During artery occlusion, [Formula: see text] followed a well-marked gradual increasing trend as ischemia progressed, reaching a median of 14.58 [17.72] ms. [Formula: see text] averages were significantly higher ( ) in the VF group than in the Non-VF group at time intervals 0-5, 5-10, 10-15, 15-20, 20-25 min after occlusion onset and at 10-15, 5-10 and 5-0 minutes prior to VF episode, with median values of 12.5, 18.8, 26.8, 24.0, 31.0, 18.6, 25.0 and 28.8 vs 6.3, 7.6, 8.0, 7.8, 7.8, 8.5, 7.2 and 6.0 ms, respectively. The [Formula: see text] interval was also significantly higher in the VF group at all analyzed time periods, but with a lower significance level. Pigs with maximum [Formula: see text] ≥ 20.0 ms and [Formula: see text] ≥ 85.4 ms had significantly higher risk for VF occurring in the early 5-10 minutes interval, with 90.0%/75.0% and 80.0%/69.0% sensitivity/specificity, respectively. Univariate Cox analysis yielded hazard ratios of 12.5 for [Formula: see text] vs 5.5 for [Formula: see text]. The time-warping-based index, [Formula: see text], is a stronger VF predictor than [Formula: see text] during ischemia in a porcine model, advising for further clinical exploration studies in humans.

Human Claustrum Connections: Robust In Vivo Detection by DWI-Based Tractography in Two Large Samples.

Despite substantial neuroscience research in the last decade revealing the claustrum's prominent role in mammalian forebrain organization, as evidenced by its extraordinarily widespread connectivity pattern, claustrum studies in humans are rare. This is particularly true for studies focusing on claustrum connections. Two primary reasons may account for this situation: First, the intricate anatomy of the human claustrum located between the external and extreme capsule hinders straightforward and reliable structural delineation. In addition, the few studies that used diffusion-weighted-imaging (DWI)-based tractography could not clarify whether in vivo tractography consistently and reliably identifies claustrum connections in humans across different subjects, cohorts, imaging methods, and connectivity metrics. To address these issues, we combined a recently developed deep-learning-based claustrum segmentation tool with DWI-based tractography in two large adult cohorts: 81 healthy young adults from the human connectome project and 81 further healthy young participants from the Bavarian longitudinal study. Tracts between the claustrum and 13 cortical and 9 subcortical regions were reconstructed in each subject using probabilistic tractography. Probabilistic group average maps and different connectivity metrics were generated to assess the claustrum's connectivity profile as well as consistency and replicability of tractography. We found, across individuals, cohorts, DWI-protocols, and measures, consistent and replicable cortical and subcortical ipsi- and contralateral claustrum connections. This result demonstrates robust in vivo tractography of claustrum connections in humans, providing a base for further examinations of claustrum connectivity in health and disease.

Exposure to aircraft noise exacerbates cardiovascular and oxidative damage in three mouse models of diabetes.

Epidemiology links noise to increased risk of metabolic diseases like diabetes and obesity. Translational studies in humans and experimental animals showed that noise causes reactive oxygen species (ROS)-mediated cardiovascular damage. The interaction between noise and diabetes, specifically potential additive adverse effects, remains to be determined. C57BL/6 mice were treated with streptozotocin (i.p. injections, 50 mg/kg/d for 5d) to induce type-1 diabetes, with S961 (subcutaneous osmotic minipumps, 0.57 mg/kg/d for 7d) or fed a high-fat diet (HFD, 20 weeks) to induce type-2 diabetes. Control and diabetic mice were exposed to aircraft noise to an average sound pressure level of 72 dB(A) for 4d. While body weight was unaffected, noise reduced insulin production in all diabetes models. The oral glucose tolerance test showed only an additive aggravation by noise in the HFD model. Noise increased blood pressure and aggravated diabetes-induced aortic, mesenteric, and cerebral arterioles endothelial dysfunction. ROS formation in cerebral arterioles, the aorta, the heart, and isolated mitochondria was consistently increased by noise in all models of diabetes. Mitochondrial respiration was impaired by diabetes and noise, however without additive effects. Noise increased ROS and caused inflammation in adipose tissue in the HFD model. RNA sequencing data and alteration of gene pathway clusters also supported additive damage by noise in the setting of diabetes. In all three models of diabetes, aircraft noise exacerbates oxidative stress, inflammation, and endothelial dysfunction in mice with pre-existing diabetes. Thus, noise may potentiate the already increased cardiovascular risk in diabetic patients.

Association between neurovascular coupling and neural signals in the resting state as revealed by a combined fMRI and magnetoencephalography study in humans.

The blood oxygenation level-dependent (BOLD) activation reflects hemodynamic events mediated by neurovascular coupling. During task performance, the BOLD hemodynamic response in a relevant area is mainly driven by the high levels of synaptic activity (reflected in local field potentials, LFPs) but, in contrast, during a task-free, resting state, the contribution to BOLD of such neural events is small, as expected by the comparatively (to the task state) low level of neural events. Concomitant recording of BOLD and LFP at rest in animal experiments has estimated the neural contribution to BOLD to ∼10%. Such experiments have not been performed in humans. As an approximation, we recorded (in the same subject, n = 57 healthy participants) at a task-free, resting state the BOLD signal and, in a different session, the magnetoencephalographic (MEG) signal, which reflects purely neural (synaptic) events. We then calculated the turnover of these signals by computing the successive moment-to-moment difference in the BOLD and MEG time series and retaining the median of the absolute value of the differenced series (BOLD and TMEG, respectively). The correlation between normalized turnovers of BOLD (TBOLD) and turnovers of MEG (TMEG) was r = 0.336 (r2 = 0.113; P = 0.011). These results estimate that 11.3% of the variance in TBOLD can be explained by the variance in TMEG. This estimate is close to the aforementioned estimate obtained by direct recordings in animal experiments. NEW & NOTEWORTHY Here, we report on a weak positive association between turnovers of blood oxygenation level-dependent (TBOLD) and magnetoencephalographic (TMEG) signals in 57 healthy human subjects in a resting, task-free state. More specifically, we found that the purely neural TMEG accounted for 11.1% of the TBOLD, a percentage remarkably close to that found between resting-state local field potentials (LFPs) and BOLD recorded concurrently in animal experiments.

Genotype imputation in human genomic studies.

Imputation is a method that supplies missing information about genetic variants that could not be directly genotyped with DNA microarrays or low-coverage sequencing. Imputation plays a critical role in genome-wide association studies (GWAS). It leads to a significant increase in the number of studied variants, which improves the resolution of the method and enhances the comparability of data obtained in different cohorts and/or by using different technologies, which is important for conducting meta-analyses. When performing imputation, genotype information from the study sample, in which only part of the genetic variants are known, is complemented using the standard (reference) sample, which has more complete genotype data (most often the results of whole-genome sequencing). Imputation has become an integral part of human genomic research due to the benefits it provides and the increasing availability of imputation tools and reference sample data. This review focuses on imputation in human genomic research. The first section of the review provides a description of technologies for obtaining information about human genotypes and characteristics of these types of data. The second section describes the imputation methodology, lists the stages of its implementation and the corresponding programs, provides a description of the most popular reference panels and methods for assessing the quality of imputation. The review concludes with examples of the use of imputation in genomic studies of samples from Russia. This review shows the importance of imputation, provides information on how to carry it out, and systematizes the results of its application using Russian samples.

Hypometric genetics: Improved power in genetic discovery by incorporating quality control flags.

Balancing the tradeoff between quantity and quality of phenotypic data is critical in omics studies. Measurements below the limit of quantification (BLQ) are often tagged in quality control fields, but these flags are currently underutilized in human genetics studies. Extreme phenotype sampling is advantageous for mapping rare variant effects. We hypothesize that genetic drivers, along with environmental and technical factors, contribute to the presence of BLQ flags. Here, we introduce "hypometric genetics" (hMG) analysis and uncover a genetic basis for BLQ flags, indicating an additional source of genetic signal for genetic discovery, especially from phenotypic extremes. Applying our hMG approach to n= 227,469UK Biobank individuals with metabolomic profiles, we reveal more than 5% heritability for BLQ flags and report biologically relevant associations, for example, at APOC3, APOA5, and PDE3B loci. For common variants, polygenic scores trained only for BLQ flags predict the corresponding quantitative traits with 91% accuracy, validating the genetic basis. For rare coding variant associations, we find an asymmetric 65.4% higher enrichment of metabolite-lowering associations for BLQ flags, highlighting the impact of putative loss-of-function variants with large effects on phenotypic extremes. Joint analysis of binarized BLQ flags and the corresponding quantitative metabolite measurements improves power in Bayesian rare variant aggregation tests, resulting in an average of 181% more prioritized genes. Our approach is broadly applicable to omics profiling. Overall, our results underscore the benefit of integrating quality control flags and quantitative measurements and highlight the advantage of joint analysis of population-based samples and phenotypic extremes in human genetics studies.

Cross-Sectional Examination of Thyroid Hormones and Environmental Exposure to Multiclass Pesticides in Women of Reproductive Age in China.

Some pesticides have been shown to interfere with thyroid functions through changes in thyroid hormone (TH) levels. However, few human studies have explored associations between TH levels and environmental exposure to currently used pesticides, including neonicotinoids, phenylpyrazoles, phenoxy acids, and azoles. Moreover, such studies often measure biomarkers of exposure in urine or blood, and thus reveal only recent exposure. In contrast, hair has been demonstrated to be a suitable matrix for assessing chronic exposure to both persistent and nonpersistent organic pollutants. We investigated 54 biomarkers of pollutant exposure in relation to tetraiodothyronine (T4), 3,3',5-triiodothyronine (T3), 3,3',5'-triiodothyronine (rT3), and 3,3'-diiodothyronine (T2). In a cross-sectional study of 196 healthy Chinese women of reproductive age (25-45 years of age), concentrations of both pollutants and THs were analyzed in the first (starting from the scalp) of the hair matrix, collected in 2016. Associations between pollutants and TH levels were explored using stability-enhanced least absolute shrinkage and selection operator (lasso) by regressing all exposures against each outcome of interest, adjusted for age, body mass index, and city. Each TH was associated with the mixture of at least eight of the examined pesticides. We found associations of -HCH, PCP, DMP, DETP, 3Me4NP, carbofuran, , imidacloprid, 2,4-D, metolachlor, difenoconazole, and tebuconazole with THs. For example, a 2-standard deviation (SD) increase in -transformed hair DMP concentration was associated with lower hair T4 concentration [ (95% CI: , )] and higher hair T3 concentration [8.16% (95% CI: 1.73, 15.0%)] in the adjusted unpenalized regression models. We also found associations of some pesticides with T3/T4, rT3/T4, and rT3/T3 molar ratios, including PCP, DMP, 2,4-D, metolachlor, difenoconazole, and tebuconazole. Our results suggest that exposure to the low levels of pesticides examined here may disrupt thyroid homeostasis in humans. Further studies are needed to confirm our results and to evaluate the long-term consequences of these subtle interferences. https://doi.org/10.1289/EHP14378.

Impact of lead and nickel contamination on metabolic health: Associations with diabetes mellitus in a pakistani cohort

Environmental exposure to heavy metals, particularly lead (Pb) and nickel (Ni), is implicated in chronic metabolic diseases, including diabetes mellitus (DM). This cross-sectional study assessed the Pb and Ni levels in groundwater using ICP-OES and urine samples collected from 2688 participants using ICP-MS. We aimed to establish the associations between Pb and Ni exposure and risk factors for DM and metabolic disorders. Groundwater analysis revealed the elevated levels of total dissolved solids, electrical conductivity, hardness, turbidity, Ni, and Pb, exceeding the WHO guidelines. The mean concentration of Pb in groundwater samples of study area was 0.025 mg/L which was higher than the WHO permissible limit of 0.01 mg/L. Similarly the mean concentration of Ni in groundwater samples of study area was 0.038 mg/L which was also higher than the WHO permissible limit of 0.02 mg/L. In human study, participants, categorized into Pb-detected and Ni-detected groups, exhibited significantly higher Pb and Ni levels and non-exposed non-diabetic groups. Ni-detected diabetics showed elevated Ni levels compared to non-exposed non-diabetics. Similarly, Pb-detected diabetics showed elevated Pb levels compared to non-exposed non-diabetics. These findings suggest a potential contribution of Pb and Ni exposure to DM development. The study also identified associations between heavy metal exposure and disruptions in various biomarkers related to DM, lipid profile, inflammation, oxidative stress, liver function, and kidney function. Pb-detected diabetics demonstrated elevated levels of glycemic index biomarkers, including fasting blood glucose (P < 0.0001) and HbA1c (P < 0.0001). Ni-detected diabetics exhibited increased inflammatory markers, such as CRP (P < 0.0001) and IL-6 (P < 0.0001). Both Pb and Ni exposure were associated with dyslipidemia, as indicated by elevated levels of total cholesterol (P < 0.0001) and LDL (P < 0.0001). Additionally, heavy metal exposure was linked to impaired liver and kidney function, supported by elevated levels of AST (P < 0.0001), ALT (P < 0.0001), creatinine (P < 0.0001), and blood urea nitrogen (P < 0.0001), with Pb exposure also associated with higher levels of MDA (P < 0.0001). Correlation analyses demonstrated significant associations between urinary Pb and Ni concentrations and various biomarkers related to DM and metabolic disorders. In conclusion, this study provides substantial evidence linking Pb and Ni exposure to the development of DM and metabolic disorders in a Pakistani population, emphasizing the need for strict regulations and preventive measures to reduce heavy metal contamination and safeguard public health. Future longitudinal studies and interventions are warranted to elucidate mechanistic links between heavy metal exposure and metabolic diseases.

The Cerebellum-Ventral Tegmental Area Microcircuit and Its Implications for Autism Spectrum Disorder: A Narrative Review.

The cerebellum has long been implicated in the etiopathogenesis of autism spectrum disorder (ASD), and emerging evidence suggests a significant contribution by reciprocal neural circuits between the cerebellum and ventral tegmental area (VTA) in symptom expression. This review provides a concise overview of morphological and functional alterations in the cerebellum and VTA associated with ASD symptoms, primarily focusing on human studies while also integrating mechanistic insights from animal models. We propose that cerebello-VTA circuit dysfunctional is a major contributor to ASD symptoms and that these circuits are promising targets for drugs and therapeutic brain stimulation methods.

Dietary protein intake and the tubular handling of indoxyl sulfate.

Chronic kidney disease (CKD) patients are advised to limit their protein intake. A high protein diet is known to induce glomerular hyperfiltration, as well as hypertrophy of the remnant kidney, and glomerulosclerosis. Whether the diet causes changes in kidney tubule transport via gut microbiome metabolites is still unknown. We hypothesized that protein intake affects not only the intestinal generation and absorption, but also the kidney disposal of microbial amino acid metabolites. We combined data from animal models and human studies. 5/6th nephrectomy rats were administered a high (HP) or low-protein (LP) diet for 7 weeks. Plasma and urine concentration of the uremic toxins (UTs) indoxyl sulfate (IS), p-cresyl sulfate (PCS), and p-cresyl glucuronide (PCG) were measured. Their fractional excretion (FE) was calculated. The expression of kidney membrane transporters OAT1, OAT3, BCRP, OCT2 and MRP4 was analyzed. Differences in FE of UTs between individuals with higher and lower protein intake in two CKD cohorts were sought. CKD rats on an HP diet showed increased plasma levels of PCS and PCG but not IS compared to rats on a LP diet. Conversely, urinary excretion and FE of IS were higher in the HP CKD group. BCRP, MRP4 and OCT2 were not influenced by the diet. OAT1 and OAT3 were upregulated in the HP CKD group. In two independent cohorts of CKD patients, individuals with a high dietary protein intake showed a significantly higher FE of IS. A HP diet leads to a higher generation and/or absorption of aminoacid-derived UT precursors in CKD rodent models and humans, most likely via gut microbiome modulation. We demonstrate that dietary protein intake modulates transcription and expression of OAT1 and OAT3, corroborating the existence of the remote sensing and signaling hypothesis. Dietary protein intake influences kidney physiology beyond glomerular filtration.