Forward genetics combined with unsupervised classifications identified zebrafish mutants affecting biliary system formation.

Impaired formation of the biliary network can lead to congenital cholestatic liver diseases; however, the genes responsible for proper biliary system formation and maintenance have not been fully identified. Combining computational network structure analysis algorithms with a zebrafish forward genetic screen, we identified 24 new zebrafish mutants that display impaired intrahepatic biliary network formation. Complementation tests suggested these 24 mutations affect 24 different genes. We applied unsupervised clustering algorithms to unbiasedly classify the recovered mutants into three classes. Further computational analysis revealed that each of the recovered mutations in these three classes has a unique phenotype on node-subtype composition and distribution within the intrahepatic biliary network. In addition, we found most of the recovered mutations are viable. In those mutant fish, which are already good animal models to study chronic cholestatic liver diseases, the biliary network phenotypes persist into adulthood. Altogether, this study provides unique genetic and computational toolsets that advance our understanding of the molecular pathways leading to biliary system malformation and cholestatic liver diseases.

Photodetector with a metalens packaging module for visible light communication based on RGBY illumination LED light source.

A novel, to the best of our knowledge, photodetector with a metalens packaging module used as the visible light communication (VLC) receiver is proposed and designed. An LED consisting of red, green, blue, and yellow chips (RGBY-LED) is adopted as the transmitter for intensity modulation direct detection VLC systems. A metalens array with a numerical aperture (NA) of 0.707 used as a polarization-insensitive planar lens of the VLC system receiver is designed at wavelengths of 457, 523, 592, and 623 nm corresponding to blue, green, yellow, and red for high efficiency. Compared with a traditional Fresnel lens positive-intrinsic-negative (PIN) photodetector module as the VLC receiver, the introduction of a metalens module can decrease the form factor of the VLC receiver module and, in particular, it is much thinner. The combination of the multi-color LED transmitter and photodetector metalens packaging module receiver can increase the modulation bandwidth due to four different wavelengths used for the VLC system. Finite-difference time domain (FDTD) simulations are performed to validate the performance of the photodetector with a metalens module. It is revealed that the corresponding efficiencies of 57.5%, 55.4%, 57%, and 56.3% were achieved at wavelengths of 623, 592, 523, and 457 nm, respectively, based on a metalens array with a 0.707 NA and 2.5 µm radius of the active area of the photodetector. It is a promising technology for indoor VLC systems such as those for smart phones and other Internet of Things devices due to the need for compact packaging for the receiver.

The Impact of Moderate or High-Intensity Combined Exercise on Systemic Inflammation Among Older Persons With and Without HIV.

BACKGROUND: We investigated whether higher-intensity exercise provided greater decrease in markers of inflammation, and whether responses differed by HIV serostatus. METHODS: People with HIV (PWH; n = 32) and controls (n = 37) aged 50-75 years completed 12 weeks moderate-intensity exercise, then were randomized to moderate- or high-intensity exercise for 12 additional weeks (n = 27 and 29, respectively). Inflammation biomarkers were measured at 0, 12, 24 weeks. Mixed and multiple regression models were adjusted for baseline inflammation, age, and body mass index. RESULTS: Baseline tumor necrosis factor-α (TNF-α), soluble TNF receptor 2 (sTNFR2), and soluble CD14 (sCD14) were significantly higher among PWH than controls (P < .04). From week 0-12, changes in interleukin-6 (IL-6), TNF-α, and sTNFR1 were not significantly different by HIV serostatus. We found no significant interaction between HIV serostatus/exercise intensity on week 12-24 changes in IL-6, TNF-α, and sTNFR1. Among high-intensity exercisers, PWH and controls had significant increases in sCD14 (P ≤ .003), controls significant increases in IL-10 (P = .01), and PWH nonsignificant decrease in highly sensitive C-reactive protein (P = .07). Other markers were not significantly different by serostatus or intensity. CONCLUSIONS: Moderate and high-intensity exercise elicited similar effects on inflammation among PWH and controls, with additional beneficial effects seen among high-intensity exercisers. Increase in sCD14 and attenuated IL-10 increase (PWH only) merit further study. CLINICAL TRIALS REGISTRATION: NCT02404792.

Synergistic function of doping and ligand engineering to enhance the photostability and electroluminescence performance of CsPbBr3quantum dots.

The photostability issue of CsPbX3(X = Cl, Br, I) quantum dots (QDs) is one of the key origins for the degradation of their luminescence performance, which hinders their application in lighting and displays. Herein, we report a new method combining doping and ligand engineering, which effectively improves the photostability of CsPbBr3QDs and the performance of QD light-emitting diodes (QLEDs). In this method, ZnBr2is doped into CsPbBr3QDs to reduce surface anion defects; didodecyldimethyl ammonium bromide (DDAB) and tetraoctylammonium bromide (TOAB) hybrid ligands, which have strong adsorption with QDs, are employed to protect the surface and enhance the conductivity of QD layer in QLEDs. The photoluminescence (PL) and transmission electron microscopy measurements prove the effectively improved photostability of CsPbX3QDs. Moreover, reduced defects and improved conductivity by doping and hybrid ligands treatment also enable the improved electroluminescence performance of CsPbX3QDs. The maximum luminance and external quantum efficiency of the QLED with optimized CsPbX3QDs are 3518.9 cd m-2and 5.07%, which are 3.6 and 2.1 times than that of the control device, respectively. Combining doping and hybrid ligands makes perovskite QDs have an extremely promising prospect in future applications of high-definition displays, high-quality lighting, as well as solar cells.

Predictive Capability of QSAR Models Based on the CompTox Zebrafish Embryo Assays: An Imbalanced Classification Problem.

The CompTox Chemistry Dashboard (ToxCast) contains one of the largest public databases on Zebrafish (Danio rerio) developmental toxicity. The data consists of 19 toxicological endpoints on unique 1018 compounds measured in relatively low concentration ranges. The endpoints are related to developmental effects occurring in dechorionated zebrafish embryos for 120 hours post fertilization and monitored via gross malformations and mortality. We report the predictive capability of 209 quantitative structure-activity relationship (QSAR) models developed by machine learning methods using penalization techniques and diverse model quality metrics to cope with the imbalanced endpoints. All these QSAR models were generated to test how the imbalanced classification (toxic or non-toxic) endpoints could be predicted regardless which of three algorithms is used: logistic regression, multi-layer perceptron, or random forests. Additionally, QSAR toxicity models are developed starting from sets of classical molecular descriptors, structural fingerprints and their combinations. Only 8 out of 209 models passed the 0.20 Matthew's correlation coefficient value defined a priori as a threshold for acceptable model quality on the test sets. The best models were obtained for endpoints mortality (MORT), ActivityScore and JAW (deformation). The low predictability of the QSAR model developed from the zebrafish embryotoxicity data in the database is mainly due to a higher sensitivity of 19 measurements of endpoints carried out on dechorionated embryos at low concentrations.

Inside Out: HIV, the Gut Microbiome, and the Mucosal Immune System.

The components of the human gut microbiome have been found to influence a broad array of pathologic conditions ranging from heart disease to diabetes and even to cancer. HIV infection upsets the delicate balance in the normal host-microbe interaction both through alterations in the taxonomic composition of gut microbial communities as well as through disruption of the normal host response mechanisms. In this article we review the current methods of gut microbiome analysis and the resulting data regarding how HIV infection might change the balance of commensal bacteria in the gut. Additionally, we cover the various effects gut microbes have on host immune homeostasis and the preliminary but intriguing data on how HIV disrupts those mechanisms. Finally, we briefly describe some of the important biomolecules produced by gut microbiota and the role that they may play in maintaining host immune homeostasis with and without HIV infection.

Clk1 deficiency promotes neuroinflammation and subsequent dopaminergic cell death through regulation of microglial metabolic reprogramming.

Clock (Clk)1/COQ7 is a mitochondrial hydroxylase that is necessary for the biosynthesis of ubiquinone (coenzyme Q or UQ). Here, we investigate the role of Clk1 in neuroinflammation and consequentially dopaminergic (DA) neuron survival. Reduced expression of Clk1 in microglia enhanced the LPS-induced proinflammatory response and promoted aerobic glycolysis. Inhibition of glycolysis abolished Clk1 deficiency-induced hypersensitivity to the inflammatory stimulation. Mechanistic studies demonstrated that mTOR/HIF-1α and ROS/HIF-1α signaling pathways were involved in Clk1 deficiency-induced aerobic glycolysis. The increase in neuronal cell death was observed following treatment with conditioned media from Clk1 deficient microglia. Increased DA neuron loss and microgliosis were observed in Clk1+/- mice after treatment with MPTP, a rodent model of Parkinson's disease (PD). This increase in DA neuron loss was due to an exacerbated microglial inflammatory response, rather than direct susceptibility of Clk1+/- DA cells to MPP+, the active species of MPTP. Exaggerated expressions of proinflammatory genes and loss of DA neurons were also observed in Clk1+/- mice after stereotaxic injection of LPS. Our results suggest that Clk1 regulates microglial metabolic reprogramming that is, in turn, involved in the neuroinflammatory processes and PD.

Cellular pregnenolone esterification by acyl-CoA:cholesterol acyltransferase.

Pregnenolone (PREG) can be converted to PREG esters (PE) by the plasma enzyme lecithin: cholesterol acyltransferase (LCAT), and by other enzyme(s) with unknown identity. Acyl-CoA:cholesterol acyltransferase 1 and 2 (ACAT1 and ACAT2) convert various sterols to steryl esters; their activities are activated by cholesterol. PREG is a sterol-like molecule, with 3-ß-hydroxy moiety at steroid ring A, but with much shorter side chain at steroid ring D. Here we show that without cholesterol, PREG is a poor ACAT substrate; with cholesterol, the V(max) for PREG esterification increases by 100-fold. The binding affinity of ACAT1 for PREG is 30-50-fold stronger than that for cholesterol; however, PREG is only a substrate but not an activator, while cholesterol is both a substrate and an activator. These results indicate that the sterol substrate site in ACAT1 does not involve significant sterol-phospholipid interaction, while the sterol activator site does. Studies utilizing small molecule ACAT inhibitors show that ACAT plays a key role in PREG esterification in various cell types examined. Mice lacking ACAT1 or ACAT2 do not have decreased PREG ester contents in adrenals, nor do they have altered levels of the three major secreted adrenal steroids in serum. Mice lacking LCAT have decreased levels of PREG esters in the adrenals. These results suggest LCAT along with ACAT1/ACAT2 contribute to control pregnenolone ester content in different cell types and tissues.

Leveraging electronic health records to identify risk factors for recurrent pregnancy loss across two medical centers: a case-control study.

Recurrent pregnancy loss (RPL), defined as 2 or more pregnancy losses, affects 5-6% of ever-pregnant individuals. Approximately half of these cases have no identifiable explanation. To generate hypotheses about RPL etiologies, we implemented a case-control study comparing the history of over 1,600 diagnoses between RPL and live-birth patients, leveraging the University of California San Francisco (UCSF) and Stanford University electronic health record databases. In total, our study included 8,496 RPL (UCSF: 3,840, Stanford: 4,656) and 53,278 Control (UCSF: 17,259, Stanford: 36,019) patients. Menstrual abnormalities and infertility-associated diagnoses were significantly positively associated with RPL in both medical centers. Age-stratified analysis revealed that the majority of RPL-associated diagnoses had higher odds ratios for patients <35 compared with 35+ patients. While Stanford results were sensitive to control for healthcare utilization, UCSF results were stable across analyses with and without utilization. Intersecting significant results between medical centers was an effective filter to identify associations that are robust across center-specific utilization patterns.

4-Piperidin-4-ylidenemethyl-benzamides as δ-opioid receptor agonists for CNS indications: identifying clinical candidates.

A series of 4-piperidin-4-ylidenemethyl-benzamide δ-opioid receptor agonists is described with an emphasis on balancing the potency, subtype selectivity and in vitro ADME and safety properties. The three sites impacting SAR are substitutions on the aryl group (R(1)), the piperidine nitrogen (R(2)), and the amide (R(3)). Each region contributes to the balance of properties for δ opioid activity and a desirable CNS profile, and two clinical candidates (20 and 24) were advanced.

Multiparameter exploration of piperazine derivatives as δ-opioid receptor agonists for CNS indications.

A novel series of piperazine derivatives exhibits sub-nanomolar binding and enhanced subtype selectivity as δ-opioid agonists. The synthesis and SAR are described as well as the application of computational models to improve in vitro ADME and safety properties suitable for CNS indications, specifically microsomal clearance, permeability, and hERG channel inhibition.

Descriptive analysis of Acute Ischemic stroke in COVID-19 patients through the course of the COVID-19 pandemic.

Coronavirus disease 2019 (COVID-19) has been associated with Acute Ischemic Stroke (AIS). Here, we characterize our institutional experience with management of COVID-19 and AIS. Baseline demographics, clinical, imaging, and outcomes data were determined in patients with COVID-19 and AIS presenting within March 2020 to October 2020, and November 2020 to August 2021, based on institutional COVID-19 hospitalization volume. Of 2512 COVID-19 patients, 35 (1.39%, mean age 63.3 years, 54% women) had AIS. AIS recognition was frequently delayed after COVID-19 symptoms (median 19.5 days). Four patients (11%) were on therapeutic anticoagulation at AIS recognition. AIS mechanism was undetermined or due to multiple etiologies in most cases (n = 20, 57%). Three patients underwent IV TPA, and three underwent mechanical thrombectomy, of which two suffered re-occlusion. Three patients had incomplete mRNA vaccination course. Fourteen (40%) died, with 26 (74%) having poor outcomes. Critical COVID-19 severity was associated with worsened mortality (p = 0.02). More patients (12/16; 75%) had either worsened or similar 3-month functional outcomes, than those with improvement, indicating the devastating impact of co-existing AIS and COVID-19. Comparative analysis showed that patients in the later cohort had earlier AIS presentation, fewer stroke risk factors, more comprehensive workup, more defined stroke mechanisms, less instance of critical COVID-19 severity, more utilization of IV TPA, and a trend towards worse outcomes for the sub-group of mild-to-moderate COVID-19 severity. AIS incidence, NIHSS, and overall outcomes were similar. Further studies should investigate outcomes beyond 3 months and their predictive factors, impact of completed vaccination course, and access to neurologic care.

Improving magnetic nanothermometry accuracy through mixing-frequency excitation.

This study proposes a temperature model for the relaxation of magnetic nanoparticles and a phase measurement method under a mixing-frequency excitation field, which can improve the accuracy of temperature measurements in magnetic nanothermometry. According to the Debye-based magnetization model for magnetic nanoparticles, phases at mixing frequencies are used to solve the problem of a delay in the relaxation phase of the magnetic field at a high frequency. This method can improve the signal-to-noise ratio of the response of the magnetic nanoparticles and weaken the phase shift of the detection coils caused by the changes in temperature. The results of experiments show that the proposed method can achieve static temperature measurement error less than 0.1 K and dynamic temperature measurement error less than 0.2 K.

An exercise intervention alters stool microbiota and metabolites among older, sedentary adults.

BACKGROUND: Physiologic aging has been associated with gut dysbiosis. Although short exercise interventions have been linked to beneficial changes in gut microbiota in younger adults, limited data are available from older populations. We hypothesized that exercise would produce beneficial shifts in microbiota and short-chain fatty acid (SCFA) levels in older persons. METHODS: Stool samples were collected before and at completion of a supervised 24-week cardiovascular and resistance exercise intervention among 50-75-year-old participants. SCFA levels were analyzed by gas chromatography and microbiome by 16S rRNA gene sequencing. Negative binomial regression models compared pre- and post-differences using false discovery rates for multiple comparison. RESULTS: A total of 22 participants provided pre-intervention samples; 15 provided samples at study completion. At baseline, the majority of participants were men (95%), mean age 58.0 (8.8) years, mean body mass index 27.4 (6.4) kg/m2. After 24 weeks of exercise, at the genus level, exercise was associated with significant increases in Bifidobacterium (and other unidentified genera within Bifidobacteriaceae), Oscillospira, Anaerostipes, and decreased Prevotella and Oribacterium (p < 0.001). Stool butyrate increased with exercise [5.44 (95% confidence interval 1.54, 9.24) mmol/g, p = 0.02], though no significant differences in acetate or propionate (p ⩾ 0.09) were seen. CONCLUSION: Our pilot study suggested that an exercise intervention is associated with changes in the microbiome of older adults and a key bacterial metabolite, butyrate. Although some of these changes could potentially reverse age-related dysbiosis, future studies are required to determine the contribution of changes to the microbiome in the beneficial effect of exercise on overall health of older adults. Clinical Trials NCT02404792.

Epidemiology of pediatric trauma in the Kingdom of Bahrain: a national pediatric trauma registry pilot study.

BACKGROUND: A pediatric trauma registry for the Kingdom of Bahrain would be a novel public health tool for the Bahraini health system. The aim of this study was to explore the epidemiology of pediatric trauma at the national level by describing the distribution of pediatric injury in the Kingdom, and quantifying the burden of injury shouldered by the study population. METHODS: This multicenter observational cross-sectional study was conducted in Bahrain using data from the Pediatric Trauma Registry (PTR), which was a short-term paper-based prospective trauma registry that collected data over a three-month period in 2018. PTR was based in the pediatric emergency departments (ED) of the three national referral hospitals in the Kingdom. By simultaneously collecting data from all three trauma hospitals in the country, it was assumed that during the data collection period all major pediatric trauma patients in the country would be captured by the study, and that the data collected would provide national estimates of trauma. Inclusion criteria for the study was any individual under the age of 14, that arrived at the ED seeking care for intentional and unintentional injuries. RESULTS: A total of 1328 patients were included in the study. Sixty-nine percent of patients were treated and discharged from the ED, 30.5% were admitted to the hospital, admitted for surgery, or seen by a specialist, and 0.5% were declared deceased. The percentage of patients documented as unrestrained during Motor Vehicle Collisions (MVC) was 92.3%, and amongst those involved in MVC, 12% were ejected from the cabin of the vehicle. CONCLUSIONS: There are significant implications that this study holds for policy implementation and practice surrounding injury prevention in the Kingdom of Bahrain. Low seatbelt utilization and the high proportion of ejection amongst MVC victims warrant immediate public health policy implementation, including enforcement of seat belt laws, strengthening of the traffic court system, and awareness campaigns for MVC prevention. Additionally, pediatric drowning prevention programs centered on constant adult supervision, pool isolation fencing, personal flotation devices, and swimming education should be created to address the mortality attributable to drowning in this study.

A Unique Gut Microbiome-Physical Function Axis Exists in Older People with HIV: An Exploratory Study.

Impairments in physical function and increased systemic levels of inflammation have been observed in middle-aged and older persons with HIV (PWH). We previously demonstrated that in older persons, associations between gut microbiota and inflammation differed by HIV serostatus. To determine whether relationships between the gut microbiome and physical function measurements would also be distinct between older persons with and without HIV, we reanalyzed existing gut microbiome and short chain fatty acid (SCFA) data in conjunction with previously collected measurements of physical function and body composition from the same cohorts of older (51-74 years), nonfrail PWH receiving effective antiretroviral therapy (N = 14) and age-balanced uninfected controls (N = 22). Associations between relative abundance (RA) of the most abundant bacterial taxa or stool SCFA levels with physical function and body composition were tested using HIV-adjusted linear regression models. In older PWH, but not in controls, greater RA of Alistipes, Escherichia, Prevotella, Megasphaera, and Subdoligranulum were associated with reduced lower extremity muscle function, decreased lean mass, or lower Short Physical Performance Battery (SPPB) scores. Conversely, greater RA of Dorea, Coprococcus, and Phascolarctobacterium in older PWH were associated with better muscle function, lean mass, and SPPB scores. Higher levels of the SCFA butyrate associated with increased grip strength in both PWH and controls. Our findings indicate that in older PWH, both negative and positive associations exist between stool microbiota abundance and physical function. Different relationships were observed in older uninfected persons, suggesting features of a unique gut-physical function axis in PWH.

Rabaptin-5-independent membrane targeting and Rab5 activation by Rabex-5 in the cell.

Rabex-5 is a guanine nucleotide exchange factor (GEF) for Rab5. Here, we report the identification of a novel functional domain of Rabex-5 that is essential for its membrane targeting and Rab5 GEF activity in vivo. The data show that full-length Rabex-5 efficiently activates Rab5 in the cell. However, the GEF domain itself (residues 135-399) is inactive in this respect, despite its activity in vitro. Generation and characterization of a series of Rabex-5 constructs reveal that the GEF domain is unable to target to early endosomes and that a sequence N-terminal to the GEF domain can restore its early endosomal targeting and its ability to activate Rab5 in the cell. This region (residues 81-135) is termed membrane-binding motif, which together with the downstream helical bundle domain (residues 135-230) forms an early endosomal targeting (EET) domain necessary and sufficient for association with early endosomes. Furthermore, several active Rabex-5 constructs do not contain the Rabaptin-5-binding domain in the C-terminal region. Thus, Rabex-5 can target to early endosomes via the EET domain and activate Rab5 in a Rabaptin-5-independent manner in vivo. We discuss a model to reconcile these in vivo data with previous in vitro results on Rabex-5 function and its interaction with Rabaptin-5.

Nerve growth factor-mediated neurite outgrowth via regulation of Rab5.

Nerve growth factor (NGF) induces neurite outgrowth and differentiation in a process that involves NGF binding to its receptor TrkA and endocytosis of the NGF-TrkA complex into signaling endosomes. Here, we find that biogenesis of signaling endosomes requires inactivation of Rab5 to block early endosome fusion. Expression of dominant-negative Rab5 mutants enhanced NGF-mediated neurite outgrowth, whereas a constitutively active Rab5 mutant or Rabex-5 inhibited this process. Consistently, inactivation of Rab5 sustained TrkA activation on the endosomes. Furthermore, NGF treatment rapidly decreased cellular level of active Rab5-GTP, as shown by pull-down assays. This Rab5 down-regulation was mediated by RabGAP5, which was shown to associate with TrkA by coimmunoprecipitation assays. Importantly, RNA interference of RabGAP5 as well as a RabGAP5 truncation mutant containing the TrkA-binding domain blocked NGF-mediated neurite outgrowth, indicating a requirement for RabGAP5 in this process. Thus, NGF signaling down-regulates Rab5 activity via RabGAP5 to facilitate neurite outgrowth and differentiation.

Maintaining critical infrastructure resilience to natural hazards during the COVID-19 pandemic: hurricane preparations by US energy companies.

The COVID-19 pandemic has the potential to compromise the ability of critical infrastructure utilities to respond to or mitigate natural hazards like wildfires and hurricanes. This article describes the ways that an energy organization, the regional transmission operator PJM, is preparing for hurricanes during the COVID-19 pandemic. PJM is using a combination of technological and organizational processes to prepare for hurricanes during the pandemic. Activities include the development of a third control room to increase redundancy and maintaining social distance at control center, investment in more resilient communications technology to maintain connectivity, and taking a holistic approach to identifying issues related to supply chain and fuel security. With this mix of organizational and technological processes, we argue that critical infrastructure resilience should be understood as a sociotechnical construct and identify several recommendations for improving resilience. The article has implications for policymakers working to maintain infrastructure resilience to natural hazards during the COVID-19 pandemic.

Efficient and Stable CdSe/CdS/ZnS Quantum Rods-in-Matrix Assembly for White LED Application.

CdSe/CdS core-shell quantum rods (QRs) are a promising prospect in optoelectronic applications but usually have a relatively low quantum efficiency and stability. Here, we report on an efficient and stable CdSe/CdS/ZnS QRs-in-matrix assembly (QRAs) by growing and embedding CdSe/CdS QRs in ZnS matrices. Structural characterizations show that the CdSe/CdS QRs are encapsulated and interconnected by ZnS in the QRAs structure. The stable ZnS encapsulation renders the CdSe/CdS QRs high quantum efficiency (QE) up to 85%. The QRAs also present high photo- and thermal-stability and can preserve 93% of the initial QE at 100 °C. The QRAs powder presents a light degradation of only 2% under continuous excitation for 100 h, displaying profound potential in optoelectronic applications. White light-emitting diodes (WLEDs) are fabricated by packaging the QRAs powder as phosphor on top of blue GaN chip. The WLED shows high optical performance and light quality.