Phase 2 Trial of Baxdrostat for Treatment-Resistant Hypertension.

BACKGROUND: Aldosterone synthase controls the synthesis of aldosterone and has been a pharmacologic target for the treatment of hypertension for several decades. Selective inhibition of aldosterone synthase is essential but difficult to achieve because cortisol synthesis is catalyzed by another enzyme that shares 93% sequence similarity with aldosterone synthase. In preclinical and phase 1 studies, baxdrostat had 100:1 selectivity for enzyme inhibition, and baxdrostat at several dose levels reduced plasma aldosterone levels but not cortisol levels. METHODS: In this multicenter, placebo-controlled trial, we randomly assigned patients who had treatment-resistant hypertension, with blood pressure of 130/80 mm Hg or higher, and who were receiving stable doses of at least three antihypertensive agents, including a diuretic, to receive baxdrostat (0.5 mg, 1 mg, or 2 mg) once daily for 12 weeks or placebo. The primary end point was the change in systolic blood pressure from baseline to week 12 in each baxdrostat group as compared with the placebo group. RESULTS: A total of 248 patients completed the trial. Dose-dependent changes in systolic blood pressure of -20.3 mm Hg, -17.5 mm Hg, -12.1 mm Hg, and -9.4 mm Hg were observed in the 2-mg, 1-mg, 0.5-mg, and placebo groups, respectively. The difference in the change in systolic blood pressure between the 2-mg group and the placebo group was -11.0 mm Hg (95% confidence interval [CI], -16.4 to -5.5; P<0.001), and the difference in this change between the 1-mg group and the placebo group was -8.1 mm Hg (95% CI, -13.5 to -2.8; P = 0.003). No deaths occurred during the trial, no serious adverse events were attributed by the investigators to baxdrostat, and there were no instances of adrenocortical insufficiency. Baxdrostat-related increases in the potassium level to 6.0 mmol per liter or greater occurred in 2 patients, but these increases did not recur after withdrawal and reinitiation of the drug. CONCLUSIONS: Patients with treatment-resistant hypertension who received baxdrostat had dose-related reductions in blood pressure. (Funded by CinCor Pharma; BrigHTN ClinicalTrials.gov number, NCT04519658.).

Early-stage use of hearing aids preserves auditory cortical structure in children with sensorineural hearing loss.

Hearing is critical to spoken language, cognitive, and social development. Little is known about how early auditory experiences impact the brain structure of children with bilateral sensorineural hearing loss. This study examined the influence of hearing aid use and residual hearing on the auditory cortex of children with severe to profound congenital sensorineural hearing loss. We evaluated cortical preservation in 103 young pediatric cochlear implant candidates (55 females and 48 males) by comparing their multivoxel pattern similarity of auditory cortical structure with that of 78 age-matched children with typical hearing. The results demonstrated that early-stage hearing aid use preserved the auditory cortex of children with bilateral congenital sensorineural hearing loss. Children with less residual hearing experienced a more pronounced advantage from hearing aid use. However, this beneficial effect gradually diminished after 17 months of hearing aid use. These findings support timely fitting of hearing aids in conjunction with early implantation to take advantage of neural preservation to maximize auditory and spoken language development.

Quantification of MicroRNA in a Single Living Cell via Ionic Current Rectification-Based Nanopore for Triple Negative Breast Cancer Diagnosis.

Accurate analysis of microRNAs (miRNAs) at the single-cell level is extremely important for deeply understanding their multiple and intricate biological functions. Despite some advancements in analyzing single-cell miRNAs, challenges such as intracellular interferences and insufficient detection limits still remain. In this work, an ultrasensitive nanopore sensor for quantitative single-cell miRNA-155 detection is constructed based on ionic current rectification (ICR) coupled with enzyme-free catalytic hairpin assembly (CHA). Benefiting from the enzyme-free CHA amplification strategy, the detection limit of the nanopore sensor for miRNA-155 reaches 10 fM and the nanopore sensor is more adaptable to complex intracellular environments. With the nanopore sensor, the concentration of miRNA-155 in living single cells is quantified to realize the early diagnosis of triple-negative breast cancer (TNBC). Furthermore, the nanopore sensor can be applied in screening anticancer drugs by tracking the expression level of miRNA-155. This work provides an adaptive and universal method for quantitatively analyzing intracellular miRNAs, which will greatly improve our understanding of cell heterogeneity and provide a more reliable scientific basis for exploring major diseases at the single-cell level.

Meta-analysis of risk of major adverse cardiovascular events in adults with type 2 diabetes treated with bexagliflozin.

AIM: To explore the risk of major adverse cardiovascular events (MACE) associated with exposure to bexagliflozin. METHODS: The analysis included 4090 participants with type 2 diabetes (T2D) enrolled in nine phase 2 and 3 double-blind randomized controlled trials. All potential MACE were adjudicated by a blinded committee. The primary endpoint for the meta-analysis was the hazard ratio (HR) for the time to first occurrence of non-fatal stroke, non-fatal myocardial infarction (MI), cardiovascular (CV) death or hospitalization for unstable angina (MACE+), tested for non-inferiority to a ratio of 1.8. The secondary endpoints were time to first occurrence of (i) non-fatal stroke, non-fatal MI or CV death (MACE), tested for non-inferiority to a ratio of 1.3; and (ii) CV death or hospitalization for heart failure, tested for superiority. RESULTS: The HR for the primary endpoint of MACE+ was 0.80 (95% confidence interval [CI] 0.58, 1.09), which fulfilled the non-inferiority objective with a P value of less than 0.0001. Non-inferiority for the first key secondary endpoint of MACE was also shown (HR = 0.82; 95% CI 0.59, 1.13; P = 0.0023). Superiority for time to CV death or first hospitalization for heart failure was not shown. CONCLUSIONS: Bexagliflozin did not increase the risk of MACE in participants with T2D when compared with placebo or active control. Both the preapproval and postapproval thresholds for CV safety were met and bexagliflozin has been approved by the US Food and Drug Administration.

Synthesis and evaluation of febrifugine derivatives as anticoccidial agents.

A series of new febrifugine derivatives with a 4(3H)-quinazolinone scaffold were synthesized and evaluated for their anticoccidial activity both in vitro and in vivo. The targets' in vitro activity against Eimeria tenella was studied using quantitative real-time reverse transcription polymerase chain reaction and Madin-Darby bovine kidney cells. Most of these compounds demonstrated anticoccidial efficacy, with inhibition ratios ranging from 3.3% to 85.7%. Specifically, compounds 33 and 34 showed significant inhibitory effects on the proliferation of E. tenella and exhibited lower cytotoxicity compared to febrifugine. The IC50 values of compounds 33 and 34 were 3.48 and 1.79 µM, respectively, while the CC50 values were >100 µM for both compounds. Furthermore, in a study involving 14-day-old chickens infected with 5 × 104 sporulated oocysts, treatment with five selected compounds (22, 24, 28, 33, and 34), which exhibited in vitro inhibition rate of over 50% at 100 µM, at a dose of 40 mg/kg in daily feed for 8 consecutive days showed that compound 34 possessed moderate in vivo activity against coccidiosis, with an anticoccidial index of 164. Structure-activity relationship studies suggested that spirocyclic piperidine may be a preferable substructure to maintain high effectiveness in inhibiting Eimeria spp., when the side chain 1-(3-hydroxypiperidin-2-yl)propan-2-one was replaced.

Efficacy of Tocilizumab in Patients Hospitalized with Covid-19.

BACKGROUND: The efficacy of interleukin-6 receptor blockade in hospitalized patients with coronavirus disease 2019 (Covid-19) who are not receiving mechanical ventilation is unclear. METHODS: We performed a randomized, double-blind, placebo-controlled trial involving patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, hyperinflammatory states, and at least two of the following signs: fever (body temperature >38°C), pulmonary infiltrates, or the need for supplemental oxygen in order to maintain an oxygen saturation greater than 92%. Patients were randomly assigned in a 2:1 ratio to receive standard care plus a single dose of either tocilizumab (8 mg per kilogram of body weight) or placebo. The primary outcome was intubation or death, assessed in a time-to-event analysis. The secondary efficacy outcomes were clinical worsening and discontinuation of supplemental oxygen among patients who had been receiving it at baseline, both assessed in time-to-event analyses. RESULTS: We enrolled 243 patients; 141 (58%) were men, and 102 (42%) were women. The median age was 59.8 years (range, 21.7 to 85.4), and 45% of the patients were Hispanic or Latino. The hazard ratio for intubation or death in the tocilizumab group as compared with the placebo group was 0.83 (95% confidence interval [CI], 0.38 to 1.81; P = 0.64), and the hazard ratio for disease worsening was 1.11 (95% CI, 0.59 to 2.10; P = 0.73). At 14 days, 18.0% of the patients in the tocilizumab group and 14.9% of the patients in the placebo group had had worsening of disease. The median time to discontinuation of supplemental oxygen was 5.0 days (95% CI, 3.8 to 7.6) in the tocilizumab group and 4.9 days (95% CI, 3.8 to 7.8) in the placebo group (P = 0.69). At 14 days, 24.6% of the patients in the tocilizumab group and 21.2% of the patients in the placebo group were still receiving supplemental oxygen. Patients who received tocilizumab had fewer serious infections than patients who received placebo. CONCLUSIONS: Tocilizumab was not effective for preventing intubation or death in moderately ill hospitalized patients with Covid-19. Some benefit or harm cannot be ruled out, however, because the confidence intervals for efficacy comparisons were wide. (Funded by Genentech; ClinicalTrials.gov number, NCT04356937.).

Bexagliflozin as an adjunct to metformin for the treatment of type 2 diabetes in adults: A 24-week, randomized, double-blind, placebo-controlled trial.

AIM: To evaluate the relative safety and effectiveness of bexagliflozin as an adjunct to metformin for the treatment of type 2 diabetes mellitus. METHODS: In total, 317 participants were randomized to receive bexagliflozin or placebo plus metformin. The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline to week 24, with secondary endpoints for systolic blood pressure (SBP), fasting plasma glucose and weight loss. An open label arm enrolled participants with HbA1c >10.5% and was analysed separately. RESULTS: The mean change in HbA1c was -1.09% (95% CI -1.24%, -0.94%) in the bexagliflozin arm and -0.56% (-0.71%, -0.41%) in the placebo arm, a difference of -0.53% (-0.74%, -0.32%; p < .0001). Excluding observations after rescue medication, the intergroup difference was -0.70% (-0.92, -0.48; p < .0001). The open label group change in HbA1c was -2.82% (-3.23%, -2.41%). Placebo-adjusted changes from baseline SBP, fasting plasma glucose and body mass were -7.07 mmHg (-9.83, -4.32; p < .0001), -1.35 mmol/L (-1.83, -0.86; p < .0001) and -2.51 kg (-3.45, -1.57; p < .0001). Adverse events affected 42.4% and 47.2% of subjects in the bexagliflozin and placebo arms, respectively; fewer subjects in the bexagliflozin arm experienced serious adverse events. CONCLUSIONS: Bexagliflozin produced clinically meaningful improvement in glycaemic control, estimated glomerular filtration rate and SBP when added to metformin in a population of adults with diabetes.

A 96-week, double-blind, randomized controlled trial comparing bexagliflozin to glimepiride as an adjunct to metformin for the treatment of type 2 diabetes in adults.

AIM: To compare the effects of bexagliflozin tablets 20 mg, with those of optimally titrated glimepiride when used to treat adults with type 2 diabetes mellitus (T2DM) inadequately controlled by metformin. METHODS: Adults with type 2 diabetes (n = 426) taking metformin, and with a glycated haemoglobin (HbA1c) level between 53 and 91 mmol/mol [7.0% and 10.5%], were randomized to receive bexagliflozin tablets 20 mg or titrated glimepiride. The primary endpoint was the intergroup difference in the change from baseline to Week 60 in percent HbA1c. Secondary endpoints included changes from baseline in body mass and systolic blood pressure (SBP), and proportion of subjects experiencing severe or documented symptomatic hypoglycaemia. RESULTS: The intergroup difference in percent HbA1c (bexagliflozin minus glimepiride) from baseline to Week 60 was -0.55 mmol/mol (95% confidence interval [CI] -2.30, 1.20)-[-0.05% (-0.21, 0.11)], establishing noninferiority of bexagliflozin to glimepiride by the prespecified margin of 3.83 mmol/mol [0.35%]. Prespecified tests gave, in order, a difference in body mass of -4.31 kg (95% CI -5.10, -3.52; P < 0.0001), a difference in SBP of -6.53 mm Hg (95% CI -10.56, -2.51; P = 0.0008), and an odds ratio of 0.12 (95% CI 0.05, 0.28; P < 0.0001) for severe or documented symptomatic hypoglycaemia. At the follow-up visit the mean difference in estimated glomerular filtration rate (eGFR) between arms was 6.05 mL min-1 per 1.73 m2 (95% CI, 3.24, 8.87; P < 0.0001). CONCLUSIONS: Bexagliflozin was noninferior to glimepiride in lowering HbA1c, was superior to glimepiride for decreases in body mass and SBP, and was associated with significantly fewer hypoglycaemic events than glimepiride. A favourable effect on eGFR was observed.

The charge effects on the hydrogen evolution reaction activity of the defected monolayer MoS2.

Doping engineering has proven to be an effective way to tune the hydrogen evolution reaction (HER) activity of MoS2. Introducing these defects could cause the overall charge imbalance of MoS2, which makes MoS2 charged. In order to understand the effect of charge on the HER activity of the defected MoS2, we systematically investigate the formation energies, hydrogen adsorption Gibbs free energy (), and electronic structures of 3d, 4d, and 5d transition metal (TM) doped monolayer MoS2 with S vacancies (Svac) based on the density functional theory (DFT) calculations. According to the formation energy calculation, Svac in the 0 and -1 charge states (S0vac and Svac1-) is found to be stable. of Svac1- is -0.16 eV, suggesting its HER catalytic activity is lower than that of Pt (), which is consistent with the experimental results. By substituting the Mo atom with TM atoms, we found that the TM atoms in groups VB-VIIB can promote the generation of Svac, forming defect complexes (TMMoSvac). is greatly affected by the charge state of defects; TMMoSvac defects (TM = V, Nb, Ta, Cr, W, Mn, and Re) in -1 charge states exhibited excellent HER activity (). Significantly, W and Re doping can promote the HER activity of MoS2 independent of the charge state and the Fermi level, which suggests that W and Re doping are most beneficial to improve the HER activity of MoS2. Therefore, the HER activity of defected MoS2 is not only influenced by as previously thought, but also by formation energies, charge state and Fermi level position of defects. The underlying physics could be deduced from the charge-induced changes in electronic structures. Our work highlights the defect charge effects on the electrochemical reactions and offers plausible mechanisms of defect charge effects.

The Design of a Low-Noise, High-Speed Readout-Integrated Circuit for Infrared Focal Plane Arrays.

This paper describes the design of a low-noise, high-speed readout-integrated circuit for use in InGaAs infrared focal plane arrays, and analyzes the working principle and noise index of the pixel circuit in detail. The design fully considers the dynamic range, noise, and power consumption of the pixel circuit in which a capacitance transimpedance amplifier structure is adopted as the input stage circuit, and chip fabrication via an XFAB 0.18 µm CMOS process is successfully realized. The ROIC adopts monolithic integration and implements various functions, such as windowing, subsampling, and different integration and readout modes. The ROIC reached an array scale of 32 × 32, a frame rate of 100 Hz, and a readout rate of 20 Mbps with an analog power consumption of less than 52 mW. The measurement results show that the input reference noise can be reduced to 143 e- via the CDS, and the fully customized scheme has certain advantages in the research of high-performance ROICs.

Effect of Mg-Modified Waste Straw Biochar on the Chemical and Biological Properties of Acidic Soils.

Biochar is important for soil improvement, fertilizer innovation, and greenhouse gas reduction. In this paper, Mg-modified biochar was prepared from rice and corn straw and mixed with soil at a 1% (w/w) addition in an indoor soil simulation experiment to study the effect of Mg-modified biochar on the chemical properties of acidic soil. The results showed that the addition of Mg-modified biochar reduced soil acidity and improved soil fertility. Compared with the control group, the Mg-modified biochar treatment significantly increased the concentrations of available potassium, available phosphorus, total phosphorus, organic carbon and exchangeable calcium and magnesium in the soil, and effectively increased the concentration of total nitrogen. Rice straw Mg-modified biochar treatment was more effective in increasing the soil-available potassium, available phosphorus, total phosphorus and exchangeable magnesium concentration, while corn straw Mg-modified biochar was more effective in increasing the soil organic carbon and exchangeable calcium concentration. In addition, the high pyrolysis temperature of Mg-modified biochar was more effective in promoting the soil-available potassium, available phosphorus and total nitrogen concentration, while the low pyrolysis temperature of Mg-modified biochar was more effective in promoting soil alkaline nitrogen, exchangeable calcium and magnesium.

Dual-Channel Recognition of Human Serum Albumin and Glutathione by Fluorescent Probes with Site-Dependent Responsive Features.

Design of chemical probes with high specificity and responses are particularly intriguing. In this work, a fluorescent probe (M-OH-SO3) with dual-channel spectral responses toward human serum albumin (HSA) is presented. By employing dinitrobenzenesulfonate as a recognition site as well as a fluorescence quencher, probe M-OH-SO3 displayed weak fluorescence, which, nevertheless, exhibits extensive yellow (575 nm) and red (660 nm) fluorescence emissions toward HSA under excitations at 400 and 500 nm, respectively. Interestingly, M-OH-SO3 displayed the best performance toward HSA with distinctly higher selectivity than that of its counterparts M-SO3, M-H-SO3, and M-F-SO3, which were prepared simply by modulating the functional group at the ortho position of the dicyanoisophorone core. Molecular docking results revealed that M-OH-SO3 possesses the lowest binding energy among the tested derivatives and accordingly the strongest binding affinity. Probe M-OH-SO3 showed a good linear relationship toward HSA in a range of 0.5-18 µM with a limit of detection of 35 nM. Cell imaging results demonstrated that probe M-OH-SO3 could visualize the variation HSA levels in hepatocarcinoma cells. In addition, probe M-OH-SO3 could also be employed for the recognition of glutathione through the cleavage of the dinitrobenzenesulfonate group along with an enhancement of emission at 575 nm. The site-dependent properties inspired a novel paradigm for design of fluorescent probes with optimized selectivity and responses.

Detection of Matrix Metalloproteinase-1 in Human Saliva Based on a Pregnancy Test Strip Platform.

Matrix metalloproteinase (MMP) is closely correlated with tumorigenesis and progression. Establishing a low-cost, simple, rapid, and sensitive method for its detection is highly desired for the broad-spectrum screening of oral cancer. Herein, we combine the MMP-specific cleavage ability with magnetic separation technology and a commercial test strip to construct a sensitive biosensor to detect MMP-1 conveniently for the first time. The method involves two DNA probes, peptide-DNA1 and hCG-DNA2, where DNA1 and DNA2 are complementary sequences, and the peptide labeled with biotin can bind streptavidin-modified magnetic nanoparticles stably. The human chorionic gonadotropin (hCG) is the target of the pregnancy test strip. The cleavage reaction mediated by MMP-1 releases peptide-DNA1 and the hybridized hCG-DNA2 into the solution, and the hCG probe in the solution can develop color on the test strip for the determination of MMP-1 after magnetic separation. This method utilizes the high specificity of MMP-1's proteolytic cleavage and the high sensitivity of the test strip to the target probe, achieving a sensitive detection of MMP-1 with a visual detection limit of 65.5 pg/mL. The method shows better anti-interference and sensitivity than the enzyme-linked immunosorbent assay in the application of a biological sample matrix, suggesting its great potential for clinical diagnosis, especially for broad-spectrum oral cancer screening.

Myeloarchitectonic plasticity in elite golf players' brains.

Human neuroimaging studies have demonstrated that exercise influences the cortical structural plasticity as indexed by gray or white matter volume. It remains elusive, however, whether exercise affects cortical changes at the finer-grained myelination structure level. To answer this question, we scanned 28 elite golf players in comparison with control participants, using a novel neuroimaging technique-quantitative magnetic resonance imaging (qMRI). The data showed myeloarchitectonic plasticity in the left temporal pole of the golf players: the microstructure of this brain region of the golf players was better proliferated than that of control participants. In addition, this myeloarchitectonic plasticity was positively related to golfing proficiency. Our study has manifested that myeloarchitectonic plasticity could be induced by exercise, and thus, shed light on the potential benefits of exercise on brain health and cognitive enhancement.

A simple fluorescent strategy for liver capillary labeling with carbon quantum dot-lectin nanoprobe.

Taking the hepatic sinusoid (HS) as the main delivery area of liver nutrients and metabolic waste, recognizing its structure is important for a deep understanding of liver function. In this paper, based on lycopersicon esculentum lectin (LEL), with targeting ability for endothelial cells, and carbon quantum dots (CQDs), with high biosafety, an LEL-coupled CQD immunofluorescence probe (CQD@LEL) that can label microvessels is designed and used for the fluorescence labeling and imaging of HS in liver tissue sections. The CQD size is approximately 2 nm. Blue fluorescence is emitted under excitation; its optimal excitation wavelength is 400 nm while the emission is at about 450 nm. Gel electrophoresis and capillary electrophoresis confirm that glutaraldehyde can couple LEL to CQD, and the obtained CQD@LEL retains the fluorescence property and has good stability. Optimization experiments show that its labeling effect is positively correlated with time and probe concentration for dyeing the blood vessels of mouse liver slices. In order to improve the effect further, a probe concentration of 0.17 mg mL-1 and incubation time of 3 h were chosen to label the liver tissue sections. The results show that the liver microvessels are formed by interstitial structures among the hepatic cords, and the HS presents a granular or patchy appearance. H&E and ultrathin section TEM show that the microvascular wall of the liver is composed of discontinuous endothelial cells, and there are Kupffer cells and other cells in the tubes, proving that our probe can clearly label the structure and morphology of liver microvessels. This work is of great significance for the visualization of HS.

Controlled release of metal phenolic network protected phage for treating bacterial infection.

Phage is a promising therapeutic agent for treating antibiotic resistant bacteria. However, in the process of treatment, phage may be cleared by the immune system and cleaved by protease, which could affect the efficacy of phage. In order to solve the above problems, phage encapsulation is usually adopted. In this study, we employed metal phenolic network (MPN) for efficient phage encapsulation which could protect phage from the cleavage of protease, and keep cytotoxicity weak. In the model of skin wound infection, the encapsulated phage could be released in response to pH change to achieve good antibacterial effect. Furthermore, the MPN encapsulation could prolong the T4 phage residence time at the wound. Our findings suggest that MPN can be a promising material for phage encapsulation.

Bile acid and receptors: biology and drug discovery for nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD), a series of liver metabolic disorders manifested by lipid accumulation within hepatocytes, has become the primary cause of chronic liver diseases worldwide. About 20%-30% of NAFLD patients advance to nonalcoholic steatohepatitis (NASH), along with cell death, inflammation response and fibrogenesis. The pathogenesis of NASH is complex and its development is strongly related to multiple metabolic disorders (e.g. obesity, type 2 diabetes and cardiovascular diseases). The clinical outcomes include liver failure and hepatocellular cancer. There is no FDA-approved NASH drug so far, and thus effective therapeutics are urgently needed. Bile acids are synthesized in hepatocytes, transported into the intestine, metabolized by gut bacteria and recirculated back to the liver by the enterohepatic system. They exert pleiotropic roles in the absorption of fats and regulation of metabolism. Studies on the relevance of bile acid disturbance with NASH render it as an etiological factor in NASH pathogenesis. Recent findings on the functional identification of bile acid receptors have led to a further understanding of the pathophysiology of NASH such as metabolic dysregulation and inflammation, and bile acid receptors are recognized as attractive targets for NASH treatment. In this review, we summarize the current knowledge on the role of bile acids and the receptors in the development of NAFLD and NASH, especially the functions of farnesoid X receptor (FXR) in different tissues including liver and intestine. The progress in the development of bile acid and its receptors-based drugs for the treatment of NASH including bile acid analogs and non-bile acid modulators on bile acid metabolism is also discussed.

Myeloarchitectonic Asymmetries of Language Regions in the Human Brain.

One prominent theory in neuroscience and psychology assumes that cortical regions for language are left hemisphere lateralized in the human brain. In the current study, we used a novel technique, quantitative magnetic resonance imaging (qMRI), to examine interhemispheric asymmetries in language regions in terms of macromolecular tissue volume (MTV) and quantitative longitudinal relaxation time (T1) maps in the living human brain. These two measures are known to reflect cortical myeloarchitecture from the microstructural perspective. One hundred and fifteen adults (55 male, 60 female) were examined for their myeloarchitectonic asymmetries of language regions. We found that the cortical myeloarchitecture of inferior frontal areas including the pars opercularis, pars triangularis, and pars orbitalis is left lateralized, while that of the middle temporal gyrus, Heschl's gyrus, and planum temporale is right lateralized. Moreover, the leftward lateralization of myelination structure is significantly correlated with language skills measured by phonemic and speech tone awareness. This study reveals for the first time a mixed pattern of myeloarchitectonic asymmetries, which calls for a general theory to accommodate the full complexity of principles underlying human hemispheric specialization.

Serum-derived exosomes from SD rats induce inflammation in macrophages through the mTOR pathway.

Inhalation of beryllium and its compounds can cause lung injuries, resulting from inflammation and oxidative stress. Multivesicular bodies (MVB), such as exosomes, are membrane vesicles produced by early and late endosomes that mediate intercellular communications. However, the role of exosomes in beryllium toxicity has not been elucidated. This current study aimed to investigate the functional role of exosomes in lung injury resulting from beryllium sulfate (BeSO4 ). Here, Sprague-Dawley (SD) rats were exposed to 4, 8, and 12 mg/kg BeSO4 by nonexposed intratracheal instillation. Murine macrophage (RAW 264.7) cells were pretreated with 50 nmol/L rapamycin (an mTOR signaling pathway inhibitor) for 30 min and then cultured for 24 h with 100 µg/mL exosomes, which had been previously isolated from the serum of 12 mg/kg BeSO4 -treated SD rats. Compared with those of the controls, exposure to BeSO4 in vivo increased LDH activity, elevated levels of inflammatory cytokines (IL-10, TNF-α, and IFN-γ) alongside inflammation-related proteins expression (COX-2 and iNOS), and enhanced secretion of exosomes from the SD rat's serum. Moreover, the BeSO4 -Exos-induced upregulation of LDH activity and inflammatory responses in RAW 264.7 cells can be alleviated following pretreatment with rapamycin. Collectively, these results suggest that serum exosomes play an important role in pulmonary inflammation induced by BeSO4 in RAW 264.7 cells via the mTOR pathway.

Hydrogen sulfide alleviates apoptosis and autophagy induced by beryllium sulfate in 16HBE cells.

Beryllium and its compounds are systemic toxicants that are widely applied in many industries. Hydrogen sulfide has been found to protect cells. The present study aimed to determine the protective mechanisms involved in hydrogen sulfide treatment of 16HBE cells following beryllium sulfate-induced injury. 16HBE cells were treated with beryllium sulfate doses ranging between 0 and 300 µM BeSO4 . Additionally, 16HBE cells were subjected to pretreatment with either a 300 µM dose of sodium hydrosulfide (a hydrogen sulfide donor) or 10 mM DL-propargylglycine (a cystathionine-γ-lyase inhibitor) for 6 hr before then being treated with 150 µM beryllium sulfate for 48 hr. This study illustrates that beryllium sulfate induces a reduction in cell viability, increases lactate dehydrogenase (LDH) release, and increases cellular apoptosis and autophagy in 16HBE cells. Interestingly, pretreating 16HBE cells with sodium hydrosulfide significantly reduced the beryllium sulfate-induced apoptosis and autophagy. Moreover, it increased the mitochondrial membrane potential and alleviated the G2/M-phase cell cycle arrest. However, pretreatment with 10 mM DL-propargylglycine promoted the opposite effects. PI3K/Akt/mTOR and Nrf2/ARE signaling pathways are also activated following pretreatment with sodium hydrosulfide. These results indicate the protection provided by hydrogen sulfide in 16HBE cells against beryllium sulfate-induced injury is associated with the inhibition of apoptosis and autophagy through the activation of the PI3K/Akt/mTOR and Nrf2/ARE signaling pathways. Therefore, hydrogen sulfide has the potential to be a promising candidate in the treatment against beryllium disease.