Germline AIP variants in sporadic young acromegaly and pituitary gigantism: clinical and genetic insights from a Han Chinese cohort.

PURPOSE: Variants in the Aryl hydrocarbon receptor-interacting protein (AIP) gene have been identified in sporadic acromegaly and pituitary gigantism, especially in young patients, with a predisposition to aggressive clinical phenotype and poor treatment efficacy. The clinical characteristics of patients with sporadic acromegaly and pituitary gigantism as well as AIP variants in Han Chinese have been rarely reported. We aimed to identify AIP gene variants and analyze the clinical characteristics of patients with sporadic acromegaly and pituitary gigantism in Han Chinese. METHODS: The study included 181 sporadic acromegaly (N = 163) and pituitary gigantism (N = 18) patients with an onset age of no more than 45 years old, who were diagnosed, treated, and followed up in Huashan Hospital. All 6 exons and their flanking regions of the AIP gene were analyzed with Sanger sequencing or NGS. The clinical characteristics were compared between groups with and without AIP variants. RESULTS: Germline AIP variants were found in 15/181 (8.29%) cases. In patients with an onset age ≤30 years old, AIP variants were identified in 12/133 (9.02%). Overall, 13 variants were detected. The pathogenic (P) variants p.R304X and p.R81X were identified in four cases, with two instances of each variant. Six exon variants (p.C254R, p.K103fs, p.Q228fs, p.Y38X, p.Q213*, and p.1115 fs) have not been reported before, which were likely pathogenic (LP). Patients with P/LP variants had younger onset ages, a higher prevalence of pituitary gigantism, larger tumor volumes, and a higher percentage of Ki-67-positive cells in tumors. In addition, the group with P/LP variants showed a less significant reduction of GH levels in an acute octreotide suppression test (OST) [17.7% (0, 65.0%) vs. 80.5% (63.9%, 90.2%), P = 0.001], and a trend of less GH decrease after the 3-month treatment with long-acting somatostatin analogs (SSAs). CONCLUSION: Germline AIP variants existed in sporadic Chinese Han acromegaly and pituitary gigantism patients and were more likely to be detected in young patients. AIP variants were associated with more aggressive tumor phenotypes and less response to SSA treatment.

The Role of Nanoparticle Morphology on Enhancing Delivery of Budesonide for Treatment of Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a chronic and recurrent inflammatory disease that affects the gastrointestinal tract. The major hurdles impeding IBD treatment are the low targeting efficiency and short retention time of drugs in IBD sites. Nanoparticles with specific shapes have demonstrated the ability to improve mucus retention and cellular uptake. Herein, mesoporous silica nanoparticles (MSNs) with various morphologies were used to deliver budesonide (BUD) for the treatment of IBD. The therapeutic efficacy is strongly dependent on their shapes. The system comprises different shapes of MSNs as carriers for budesonide (BUD), along with Eudragit S100 as the enteric release shell. The encapsulation of Eudragit S100 not only improved the stability of MSNs-BUD in the gastrointestinal tract but also conferred pH-responsive drug release properties. Then, MSNs efficiently deliver BUD to the colon site, and the special shape of MSNs plays a critical role in enhancing their permeability and retention in the mucus layer. Among them, dendritic MSNs (MSND) effectively reduced myeloperoxidase (MPO) activity and levels of inflammatory cytokines in the colon due to long retention time and rapid release in IBD sites, thereby enhancing the therapeutic efficacy against colitis. Given the special shapes of MSNs and pH-responsivity of Eudragit S100, BUD loaded in the voids of MSND (E@MSNs-BUD) could penetrate the mucous layer and be accurately delivered to the colon with minor side effects. This system is expected to complement current treatment strategies for the IBD.

[Effect of Photoaging on Adsorption of Cu(â ¡) by Polystyrene Microplastics with Different Particle Sizes].

In order to evaluate the effect of aging and particle size on the adsorption of heavy metals by microplastics, the adsorption behavior of Cu(Ⅱ) by three different particle sizes of polystyrene (PS; 1, 50, and 100 µm) under UV irradiation was systematically studied. The results demonstrated that UV aging significantly changed the surface morphology and physicochemical properties of PS, and 1 µm PS had the strongest aging degree. The adsorption kinetics of PS on Cu(Ⅱ) conformed to the pseudo-second-order kinetic model, and the Freundlich model was more suitable for the experimental data of isothermal adsorption of Cu(Ⅱ) by PS. These results indicated that the adsorption of Cu(Ⅱ) by PS occurred on the non-uniform surface of PS, and the adsorption behavior was multilayer adsorption. Parameter "n" of the Freundlich model was less than 1, indicating that the adsorption behavior of PS on Cu(Ⅱ) was a higher intensity physical adsorption behavior. The order of theoretical maximum adsorption capacity of different particle sizes PS for Cu(Ⅱ) was as follows:1 µm > 50 µm > 100 µm, indicating that the size of PS was an important influence factor for the adsorption capacity of PS to pollutants. For the same particle size PS, aging enhanced its adsorption capacity for Cu(Ⅱ). The results on the adsorption of Cu(Ⅱ) by PS under different environmental conditions indicated that the adsorption capacity of PS for Cu (II) increased with the increase in pH, whereas an increase in salinity had the opposite effect. Surface complexation and electrical adsorption were the main mechanisms of adsorption of Cu(Ⅱ) by PS. This study provides an important scientific basis for understanding the adsorption behavior of microplastics to heavy metals in the environment.

Light-driven rGO/Cu2 + 1O tubular nanomotor with active targeted drug delivery for combination treatment of cancer cells.

The unprecedented navigation ability in micro/nanoscale and tailored functionality tunes micro/nanomotors as new target drug delivery systems, open up new horizons for biomedical applications. Herein, we designed a light-driven rGO/Cu2 + 1O tubular nanomotor for active targeting of cancer cells as a drug delivery system. The propulsion performance is greatly enhanced in real cell media (5% glucose cells isotonic solution), attributing to the introduction of oxygen vacancy and reduced graphene oxide (rGO) layer for separating photo-induced electron-hole pairs. The motion speed and direction can be readily modulated. Meanwhile, doxorubicin (DOX) can be loaded quickly on the rGO layer because of π-π bonding effect. The Cu2 + 1O matrix in the tiny robots not only serves as a photocatalyst to generate a chemical concentration gradient as the driving force but also acts as a nanomedicine to kill cancer cells as well. The strong propulsion of light-driven rGO/Cu2 + 1O nanomotors coupled with tiny size endow them with active transmembrane transport, assisting DOX and Cu2 + 1O breaking through the barrier of the cell membrane. Compared with non-powered nanocarrier and free DOX, light-propelled rGO/Cu2 + 1O nanomotors exhibit greater transmembrane transport efficiency and significant therapeutic efficacy. This proof-of-concept nanomotor design presents an innovative approach against tumor, enlarging the list of biomedical applications of light-driven micro/nanomotors to the superficial tissue treatment.

Phillyrin and its metabolites treat pulmonary embolism by targeting PLCß3 to inhibit platelet activation.

ETHNOPHARMACOLOGICAL RELEVANCE: Lian Qiao (LQ), the dried fruit of Forsythia suspensa (Thunb.) Vahl, is a well-documented traditional Chinese medicine known for its detoxifying and heat-clearing properties. Clinically, compounds containing LQ are widely used to treat thrombotic diseases, indicating that it may have antithrombotic effects. However, its exact mechanism of action remains unknown. AIM OF THE STUDY: This study aimed to verify the antithrombotic effect of LQ and further explore the material basis and target mechanism of its antithrombotic effect using various biological methods. MATERIALS AND METHODS: An epinephrine-collagen-thrombin-induced mouse model of acute pulmonary embolism (APE) was established to study the effects of LQ on thrombus development. A UPLC/Q/TOF-MS screening and identification system based on the inhibition of platelet aggregation and Ca2+ antagonism was established to determine the pharmacodynamic components of LQ that inhibit platelet activation. The inhibitory effect of active ingredients on platelet activation, and the determination of the target of their inhibitory effect on platelet activation have been studied using chemical proteomics. Furthermore, based on the structure and function of the target protein, a multidisciplinary approach was adopted to analyze the molecular mechanism of active ingredient binding to target proteins and to evaluate the effects of active ingredients on the downstream signaling pathways of target proteins. RESULTS: LQ showed significant anticoagulant effects in APE model mice. Phillyrin and phillygenin were the antiplatelet-activating components of LQ. PLCß3 was identified as a target for inhibiting platelet activation by phillyrin and its metabolites. The mechanism underlying the effect involves phillyrin and its metabolites inhibiting PLCß3 activity by blocking the binding of PLCß3 to Gαq through non-covalently targeting the ASN260 of PLCß3, thus inhibiting the downstream Gαq-PLCß3-Ca2+ signaling pathway, effectively hindering platelet activation and therefore playing an anticoagulant role. CONCLUSION: This study not only proposes and validates the antithrombotic effect of LQ for the first time but also finds that phillyrin and phillygenin are the main pharmacological substances through which LQ exerts antithrombotic activity and reveals a novel mechanism by which they exert antiplatelet activity by directly targeting and inhibiting PLCß3 activity. These findings significantly contribute to our understanding of the therapeutic potential of phillyrin and provide important clues for the discovery and development of new antiplatelet drugs.

Associations of serum uric acid variability with neuroimaging metrics and cognitive decline: a population-based cohort study.

BACKGROUND: The relationship between variation in serum uric acid (SUA) levels and brain health is largely unknown. This study aimed to examine the associations of long-term variability in SUA levels with neuroimaging metrics and cognitive function. METHODS: This study recruited 1111 participants aged 25-83 years from a multicenter, community-based cohort study. The SUA concentrations were measured every two years from 2006 to 2018. We measured the intraindividual SUA variability, including the direction and magnitude of change by calculating the slope value. The associations of SUA variability with neuroimaging markers (brain macrostructural volume, microstructural integrity, white matter hyperintensity, and the presence of cerebral small vessel disease) and cognitive function were examined using generalized linear models. Mediation analyses were performed to assess whether neuroimaging markers mediate the relationship between SUA variation and cognitive function. RESULTS: Compared with the stable group, subjects with increased or decreased SUA levels were all featured by smaller brain white matter volume (beta = - 0.25, 95% confidence interval [CI] - 0.39 to - 0.11 and beta = - 0.15, 95% CI - 0.29 to - 0.02). Participants with progressively increased SUA exhibited widespread disrupted microstructural integrity, featured by lower global fractional anisotropy (beta = - 0.24, 95% CI - 0.38 to - 0.10), higher mean diffusivity (beta = 0.16, 95% CI 0.04 to 0.28) and radial diffusivity (beta = 0.19, 95% CI 0.06 to 0.31). Elevated SUA was also associated with cognitive decline (beta = - 0.18, 95% CI - 0.32 to - 0.04). White matter atrophy and impaired brain microstructural integrity mediated the impact of SUA increase on cognitive decline. CONCLUSIONS: It is the magnitude of SUA variation rather than the direction that plays a critical negative role in brain health, especially for participants with hyperuricemia. Smaller brain white matter volume and impaired microstructural integrity mediate the relationship between increased SUA level and cognitive function decline. Long-term stability of SUA level is recommended for maintaining brain health and preventing cognitive decline.

Cell-Impermeable Buffering Fluorogenic Probes for Live-Cell Super-Resolution Imaging of Plasma Membrane Morphology Dynamics.

Super-resolution fluorescence imaging has emerged as a potent tool for investigating the nanoscale structure and function of the plasma membrane (PM). Nevertheless, the challenge persists in achieving super-resolution imaging of PM dynamics due to limitations in probe photostability and issues with cell internalization staining. Herein, we report assembly-mediated buffering fluorogenic probes BMP-14 and BMP-16 exhibiting fast PM labeling and extended retention time (over 2 h) on PM. The incorporation of alkyl chains proves effective in promoting the aggregation of BMP-14 and BMP-16 into nonfluorescent nanoparticles to realize fluorogenicity and regulate the buffering capacity to rapidly replace photobleached probes ensuring stable long-term super-resolution imaging of PM. Utilizing these PM-buffering probes, we observed dynamic movements of PM filopodia and continuous shrinkage, leading to the formation of extracellular vesicles (EVs) using structured illumination microscopy (SIM). Furthermore, we discovered two distinct modes of EV fusion: one involving fusion through adjacent lipids and the other through filamentous lipid traction. The entire process of EV fusion outside the PM was dynamically tracked. Additionally, BMP-16 exhibited a unique capability of inducing single-molecule fluorescence blinking when used for cell membrane staining. This property makes BMP-16 suitable for the PAINT imaging of cell membranes.

MEMS Oscillators-Network-Based Ising Machine with Grouping Method.

Combinatorial optimization (CO) has a broad range of applications in various fields, including operations research, computer science, and artificial intelligence. However, many of these problems are classified as nondeterministic polynomial-time (NP)-complete or NP-hard problems, which are known for their computational complexity and cannot be solved in polynomial time on traditional digital computers. To address this challenge, continuous-time Ising machine solvers have been developed, utilizing different physical principles to map CO problems to ground state finding. However, most Ising machine prototypes operate at speeds comparable to digital hardware and rely on binarizing node states, resulting in increased system complexity and further limiting operating speed. To tackle these issues, a novel device-algorithm co-design method is proposed for fast sub-optimal solution finding with low hardware complexity. On the device side, a piezoelectric lithium niobate (LiNbO3) microelectromechanical system (MEMS) oscillator network-based Ising machine without second-harmonic injection locking (SHIL) is devised to solve Max-cut and graph coloring problems. The LiNbO3 oscillator operates at speeds greater than 9 GHz, making it one of the fastest oscillatory Ising machines. System-wise, an innovative grouping method is used that achieves a performance guarantee of 0.878 for Max-cut and 0.658 for graph coloring problems, which is comparable to Ising machines that utilize binarization.

A novel glycoglycerolipid from Holotrichia diomphalia Bates: Structure characteristics and protective effect against DNA damage.

A lipidated polysaccharide, HDPS-2II, was isolated from the dried larva of Holotrichia diomphalia, which is used in traditional Chinese medicine. The molecular weight of HDPS-2II was 5.9 kDa, which contained a polysaccharide backbone of →4)-ß-Manp-(1 â†’ 4,6)-ß-Manp-(1 â†’ [6)-α-Glcp-(1]n â†’ 6)-α-Glcp→ with the side chain α-Glcp-(6 â†’ 1)-α-Glcp-(6 â†’ linked to the C-4 of ß-1,4,6-Manp and four types of lipid chains including 4-(4-methyl-2-(methylamino)pentanamido)pentanoic acid, 5-(3-(tert-butyl)phenoxy)hexan-2-ol, N-(3-methyl-5-oxopentan-2-yl)palmitamide, and N-(5-amino-3-methyl-5-oxopentan-2-yl)stearamide. The lipid chains were linked to C-1 of terminal α-1,6-Glcp in carbohydrate chain through diacyl-glycerol. HDPS-2II exhibited DNA protective effects and antioxidative activity on H2O2- or adriamycin (ADM)-induced Chinese hamster lung cells. Furthermore, HDPS-2II significantly ameliorated chromosome aberrations and the accumulation of reactive oxygen species (ROS), reduced γ-H2AX signaling and the expressions of NADPH oxidase (NOX)2, NOX4, P22phox, and P47phox in ADM-induced cardiomyocytes. Mechanistically, HDPS-2II suppressed ADM-induced up-regulation of NOX2 and NOX4 in cardiomyocytes, but not in NOX2 or NOX4 knocked-down cardiomyocytes, indicating that HDPS-2II could relieve intracellular DNA damage by regulating NOX2/NOX4 signaling. These findings demonstrate that HDPS-2II is a new potential DNA protective agent.

Amino Group-Driven Adsorption of Sodium p-Perfluorous Nonenoxybenzene Sulfonate in Water by the Modified Graphene Oxide.

Sodium p-perfluorous nonenoxybenzene sulfonate (OBS) is one of the key alternatives to perfluoroalkyl substances (PFASs). Its widespread tendency has increased extensive contamination in the aquatic environment. However, the present treatment technology for OBS exhibited insignificant adsorption capacity and long adsorption time. In this study, three proportions (1:5, 3:5, and 10:1) of chitosan-modified amino-driven graphene oxide (CS-GO) were innovated to strengthen the OBS adsorption capacity, compared with graphene oxide (GO) and graphene (GH). Through the characterization of SEM, BET, and FTIR, it was discovered that CS was synthetized on GO surfaces successfully with a low specific surface area. Subsequently, batch single influence factor studies on OBS removal from simulated wastewater were investigated. The optimum removal efficiency of OBS could be achieved up to 95.4% within 2 h when the adsorbent was selected as CS-GO (10:1), the dosage was 2 mg, and the pH was 3. The addition of inorganic ions could promote the adsorption efficiency of OBS. In addition, CS-GO presented the maximum adsorption energy due to additional functional groups of -NH3, and electrostatic interaction was the foremost motive for improving the adsorption efficiency of OBS. Moreover, OBS exhibited the fastest diffusion coefficient in the CS-GO-OBS solution, which is consistent with the fitting results of adsorption kinetics.

Celastrol induced the autophagy of spermatogonia cells contributed to tripterygium glycosides-related testicular injury.

Tripterygium glycosides (TG) is extracted from the roots of Chinese herbal medicine named Tripterygium wilfordii Hook F (TwHF). TG tablets are the representative TwHF-based agents with anti-inflammatory and immunomodulatory activities for treating rheumatoid arthritis. Although the curative effect of TG is remarkable, the clinical application is limited by a variety of organ toxicity. One of the most serious side-effects induced by TG is damage of the male reproductive system and the toxic mechanism is still not fully elucidated. TG-induced testicular injury was observed in male mice by treated with different concentrations of TG. The results showed that TG induced a significant decrease in testicular index. Pathological observation showed that spermatogenic cells were obviously shed, arranged loosely, and the spermatogenic epithelium was thin compared with control mice. In addition, the toxic effect of TG on mouse spermatogonia GC-1 cells was investigated. The results displayed that TG induced significant cytotoxicity in mouse GC-1 cells. To explore the potential toxic components that triggered testicular injury, the effects of 8 main components of TG on the viability of GC-1 cells were detected. The results showed that celastrol was the most toxic component of TG to GC-1 cells. Western blot analysis showed that LC3-II and the ratio of LC3-II/LC3-I were significantly increased and the expression level of p62 were decreased in both TG and celastrol treated cells, which indicated the significant activation of autophagy in spermatogonia cells. Therefore, autophagy plays an important role in the testicular injury induced by TG, and inhibition of autophagy is expected to reduce the testicular toxicity of TG.

Maternal cardiovascular health in early pregnancy and the risk of congenital heart defects in offspring.

BACKGROUND: Congenital heart disease (CHD) is the predominant birth defect. This study aimed to explore the association between maternal cardiovascular health (CVH) and the CHD risk in offspring. METHODS: We used the prospective data from the Fujian Birth Cohort Study, collected from March 2019 to December 2022 on pregnant women within 14 weeks of gestation. Overall maternal CVH was assessed by seven CVH metrics (including physical activity, smoking, sleep duration, body mass index, blood pressure, total cholesterol, and fasting plasma glucose), with each metric classified as ideal, intermediate or poor with specific points. Participants were further allocated into high, moderate and low CVH categories based on the cumulative CVH score. The association with offspring CHD was determined with log-binominal regression models. RESULTS: A total of 19810 participants aged 29.7 (SD: 3.9) years were included, with 7846 (39.6%) classified as having high CVH, 10949 (55.3%) as having moderate CVH, and 1015 (5.1%) as having low CVH. The average offspring CHD rate was 2.52%, with rates of 2.35%, 2.52% and 3.84% across the high, moderate and low CVH categories, respectively (P = 0.02). Adjusted relative risks (RRs) of having offspring CHD were 0.64 (95% CI: 0.45-0.90, P = 0.001) for high CVH and 0.67 (95% CI: 0.48-0.93, P = 0.02) for moderate CVH compared to low CVH. For individual metrics, only ideal total cholesterol was significantly associated with lower offspring CHD (RR: 0.73, 95% CI: 0.59-0.83, P = 0.002). CONCLUSIONS: Pregnant women of high or moderate CVH categories in early pregnancy had reduced risks of CHD in offspring, compared to those of low CVH. It is important to monitor and improve CVH during pre-pregnancy counseling and early prenatal care.

Ligustilide covalently binds to Cys703 in the pre-S1 helix of TRPA1, blocking the opening of channel and relieving pain in rats with acute soft tissue injury.

ETHNOPHARMACOLOGICAL RELEVANCE: The natural anodyne Ligustilide (Lig), derived from Angelica sinensis (Oliv.) Diels and Ligusticum chuanxiong Hort., has been traditionally employed for its analgesic properties in the treatment of dysmenorrhea and migraine, and rheumatoid arthritis pain. Despite the existing reports on the correlation between TRP channels and the analgesic effects of Lig, a comprehensive understanding of their underlying mechanisms of action remains elusive. AIM OF THE STUDY: The objective of this study is to elucidate the mechanism of action of Lig on the analgesic target TRPA1 channel. METHODS: The therapeutic effect of Lig was evaluated in a rat acute soft tissue injury model. The analgesic target was identified through competitive inhibition of TRP channel agonists at the animal level, followed by Fluo-4/Ca2+ imaging on live cells overexpressing TRP proteins. The potential target was verified through in-gel imaging, colocalization using a Lig-derived molecular probe, and a drug affinity response target stability assay. The binding site of Lig was identified through protein spectrometry and further analyzed using molecular docking, site-specific mutation, and multidisciplinary approaches. RESULTS: The administration of Lig effectively ameliorated pain and attenuated oxidative stress and inflammatory responses in rats with soft tissue injuries. Moreover, the analgesic effects of Lig were specifically attributed to TRPA1. Mechanistic studies have revealed that Lig directly activates TRPA1 by interacting with the linker domain in the pre-S1 region of TRPA1. Through metabolic transformation, 6,7-epoxyligustilide (EM-Lig) forms a covalent bond with Cys703 of TRPA1 at high concentrations and prolonged exposure time. This irreversible binding prevents endogenous electrophilic products from entering the cysteine active center of ligand-binding pocket of TRPA1, thereby inhibiting Ca2+ influx through the channel opening and ultimately relieving pain. CONCLUSIONS: Lig selectively modulates the TRPA1 channel in a bimodal manner via non-electrophilic/electrophilic metabolic conversion. The epoxidized metabolic intermediate EM-Lig exerts analgesic effects by irreversibly inhibiting the activation of TRPA1 on sensory neurons. These findings not only highlight the analgesic mechanism of Lig but also offer a novel nucleophilic attack site for the development of TRPA1 antagonists in the pre-S1 region.

Metabolomics analysis revealed the neuroprotective role of 2-phosphoglyceric acid in hypoxic-ischemic brain damage through GPX4/ACSL4 axis regulation.

Hypoxic-ischemic brain damage (HIBD) is a cerebral injury resulting from the combination of ischemia and hypoxia in neonatal brain tissue. Presently, there exists no efficacious remedy for HIBD. A mounting body of evidence indicates that dynamic metabolites formed during metabolic procedures assume a vital role in neuronal maturation and recuperation. However, it remains unclear whether any endogenous metabolites are involved in the pathogenesis of HIBD. Here, an untargeted metabolomics analysis was conducted by gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry (GC/LC-MS) in OGD/R (oxygen-glucose deprivation/reoxygenation)-induced HT-22 cells. We observed that ferroptosis signaling plays an essential role in HI-induced neuronal injury. Interestingly, we also found that the differentially expressed metabolite, 2-phosphoglyceric acid, significantly improved the neuronal cell survival of OGD/R HT-22 cells by inhibiting ferroptosis. Moreover, 2-phosphoglyceric acid effectively rescued the cell activity of HT-22 cells treated with the ferroptosis inducer RSL-3. Furthermore, 2-phosphoglyceric acid alleviated cerebral infarction and reduced HIBD-induced neuronal cell loss of the central nervous system in neonatal rats by regulating GPX4 expression. Taken together, we found that 2-phosphoglyceric acid, which was downregulated in HT-22 cells induced by OGD/R, exerted neuronal protective effects on OGD/R-treated HT-22 cells and HIBD-induced neonatal rats by inhibiting hypoxic-ischemic-induced ferroptosis through the regulation of the GPX4/ACSL4 axis.

miR-306-5p is involved in chitin metabolism in Aedes albopictus pupae via linc8338-miR-306-5p-XM_019678125.2 axis.

Aedes albopictus can transmit several lethal arboviruses. This mosquito has become a sever public health threat due to its rapidly changing global distribution. Chitin, which is the major component of the cuticle and peritrophic membrane (PM), is crucial for the growth and development of insect. microRNAs (miRNAs) play important roles in the posttranscriptional level regulation of gene expression, thereby influencing many biological processes in insects. In this study, an attempt was made to evaluate the role of miR-306-5p in regulating chitin metabolism in Ae. albopictus pupae. Overexpression of miR-306-5p resulted in a significantly reduced survival rate in pupae and an increased malformation rate in adults. Both in vivo and in vitro evidence confirmed the presence of the competing endogenous RNA (ceRNA) regulatory axis (linc8338-miR-306-5p-XM_019678125.2). RNAi of linc8338 and XM_019678125.2 had effects on pupae similar to those of miR-306-5p. The highest expression level of miR-306-5p was found in the midgut, and alteration in the expression of miR-306-5p, XM_019678125.2 and linc8338 induced increased transcript levels of chitin synthase 2 (AaCHS2) and decreased chitinase 10 (AaCht10); as well as increased thickness of the midgut and enlarged midgut epithelial cells. The results of this study highlight the potential of miR-306-5p as a prospective target in mosquito control and confirm that the ceRNA mechanism is involved in chitin metabolism. These findings will provide a basis for further studies to uncover the molecular mechanisms through which ncRNAs regulate chitin metabolism.

Association of sleep duration and sleep quality with gestational diabetes mellitus in pregnant women after treatment with assisted reproductive technology: A birth cohort study.

Maternal sleep is closely related to subsequent gestational diabetes mellitus (GDM) in natural pregnancies. However, whether this connection exists in pregnant women conceiving with the help of assisted reproductive technology (ART) has not been confirmed. Hence, in this study, we evaluated whether early pregnancy sleep duration or sleep quality is associated with gestational diabetes mellitus in ART-pregnant women, as well as the influence of maternal age on this association. This prospective birth cohort study included 856 pregnant women who successfully conceived with the help of ART treatment. The sleep parameters of ART-pregnant women were assessed using the Pittsburgh Sleep Quality Index (PSQI) in early pregnancy. We explored the association between sleep and the risk of gestational diabetes mellitus using an unconditional binary logistic regression model. Different models were constructed to examine the robustness of the estimation by incorporating different confounding factors. Multivariable logistic regression revealed that sleep duration of more than 10 h among ART-pregnant women was significantly associated with the risk of GDM, and the association between sleep duration and gestational diabetes mellitus varied by maternal age. We found an increased risk of subsequent gestational diabetes mellitus with increasing sleep duration only in pregnant women aged <35 years. Additionally, no statistically significant association between sleep quality and gestational diabetes mellitus was found in this study. In conclusion, excessive sleep duration (≥10 h) is associated with a high risk of gestational diabetes mellitus in pregnant women who conceived with the help of assisted reproductive technology, and maternal age may modify this effect.

Association between Body Mass Index and Brain Health in Adults: A 16-Year Population-Based Cohort and Mendelian Randomization Study.

Background: The cumulative effect of body mass index (BMI) on brain health remains ill-defined. The effects of overweight on brain health across different age groups need clarification. We analyzed the effect of cumulative BMI on neuroimaging features of brain health in adults of different ages. Methods: This study was based on a multicenter, community-based cohort study. We modeled the trajectories of BMI over 16 years to evaluate cumulative exposure. Multimodality neuroimaging data were collected once for volumetric measurements of the brain macrostructure, white matter hyperintensity (WMH), and brain microstructure. We used a generalized linear model to evaluate the association between cumulative BMI and neuroimaging features. Two-sample Mendelian randomization analysis was performed using summary level of BMI genetic data from 681,275 individuals and neuroimaging genetic data from 33,224 individuals to analyze the causal relationships. Results: Clinical and neuroimaging data were obtained from 1,074 adults (25 to 83 years). For adults aged under 45 years, brain volume differences in participants with a cumulative BMI of >26.2 kg/m2 corresponded to 12.0 years [95% confidence interval (CI), 3.0 to 20.0] of brain aging. Differences in WMH were statistically substantial for participants aged over 60 years, with a 6.0-ml (95% CI, 1.5 to 10.5) larger volume. Genetic analysis indicated causal relationships between high BMI and smaller gray matter and higher fractional anisotropy in projection fibers. Conclusion: High cumulative BMI is associated with smaller brain volume, larger volume of white matter lesions, and abnormal microstructural integrity. Adults younger than 45 years are suggested to maintain their BMI below 26.2 kg/m2 for better brain health. Trial Registration: This study was registered on clinicaltrials.gov (Clinical Indicators and Brain Image Data: A Cohort Study Based on Kailuan Cohort; No. NCT05453877; https://clinicaltrials.gov/ct2/show/NCT05453877).

Causal relationship between multiparameter brain MRI phenotypes and age: evidence from Mendelian randomization.

To explore the causal relationship between age and brain health (cortical atrophy, white matter integrity, white matter hyperintensities and cerebral microbleeds in various brain regions) related multiparameter imaging features using two-sample Mendelian randomization. Age was determined as chronological age of the subject. Cortical volume, white matter micro-integrity, white matter hyperintensity volume and cerebral microbleeds of each brain region were included as phenotypes for brain health. Age and imaging of brain health related genetic data were analysed to determine the causal relationship using inverse-variance weighted model, validated by heterogeneity and horizontal pleiotropy variables. Age is causally related to increased volumes of white matter hyperintensities (ß = 0.151). For white matter micro-integrity, fibres of the inferior cerebellar peduncle (axial diffusivity ß = -0.128, orientation dispersion index ß = 0.173), cerebral peduncle (axial diffusivity ß = -0.136), superior fronto-occipital fasciculus (isotropic volume fraction ß = 0.163) and fibres within the limbic system were causally deteriorated. We also detected decreased cortical thickness of multiple frontal and temporal regions (P < 0.05). Microbleeds were not related with aging (P > 0.05). Aging is a threat of brain health, leading to cortical atrophy mainly in the frontal lobes, as well as the white matter degeneration especially abnormal hyperintensity and deteriorated white matter integrity around the hippocampus.

Nicotinamide protects against diabetic kidney disease through regulation of Sirt1.

PURPOSE: To investigate the effect of nicotinamide (Nam) on diabetic kidney disease (DKD) in mice and explore its mechanism. METHODS: Thirty DBA/2 J mice were randomly assigned to three groups. After 8 weeks of hyperglycemia induced by streptozocin (STZ), Nam and saline were administrated to STZ + Nam and STZ + NS mice, respectively, for 8 weeks. Non-diabetic mice (NDM) were used as control group. Twenty In2-/- Akita mice were randomly divided into two groups. After 8 weeks of hyperglycemia, Nam and saline were administered to Akita + Nam and Akita + NS mice, respectively, for 6 weeks. Wild-type littermates were used as control group. Markers of renal injury were analyzed, and the molecular mechanisms were explored in human proximal tubular HK2 cells. RESULTS: Urinary albumin-to-creatinine ratio (UACR) and kidney injury molecule 1 (KIM-1) decreased in the STZ + Nam and Akita + Nam groups. Pathological analysis showed that Nam improved the structure of glomerular basement membrane, ameliorated glomerular sclerosis, and decreased the accumulation of extracellular matrix and collagen. Compared to the diabetic control group, renal fibrosis, inflammation, and oxidative stress were reduced in the Nam-treated mice. The expression of sirtuin 1 (Sirt1) in human proximal tubular HK2 cells was inhibited by high glucose and Nam treatment enhanced its expression. However, in HK2 cells with Sirt1 knockdown, the protective effect of Nam was abolished, indicating that the beneficial effect of Nam was partially dependent on Sirt1. CONCLUSIONS: Nam has a renoprotective effect against renal injury caused by hyperglycemia and may be a potential target for the treatment of DKD.

Normal weight obesity is associated with lower AFC and adverse IVF outcomes.

Background: Body weight could be classified into underweight, normal weight and overweight according to percentage of body fat (%BF), and normal weight obesity (NWO) is defined as a normal BMI but a high %BF. While the impact of NWO in women fecundity remain unknow. Therefore, this study aimed to investigate the associations between %BF and reproductive outcomes among in vitro fertilization (IVF) women with normal BMI. Methods: A total of 469 women were included in this study and were classified into low %BF, normal %BF and high %BF according to previous study. Multivariate generalized regression models were employed to evaluate the associations of %BF with ovarian reserve parameters, IVF outcomes and early pregnancy outcomes. We further run sensitivity analyses by restricted the analysis to young women and those only with tubal factor, respectively. Results: About 32.2% of normal BMI women were misclassified according %BF, with 16.4% of them were low %BF and 15.8% were high %BF. The high %BF group had significantly lower antral follicle count (AFC) than normal %BF groups, and the AFC showed a tendency of decrease as %BF increased. In sensitivity analysis in young women, high %BF group also had significantly lower number of good-quality embryos when compared to normal %BF groups. The results expanded to all IVF outcomes when analysis restricted to tubal factor women. Conclusion: In summary, misclassifications of body weight status based on BMI are common according to %BF, and NWO is associated with adverse reproductive outcomes.