Mechano-regulation of Peptide-MHC Class I Conformations Determines TCR Antigen Recognition.

TCRs recognize cognate pMHCs to initiate T cell signaling and adaptive immunity. Mechanical force strengthens TCR-pMHC interactions to elicit agonist-specific catch bonds to trigger TCR signaling, but the underlying dynamic structural mechanism is unclear. We combined steered molecular dynamics (SMD) simulation, single-molecule biophysical approaches, and functional assays to collectively demonstrate that mechanical force induces conformational changes in pMHCs to enhance pre-existing contacts and activates new interactions at the TCR-pMHC binding interface to resist bond dissociation under force, resulting in TCR-pMHC catch bonds and T cell activation. Intriguingly, cancer-associated somatic mutations in HLA-A2 that may restrict these conformational changes suppressed TCR-pMHC catch bonds. Structural analysis also indicated that HLA polymorphism might alter the equilibrium of these conformational changes. Our findings not only reveal critical roles of force-induced conformational changes in pMHCs for activating TCR-pMHC catch bonds but also have implications for T cell-based immunotherapy.

NKG2D discriminates diverse ligands through selectively mechano-regulated ligand conformational changes.

Stimulatory immune receptor NKG2D binds diverse ligands to elicit differential anti-tumor and anti-virus immune responses. Two conflicting degeneracy recognition models based on static crystal structures and in-solution binding affinities have been considered for almost two decades. Whether and how NKG2D recognizes and discriminates diverse ligands still remain unclear. Using live-cell-based single-molecule biomechanical assay, we characterized the in situ binding kinetics of NKG2D interacting with different ligands in the absence or presence of mechanical force. We found that mechanical force application selectively prolonged NKG2D interaction lifetimes with the ligands MICA and MICB, but not with ULBPs, and that force-strengthened binding is much more pronounced for MICA than for other ligands. We also integrated steered molecular dynamics simulations and mutagenesis to reveal force-induced rotational conformational changes of MICA, involving formation of additional hydrogen bonds on its binding interface with NKG2D, impeding MICA dissociation under force. We further provided a kinetic triggering model to reveal that force-dependent affinity determines NKG2D ligand discrimination and its downstream NK cell activation. Together, our results demonstrate that NKG2D has a discrimination power to recognize different ligands, which depends on selective mechanical force-induced ligand conformational changes.

Ibrutinib plus Bendamustine and Rituximab in Untreated Mantle-Cell Lymphoma.

BACKGROUND: Ibrutinib, a Bruton's tyrosine kinase inhibitor, may have clinical benefit when administered in combination with bendamustine and rituximab and followed by rituximab maintenance therapy in older patients with untreated mantle-cell lymphoma. METHODS: We randomly assigned patients 65 years of age or older to receive ibrutinib (560 mg, administered orally once daily until disease progression or unacceptable toxic effects) or placebo, plus six cycles of bendamustine (90 mg per square meter of body-surface area) and rituximab (375 mg per square meter). Patients with an objective response (complete or partial response) received rituximab maintenance therapy, administered every 8 weeks for up to 12 additional doses. The primary end point was progression-free survival as assessed by the investigators. Overall survival and safety were also assessed. RESULTS: Among 523 patients, 261 were randomly assigned to receive ibrutinib and 262 to receive placebo. At a median follow-up of 84.7 months, the median progression-free survival was 80.6 months in the ibrutinib group and 52.9 months in the placebo group (hazard ratio for disease progression or death, 0.75; 95% confidence interval, 0.59 to 0.96; P = 0.01). The percentage of patients with a complete response was 65.5% in the ibrutinib group and 57.6% in the placebo group (P = 0.06). Overall survival was similar in the two groups. The incidence of grade 3 or 4 adverse events during treatment was 81.5% in the ibrutinib group and 77.3% in the placebo group. CONCLUSIONS: Ibrutinib treatment in combination with standard chemoimmunotherapy significantly prolonged progression-free survival. The safety profile of the combined therapy was consistent with the known profiles of the individual drugs. (Funded by Janssen Research and Development and Pharmacyclics; SHINE ClinicalTrials.gov number, NCT01776840.).

Oxaloacetic acid induces muscle energy substrate depletion and fatigue by JNK-mediated mitochondrial uncoupling.

Fatigue is a common phenomenon closely related to physical discomfort and numerous diseases, which is severely threatening the life quality and health of people. However, the exact mechanisms underlying fatigue are not fully characterized. Herein, we demonstrate that oxaloacetic acid (OAA), a crucial tricarboxylic acid cycle intermediate, modulates the muscle fatigue. The results showed that serum OAA level was positively correlated with fatigue state of mice. OAA-treated induced muscle fatigue impaired the exercise performance of mice. Mechanistically, OAA increased the c-Jun N-terminal kinase (JNK) phosphorylation and uncoupling protein 2 (UCP2) levels in skeletal muscle, which led to decreased energy substrate and enhanced glycolysis. On the other hand, OAA boosted muscle mitochondrial oxidative phosphorylation uncoupled with energy production. In addition, either UCP2 knockout or JNK inhibition totally reversed the effects of OAA on skeletal muscle. Therein, JNK mediated UCP2 activation with OAA-treated. Our studies reveal a novel role of OAA in skeletal muscle metabolism, which would shed light on the mechanism of muscle fatigue and weakness.

Caffeic acid inhibits Staphylococcus aureus-induced endometritis through regulating AMPKα/mTOR/HIF-1α signalling pathway.

Endometritis is mostly caused by childbirth or postpartum uterine infection. It is one of the important reasons leading to female infertility. Caffeic acid (CA) and its derivatives are widely found in some foods and traditional Chinese medicine, and have biological activities such as antioxidant, free radical scavenging, anti-inflammatory, and anti-infection. In this study, we aimed to explore the effect of CA on Staphylococcus aureus-induced endometritis. The contents of TNF-α and IL-1ß were detected by ELISA in S. aureus-induced endometritis model. Western blot assay was used to detect the expression of AMPKα/mTOR/HIF-1α pathway related proteins and GPX4 expression. In addition, the concentrations of MDA, GSH, and iron were tested by the assay kits. Compared with the model group, CA treatment significantly alleviated S. aureus-induced uterine injury, MPO activity, the contents of inflammatory factors TNF-α and IL-1ß, and NF-κB activation. Meanwhile, CA significantly inhibited S. aureus-induced ferroptosis, as confirmed by decreased MDA and iron concentration and up-regulated GPX4 expression and GSH level. Furthermore, CA attenuated S. aureus-induced HIF-1α and phosphorylated mTOR expression and increased phosphorylated AMPK expression. In conclusion, CA inhibits inflammation and ferroptosis by regulating AMPKα/mTOR/HIF-1α signalling pathway to alleviate S. aureus-induced endometritis in mice.

Improvement of Quality and Disease Resistance for a Heavy-Panicle Hybrid Restorer Line, R600, in Rice (Oryza sativa L.) by Gene Pyramiding Breeding.

The utilization of heavy-panicle hybrid rice exemplifies the successful integration of architectural enhancement and heterosis, which has been widely adopted in the southwest rice-producing area of China. Iterative improvement in disease resistance and grain quality of heavy-panicle hybrid rice varieties is crucial to promote their sustainable utilization. Here, we performed a molecular design breeding strategy to introgress beneficial alleles of broad-spectrum disease resistance and grain quality into a heavy-panicle hybrid backbone restorer line Shuhui 600 (R600). We successfully developed introgression lines through marker-assisted selection to pyramid major genes (Wxb + ALKA-GC + Pigm + Xa23) derived from three parents (Huanghuazhan, I135, I488), which significantly enhance grain quality and confer resistance to rice blast and bacterial blight (BB). The improved parental R600 line (iR600) exhibited superior grain quality and elevated disease resistance while maintaining the heavy-panicle architecture and high-yield capacity of R600. Moreover, the iR600 was crossed with male sterility line 608A to obtain a new heavy-panicle hybrid rice variety with excellent eating and cooking quality (ECQ) and high yield potential. This study presents an effective breeding strategy for rice breeders to expedite the improvement of grain quality and disease resistance in heavy-panicle hybrid rice.

Multi-omics analysis reveals spatiotemporal regulation and function of heteromorphic leaves in Populus.

Despite the high economic and ecological importance of forests, our knowledge of the adaptive evolution of leaf traits remains very limited. Euphrates poplar (Populus euphratica), which has high tolerance to arid environment, has evolved four heteromorphic leaf forms, including narrow (linear and lanceolate) and broad (ovate and broad-ovate) leaves on different crowns. Here, we revealed the significant functional divergence of four P. euphratica heteromorphic leaves at physiological and cytological levels. Through global analysis of transcriptome and DNA methylation across tree and leaf developmental stages, we revealed that gene expression and DNA epigenetics differentially regulated key processes involving development and functional adaptation of heteromorphic leaves, such as hormone signaling pathways, cell division, and photosynthesis. Combined analysis of gene expression, methylation, ATAC-seq, and Hi-C-seq revealed longer interaction of 3D genome, hypomethylation, and open chromatin state upregulates IAA-related genes (such as PIN-FORMED1 and ANGUSTIFOLIA3) and promotes the occurrence of broad leaves while narrow leaves were associated with highly concentrated heterochromatin, hypermethylation, and upregulated abscisic acid pathway genes (such as Pyrabactin Resistance1-like10). Therefore, development of P. euphratica heteromorphic leaves along with functional divergence was regulated by differentially expressed genes, DNA methylation, chromatin accessibility, and 3D genome remodeling to adapt to the arid desert. This study advances our understanding of differential regulation on development and functional divergence of heteromorphic leaves in P. euphratica at the multi-omics level and provides a valuable resource for investigating the adaptive evolution of heteromorphic leaves in Populus.

Maternal Dietary Cholesterol and Egg Intake during Pregnancy and Large-for-Gestational-Age Infants: A Prospective Cohort Study.

BACKGROUND: Cholesterol plays a vital role in fetal growth and development during pregnancy. There remains controversy over whether pregnant females should limit their cholesterol intake. OBJECTIVES: The objective of this study was to investigate the association between maternal dietary cholesterol intake during pregnancy and infant birth weight in a Chinese prospective cohort study. METHODS: A total of 4146 mother-child pairs were included based on the Jiangsu Birth Cohort study. Maternal dietary information was assessed with a semiquantitative food-frequency questionnaire. Birth weight z-scores and large-for-gestational-age (LGA) infants were converted by the INTERGROWTH-21st neonatal weight-for-gestational-age standard. Poisson regression and generalized estimating equations were employed to examine the relationships between LGA and maternal dietary cholesterol across the entire pregnancy and trimester-specific cholesterol intake, respectively. RESULTS: The median intake of maternal total dietary cholesterol during the entire pregnancy was 671.06 mg/d, with eggs being the main source. Maternal total dietary cholesterol and egg-sourced cholesterol were associated with an increase in birth weight z-score, with per standard deviation increase in maternal total and egg-sourced dietary cholesterol being associated with an increase of 0.16 [95% confidence interval (CI): 0.07, 0.25] and 0.06 (95% CI: 0.03, 0.09) in birth weight z-score, respectively. Egg-derived cholesterol intake in the first and third trimesters was positively linked to LGA, with an adjusted relative risk of 1.11 (95% CI: 1.04, 1.18) and 1.09 (95% CI: 1.00, 1.18). Compared with mothers consuming ≤7 eggs/wk in the third trimester, the adjusted relative risk for having an LGA newborn was 1.37 (95% CI: 1.09, 1.72) for consuming 8-10 eggs/wk and 1.45 (95% CI: 1.12, 1.86) for consuming >10 eggs/wk (P-trend = 0.015). CONCLUSIONS: Maternal total dietary cholesterol intake, as well as consuming over 7 eggs/wk during pregnancy, displayed significant positive relationships with the incidence of LGA, suggesting that mothers should avoid excessive cholesterol intake during pregnancy to prevent adverse birth outcomes.

Epidemiology and genetic characterization of human parainfluenza virus-1 infection in pediatric patients from Hangzhou China, 2021-2022.

BACKGROUND: Human parainfluenza virus-1 (HPIV-1) is a notable pathogen instigating acute respiratory tract infections in children. The article is to elucidate the epidemiological and genetic characteristics of HPIV-1 circulating in Hangzhou during the period of 2021-2022. METHODS: A cohort of 2360 nasopharyngeal swabs were amassed and subsequently examined via RT-PCR, with HPIV-1 positive samples undergoing P gene sequencing. RESULTS: The highest HPIV-1 infection rates were found in children aged between 3 and 6 years. A pronounced positive rate persisted through the latter half of 2021, with a notable decline observed in the initial half of 2022. All HPIV-1 strains could be clustered into 2 groups: Cluster 1, with strains similar to those found in Japan (LC764865, LC764864), and Cluster 2, with strains similar to the Beijing strain (MW575643). CONCLUSION: In conclusion, our study contributes to the comprehensive data on the epidemiological and genetic characteristics of HPIV-1 in pediatric patients from Hangzhou, post the COVID-19 peak.

Potential Associations Between Vitamin Intake and Leukemia: A Cross-Sectional Study.

The present study assessed potential associations between vitamin intake and leukemia in a national sample of adults in the United States. A total of 5520 participants were included in this cross-sectional study to investigate the relationship between vitamin intake (including vitamins A, C, D, and E) and leukemia. Results revealed negative associations between vitamin C and E intake and leukemia, whereas associations between vitamin A and D and leukemia were not statistically significant. For vitamin C, compared with the first tertile, the odds ratio (OR) and corresponding 95% confidential interval (CI) was 0.90 (0.75-0.95) for the second tertile and 0.82 (0.61-0.90) for the third tertile (p < 0.01). For vitamin E, compared with the first tertile, the OR and 95% CI was 0.92 (0.80-0.96) for the second tertile and 0.86 (0.71-0.92) for the third tertile (p < 0.01). Furthermore, the inverse relationship between intake of vitamins C and E and leukemia were more evident for individuals ≥60 years of age and those with a body mass index >30 kg/m2. Results of this study provide evidence suggesting that intake of vitamin C and E intake may decrease the prevalence of leukemia; however, further large-scale prospective cohort studies are needed to verify these findings.

Prenatal Parental Exposure to Metals and Birth Defects: A Prospective Birth Cohort Study.

While maternal exposure to high metal levels during pregnancy is an established risk factor for birth defects, the role of paternal exposure remains largely unknown. We aimed to assess the associations of prenatal paternal and maternal metal exposure and parental coexposure with birth defects in singletons. This study conducted within the Jiangsu Birth Cohort recruited couples in early pregnancy. We measured their urinary concentrations for 25 metals. A total of 1675 parent-offspring trios were included. The prevalence of any birth defects among infants by one year of age was 7.82%. Paternal-specific gravity-corrected urinary concentrations of titanium, vanadium, chromium, manganese, cobalt, nickel, copper, and selenium and maternal vanadium, chromium, nickel, copper, selenium, and antimony were associated with a 21-91% increased risk of birth defects after adjusting for covariates. These effects persisted after mutual adjustment for the spouse's exposure. Notably, when assessing the parental mixture effect by Bayesian kernel machine regression, paternal and maternal chromium exposure ranked the highest in relative importance. Parental coexposure to metal mixture showed a pronounced joint effect on the risk of overall birth defects, as well as for some specific subtypes. Our findings suggested a couple-based prevention strategy for metal exposure to reduce birth defects in offspring.

Quantification of alkalinity of deep eutectic solvents based on (H-) and NMR.

Alkaline deep eutectic solvents (DESs) have been widely employed across diverse fields. A comprehensive understanding of the alkalinity data is imperative for the comprehension of their performance. However, the current range of techniques for quantifying alkalinity is constrained. In this investigation, we formulated a series of alkaline DESs and assessed their basicity properties through a comprehensive methodology of Hammett functions alongside 1H NMR analysis. A correlation was established between the composition, structure and alkalinity of solvents. Furthermore, a strong linear correlation was observed between the Hammett basicity (H-) of solvents and initial CO2 adsorption rate. Machine learning techniques were employed to predict the significant impact of alkaline functional components on alkalinity levels and CO2 capture capacity. This study offers valuable insights into the design, synthesis and structure-function relationship of alkaline DESs.

An innovative deep eutectic solvent: chalcogen bonding as the primary driving force.

Chalcogen bonding (ChB) interactions have drawn intensive attention in the last few decades as interesting alternatives to hydrogen bonding. The applications of ChB were mostly centered on the solid state and have rarely been explored in solution. In this work, a novel strategy for forming ChB-based deep eutectic solvents (DESs) was exploited. We set forth the formation, physicochemical properties, and interaction sites in detail. This work not only provides a new idea to design DES systems but also to exploit the potential application of ChB complexes.

Associations of three differential white blood cell counts, platelet counts, and their derived inflammatory indices with cancer-related fatigue in patients with breast cancer undergoing chemotherapy.

PURPOSE: Inflammation is thought to be a vital element in the etiology of cancer-related fatigue (CRF), and circulating blood cell parameters could be important markers of inflammatory response. However, the associations of several major blood cell counts and their derived inflammatory indices with CRF are not well described. The present study aimed to establish whether a relationship exists between the counts of three white blood cell (WBC) types, platelets, and CRF and investigate whether several systemic inflammatory indices were associated with CRF in patients with breast cancer (BC). METHODS: A cross-sectional survey was conducted with a sample of 824 patients with BC undergoing chemotherapy. The cancer fatigue scale was administered to assess CRF. Hematological indicators, including neutrophils, lymphocytes, monocytes, and platelets, were retrieved from routine blood test. Network analyses were used to examine the associations among them. RESULTS: Among 824 participants, the mean score of CRF was (27 ± 10), ranging from 0 to 57. The results of network models indicated that physical fatigue was negatively linked to lymphocyte counts (weight = - 0.161), and affective fatigue was positively associated with neutrophil counts (weight = 0.070). Additionally, physical fatigue was positively linked to the platelet-to-lymphocyte ratio (PLR) (weight = 0.049). CONCLUSION: There were preliminary associations of counts of three WBC types, platelet counts, and systemic inflammatory indices, with distinct dimensions of CRF in patients with BC. Findings provide empirical support for the cellular basis of fatigue-associated inflammatory states.

Efficacy of varenicline or bupropion and its association with nicotine metabolite ratio among smokers with COPD.

BACKGROUND AND OBJECTIVE: Nicotine metabolic ratio (NMR) has been associated with nicotine metabolism and smoking characteristics. However, there are few studies on the potential association between NMR and smoking cessation efficacy in smokers with chronic obstructive pulmonary disease (COPD) in China or elsewhere. METHODS: This study was a stratified block randomized controlled trial for smoking cessation in Chinese smokers with COPD. NMR was used as a stratification factor; slow metabolizers were defined as those with NMR <0.31, and normal metabolizers as those with NMR ≥0.31. Participants were randomly assigned to the varenicline or bupropion group. Follow-up visits were conducted at 1, 2, 4, 6, 9, 12 and 24 weeks. RESULTS: Two hundred twenty-four participants were recruited and analysed from February 2019 to June 2022. In normal metabolizers, the 9-12 weeks continuous abstinence rate of varenicline (43.1%) was higher than in bupropion (23.5%) (OR = 2.47, 95% CI 1.05-5.78, p = 0.038). There was no significant difference in abstinence rates between treatment groups in slow metabolizers (54.1% vs. 45.9%, OR = 1.39, 95% CI 0.68-2.83, p = 0.366). For slow metabolizers, the total score of side effects in the varenicline group was significantly higher than the bupropion group (p = 0.048), while there was no significant difference in side effects between groups for normal metabolizers (p = 0.360). CONCLUSION: Varenicline showed better efficacy than bupropion in normal metabolizers, and bupropion showed equivalent efficacy in slow metabolizers with less side effects. According to our study, NMR provides a better justification for both scientific research and tailoring optimal pharmacotherapy for smoking cessation among smokers in COPD.

Associations of inflammation related prenatal adversities with neurodevelopment of offspring in one year: a longitudinal prospective birth cohort study.

BACKGROUND: The recent Maternal Immune Activation (MIA) theory suggests maternal systemic inflammation may serve as a mediator in associations between prenatal maternal adversities and neurodevelopmental diseases in offspring. Given the co-exposure to multiple adversities may be experienced by pregnant person, it is unclear whether a quantitative index can be developed to characterize the inflammation related exposure level, and whether this index is associated with neurodevelopmental delays in offspring. METHODS: Based on Jiangsu Birth Cohort (JBC), a total of 3051 infants were included in the analysis. Inflammation related Prenatal Adversity Index (IPAI) was constructed using maternal data. Neurodevelopmental outcomes were assessed using the Bayley Scales of Infant and Toddler Development, third edition, screening test in one year. Multivariate linear regression and Poisson regression model were performed to analyze the associations between IPAI and neurodevelopment in offspring. RESULTS: Compared with "low IPAI" group, offspring with "high IPAI" have lower scores of cognition, receptive communication, expressive communication, and fine motor. The adjusted ß were - 0.23 (95%CI: -0.42, -0.04), -0.47 (95%CI: -0.66, -0.28), -0.30 (95%CI: -0.49, -0.11), and - 0.20 (95%CI: -0.33, -0.06). Additionally, the elevated risk for noncompetent development of cognition and receptive communication among "high IPAI" group was observed. The relative risk [RR] and 95% confidence interval [CI] were 1.35 (1.01, 1.69) and 1.37 (1.09, 1.72). CONCLUSIONS: Our results revealed a significant association between higher IPAI and lower scores across cognition, receptive communication, expressive communication, and fine motor domains, and an increased risk of noncompetent development in the cognition and receptive communication domains.

Prevalence data for total corneal astigmatism in cataract patients.

PURPOSE: To report the prevalence data for total corneal astigmatism (TCA) in cataract patients. METHODS: The authors retrospectively collected and analyzed the preoperative biometric data of the patients who underwent cataract surgery in the Department of Ophthalmology, Peking University Third Hospital, from January 2019 to May 2023. RESULTS: The mean age of the 10817 patients was 71 ± 10 years; the male/female ratio was 4653/6164. The mean TCA obtained by the IOLMaster 700 (Carl Zeiss Meditec AG, Jena, Germany), the Abulafia-Koch (AK) formula, and the Barrett toric calculator was 1.11 ± 0.81 diopter (D), 1.13 ± 0.75 D, and 1.12 ± 0.74 D respectively, which was significantly greater than the mean standard keratometric (K) astigmatism (0.99 ± 0.75 D) obtained by IOLMaster 700. Against-the-rule (ATR) astigmatism was dominant in all the TCA measurements, and its proportion increased with age. TCA measurements by different methods exhibit high variability, with a total of 1574 (8.9%) data sets from 1016 (9.4%) patients showing a difference larger than 0.5 D in at least one pair of TCA measurements. CONCLUSION: The use of TCA rather than K astigmatism significantly influenced the choice of intraocular lenses (IOLs) as more patients would be candidates for toric IOLs. It was essential to carefully compare and select TCA obtained with multiple methods for optimal postoperative visual quality.

Acute and long COVID-19 symptoms and associated factors in the omicron-dominant period: a nationwide survey via the online platform Wenjuanxing in China.

BACKGROUNDS: To our knowledge, there is no available nationwide data on omicron symptom patterns in China mainland. We aim to determine the acute and long COVID-19 symptoms in the omicron-dominant period and to evaluate its association with risk factors. METHODS: We designed a cross-sectional nationwide study and data about self-reported symptoms were collected by an online platform named Wenjuanxing. Eligible participants were aged 25-65 years and were symptomatic. In this study, the ratios of the number of people of different ages and genders were weighted by the data from the Seventh National Census (2020 years), and validated by a published nationwide representative study through comparing smoking rates. Descriptive indicators were calculated for demographic characteristics, diagnosis ways, and duration time, acute symptoms, hospitalization, severity and long COVID-19 symptoms. And, the associations between risk factors and acute and long COVID-19 symptoms were analyzed by multivariable logistic regression models. RESULTS: A total of 32,528 individuals diagnosed as COVID-19 infection from October 1, 2022 to February 21, 2023 were included. The first three acute symptoms of COVID-19 infection were fever (69.90%), headache (62.63%), and sore throat (54.29%), respectively. The hospitalization rate within 7 days was 3.07% and symptoms disappearance rate within 21 days was 68.84%, respectively. Among 3983 COVID-19 patients with 3 months or more time difference between first infection and participation into the study, the long COVID-19 rate was 19.68% and the primary symptoms were muscle weakness (19.39%), headache (17.98%) and smell/taste disorder (15.18%). Age groups, smoking, marriage status and vaccination were risk factors for numbers of acute phase symptoms and long COVID-19 symptoms. Lastly, female and current smokers also showed more numbers of symptoms during acute infection period. CONCLUSIONS: In Chinese mainland, our respondent indicated that current smokers and women were associated with acute COVID-19 symptoms, which should be treated with caution due to the lack of representative.

Gray matter asymmetry alterations in children and adolescents with comorbid autism spectrum disorder and attention-deficit/hyperactivity disorder.

Despite the high coexistence of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) (ASD + ADHD), the underlying neurobiological basis of this disorder remains unclear. Altered brain structural asymmetries have been verified in ASD and ADHD, respectively, making brain asymmetry a candidate for characterizing this coexisting disorder. Here, we measured the gray matter (GM) volume asymmetry in ASD + ADHD versus ASD without ADHD (ASD-only), ADHD without ASD (ADHD-only), and typically developing controls (TDc). High-resolution T1-weighted data from 48 ASD + ADHD, 63 ASD-only, 32 ADHD-only, and 211 matched TDc were included in our study. We also assessed brain-behavior relationships and the effects of age on GM asymmetry. We found that there were both shared and disorder-specific GM volume asymmetry alterations in ASD + ADHD, ASD-only, and ADHD-only compared with TDc. This finding demonstrates that ASD + ADHD is neither an endophenocopy nor an additive pathology of ASD and ADHD, but an entirely different neuroanatomical pathology. In addition, ASD + ADHD displayed altered GM volume asymmetries in the prefrontal regions responsible for executive function and theory of mind compared with ASD-only. We also found significant effects of age on GM asymmetry. The present study may provide structural insights into the neural basis of ASD + ADHD.

Frequency-Specific Alterations of Fractional Amplitude of Low-Frequency Fluctuations in Adult-Onset Hypothyroidism.

BACKGROUND: The neuropathophysiological mechanisms of brain damage underlying hypothyroidism remain unclear. Fractional amplitude of low-frequency fluctuations (fALFF) has been established as a reliable indicator for investigation of abnormal spontaneous brain activity that occurs at specific frequencies in different types of mental disorder. However, the changes of fALFF in specific frequency bands in hypothyroidism have not yet been investigated. METHODS: Fifty-three hypothyroid patients and 39 healthy controls (HCs) underwent thyroid-related hormone levels tests, neuropsychological assessment, and magnetic resonance imaging (MRI) scans. The fALFF in the standard band (0.01-0.1 Hz), slow-4 (0.027-0.073 Hz), and slow-5 bands (0.01-0.027 Hz) were analyzed. An analysis of Pearson correlation was conducted between fALFF, thyroid-related hormone levels, and neuropsychological scores in hypothyroid patients. RESULTS: Compared to HCs, within the routine band, hypothyroidism group showed significantly decreased fALFF in left lingual gyrus, middle temporal gyrus (MTG), precentral gyrus, calcarine cortex, and right inferior occipital gyrus; within the slow-5 band, the hypothyroidism group exhibited decreased fALFF in left lingual gyrus, MTG, superior temporal gyrus, postcentral gyrus, and paracentral lobule, and increased fALFF in supplementary motor area (SMA) and right middle frontal gyrus; additionally, fALFF in the left lingual gyrus within the routine and slow-5 bands were negatively correlated with the level of thyroid stimulating hormone. CONCLUSIONS: In this study, the slow-5 frequency band exhibits better sensitivity than the standard band in detecting fALFF values. A decrease of fALFF values in the lingual gyrus and MTG was observed in both the standard and slow-5 bands and might present potential neuroimaging biomarkers for hypothyroidism. CLINICAL TRIAL REGISTRATION: No: ChiCTR2000028966. Registered 9 January, 2020, https://www.chictr.org.cn.