Lipid metabolic reprogramming mediated by circulating Nrg4 alleviates metabolic dysfunction-associated steatotic liver disease during the early recovery phase after sleeve gastrectomy.

BACKGROUND: The metabolic benefits of bariatric surgery that contribute to the alleviation of metabolic dysfunction-associated steatotic liver disease (MASLD) have been reported. However, the processes and mechanisms underlying the contribution of lipid metabolic reprogramming after bariatric surgery to attenuating MASLD remain elusive. METHODS: A case-control study was designed to evaluate the impact of three of the most common adipokines (Nrg4, leptin, and adiponectin) on hepatic steatosis in the early recovery phase following sleeve gastrectomy (SG). A series of rodent and cell line experiments were subsequently used to determine the role and mechanism of secreted adipokines following SG in the alleviation of MASLD. RESULTS: In morbidly obese patients, an increase in circulating Nrg4 levels is associated with the alleviation of hepatic steatosis in the early recovery phase following SG before remarkable weight loss. The temporal parameters of the mice confirmed that an increase in circulating Nrg4 levels was initially stimulated by SG and contributed to the beneficial effect of SG on hepatic lipid deposition. Moreover, this occurred early following bariatric surgery. Mechanistically, gain- and loss-of-function studies in mice or cell lines revealed that circulating Nrg4 activates ErbB4, which could positively regulate fatty acid oxidation in hepatocytes to reduce intracellular lipid deposition. CONCLUSIONS: This study demonstrated that the rapid effect of SG on hepatic lipid metabolic reprogramming mediated by circulating Nrg4 alleviates MASLD.

Swimming trapper decreases the proportion of chromosomally unbalanced spermatozoa in human Robertsonian translocation carriers.

BACKGROUND: Carriers of reciprocal translocations often have more unbalanced spermatozoa and higher DNA fragmentation rates, elevating reproductive risk. The simple swim-up method (SSUM) can decrease the amount of spermatozoa with abnormal chromatin structure and fragmented DNA, however, it has limited efficacy in eliminating chromosomally unbalanced sperm. METHODS: The spermatozoa of eight Robertsonian translocation (Rob) carriers were split into three groups: original raw semen group (control group); SSUM and swimming trapper method group (STM) processed semen samples. After different semen preparation procedures, semen qualities, sperm chromosomal aneuploidy, and sperm fragmented DNA were evaluated. RESULTS: Although spermatozoa with higher motility was obtained by both SSUM and STM, the population of faster forward moving sperm was greater with STM as compared to SSUM. While the rates of DNA fragmentation were statistically much lower in both groups than ejaculated semen sample, our data showed better effect on the decrease of DNA fragmentation index (DFI) after selection by STM for patients who have high DFI (>20%) in neat semen. For all patients, significant decrease in the frequency of chromosomally unbalanced spermatozoa was observed after selection using STM. Although similar trends can be seen in the SSUM group, a significant difference was identified in one patient only. CONCLUSIONS: Use of swimming trapper (STM) is superior for enriching high-motile and genetically competent sperm in comparison with SSUM.

Should non-invasive prenatal testing be recommended for patients who achieve pregnancy with PGT?

OBJECTIVE: To determine whether non-invasive prenatal testing is an alternative testing option to preimplantation genetic testing (PGT) in pregnant patients. METHODS: This was a retrospective study of the clinical outcomes of patients who underwent PGT and invasive or non-invasive pregnancy testing after euploid blastocyst transfer at our IVF centre between January 2017 and December 2022. RESULTS: In total, 321 patients were enrolled in this study, 138 (43.0%) received invasive pregnancy testing, and 183 (57.0%) patients underwent non-invasive testing. The mean age of the patients in Group 2 was higher than that of the patients in Group 1 (35.64 ± 4.74 vs. 31.04 ± 4.15 years, P < 0.001). The basal LH and AMH levels were higher in Group 1 than in Group 2 (4.30 ± 2.68 vs. 3.40 ± 1.88, P = 0.003; 5.55 ± 11.22 vs. 4.09 ± 3.55, P = 0.012), but the clinical outcomes were not significantly different. Furthermore, the clinical outcomes of patients undergoing invasive testing were similar to those of patients undergoing non-invasive testing with the same PGT indication. CONCLUSION: Our results suggest that non-invasive pregnancy testing is a suitable alternative option for detecting the foetal chromosomal status in a PGT cycle. However, the usefulness of non-invasive testing in PGT-M patients is still limited.

Agriculture land use transformation: A threat to sustainable food production systems, rural food security, and farmer well-being?

The acquisition of agricultural land is a crucial aspect of survival for numerous rural communities, serving as a fundamental tool for combating poverty and food insecurity and promoting equitable sustainable economic progress. The expropriation of land offers a promising prospect for remedying past inequities and promoting both economic progress and food sufficiency. Limited research has examined the association between land expropriation and food security, livelihood shocks, and the well-being of rural households worldwide. Therefore, this research explores the implications of land expropriation on food security, livelihood shocks, and well-being of land lost rural communities. The data were collected from 384 farmers selected through stratified sampling techniques using face-to-face surveys in rural China. The data were analyzed using descriptive and logit regression models. The descriptive findings showed that land expropriation has detrimental effects on the livelihood, food security, and well-being of the farmers. Furthermore, these impacts are more harmful among land-expropriated households with a lower educational level, a large family size, and women farmers in less developed rural communities. The econometric results evinced that gender, age, education level, marital status, family size, and negative changes in income all significantly affect the impact of land expropriation on the food security of farmers. Similarly, the findings revealed that farmers with lower education levels were more likely to be affected by land loss as compared to farmers with medium and high education levels. Farmers with complete land loss were 1.70 times more likely to suffer livelihood shocks than those with partial land loss. The results also evinced that the well-being of all farmers was not affected equally, and some farmers' well-being was affected more than others due to various socioeconomic backgrounds. Therefore, this study suggests the implementation of public policies that provide support to farmers who have been marginalized due to land acquisition.

Spatial proteomics of immune microenvironment in nonalcoholic steatohepatitis-associated hepatocellular carcinoma.

BACKGROUND AND AIMS: NASH-HCC is inherently resistant to immune checkpoint blockade, but its tumor immune microenvironment is largely unknown. APPROACH AND RESULTS: We applied the imaging mass cytometry to construct a spatially resolved single-cell atlas from the formalin-fixed and paraffin-embedded tissue sections from patients with NASH-HCC, virus-HCC (HBV-HCC and HCV-HCC), and healthy donors. Based on 35 biomarkers, over 750,000 individual cells were categorized into 13 distinct cell types, together with the expression of key immune functional markers. Higher infiltration of T cells, myeloid-derived suppressor cell (MDSCs), and tumor-associated macrophages (TAMs) in HCC compared to controls. The distribution of immune cells in NASH-HCC is spatially heterogeneous, enriched at adjacent normal tissues and declined toward tumors. Cell-cell connections analysis revealed the interplay of MDSCs and TAMs with CD8 + T cells in NASH-HCC. In particular, exhausted programmed cell death 1 (PD-1 + )CD8 + T cells connected with programmed cell death-ligand 1 (PD-L1 + )/inducible T cell costimulator (ICOS + ) MDSCs and TAMs in NASH-HCC, but not in viral HCC. In contrast, CD4 + /CD8 + T cells with granzyme B positivity were reduced in NASH-HCC. Tumor cells expressed low PD-L1 and showed few connections with immune cells. CONCLUSIONS: Our work provides the first detailed spatial map of single-cell phenotypes and multicellular connections in NASH-HCC. We demonstrate that interactions between MDSCs and TAMs with effector T cells underlie immunosuppression in NASH-HCC and are an actionable target.

Enhancing Vibrio vulnificus infection diagnosis for negative culture patients with metagenomic next-generation sequencing.

Objective: To evaluate the diagnostic value of metagenomic next-generation sequencing (mNGS) in Vibrio vulnificus (V. vulnificus) infection. Methods: A retrospective analysis of patients with V. vulnificus infection at the Fifth Affiliated Hospital of Sun Yat-Sen University from January 1, 2020 to April 23, 2023 was conducted. 14 enrolled patients were diagnosed by culture or mNGS. The corresponding medical records were reviewed, and the clinical data analyzed included demographics, epidemiology laboratory findings, physical examination, symptoms at presentation, antibiotic and surgical treatment, and outcome. Results: In this study, 78.6% (11/14) patients had a history of marine trauma (including fish stab, shrimp stab, crab splints and fish hook wounds), 7.1% (1/14) had eaten seafood, and the remaining 14.3% (2/14) had no definite cause. Isolation of V. vulnificus from clinical samples including blood, tissue, fester and secreta. 9 cases were positive for culture, 5 cases were detected synchronously by mNGS and got positive for V. vulnificus. 85.7% (12/14) cases accepted surgical treatment, with 1 patient suffering finger amputated. 14 enrolled patients received appropriate antibiotic therapy, and all of them had recovered and discharged. 9 strains V. vulnificus isolated in this study were sensitive to most beta-lactam antibiotics, aminoglycosides, quinolones, etc. Conclusion: Vibrio vulnificus infection is a common water-exposed disease in Zhuhai, which requires identification of a number of pathogens. Of severe infections with unknown pathogen, mNGS can be used simultaneously, and the potential to detect multiple pathogens is of great help in guiding treatment.

Intravenous Administration of an AAV9 Vector Ubiquitously Expressing C1orf194 Gene Improved CMT-Like Neuropathy in C1orf194-/- Mice.

Charcot-Marie-Tooth (CMT) disease, also known as hereditary motor sensory neuropathy, is a group of rare genetically heterogenous diseases characterized by progressive muscle weakness and atrophy, along with sensory deficits. Despite extensive pre-clinical and clinical research, no FDA-approved therapy is available for any CMT type. We previously identified C1ORF194, a novel causative gene for CMT, and found that both C1orf194 knock-in (I121N) and knockout mice developed clinical phenotypes similar to those in patients with CMT. Encouraging results of adeno-associated virus (AAV)-mediated gene therapy for spinal muscular atrophy have stimulated the use of AAVs as vehicles for CMT gene therapy. Here, we present a gene therapy approach to restore C1orf194 expression in a knockout background. We used C1orf194-/- mice treated with AAV serotype 9 (AAV9) vector carrying a codon-optimized WT human C1ORF194 cDNA whose expression was driven by a ubiquitously expressed chicken ß-actin promoter with a CMV enhancer. Our preclinical evaluation demonstrated the efficacy of AAV-mediated gene therapy in improving sensory and motor abilities, thus achieving largely normal gross motor performance and minimal signs of neuropathy, on the basis of neurophysiological and histopathological evaluation in C1orf194-/- mice administered AAV gene therapy. Our findings advance the techniques for delivering therapeutic interventions to individuals with CMT.

Cationic Proteins Rich in Lysine Residue Trigger Formation of Non-bilayer Lipid Phases in Model and Biological Membranes: Biophysical Methods of Study.

Cationic membrane-active toxins are the most abundant group of proteins in the venom of snakes and insects. Cationic proteins such as cobra venom cytotoxin and bee venom melittin are known for their pharmacological reactions including anticancer and antimicrobial effects which arise from the toxin-induced alteration in the dynamics and structure of plasma membranes and membranes of organelles. It has been established that these cationic toxins trigger the formation of non-bilayer lipid phase transitions in artificial and native mitochondrial membranes. Remarkably, the toxin-induced formation of non-bilayer lipid phase increases at certain conditions mitochondrial ATP synthase activity. This observation opens an intriguing avenue for using cationic toxins in the development of novel drugs for the treatment of cellular energy deficiency caused by aging and diseases. This observation also warrants a thorough investigation of the molecular mechanism(s) of lipid phase polymorphisms triggered by cationic proteins. This article presents a review on the application of powerful biophysical methods such as resonance spectroscopy (31P-, 1H-, 2H-nuclear magnetic resonance, and electron paramagnetic resonance), luminescence, and differential scanning microcalorimetry in studies of non-bilayer lipid phase transitions triggered by cationic proteins in artificial and biological membranes. A phenomenon of the triggered by cationic proteins the non-bilayer lipid phase transitions occurring within 10-2-10-11 s is discussed in the context of potential pharmacological applications of cationic proteins. Next to the ATP dimer is an inverted micelle made of cardiolipin that serves as a vehicle for the transport of H+ ions from the intra-crista space to the matrix. It is proposed that such inverted micelles are triggered by the high density of H+ ions and the cationic proteins rich in lysine residue which compete with the conserved lysine residues of the ATP synthase rotor for binding to cardiolipin in the inner mitochondrial membrane and perturb the bilayer lipid packing of cristae. Phospholipids with a blue polar head represent cardiolipin and those with a red polar head represent other phospholipids found in the crista membrane.

Single-cell RNA-sequencing reveals heterogeneity and intercellular crosstalk in human tuberculosis lung.

Lung inflammation indicated by 18F-labeled fluorodeoxyglucose (FDG) in patients with tuberculosis is associated with disease severity and relapse risk upon treatment completion. We revealed the heterogeneity and intercellular crosstalk in lung tissues with 18F-FDG avidity and adjacent uninvolved tissues from 6 tuberculosis patients by single-cell RNA-sequencing. Tuberculous lungs had an influx of regulatory T cells (Treg), exhausted CD8 T cells, immunosuppressive myeloid cells, conventional DC, plasmacytoid DC, and neutrophils. Immune cells in inflamed lungs showed general up-regulation of ATP synthesis and interferon-mediated signaling. Immunosuppressive myeloid and Treg cells strongly displayed transcriptions of genes related to tuberculosis disease progression. Intensive crosstalk between IL4I1-expressing myeloid cells and Treg cells involving chemokines, costimulatory molecules, and immune checkpoints, some of which are specific in 18F-FDG-avid lungs, were found. Our analysis provides insights into the transcriptomic heterogeneity and cellular crosstalk in pulmonary tuberculosis and guides unveiling cellular and molecular targets for tuberculosis therapy.

The Roles of Cultural Capital in Teacher-Student Interactions in China: A Qualitative Study of Students in Higher Vocational Colleges.

The theory of cultural capital has long been applied to explain academic achievement. This qualitative study investigated first-year students in higher vocational colleges and, taking this low cultural capital group as an example, explored how cultural capital has affected their past teacher-student interactions. Participants described their experience of interacting with their teachers. We found that these students primarily experienced authoritative and laissez-faire teacher-student interactions. Students' embodied and institutionalized cultural capital profoundly affected different aspects of the teacher-student interaction. In modern China, vocational and academic education are of the same status, so teachers should modify their evaluations based solely on academic achievement. When interacting with students, teachers should be more understanding and interact in a more student-centred way. Teacher training programmes should also be reformed, and training for teachers in general and vocational schools should be distinguished.

Firing up neutrophil anti-tumor immunity with cocktails.

Neutrophils constitute a considerable proportion of all leukocytes found in tumors and are essential for promoting tumor growth. In this issue, Linde et al. demonstrate that an antibody cocktail therapy consisting of tumor necrosis factor (TNF), anti-CD40 monoclonal antibody, and tumor-binding antibody can boost the anti-tumor activity of neutrophils.

A novel splicing mutation in 5'UTR of GJB1 causes X-linked Charcot-Marie-tooth disease.

BACKGROUND: Charcot-Marie-Tooth (CMT) disease is the most frequent hereditary motor sensory neurological disease. GJB1 gene is the second most frequent cause of CMT, accounting for approximately 10% of CMT cases worldwide. We identified a large Han family with X-linked CMT disease. METHODS: In this study, the probands and his mother underwent electrophysiological examinations and other family members were assessed retrospectively. Whole-exome sequencing, Sanger sequencing, and SNP array linkage analysis were performed to find and confirm the variant. The functional effect of the identified variant was further investigated in HEK293 cells and MCF-7 cells by minigene splicing assay. RESULTS: The affected individuals had some clinical symptoms including symmetric atrophy and progressive weakness of the distal muscles in their twenties. Electrophysiological examinations result in peripheral nerve injury of the upper and lower limbs. Whole-exome sequencing identified a novel hemizygous deletion mutation (NM_000166: c.-16-8_-14del) in the GJB1 gene. SNP array linkage analysis and co-segregation analysis confirmed this mutation. Minigene splicing assay verified that this mutation leads to the activation of cryptic splicing sites in exon 2 which results in the deletion of exon 2. CONCLUSION: Our study provides theoretical guidance for prenatal diagnosis and subsequent fertility of this family. This result expands the spectrum of mutations in GJB1 known to be associated with CMTX and contributes to the diagnosis of CMT and clinical genetic counseling.

Dynamic network biomarker analysis and system pharmacology methods to explore the therapeutic effects and targets of Xiaoyaosan against liver cirrhosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Xiaoyaosan is a traditional Chinese herbal formula that has long been used to treat liver cirrhosis, liver failure, and hepatocarcinoma (HCC). However, little is known about its mechanism of action and targets in treating chronic liver disease. AIM OF THE STUDY: This study aimed to detect the critical transition of HCC progression and to explore the regulatory mechanism and targets of Xiaoyaosan treating liver cirrhosis (cirrhosis) using integrative medicinal research involving system biology and pharmacology. MATERIALS AND METHODS: We recruited chronic liver disease participants to obtain gene expression data and applied the dynamic network biomarker (DNB) method to identify molecular markers and the critical transition. We combined network pharmacology and DNB analysis to locate the potential DNBs (targets). Then we validated the DNBs in the liver cirrhosis rat models using Xiaoyaosan treatment. The expression of genes encoding the four DNBs, including Cebpa, Csf1, Egfr, and Il7r, were further validated in rat liver tissue using Western blot analysis. RESULTS: We found EGFR, CEBPA, Csf1, Ccnb1, Rrmm2, C3, Il7r, Ccna2, and Peg10 overlap in the DNB list and Xiaoyaosan-Target-Disease (XTD) network constructed using network pharmacology databases. We investigated the diagnostic ability of each member in the DNB cluster and found EGFR, CEBPA, CSF1, and IL7R had high diagnostic abilities with AUC >0.7 and P-value < 0.05. We validated these findings in rats and found that liver function improved significantly and fibrotic changes were relieved in the Xiaoyaosan treatment group. The expression levels of CSF1 and IL7R in the Xiaoyaosan group were significantly lower than those in the cirrhosis model group. In contrast, CEBPA expression in the Xiaoyaosan group was significantly higher than that in the cirrhosis model group. The expression of EGFR in the Xiaoyaosan group was slightly decreased than in the model group but not significantly. CONCLUSION: Using the DNB method and network pharmacology approach, this study revealed that CEBPA, IL7R, EGFR, and CSF1 expression was remarkably altered in chronic liver disease and thus, may play an important role in driving the progression of cirrhosis. Therefore, CEBPA, IL7R, EGFR, and CSF1 may be important targets of Xiaoyaosan in treating cirrhosis and can be considered for developing novel therapeutics.

Cell-type-specific synaptic modulation of mAChR on SST and PV interneurons.

The muscarinic acetylcholine receptor (mAChR) antagonist, scopolamine, has been shown to have a rapid antidepressant effect. And it is believed that GABAergic interneurons play a crucial role in this action. Therefore, characterizing the modulation effects of mAChR on GABAergic interneurons is crucial for understanding the mechanisms underlying scopolamine's antidepressant effects. In this study, we examined the effect of mAChR activation on the excitatory synaptic transmissions in two major subtypes of GABAergic interneurons, somatostatin (SST)- and parvalbumin (PV)-expressing interneurons, in the anterior cingulate cortex (ACC). We found that muscarine, a mAChR agonist, non-specifically facilitated the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in both SST and PV interneurons. Scopolamine completely blocked the effects of muscarine, as demonstrated by recovery of sESPCs and mEPSCs in these two types of interneurons. Additionally, individual application of scopolamine did not affect the EPSCs of these interneurons. In inhibitory transmission, we further observed that muscarine suppressed the frequency of both spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs) in SST interneurons, but not PV interneurons. Interestingly, scopolamine directly enhanced the frequency of both sIPSCs and mIPSCs mainly in SST interneurons, but not PV interneurons. Overall, our results indicate that mAChR modulates excitatory and inhibitory synaptic transmission to SST and PV interneurons within the ACC in a cell-type-specific manner, which may contribute to its role in the antidepressant effects of scopolamine.

Concept for Efficient Light Harvesting in Perovskite Materials via Solar Harvester with Multi-Functional Folded Electrode.

Conventional electrodes in typical photodetectors only conduct electrical signals and introduce high optical reflection, impacting the optical-to-electrical conversion efficiency. The created surface solar harvester with a multi-functional folded electrode (MFFE) realizes both a three-dimensional Schottky junction with a larger light detecting area as well as low optical reflection from 300 nm (ultra-violet light) to 1100 nm (near-infrared light) broadly without an additional anti-reflection layer. The MFFE needs silicon etching following the lithography process. The metal silver was deposited over structured silicon, completing the whole device simply. According to the experimental results, the width ratio of the bottom side to the top side in MFFE was 15.75, and it showed an optical reflection of 5-7% within the major solar spectrum of AM1.5G by the gradient refractive index effect and the multi-scattering phenomenon simultaneously. While the perovskite materials were deposited over the MFFE structure of the solar harvester, the three-dimensional electrode with lower optical reflection benefitted the perovskite solar cell with a larger detecting area and an additional anti-reflection function to absorb solar energy more efficiently. In this concept, because of the thin stacked film in the perovskite solar cell, the solar energy could be harvested by the prepared Schottky junction of the solar harvester again, except for the optical absorption of the perovskite materials. Moreover, the perovskite materials deposited over the MFFE structure could not absorb near-infrared (NIR) energies to become transparent. The NIR light could be harvested by the light detecting junction of the solar harvester to generate effective photocurrent output additionally for extending the detection capability of perovskite solar cell further. In this work, the concept of integration of a conventional perovskite solar cell with a silicon-based solar harvester having an MFFE structure was proposed and is expected to harvest broadband light energies under low optical reflection and enhance the solar energy conversion efficiency.

VPS4B deficiency causes early embryonic lethality and induces signal transduction disorders of cell endocytosis.

VPS4B (vacuolar protein sorting 4B), a member of the ATPase associated with diverse cellular activities (AAA) protein family, is a component of the endosomal sorting complexes required for transport machinery which regulates the internalization and lysosomal degradation of membrane proteins. We previously reported that VPS4B is one of the pathogenic genes related to dentin dysplasia type I, although its function was largely unknown. To investigate the role of VPS4B in tooth development, we deleted the Vps4b gene in mice. We found that heterozygous knockout mice (Vps4b+/- ) developed normally and were fertile. However, homozygous deletion of the Vps4b gene resulted in early embryonic lethality of Vps4b-/- mice at approximately embryonic day 9.5 (E9.5). To investigate the underlying molecular mechanisms, we examined the molecular functions of VPS4B in vivo and in vitro. Cell experiments showed that VPS4B influenced the proliferation, apoptosis, and cell cycle of transfected human neuroblastoma cells (IMR-32 cells) with over-expression or knockdown of VPS4B. Moreover, qRT-PCR detection showed that the mRNA expression levels of apoptosis-, cell cycle-, and endocytosis-related genes was significantly down or up-regulated in RNA interference-mediated knockdown of VPS4B in IMR-32 cells and Vps4b+/- E12.5 embryos. We accordingly speculated that signal transduction disorders of cell endocytosis are a contributing factor to the prenatal lethality of Vps4b-/- mice.

The gain-of-function FAM83H mutation caused hypocalcification amelogenesis imperfecta in a Chinese family.

OBJECTIVES: Autosomal-dominant hypocalcification amelogenesis imperfecta (ADHCAI) is a hereditary disease characterized by enamel defects. ADHCAI is mainly caused by nonsense mutations in a gene called family with sequence similarity 83 member H (FAM83H). To study the pathogenesis of ADHCAI, a Chinese ADHCAI family was investigated. MATERIALS AND METHODS: The ultrastructure of enamel was analyzed by micro-CT and scanning electron microscopy. Whole-exome sequencing (WES) was performed to identify the pathogenic gene. The function of the mutant FAM83H was studied by real-time PCR, western blotting, subcellular localization, and protein degradation pathway analyses. RESULTS: WES identified a known nonsense mutation (c.1915A > T) in exon 5 of the FAM83H gene, causing a truncated protein (p.Lys639*). However, the cases reported herein exhibited significant differences in the clinical phenotype compared with that the previously reported case. An abnormal enamel rod head structure was observed in affected teeth. In vitro functional studies showed altered protein localization and a decreased protein degradation rate for mutant FAM83H. CONCLUSIONS: We verified the FAM83H p.Lys639* protein as a gain-of-function variant causing ADHCAI. Abnormal enamel rod head structure was observed in teeth with mutant FAM83H proteins. We also investigated the molecular pathogenesis and presented data on the abnormal degradation of mutant FAM83H proteins. CLINICAL RELEVANCE: This study helped the family members to understand the disease progression and provided new insights into the pathogenesis of ADHCAI. Due to the large heterogeneity of ADHCAI, this study also provided a genetic basis for individuals who exhibit similar clinical phenotypes.

The effect of mGlu2/3 receptors on synaptic activities to different types of GABAergic interneurons in the anterior cingulate cortex.

Antagonists of the group II metabotropic glutamate (mGlu) 2/3 receptors have been shown to have a rapid antidepressant effect. GABAergic interneurons play a crucial role in major depressive disorder (MDD) and possibly mediate the rapid antidepressant effect. However, how mGlu2/3 receptors regulate synaptic activities to GABAergic interneurons is not fully understood. In the present work, we studied the effect of mGlu2/3 receptors on excitatory and inhibitory synaptic activities to somatostatin (SST)- and parvalbumin (PV)-expressing interneurons, two major types of GABAergic interneurons, in the anterior cingulate cortex (ACC) that is strongly indicated in MDD. We found that activation of mGlu2/3 receptors by (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl) glycine (DCG-IV), an agonist of mGlu2/3 receptors, remarkably reduced the frequency, but not the amplitude, of spontaneous and miniature excitatory postsynaptic currents (sEPSCs and mEPSCs) and the amplitude of evoked EPSCs in both types. The reduction in the frequency of sEPSCs and the amplitude of evoked EPSCs was more pronounced in SST interneurons. DCG-IV, however, did not affect spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs) and evoked IPSCs in both types. LY341495, an antagonist of mGlu2/3 receptors, enhanced the amplitude of evoked EPSCs without affecting sEPSCs and mEPSCs in both types. It also did not affect sIPSCs and evoked IPSCs except slightly increasing the frequency of mIPSCs in SST interneurons. Our results indicate that mGlu2/3 receptors primarily regulate excitatory synaptic activities to the two types of GABAergic interneurons in the ACC.

Erratum: Author Correction: "Dysfunctions" induced by Roux-en-Y gastric bypass surgery are concomitant with metabolic improvement independent of weight loss.

[This corrects the article DOI: 10.1038/s41421-019-0138-2.].

"Dysfunctions" induced by Roux-en-Y gastric bypass surgery are concomitant with metabolic improvement independent of weight loss.

Metabolic surgery has been increasingly recommended for obese diabetic patients, but questions remain as to its molecular mechanism that leads to improved metabolic parameters independently of weight loss from a network viewpoint. We evaluated the role of the Roux limb (RL) in Roux-en-Y gastric bypass (RYGB) surgery in nonobese diabetic rat models. Improvements in metabolic parameters were greater in the long-RL RYGB group. Transcriptome profiles reveal that amelioration of diabetes state following RYGB differs remarkably from both normal and diabetic states. According to functional analysis, RYGB surgery significantly affected a major gene group, i.e., the newly changed group, which represented diabetes-irrelevant genes abnormally expressed after RYGB. We hypothesize that novel "dysfunctions" carried by this newly changed gene group induced by RYGB rebalance diabetic states and contribute to amelioration of metabolic parameters. An unusual increase in cholesterol (CHOL) biosynthesis in RL enriched by the newly changed group was concomitant with ameliorated metabolic parameters, as demonstrated by measurements of physiological parameters and biodistribution analysis using [14C]-labeled glucose. Our findings demonstrate RYGB-induced "dysfunctions" in the newly changed group as a compensatory role contributes to amelioration of diabetes. Rather than attempting to normalize "abnormal" molecules, we suggest a new disease treatment strategy of turning "normal" molecules "abnormal" in order to achieve a new "normal" physiological balance. It further implies a novel strategy for drug discovery, i.e. targeting also on "normal" molecules, which are traditionally ignored in pharmaceutical development.