MYT1L haploinsufficiency in human neurons and mice causes autism-associated phenotypes that can be reversed by genetic and pharmacologic intervention.

MYT1L is an autism spectrum disorder (ASD)-associated transcription factor that is expressed in virtually all neurons throughout life. How MYT1L mutations cause neurological phenotypes and whether they can be targeted remains enigmatic. Here, we examine the effects of MYT1L deficiency in human neurons and mice. Mutant mice exhibit neurodevelopmental delays with thinner cortices, behavioural phenotypes, and gene expression changes that resemble those of ASD patients. MYT1L target genes, including WNT and NOTCH, are activated upon MYT1L depletion and their chemical inhibition can rescue delayed neurogenesis in vitro. MYT1L deficiency also causes upregulation of the main cardiac sodium channel, SCN5A, and neuronal hyperactivity, which could be restored by shRNA-mediated knockdown of SCN5A or MYT1L overexpression in postmitotic neurons. Acute application of the sodium channel blocker, lamotrigine, also rescued electrophysiological defects in vitro and behaviour phenotypes in vivo. Hence, MYT1L mutation causes both developmental and postmitotic neurological defects. However, acute intervention can normalise resulting electrophysiological and behavioural phenotypes in adulthood.

Development and validation of a predictive model for acute kidney injury in patients with ureterolithiasis.

OBJECTIVES: This study aims to identify risk factors for acute kidney injury (AKI) in patients with ureterolithiasis and to develop a predictive model for early AKI detection in this population. METHODS: A retrospective analysis was conducted on data from 1,016 patients with ureterolithiasis who presented to our outpatient emergency department between January 2021 and December 2022. Using multifactorial logistic regression, we identified independent risk factors for AKI and constructed a nomogram to predict AKI risk. The predictive model's efficacy was assessed through the area under the ROC curve, calibration curves, Hosmer-Lemeshow (HL) test, and decision curve analysis (DCA). RESULTS: AKI was diagnosed in 18.7% of the patients. Independent risk factors identified included age, fever, diabetes, hyperuricemia, bilateral calculi, functional solitary kidney, self-medication, and prehospital delay. The nomogram demonstrated excellent discriminatory capabilities, with AUCs of 0.818 (95% CI, 0.775-0.861) for the modeling set and 0.782 (95% CI, 0.708-0.856) for the validation set. Both calibration curve and HL test results confirmed strong concordance between the model's predictions and actual observations. DCA highlighted the model's significant clinical utility. CONCLUSIONS: The predictive model developed in this study provides clinicians with a valuable tool for early identification and management of patients at high risk for AKI, thereby potentially enhancing patient outcomes.

Quantitative proteomics analysis reveals the key proteins related to semen quality in Niangya yaks.

BACKGROUND: Proteins related to sperm motility and sperm morphology have an important impact on sperm function such as metabolism, motility and fertilisation etc. An understanding of the key proteins related to semen quality in Niangya yaks would help to provide support for breeding. However, the key proteins that affect semen quality in Niangya yaks remain unclear. METHODS: Herein, we applied tandem mass tag (TMT) labeling and liquid chromatography-tandem mass spectrometry (LC‒MS/MS) to analyze the expression levels of sperm proteins in groups of high- and low-quality semen from Niangya yaks. And fifteen differentially expressed proteins (DEPs) were randomly selected for expression level validation by parallel reaction monitoring (PRM). RESULTS: Of the 2,092 quantified proteins, 280 were identified as DEPs in the high-quality group versus the low-quality group. Gene Ontology (GO) analysis revealed that in terms of biological pathways, the DEPs were mainly involved in metabolic processes, cell transformation processes, and single organism metabolic processes. In terms of cell composition, the DEPs were mainly located in the cell membrane, organelle, molecular complex. In terms of molecular functions, the most abundant functions of the DEPs were catalytic activity, binding activity, transport activity, and enzyme regulation activity. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that the DEPs were mainly involved in the cytokine and cytokine receptor interaction, notch signaling pathway, lysine biosynthesis, renal function-related protein and proteasome pathway. From protein-protein interaction (PPI) analysis of DEPs involved in important pathways, 6 related proteins affecting the semen quality of Niangya yaks were identified. And the results of the PRM and TMT analysis were consistent. CONCLUSIONS: The differential sperm proteomic analysis of high- and low-quality semen from Niangya yaks, revealed 6 proteins (PSMC5, PSMD8, PSMB3, HSP90AA1, UGP2 and HSPB1), were mainly concentrated in energy production and metabolism, might play important roles in semen quality, which could serve as candidates for the selection and breeding of Niangya yaks.

The Selective Trigeminal Nerve Motor Branching Transfer: an Preliminary Clinical Application for Facial Reanimation.

OBJECTIVE: To investigate the effectiveness and feasibility of selective trigeminal nerve motor branching in the repair of facial palsy. MATERIALS AND METHODS: The clinical data of patients with advanced facial palsy from 2016 to 2021 were retrospectively analyzed, including pictures and videos before and 18 months after surgery. The House-Brackmann grading system was used to evaluate facial nerve function before and after repair, and the symmetry scale of oral commissure at rest and Terzis' smile functional evaluation scale were used to qualitatively assess the symmetry of the mouth angle and smile function. The distance of oral commissure movement was assessed to evaluate the dynamic repair effect, and the FaCE facial muscle function scale was used to assess patients' subjective perception before and after surgery. RESULTS: A total of four patients were included in the study, all of whom showed signs of recovery of facial nerve function within six months. In all four cases, significant improvements were observed in House-Brackmann ratings, the smile function score and the symmetry scale of oral commissure at rest. Compared to the pre-operative period, the four patients demonstrated various degrees of eye-closing function recovery, and a significant improvement in oral commissure movement was observed ( P <0.001). FaCE scores also improved significantly after surgery ( P =0.019). CONCLUSION: Concurrent selective facial nerve repair with trigeminal branch-facial nerve anastomosis resulted in eye-closing function recovery while improving static and dynamic symmetry, yielding acceptable postoperative results.

Evaluation of antioxidation, regulation of glycolipid metabolism and potential as food additives of exopolysaccharide from Sporidiobolus pararoseus PFY-Z1.

At present, there are relatively few studies on the production of exopolysaccharide (EPS) by yeasts. Therefore, exploring the properties of EPS produced by yeast can not only enrich the source of EPS, but also play an important role in its future application in the food field. The aim of this study was to explore the biological activities of EPS (named SPZ) from Sporidiobolus pararoseus PFY-Z1, as well as the dynamic changes in physical and chemical properties that occur during simulated gastrointestinal digestion, and the effects of SPZ on microbial metabolites during fecal fermentation in vitro. The results revealed that SPZ had good water solubility index, water-holding capacity, emulsifying ability, coagulated skim milk, antioxidant properties, hypoglycemic activities, and bile acid-binding abilities. Furthermore, the content of reducing sugars increased from 1.20 ± 0.03 to 3.34 ± 0.11 mg/mL after gastrointestinal digestion, and had little effect on antioxidant activities. Moreover, SPZ could promote the production of short-chain fatty acids during fermentation for 48 h, in particular, propionic acid and n-butyric acid increased to 1.89 ± 0.08 and 0.82 ± 0.04 mmol/L, respectively. Besides this, SPZ could inhibit LPS production. In general, this study can help us to better understand the potential bioactivities, and the changes in bio-activities of compounds after digestion of SPZ.

Unravelling the Superiority of Nonbenzenoid Acepleiadylene as a Building Block for Organic Semiconducting Materials.

Acepleiadylene (APD), a nonbenzenoid isomer of pyrene, exhibits a unique charge-separated character with a large molecular dipole and a small optical gap. However, APD has never been explored in optoelectronic materials to take advantage of these appealing properties. Here, we employ APD as a building block in organic semiconducting materials for the first time, and unravel the superiority of nonbenzenoid APD in electronic applications. We have synthesized an APD derivative (APD-IID) with APD as the terminal donor moieties and isoindigo (IID) as the acceptor core. Theoretical and experimental investigations reveal that APD-IID has an obvious charge-separated structure and enhanced intermolecular interactions as compared with its pyrene-based isomers. As a result, APD-IID displays significantly higher hole mobilities than those of the pyrene-based counterparts. These results imply the advantages of employing APD in semiconducting materials and great potential of nonbenzenoid polycyclic arenes for optoelectronic applications.

Development of SSR markers and genetic diversity analysis based on RAD-seq technology among Chinese populations of Daphnia magna.

BACKGROUND: Daphnia magna belongs to the Cladocera order and plays an important role in the aquatic ecosystem. With the intensification of water pollution, the wild population of D. magna has declined rapidly in recent years, and insufficient molecular markers have limited effective research and conservation of this species. METHODS AND RESULTS: 26 novel microsatellite (SSR) markers were developed in an artificially domesticated D. magna and 12 wild D. magna populations using restriction site-associated DNA sequencing (RAD-seq). The results showed that the observed heterozygosity (Ho) and expected heterozygosity (He) ranged from 0.083 to 0.999 and 0.085 to 0.862, respectively. The PIC ranged from 0.368 to 0.805. These results indicate that the developed SSR marker is highly polymorphic. Nei's genetic identity (H) ranged from 0.0926 to 0.3462. Shannon's Information index (I) ranged from 0.1333 to 0.4799. Genetic distance and Nei's genetic identity analysis, NJ tree diagram analysis, and PCoA analysis were conducted on populations of D. magna from different regions. The results show that the D. magna genetic relationship between Liaoning and Shanxi, Hunan and Anhui, and Beijing and Hainan are relatively close, while the genetic structure of D. magna in Guangdong, Jiangsu, and Sichuan is quite different from other sampling sites. An analysis of population genetic structure divided the D. magna samples into two major groups. CONCLUSIONS: These results indicate that the genetic structure of D. magna differs considerably in different regions. Our research results and the newly developed polymorphic SSR markers for D. magna are of great significance in terms of the genetic breeding of D. magna, identification of wild and artificially domesticated populations and conservation genetics research.

Production, characterization and antioxidant activity of exopolysaccharide from Sporidiobolus pararoseus PFY-Z1.

At present, the study on exopolysaccharid is mainly focused on lactic acid bacteria, and the research on exopolysaccharide produced by yeast, especially Sporidiobolus pararoseus, is relatively few. Therefore, the aim of this study was to explore the characterization and antioxidant activities of a novel neutral exopolysaccharide SPZ, which was isolated and purified from S. pararoseus PFY-Z1. The results showed that SPZ was mainly composed of mannose, followed by glucose, with a molecular weight was 24.98 kDa, had O-glycosidic bonds, no crystalline, and no triple helix structure. Based on fourier transform-infrared, high-performance liquid chromatography and nuclear magnetic resonance analyses, SPZ was identified to be a exopolysaccharide with some side chains, presence of α-, ß-pyranose ring and nine sugar residues. Furthermore, the morphology features of SPZ have performed a relatively rough and uneven surface, covered with small pores and fissures. Moreover, SPZ had higher antioxidant activities and the maximum scavenging abilities of ⋅OH, NO2- and reducing power were 28.05 ± 0.73%, 92.76 ± 1.86% and 0.345 ± 0.024, respectively. Hence, SPZ could be used as a potential antioxidant application in the food and pharmaceutical industries.

Tuning Intramolecular Stacking of Rigid Heteroaromatic Compounds for High-Efficiency Deep-Blue Through-Space Charge-Transfer Emission.

A series of ultrapure-blue thermally activated delayed fluorescence (TADF) emitters featuring through-space charge transfer (TSCT) have been constructed by close stacking between the donor and acceptor moieties in rigid heteroaromatic compounds. The obviously accelerated radiative transition of singlet excitons, the diminished vibrionic relaxation of ground and excited states, and the consequent reduced Stokes shift and the narrow emission are evident. The corresponding organic light-emitting diodes (OLEDs) based on AC-BO realize the best performance among all deep-blue TSCT-TADF emitters, with an external quantum efficiency (EQEmax ) of 19.3 %. Furthermore, the OLEDs based on QAC-BO display an EQEmax of 15.8 %, and achieve the first high-efficiency ultrapure-blue TSCT-TADF material with an excellent Commission Internationale de L'Eclairage coordinate (CIE) of (0.145, 0.076) which perfectly matches the ultrapure-blue CIE requirements (0.14, 0.08) defined by the National Television System Committee.

Asymmetrical-Dendronized TADF Emitters for Efficient Non-doped Solution-Processed OLEDs by Eliminating Degenerate Excited States and Creating Solely Thermal Equilibrium Routes.

The mechanism of thermally activated delayed fluorescence (TADF) in dendrimers is not clear. We report that fully-conjugated or fully-nonconjugated structures cause unwanted degenerate excited states due to multiple identical dendrons, which limit their TADF efficiency. We have synthesized asymmetrical "half-dendronized" and "half-dendronized-half-encapsulated" emitters. By eliminating degenerate excited states, the triplet locally excited state is ≥0.3 eV above the lowest triplet charge-transfer state, assuring a solely thermal equilibrium route for an effective spin-flip process. The isolated encapsulating tricarbazole unit can protect the TADF unit, reducing nonradiative decay and enhancing TADF performance. Non-doped solution-processed devices reach a high external quantum efficiency (EQEmax ) of 24.0 % (65.9 cd A-1 , 59.2 lm W-1 ) with CIE coordinates of (0.24, 0.45) with a low efficiency roll-off and EQEs of 23.6 % and 21.3 % at 100 and 500 cd m-2 .

Photoluminescent Behaviors of Thermally Activated Delayed Fluorescence Polymeric Emitters in Nanofibers.

Anisotropic 1D nanostructures with high surface-area-to-volume ratio display the enhanced optoelectronic properties of light-emitting compounds compared to bulk or 2D systems. To study the effect of nanometer-constrained space on photoluminescent behavior of thermally activated delayed fluorescence (TADF) polymeric emitters, electrospinning technique is used to produce nanofibers of TADF emitters. Herein, two TADF polymer (P1 and P3) nanofibers with 90% polyacrylonitrile (PAN) are fabricated and their photophysical properties are studied and compared with their spin-coated film counterparts. The distinguishing polarized photoluminescencent properties of P1/PAN or P3/PAN electrospun nanofibers are obtained due to high orientation degree and superior molecular arrangement. Moreover, the better TADF properties in nanofibers can be observed comparing with their spin-coated films, including longer-lived excited states, higher photoluminescence quantum efficiency, lower internal conversion decay rate, and higher reverse intersystem crossing rate constant.

Peri-operative diaphragm ultrasound as a new method of recognizing post-operative residual curarization.

BACKGROUND: This study sought to evaluate the diagnostic accuracy of peri-operative diaphragm ultrasound in assessing post-operative residual curarization (PORC). METHODS: Patients undergoing non-thoracic and non-abdominal surgery under general anaesthesia were enrolled from July 2019 to October 2019 at Peking Union Medical College Hospital. A train-of-four ratio (TOFr) lower than 0.9 was considered as the gold standard for PORC. Diaphragm ultrasound parameters included diaphragmatic excursion (DE) and diaphragm thickening fraction (DTF) during quiet breathing (QB) and deep breathing (DB). The diaphragm excursion fraction (DEF) was calculated as the DE-QB divided by the DE-DB. The diaphragm excursion difference (DED) was defined as DE-DB minus DE-QB. Receiver operating characteristic curve analysis was used to determine the cut-off values of ultrasound parameters for the prediction of PORC. RESULTS: In total, 75 patients were included, with a PORC incidence of 54.6%. The DE-DB and DED were positively correlated with the TOFr, while the DEF was negatively correlated with the TOFr. The DE-DB cut-off value for predicting PORC was 3.88 cm, with a sensitivity of 85.4% (95% confidence interval [CI]: 70.1-93.9%), specificity of 64.7% (95% CI: 46.4-79.7%), positive likelihood ratio of 2.42 (95% CI 1.5-3.9), and negative likelihood ratio of 0.23 (95% CI: 0.1-0.5). The DED cut-off value was 1.5 cm, with a specificity of 94.2% (95% CI: 80.3-99.3%), sensitivity of 63.4% (95% CI: 46.9-77.9%), positive likelihood ratio of 10.78 (95% CI: 2.8-42.2), and negative likelihood ratio of 0.39 (95% CI: 0.3-0.6). CONCLUSIONS: Peri-operative diaphragm ultrasound may be an additional method aiding the recognition of PORC, with DED having high specificity.

Clinical features and outcomes of patients with cblC type methylmalonic acidemia carrying gene c.609G>A mutation.

To explore the clinical features and long-term outcomes of patients with cblC type methylmalonic acidemia (MMA) carrying c.609G>A (p.W203X) mutation of gene. The clinical and laboratory findings of 720 patients with MMA carrying the c.609G>A mutation were retrospectively analyzed. There were 172 cases carrying homozygous mutations of c.609G>A (group A), 169 cases carrying compound heterozygous mutations of c.609G>A with c.482G>A (p.R161Q), c.80A>G or c.394C>T (p.R132X) (group B), and 379 cases carrying compound heterozygous mutations of c.609G>A with c.658_660delAAG(p.K220del), c.315A>Tor c.567dupT(p.I190fs13)(group C).The clinical manifestations, the level of blood acylcarnitine, homocysteine and urinary organic acid, and the therapeutic efficacy were compared among groups. Logistic regression was used to analyze the factors influencing the prognosis of patients. There were 306 patients (42.5%) detected from newborn screening, including 156 cases with disease onset; and 414 patients were not detected from the screening, among whom 10 cases were diagnosed by testing after the sibling confirmed, and the remaining 404 were clinical cases. In 560 patients with disease onset, the median onset age is (3 days to 20 years). The onset age of patients in group B was later than that in group A and group C (<0.01). Patients aged mostly manifested as vomiting, diarrhea, feeding difficulties and convulsions, while those year mostly manifested as movement disorders and mental retardation. Patients with renal disease all carried mutations of c.80A>G or c.482G>A, and patients with pulmonary hypertension all carried c.80A>G mutations. A total of 621 cases had long-term follow-up, 156 cases (25.1%) developed well, 433 cases (69.7%) had development delay and 32 cases (5.2%) died. The available data of 559 cases were analyzed by logistic regression, and the results showed that the neonatal screening, disease onset, age of onset and gene mutation site were significantly associated with the prognosis of patients (<0.05 or <0.01). The c.609G>A mutation in gene is associated with early-onset MMA, and most patients, clinical onset occurred within 1 month after birth. The neonatal screening and early treatment can improve the prognosis of patients,whereas clinical onset is unfavorable for prognosis. Patients with c.609G>A homozygous mutation have a worse prognosis than those with the compound heterozygous mutation of c.609G>A with other mutations.

[A preliminary pharmacophylogenetic study of Solanaceae medicinal plants containing tropane alkaloids].

The Solanaceae plants distributed in China belong to 105 species and 35 varietas of 24 genera. Some medicinal plants of Solanaceae are rich in tropane alkaloids(TAs), which have significant pharmacological activities. In this paper, the geographical distribution, chemical components, traditional therapeutic effect, pharmacological activities, and biosynthetic pathways of TAs in Solanaceous plants were summarized. Besides, the phylogeny of medicinal plants belonging to Solanaceae was visualized by network diagram. Fourteen genera of Solanaceae plants in China contain TAs and have medical records. TAs mainly exist in Datura, Anisodus, Atropa, Physochlaina, and Hyoscyamus. The TAs-containing species were mainly concentrated in Southwest China, and the content of TAs was closely related to plant distribution area and altitude. The Solanaceae plants containing TAs mainly have antispasmodic, analgesic, antiasthmatic, and antitussive effects. Modern pharmacological studies have proved the central sedative, pupil dilating, glandular secretion-inhibiting, and anti-asthma activities of TAs. These pharmacological activities provide a reasonable explanation for the traditional therapeutic efficacy of tropane drugs. In this paper, the geographical distribution, chemical components, traditional therapeutic effect, and modern pharmacological activities of TAs-containing species in Solanaceae were analyzed for the first time. Based on these data, the genetic relationship of TAs-containing Solanaceae species was preliminarily discussed, which provided a scientific basis for the basic research on TAs-containing solanaceous species and was of great significance for the development of natural medicinal plant resources containing TAs.

Enhanced Na+ -K+ -2Cl- cotransporter 1 underlies motor dysfunction in huntington's disease.

BACKGROUND: Altered γ-aminobutyric acid signaling is believed to disrupt the excitation/inhibition balance in the striatum, which may account for the motor symptoms of Huntington's disease. Na-K-2Cl cotransporter-1 is a key molecule that controls γ-aminobutyric acid-ergic signaling. However, the role of Na-K-2Cl cotransporter-1 and efficacy of γ-aminobutyric acid-ergic transmission remain unknown in Huntington's disease. METHODS: We determined the levels of Na-K-2Cl cotransporter-1 in brain tissue from Huntington's disease mice and patients by real-time quantitative polymerase chain reaction, western blot, and immunocytochemistry. Gramicidin-perforated patch-clamp recordings were used to measure the Eγ-aminobutyric acid in striatal brain slices. To inhibit Na-K-2Cl cotransporter-1 activity, R6/2 mice were treated with an intraperitoneal injection of bumetanide or adeno-associated virus-mediated delivery of Na-K-2Cl cotransporter-1 short-hairpin RNA into the striatum. Motor behavior assays were employed. RESULTS: Expression of Na-K-2Cl cotransporter-1 was elevated in the striatum of R6/2 and Hdh150Q/7Q mouse models. An increase in Na-K-2Cl cotransporter-1 transcripts was also found in the caudate nucleus of Huntington's disease patients. Accordingly, a depolarizing shift of Eγ-aminobutyric acid was detected in the striatum of R6/2 mice. Expression of the mutant huntingtin in astrocytes and neuroinflammation were necessary for enhanced expression of Na-K-2Cl cotransporter-1 in HD mice. Notably, pharmacological or genetic inhibition of Na-K-2Cl cotransporter-1 rescued the motor deficits of R6/2 mice. CONCLUSIONS: Our findings demonstrate that aberrant γ-aminobutyric acid-ergic signaling and enhanced Na-K-2Cl cotransporter-1 contribute to the pathogenesis of Huntington's disease and identify a new therapeutic target for the potential rescue of motor dysfunction in patients with Huntington's disease. © 2019 International Parkinson and Movement Disorder Society.

Is adjuvant chemotherapy necessary for patients with pathological complete response after neoadjuvant chemoradiotherapy and radical surgery in locally advanced rectal cancer? Long-term analysis of 40 ypCR patients at a single center.

OBJECTIVES: According to practice guidelines, adjuvant chemotherapy (ACT) is required for all patients with locally advanced rectal cancer who have received neoadjuvant chemoradiotherapy (NCRT) and total mesorectal excision (TME). The objective of this study was to determine whether ACT is necessary for patients achieving pathological complete response (pCR) after NCRT followed by surgery. METHODS: By retrospectively reviewing a prospectively collected database in our single tertiary care center, 210 patients with locally advanced rectal cancer who underwent NCRT followed by TME were identified between February 2005 and August 2013. All patients achieving ypCR were enrolled in this study, in which who underwent ACT (chemo group) and who did not (non-chemo group) were compared in terms of local recurrence (LR) rate, 5-year disease-free survival (DFS) rate and overall survival (OS) rate. RESULTS: Forty consecutive patients with ypCR were enrolled, 19 (47.5 %) in chemo group and 21 (52.5 %) in non-chemo group. After a median follow-up of 57 months, five patients developed systemic recurrences, with the 5y-DFS rate of 83.5 %. No LR occurred in the two groups. The 5y-DFS rates for patients in chemo group and non-chemo group was 90.9 and 76.0 %, respectively, showing no statistically significant difference (p = 0.142). Multivariate analysis showed that tumor grade was the only independent prognostic factor for 5y-DFS and 5y-OS. CONCLUSIONS: Results of this study suggested that it may not be necessary for all rectal cancer patients with ypCR after NCRT and radical surgery to receive ACT. Prospective randomized trials are warranted to further determine the value of ACT for ypCR patients.

Revisiting the Lamotrigine-Mediated Effect on Hippocampal GABAergic Transmission.

Lamotrigine (LTG) is generally considered as a voltage-gated sodium (Nav) channel blocker. However, recent studies suggest that LTG can also serve as a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel enhancer and can increase the excitability of GABAergic interneurons (INs). Perisomatic inhibitory INs, predominantly fast-spiking basket cells (BCs), powerfully inhibit granule cells (GCs) in the hippocampal dentate gyrus. Notably, BCs express abundant Nav channels and HCN channels, both of which are able to support sustained action potential generation. Using whole-cell recording in rat hippocampal slices, we investigated the net LTG effect on BC output. We showed that bath application of LTG significantly decreased the amplitude of evoked compound inhibitory postsynaptic currents (IPSCs) in GCs. In contrast, simultaneous paired recordings from BCs to GCs showed that LTG had no effect on both the amplitude and the paired-pulse ratio of the unitary IPSCs, suggesting that LTG did not affect GABA release, though it suppressed cell excitability. In line with this, LTG decreased spontaneous IPSC (sIPSC) frequency, but not miniature IPSC frequency. When re-examining the LTG effect on GABAergic transmission in the cornus ammonis region 1 (CA1) area, we found that LTG markedly inhibits both the excitability of dendrite-targeting INs in the stratum oriens and the concurrent sIPSCs recorded on their targeting pyramidal cells (PCs) without significant hyperpolarization-activated current (Ih) enhancement. In summary, LTG has no effect on augmenting Ih in GABAergic INs and does not promote GABAergic inhibitory output. The antiepileptic effect of LTG is likely through Nav channel inhibition and the suppression of global neuronal network activity.

Rapid dynamic changes of dendritic inhibition in the dentate gyrus by presynaptic activity patterns.

The dentate gyrus (DG) serves as a primary gate to control information transfer from the cortex to the hippocampus. Activation of incoming cortical inputs results in rapid synaptic excitation followed by slow GABA-mediated (GABAergic) synaptic inhibition onto DG granule cells (GCs). GABAergic inhibitory interneurons (INs) in the DG comprise fast-spiking (FS) and non-fast-spiking (non-FS) cells. Anatomical analyses of DG INs reveal that FS cells are soma-targeting INs, whereas non-FS cells are dendrite-targeting INs. These two IN classes are differentially recruited by excitatory inputs and in turn provide exquisite spatiotemporal control over GC activity. Yet, little is known how FS and non-FS cells transform their presynaptic dynamics into varying postsynaptic response amplitudes. Using paired recordings in rat hippocampal slices, we show that inhibition in the DG is dominated by somatic GABAergic inputs during periods of sparse presynaptic activity, whereas dendritic GABAergic inputs are rapidly shifted to powerful and sustained inhibition during periods of intense presynaptic activity. The variant dynamics of dendritic inhibition is dependent on presynaptic IN subtypes and their activity patterns and is attributed to Ca(2+)-dependent increases in the probability of release and the size of the readily releasable pool. Furthermore, the degree of dynamic GABA release can be reduced by blocking voltage-gated K(+) channels, which increases the efficacy of dendrite-targeting IN output synapses during sparse firing. Such rapid dynamic modulation of dendritic inhibition may act as a frequency-dependent filter to prevent overexcitation of GC dendrites and thus set the excitatory-inhibitory synaptic balance in the DG circuits.

Preoperative 6-minute walk distance is associated with postoperative complications in patients undergoing laparoscopic gastrointestinal cancer surgery.

OBJECTIVE: The 6-min walk test (6MWT) is a simple and valid method to evaluate cardiopulmonary function. We performed this prospective study in patients undergoing laparoscopic gastrointestinal cancer surgery to explore the association between preoperative 6MWT performance and overall postoperative complications. METHODS: This study was registered at clinicaltrials.gov (NCT03711526). The study consecutively enrolled patients receiving laparoscopic gastrointestinal cancer surgery in our institution. All patients performed the 6MWT upon recruitment and received 30 days of postoperative follow-up. The primary outcome was overall complications, defined by ≥ grade I Clavien-Dindo (CD) classification (2004) complications. Multivariable logistic regression was used to test the association of 6-min walk distance (6MWD) with the outcome. RESULTS: A total of 184 patients were included in the final analyses. In the 37 (20.1 %) patients with overall complications, the mean (standard deviation) preoperative 6MWD was 469.1 (86.8) m. In patients with no complications, the 6MWD was 502.6 (90.2) m. The mean difference was 33.5 m (95 % confidence interval, 1.3, 65.7; P = 0.042). A longer preoperative 6MWD was associated with a lower odds of developing postoperative complications (odds ratio, 0.994 per meter increase; 95 % confidence interval, 0.989, 0.999; p = 0.023). CONCLUSION: This study indicated an association between the preoperative 6MWD and postoperative complications in patients undergoing laparoscopic gastrointestinal cancer surgery.