Central inhibition of HDAC6 re-sensitizes leptin signaling during obesity to induce profound weight loss.

Leptin resistance during excess weight gain significantly contributes to the recidivism of obesity to leptin-based pharmacological therapies. The mechanisms underlying the inhibition of leptin receptor (LepR) signaling during obesity are still elusive. Here, we report that histone deacetylase 6 (HDAC6) interacts with LepR, reducing the latter's activity, and that pharmacological inhibition of HDAC6 activity disrupts this interaction and augments leptin signaling. Treatment of diet-induced obese mice with blood-brain barrier (BBB)-permeable HDAC6 inhibitors profoundly reduces food intake and leads to potent weight loss without affecting the muscle mass. Genetic depletion of Hdac6 in Agouti-related protein (AgRP)-expressing neurons or administration with BBB-impermeable HDAC6 inhibitors results in a lack of such anti-obesity effect. Together, these findings represent the first report describing a mechanistically validated and pharmaceutically tractable therapeutic approach to directly increase LepR activity as well as identifying centrally but not peripherally acting HDAC6 inhibitors as potent leptin sensitizers and anti-obesity agents.

SC_LPR: Semantically Consistent LiDAR Place Recognition Based on Chained Cascade Network in Long-Term Dynamic Environments.

In large-scale long-term dynamic environments, high-frequency dynamic objects inevitably lead to significant changes in the appearance of the scene at the same location at different times, which is catastrophic for place recognition (PR). Therefore, how to eliminate the influence of dynamic objects to achieve robust PR has universal practical value for mobile robots and autonomous vehicles. To this end, we suggest a novel semantically consistent LiDAR PR method based on chained cascade network, called SC_LPR, which mainly consists of a LiDAR semantic image inpainting network (LSI-Net) and a semantic pyramid Transformer-based PR network (SPT-Net). Specifically, LSI-Net is a coarse-to-fine generative adversarial network (GAN) with a gated convolutional autoencoder as the backbone. To effectively address the challenges posed by variable-scale dynamic object masks, we integrate the updated Transformer block with mask attention and gated trident block into LSI-Net. Sequentially, in order to generate a discriminative global descriptor representing the point cloud, we design an encoder with pyramid Transformer block to efficiently encode long-range dependencies and global contexts between different categories in the inpainted semantic image, followed by an augmented NetVALD, a generalized VLAD (Vector of Locally Aggregated Descriptors) layer that adaptively aggregates salient local features. Last but not least, we first attempt to create a LiDAR semantic inpainting dataset, called LSI-Dataset, to effectively validate the proposed method. Experimental comparisons show that our method not only improves semantic inpainting performance by about 6%, but also improves PR performance in dynamic environments by about 8% compared to the representative optimal baseline. LSI-Dataset will be publicly available at https://github.KD.LPR.com/.

Effect of bolus materials on dose deposition in deep tissues during electron beam radiotherapy.

Several materials are utilized in the production of bolus, which is essential for superficial tumor radiotherapy. This research aimed to compare the variations in dose deposition in deep tissues during electron beam radiotherapy when employing different bolus materials. Specifically, the study developed general superficial tumor models (S-T models) and postoperative breast cancer models (P-B models). Each model comprised a bolus made of water, polylactic acid (PLA), polystyrene, silica-gel or glycerol. Geant4 was employed to simulate the transportation of electron beams within the studied models, enabling the acquisition of dose distributions along the central axis of the field. A comparison was conducted to assess the dose distributions in deep tissues. In regions where the percentage depth dose (PDD) decreases rapidly, the relative doses (RDs) in the S-T models with silica-gel bolus exhibited the highest values. Subsequently, RDs for PLA, glycerol and polystyrene boluses followed in descending order. Notably, the RDs for glycerol and polystyrene boluses were consistently below 1. Within the P-B models, RDs for all four bolus materials are consistently below 1. Among them, the smallest RDs are observed with the glycerol bolus, followed by silica-gel, PLA and polystyrene bolus in ascending order. As PDDs are ~1-3% or smaller, the differences in RDs diminish rapidly until are only around 10%. For the S-T and P-B models, polystyrene and glycerol are the most suitable bolus materials, respectively. The choice of appropriate bolus materials, tailored to the specific treatment scenario, holds significant importance in safeguarding deep tissues during radiotherapy.

[Meta-analysis on the Effects of Nitrogen Addition on Soil Organic Carbon Content in Terrestrial Ecosystems].

Several studies have demonstrated that the increased deposition of nitrogen(N) has significantly affected the content of soil organic carbon(SOC); however, the change significantly varies in different regions. In this study, Meta-analysis, Meta-regression, and linear regression were performed to systematically evaluate the effects of climate, soil properties, and field design factors on the responses of SOC to N addition based on 408 data points from 49 field experiments in China. The results revealed that the response of SOC to N addition was significantly positively correlated with the mean annual temperature(MAT) and mean annual precipitation(MAP) of the sample sites(P<0.05). In the regions with lower MAT(<3℃) or MAP(<500 mm), SOC significantly decreased after N addition. In the areas with higher MAT(>3℃) or MAP(>500 mm); however, SOC significantly increased. For soil properties, SOC significantly accumulated after N addition in the plots with a higher soil C:N ratio(>15) or acidic soil(pH<6.5) but less changed in the plots with a lower C:N ratio(≤ 15) or higher pH(≥ 6.5). For ecotype, after N addition, SOC decreased significantly in the grassland ecosystem(-5.34%) but less changed in the wetland ecosystem. SOC accumulated the most after N addition in the forest ecosystem(10.52%), particularly in the broad-leaved forest ecosystem(13.10%). Further analysis showed that the soil C:N ratio was the most important factor. For type of N application, the addition of ammonium nitrate or urea increased the SOC content significantly, but the effect of nitrate was not significant. In summary, when accurately evaluating, predicting, and analyzing the effects of N addition on SOC content, the effects of climatic characteristics and soil properties of sample sites and field design factors should be comprehensively considered.

The surgical strategy and technical nuances of in situ side-to-side bypass for the management of complex intracranial aneurysms.

Background: Despite continuous advances in microsurgical and endovascular techniques, the treatment of complex aneurysms remains challenging. Aneurysms that are dilemmatic for conventional clipping or endovascular coiling often require bypass as part of a strategy to reduce the risk of ischemic complications. In anatomically favorable sites, the intracranial-intracranial in situ bypass may be an appealing choice. This article details the surgical strategies, operative nuances, and clinical outcomes of this technique with a consecutive series in our department. Methods: A retrospective review of a prospectively maintained neurosurgical patient database was performed to identify all patients treated with side-to-side in situ bypass from January 2016 to June 2022. In total, 12 consecutive patients, including 12 aneurysms, were identified and included in the series. The medical records, surgical videos, neuroimaging studies, and follow-up clinic notes were reviewed for every patient. Results: Of the 12 aneurysms, there were 5 middle cerebral artery aneurysms, 4 anterior cerebral artery aneurysms, and 3 posterior inferior cerebellar artery aneurysms. The morphology of the aneurysms was fusiform in 8 patients and saccular in the remaining 4 patients. There were 3 patients presented with subarachnoid hemorrhage. The treatment modality was simple in situ bypass in 8 cases and in situ bypass combined with other modalities in 4 cases. Bypass patency was confirmed in all cases by intraoperative micro-doppler probe and (or) infrared indocyanine green (ICG) video angiography intraoperatively and with digital subtraction angiography (DSA) or computed tomography angiography (CTA) postoperatively. None of the patients developed a clinically manifested stroke due to the procedure though a callosomarginal artery was intentionally removed in one patient. The median follow-up period was 16.2 months (6-36). All patients had achieved improved or unchanged modified Rankin scale scores at the final follow-ups. Conclusion: Cerebral revascularization technique remains an essential skill for the treatment of complex aneurysms. The in situ bypass is one of the most effective techniques to revascularize efferent territory when vital artery sacrifice or occlusion is unavoidable. The configuration of in situ bypass should be carefully tailored to each case, with consideration of variations in anatomy and pathology of the complex aneurysms.

Abnormal centriolar biomarker ratios correlate with unexplained bull artificial insemination subfertility: a pilot study.

The mechanisms underlying male infertility are poorly understood. Most mammalian spermatozoa have two centrioles: the typical barrel-shaped proximal centriole (PC) and the atypical fan-like distal centriole (DC) connected to the axoneme (Ax). These structures are essential for fertility. However, the relationship between centriole quality and subfertility (reduced fertility) is not well established. Here, we tested the hypothesis that assessing sperm centriole quality can identify cattle subfertility. By comparing sperm from 25 fertile and 6 subfertile bulls, all with normal semen analyses, we found that unexplained subfertility and lower sire conception rates (pregnancy rate from artificial insemination in cattle) correlate with abnormal centriolar biomarker distribution. Fluorescence-based Ratiometric Analysis of Sperm Centrioles (FRAC) found only four fertile bulls (4/25, 16%) had positive FRAC tests (having one or more mean FRAC ratios outside of the distribution range in a group's high-quality sperm population), whereas all of the subfertile bulls (6/6, 100%) had positive FRAC tests (P = 0.00008). The most sensitive biomarker was acetylated tubulin, which had a novel labeling pattern between the DC and Ax. These data suggest that FRAC and acetylated tubulin labeling can identify bull subfertility that remains undetected by current methods and may provide insight into a novel mechanism of subfertility.

Centrosomal organization of Cep152 provides flexibility in Plk4 and procentriole positioning.

Centriole duplication is a high-fidelity process driven by Polo-like kinase 4 (Plk4) and a few conserved initiators. Dissecting how Plk4 and its receptors organize within centrosomes is critical to understand the centriole duplication process and biochemical and architectural differences between centrosomes of different species. Here, at nanoscale resolution, we dissect centrosomal localization of Plk4 in G1 and S phase in its catalytically active and inhibited state during centriole duplication and amplification. We build a precise distribution map of Plk4 and its receptor Cep152, as well as Cep44, Cep192, and Cep152-anchoring factors Cep57 and Cep63. We find that Cep57, Cep63, Cep44, and Cep192 localize in ninefold symmetry. However, during centriole maturation, Cep152, which we suggest is the major Plk4 receptor, develops a more complex pattern. We propose that the molecular arrangement of Cep152 creates flexibility for Plk4 and procentriole placement during centriole initiation. As a result, procentrioles form at variable positions in relation to the mother centriole microtubule triplets.

Meta-analysis on the effects of nitrogen deposition on soil N2O flux in different habitats.

We carried out a meta-analysis to explore the effects of site characteristics (climatic factors and soil properties) and nitrogen (N) factors on soil nitrous oxide (N2O) flux after N addition based on 290 data from 66 field N addition experiments in China. The results showed that mean annual precipitation, mean annual temperature, ambient N deposition rate, and soil C/N of sites were positively correlated with the increases of N2O flux after N addition. Soil pH was negatively correlated with the increases of N2O flux after N addition. Furthermore, soils in wetland ecosystem were most sensitive to N addition, followed by forest ecosystem, and grassland showed the lowest sensitivity. Among all the site characteristics, soil pH and C/N were the most important factors driving the responses of N2O flux to N addition. Soil N2O flux increased the greatest after nitrate addition. The increase of N2O flux was similar after the addition of urea and ammonium, while N2O flux increased the least when ammonium nitrate was added. In summary, to accurately assess and predict the response of soil N2O flux to N deposition, the effects of site characteristics and N fertilizer types should be comprehensively considered.

Multiple Mesh-type Real Human Cell Models for Dosimetric Application Coupled with Monte Carlo Simulations.

The mesh-type models are superior to voxel models in cellular dose assessment coupled with Monte Carlo codes. The aim of this study was to expand the micron-scale mesh-type models based on the fluorescence tomography of real human cells, and to investigate the feasibility of these models in the application of various irradiation scenarios and Monte Carlo codes. Six different human cell lines, including pulmonary epithelial BEAS-2B, embryonic kidney 293T, hepatocyte L-02, B-lymphoblastoid HMy2.CIR, Gastric mucosal GES-1, and intestine epithelial FHs74Int, were adopted for single mesh-type models reconstruction and optimization based on laser confocal tomography images. Mesh-type models were transformed into the format of polygon mesh and tetrahedral mesh for the GATE and PHITS Monte Carlo codes, respectively. The effect of model reduction was analyzed by dose assessment and geometry consideration. The cytoplasm and nucleus doses were obtained by designating monoenergetic electrons and protons as external irradiation, and S values with different "target-source" combinations were calculated by assigning radioisotopes as internal exposure. Four kinds of Monte Carlo codes were employed, i.e., GATE with "Livermore," "Standard" and "Standard and Geant4-DNA mixed" models for electrons and protons, as well as PHITS with "EGS" mode for electrons and radioisotopes. Multiple mesh-type real human cellular models can be applied to Monte Carlo codes directly without voxelization when combined with certain necessary surface reduction. Relative deviations between different cell types were observed among various irradiation scenarios. The relative deviation of nucleus S value reaches up to 85.65% between L-02 and GES-1 cells by 3H for the "nucleus-nucleus" combination, while that of 293T and FHs74Int nucleus dose for external beams at a 5.12 cm depth of water is 106.99%. Nucleus with smaller volume is far more affected by physical codes. There is a considerable deviation for dose within BEAS-2B at the nanoscale. The multiple mesh-type real cell models were more versatile than voxel models and mathematical models. The present study provided several models which can easily be extended to other cell types and irradiation scenarios for RBE estimations and biological effect predictions, including radiation biological experiments, radiotherapy and radiation protection.

Psychological workplace violence and its influence on professional commitment among nursing interns in China: A multicenter cross-sectional study.

Background: Psychological workplace violence (WPV) is the primary form of workplace violence suffered by nursing interns. Psychological WPV not only damages the physical and mental health of nursing interns, but also has a negative impact on their work quality and career choice. Aim: To investigate the characteristics and types of psychological WPV suffered by nursing interns in China, analyze the influencing factors of psychological WPV among nursing interns, and explore the influence of psychological WPV on the professional commitment of nursing interns. Methods: The subjects were 1,095 nursing interns from 14 medical colleges in Shandong Province. The data were collected electronically using the psychological WPV against nursing interns questionnaire and the professional commitment scale of nursing. The frequency and component ratio were used to describe the incidence and characteristics of psychological WPV. Binary logistic regression was used to analyze the influencing factors of psychological WPV, and linear regression investigated the influence of psychological WPV on the professional commitment of nursing interns. Results: In the study, 45.0% (n = 493) of nursing interns suffered at least one incidence of psychological WPV during clinical practice, mainly discrimination and verbal abuse. Patients and their relatives were the main perpetrators of psychological WPV. Discrimination and lack of trust were the two main reasons behind psychological WPV. Furthermore, 75.9% of psychological WPV incidents were not effectively reported. Logistic regression showed that clinical internship duration, place of family residence, and hospital level were the influencing factors of psychological WPV among nursing interns. Linear regression results showed that psychological WPV had a negative effect on nursing interns' professional commitment. Conclusion: Psychological WPV against nursing interns is highly prevalent in China, negatively impacting their professional commitment. It is suggested that colleges should introduce courses for nursing interns to understand and cope with psychological WPV before entering clinical practice, and hospitals should establish a mechanism to prevent, cope with, report, and deal with psychological WPV to effectively reduce the incidence of psychological WPV against nursing interns, improve their ability to cope with psychological WPV, and enhance their professional commitment.

Impaired Endogenous Neurosteroid Signaling Contributes to Behavioral Deficits Associated With Chronic Stress.

BACKGROUND: Chronic stress is a major risk factor for psychiatric illnesses, including depression. However, the pathophysiological mechanisms whereby stress leads to mood disorders remain unclear. Allopregnanolone acts as a positive allosteric modulator preferentially on δ subunit-containing GABAA (gamma-aminobutyric acid A) receptors. Accumulating clinical and preclinical evidence supports the antidepressant effects of exogenous administration of allopregnanolone analogs; yet, the role of endogenous allopregnanolone in the pathophysiology of depression remains unknown. METHODS: We utilized a chronic unpredictable stress (CUS) mouse model, followed by behavioral and biochemical assays, to examine whether altered neurosteroid signaling contributes to behavioral outcomes following CUS. We subsequently performed in vivo CRISPR (clustered regularly interspaced short palindromic repeats) knockdown of rate-limiting enzymes involved in allopregnanolone synthesis, 5α-reductase type 1 and 2 (5α1/2), in addition to lentiviral overexpression of 5α1/2 in the basolateral amygdala (BLA) of mice that underwent CUS to assess the impact of 5α1/2 on behavioral outcomes. RESULTS: The expression of δ subunit-containing GABAA receptors and endogenous levels of allopregnanolone were reduced in the BLA following CUS. Treatment with an exogenous allopregnanolone analog, SGE-516, was sufficient to increase allopregnanolone levels in the BLA following CUS. Knockdown of 5α1/2 in the BLA mimicked the behavioral outcomes associated with CUS. Conversely, overexpression of 5α1/2 in the BLA improved behavioral outcomes following CUS. CONCLUSIONS: Our findings demonstrate that chronic stress impairs endogenous neurosteroid signaling in the BLA, which is sufficient to induce behavioral deficits. Further, these studies suggest that allopregnanolone-based treatments may directly target the underlying pathophysiology of mood disorders suggesting that targeting endogenous neurosteroidogenesis may offer a novel therapeutic strategy.

Dichotomous regulation of striatal plasticity by dynorphin.

Modulation of corticostriatal plasticity alters the information flow throughout basal ganglia circuits and represents a fundamental mechanism for motor learning, action selection, and reward. Synaptic plasticity in the striatal direct- and indirect-pathway spiny projection neurons (dSPNs and iSPNs) is regulated by two distinct networks of GPCR signaling cascades. While it is well-known that dopamine D2 and adenosine A2a receptors bi-directionally regulate iSPN plasticity, it remains unclear how D1 signaling modulation of synaptic plasticity is counteracted by dSPN-specific Gi signaling. Here, we show that striatal dynorphin selectively suppresses long-term potentiation (LTP) through Kappa Opioid Receptor (KOR) signaling in dSPNs. Both KOR antagonism and conditional deletion of dynorphin in dSPNs enhance LTP counterbalancing with different levels of D1 receptor activation. Behaviorally, mice lacking dynorphin in D1 neurons show comparable motor behavior and reward-based learning, but enhanced flexibility during reversal learning. These findings support a model in which D1R and KOR signaling bi-directionally modulate synaptic plasticity and behavior in the direct pathway.

Human CIDEC transgene improves lipid metabolism and protects against high-fat diet-induced glucose intolerance in mice.

Cell death-inducing DNA fragmentation factor-like effector C (CIDEC) expression in adipose tissue positively correlates with insulin sensitivity in obese humans. Further, E186X, a single-nucleotide CIDEC variant is associated with lipodystrophy, hypertriglyceridemia, and insulin resistance. To establish the unknown mechanistic link between CIDEC and maintenance of systemic glucose homeostasis, we generated transgenic mouse models expressing CIDEC (Ad-CIDECtg) and CIDEC E186X variant (Ad-CIDECmut) transgene specifically in the adipose tissue. We found that Ad-CIDECtg but not Ad-CIDECmut mice were protected against high-fat diet-induced glucose intolerance. Furthermore, we revealed the role of CIDEC in lipid metabolism using transcriptomics and lipidomics. Serum triglycerides, cholesterol, and low-density lipoproteins were lower in high-fat diet-fed Ad-CIDECtg mice compared to their littermate controls. Mechanistically, we demonstrated that CIDEC regulates the enzymatic activity of adipose triglyceride lipase via interacting with its activator, CGI-58, to reduce free fatty acid release and lipotoxicity. In addition, we confirmed that CIDEC is indeed a vital regulator of lipolysis in adipose tissue of obese humans, and treatment with recombinant CIDEC decreased triglyceride breakdown in visceral human adipose tissue. Our study unravels a central pathway whereby adipocyte-specific CIDEC plays a pivotal role in regulating adipose lipid metabolism and whole-body glucose homeostasis. In summary, our findings identify human CIDEC as a potential 'drug' or a 'druggable' target to reverse obesity-induced lipotoxicity and glucose intolerance.

Orexin neurons inhibit sleep to promote arousal.

Humans and animals lacking orexin neurons exhibit daytime sleepiness, sleep attacks, and state instability. While the circuit basis by which orexin neurons contribute to consolidated wakefulness remains unclear, existing models posit that orexin neurons provide their wake-stabilizing influence by exerting excitatory tone on other brain arousal nodes. Here we show using in vivo optogenetics, in vitro optogenetic-based circuit mapping, and single-cell transcriptomics that orexin neurons also contribute to arousal maintenance through indirect inhibition of sleep-promoting neurons of the ventrolateral preoptic nucleus. Activation of this subcortical circuit rapidly drives wakefulness from sleep by differentially modulating the activity of ventrolateral preoptic neurons. We further identify and characterize a feedforward circuit through which orexin (and co-released glutamate) acts to indirectly target and inhibit sleep-promoting ventrolateral preoptic neurons to produce arousal. This revealed circuitry provides an alternate framework for understanding how orexin neurons contribute to the maintenance of consolidated wakefulness and stabilize behavioral state.

CPAP insufficiency leads to incomplete centrioles that duplicate but fragment.

Centrioles are structures that assemble centrosomes. CPAP is critical for centrosome assembly, and its mutations are found in patients with diseases such as primary microcephaly. CPAP's centrosomal localization, its dynamics, and the consequences of its insufficiency in human cells are poorly understood. Here we use human cells genetically engineered for fast degradation of CPAP, in combination with superresolution microscopy, to address these uncertainties. We show that three independent centrosomal CPAP populations are dynamically regulated during the cell cycle. We confirm that CPAP is critical for assembly of human centrioles, but not for recruitment of pericentriolar material on already assembled centrioles. Further, we reveal that CPAP insufficiency leads to centrioles with incomplete microtubule triplets that can convert to centrosomes, duplicate, and form mitotic spindle poles, but fragment owing to loss of cohesion between microtubule blades. These findings further our basic understanding of the role of CPAP in centrosome biogenesis and help understand how CPAP aberrations can lead to human diseases.

Incidence, risk factors and medical cost of peripheral intravenous catheter-related complications in hospitalised adult patients.

BACKGROUND: Peripheral intravenous catheters (PVCs) are widely used vascular access devices for infusion therapy; however, they are associated with relatively high failure rates. This study aimed to identify the incidence, risk factors and medical costs of PVC-induced complications in adult hospitalised adult patients in China. METHODS: An observational, prospective study on 1069 patients lasting 5 months was conducted at a tertiary teaching hospital. RESULTS: Infiltration ranked first among PVC complications with an incidence of 17.8%, followed by occlusion (10.8%) and phlebitis (10.5%). Most complications in phlebitis (88.4%) and infiltration (93.7%) were Grade 1. Catheters left in for over 96 h did not show a higher incidence of complications. Patients from the surgical department were more susceptible to infiltration, phlebitis and occlusion. The 26 gauge (Ga) catheters decreased the risk of phlebitis and occlusion, whereas 24Ga catheters increased infiltration rates. Infusing irritant drugs increased phlebitis and infiltration rates. The presence of comorbidities and non-use of needleless connectors were associated with occlusion. Compared with forearm insertion, the risk of occlusion nearly doubled with the dorsum of the hand insertion and the risk of infiltration tripled with antecubital fossa insertion. Medical treatment costs for PVC complications ranged from 0.3 to 140.0 CNY. CONCLUSIONS: Infiltration is the most common PVC-related adverse event. Clinically-indicated instead of routine replacement of catheters is safe. More efforts are warranted to improve nurses' adherence to recent guidelines in terms of insertion site selection and needleless connector utilisation to reduce medical costs associated with catheter replacement.

Retrospective study of total neoadjuvant therapy for locally advanced rectal cancer.

Aim: To compare treatment outcomes of total neoadjuvant therapy (TNT) and the standard treatment for locally advanced rectal cancer (LARC). Materials & methods: Patients with LARC (cT2-4 and/or cN1-2) who were treated with preoperative chemoradiotherapy plus induction and consolidation chemotherapy followed by surgery or the standard treatment were recruited. Pathologic complete response (pCR) rate, overall survival, disease-free survival and the sphincter preservation rate as well as safety were evaluated. Results: 49 cases were treated with TNT and 71 cases received the standard treatment. Multivariate analysis demonstrated that TNT and tumor size were independent risk factors for pCR. Grade 3 chemoradiotherapy toxicity and postoperative complications were similar between the two groups. Conclusion: TNT improved the pCR rate for patients with LARC, with tolerable toxicities.

Plain language summary Outcomes of two treatment schemes were compared for locally advanced rectal cancer (LARC), including the new preoperative treatment strategy and conventional standard preoperative chemoradiotherapy. The new preoperative treatment strategy includes the addition of four cycles of preoperative chemotherapy to the standard treatment. A total of 49 cases were treated with the new preoperative treatment strategy and 71 cases received the standard treatment. Patients treated with the new preoperative treatment demonstrated higher rates of tumor regression and organ preservation. Additionally, chemoradiotherapy-related toxicity and postoperative complications were similar between the two treatment schemes. However, neither treatment strategy prolonged the survival of patients with LARC. This new preoperative treatment strategy should be recommended first for LARC.

Blocking stanniocalcin 2 reduces sunitinib resistance in clear cell renal cell carcinoma.

Stanniocalcin 2 (STC2) has been identified as a prognostic marker in renal cell carcinoma. However, the role of STC2 in renal cell carcinoma is still unclear. In this study, we investigated the relationship between high expression of STC2 and sunitinib resistance in cells and the underlying mechanism. Through GEPIA platform analysis based on TCGA database, it showed that the expression of STC2 in kidney renal clear cell carcinoma (KIRC) was significantly higher than that in the normal population. Real-time quantitative PCR and western blotting detected significantly higher expression levels of STC2 in clear cell renal cell carcinoma (ccRCC) cells than that in normal renal cells. Enzyme-linked immunosorbent assay (ELISA) determined whether there is a high secretion of STC2 in ccRCC cells. The sunitinib resistance could be significantly reduced by STC2 neutralizing antibody but aggravated by the addition of recombinant human STC2 in ccRCC cells. Sunitinib suppressed STC2 expression and secretion, destroyed lysosomal acidic pH, and accumulated in the cells. However, STC2 neutralizing antibody can reduce the accumulation of sunitinib in cells to improve the inhibitory efficiency of sunitinib on cell proliferation. This study suggested STC2 could serve as a potential novel target for the treatment of ccRCC, anti-STC2 antibody might be an option of immunotherapy in the future.

Orexin receptors 1 and 2 in serotonergic neurons differentially regulate peripheral glucose metabolism in obesity.

The wake-active orexin system plays a central role in the dynamic regulation of glucose homeostasis. Here we show orexin receptor type 1 and 2 are predominantly expressed in dorsal raphe nucleus-dorsal and -ventral, respectively. Serotonergic neurons in ventral median raphe nucleus and raphe pallidus selectively express orexin receptor type 1. Inactivation of orexin receptor type 1 in serotonin transporter-expressing cells of mice reduced insulin sensitivity in diet-induced obesity, mainly by decreasing glucose utilization in brown adipose tissue and skeletal muscle. Selective inactivation of orexin receptor type 2 improved glucose tolerance and insulin sensitivity in obese mice, mainly through a decrease in hepatic gluconeogenesis. Optogenetic activation of orexin neurons in lateral hypothalamus or orexinergic fibers innervating raphe pallidus impaired or improved glucose tolerance, respectively. Collectively, the present study assigns orexin signaling in serotonergic neurons critical, yet differential orexin receptor type 1- and 2-dependent functions in the regulation of systemic glucose homeostasis.

Anterior thalamic dysfunction underlies cognitive deficits in a subset of neuropsychiatric disease models.

Neuropsychiatric disorders are often accompanied by cognitive impairments/intellectual disability (ID). It is not clear whether there are converging mechanisms underlying these debilitating impairments. We found that many autism and schizophrenia risk genes are expressed in the anterodorsal subdivision (AD) of anterior thalamic nuclei, which has reciprocal connectivity with learning and memory structures. CRISPR-Cas9 knockdown of multiple risk genes selectively in AD thalamus led to memory deficits. While the AD is necessary for contextual memory encoding, the neighboring anteroventral subdivision (AV) regulates memory specificity. These distinct functions of AD and AV are mediated through their projections to retrosplenial cortex, using differential mechanisms. Furthermore, knockdown of autism and schizophrenia risk genes PTCHD1, YWHAG, or HERC1 from AD led to neuronal hyperexcitability, and normalization of hyperexcitability rescued memory deficits in these models. This study identifies converging cellular to circuit mechanisms underlying cognitive deficits in a subset of neuropsychiatric disease models.