Clinical characteristics, imaging diagnostic accuracy, and prognosis of autoimmune pancreatitis: A real-world study in China.

OBJECTIVE: In this study we aimed to comprehensively evaluate the clinical features and treatment outcomes of Chinese patients with autoimmune pancreatitis (AIP) through a single-center real-world study. METHODS: Patients diagnosed with AIP in Changhai Hospital, Naval Medical University from January 2014 to December 2021 were included. Baseline characteristics, laboratory test results, cross-sectional imaging and endoscopic ultrasound (EUS) findings, and long-term follow-up data were obtained. The differences in these characteristics between type 1 and type 2 AIP patients were analyzed. RESULTS: Among all 320 patients, 271 (84.7%) and 49 (15.3%) had type 1 and type 2 AIP, respectively. The most common initial symptom was abdominal discomfort (58.1%), followed by obstructive jaundice (32.5%). Extrapancreatic organ involvement was identified in 126 (39.4%) patients, with the biliary system being the most commonly involved (36.6%). Elevated serum IgG4 level was rare in type 2 AIP patients. The diagnostic accuracy of computed tomography (CT), magnetic resonance imaging (MRI), and EUS for definitive and probable AIP were 78.0%, 68.7%, and 80.5%, respectively. EUS-guided tissue acquisition with immunohistochemical staining helped establish a final diagnosis in 39.7% of patients. During the follow-up period of 60 months, 18.6% of patients experienced relapse. The 1-, 3-, and 5-year relapse rates were higher in type 1 AIP patients, with an accumulated rate of 8.0%, 12.6%, and 15.1%, when compared with those with type 2 AIP. CONCLUSIONS: Type 2 AIP is not uncommon in Chinese population. The diagnostic accuracy of CT and EUS for AIP might be superior to that of MRI.

[Comparative study of total knee arthroplasty assisted by robot and remote sensing navigation system].

OBJECTIVE: To compare clinical efficacy of robot-assisted (RA) and remote sensing navigation alignment (RSNA) system-assisted total knee arthroplasty (TKA). METHODS: From March 2023 to June 2023, 60 patients who underwent the first unilateral TKA due to severe knee osteoarthritis (KOA) were admitted and divided into RSNA group and RA group according to different treatment methods, with 30 patients in each group. There were 5 males and 25 females in RSNA group, aged from 56 to 81 years old with an average of(66.33±7.16) years old;body mass index(BMI) ranged from 19.87 to 38.54 kg·m-2 with an average of (28.40±6.18) kg·m-2;the courses of disease ranged from 5 to 36 months with an average of (18.20±8.98) months; RSNA system was used to assist the positioning of osteotomy. There were 7 males and 23 females in RA group, aged from 55 to 82 years old with an average of (67.83±8.61) years old;BMI ranged from 19.67 to 37.25 kg·m-2 with an average of (28.01±4.89) kg·m-2; the courses of disease ranged from 3 to 33 months with an average of (17.93±9.20) months;RA was performed. Operation time, incision length, latent blood loss at 2 weeks after operation and incidence of lower extremity thrombosis were compared between two groups. Hip-knee ankle angle (HKAA), HKAA deviation, lateral distal femoral angle ( LDFA), medial proximal tibial angle (MPTA) and posterior tibial slope (PTS) were compared between two groups;Western Ontario McMaster Universities Osteoarthritis Index (WOMAC) and Knee Society score (KSS) were used to evaluate functional recovery before operation, 3 and 6 months after operation. RESULTS: The operation was performed successfully in both groups, and there were no serious complications such as vascular and nerve injury during operation. The wound healed well at stageⅠafter operation, and the follow-up time was 6 months. The operation time, latent blood loss at 2 weeks after operation and incision length in RSNA group were (94.35±5.75) min, (130.54±17.53) ml and (14.73±2.14) cm, respectively;while (102.57±6.88) min, (146.33±19.47) ml and (16.78±2.32) cm in RA group, respectively. RSNA group was better than RA group (P<0.05). No deep vein thrombosis occurred in both groups at 2 weeks after operation, 5 patients occurred intermuscular vein thrombosisin in RSNA group and 8 patients in RA group, the difference was not statistically significant (P>0.05). In RSNA group, HKAA, LDFA and MPTA were (173.00±5.54) °, (86.96±3.45) °, (82.79±3.35) ° before operation, and (178.34±1.85) °, (89.92±0.42) °, (89.84±0.73) ° at 1 week after operation, respectively. In RA group, HKAA, LDFA and MPTA were (173.31±6.48) °, (87.15±3.40) ° and (82.99±3.05) ° before operation, and (178.52±1.79) °, (90.03±0.39) ° and (90.15±0.47) ° at 1 week after operation, respectively. HKAA, LDFA and MPTA were significantly improved in both groups at 1 week after operation (P<0.05). There were no significant difference in HKAA, LDFA, MPTA and PTS between two groups before operation and 1 week after operation (P>0.05). There was no significant difference in deviation distribution of HKAA at 1 week after operation (χ2=2.611, P=0.456). There were no significant difference in WOMAC and KSS between two groups before operation, 3 and 6 months after operation (P>0.05), and postoperative WOMAC and KSS at 3 and 6 months between two groups were improved compared with those before operation (P<0.05). CONCLUSION: Both RA and RSNA system assisted TKA could obtain accurate osteotomy, RA has higher surgical accuracy, RSNA system assisted operation has less trauma, and operation is simpler.

[Application of remote sensing navigation system in total knee arthroplasty].

OBJECTIVE: To explore clinical accuracy of remote sensing navigation alignment (RSNA) system in total knee arthroplasty (TKA) and its influence on postoperative clinical efficacy. METHODS: From May 2021 to May 2022, 60 knee osteoarthritis (KOA) patients with Kellgren-Lawrence (K-L) grade Ⅲ to Ⅳ treated by unilateral primary TKA were selected and divided into RSNA group and traditional operation group according to treatment methods, and 30 patients in each group. There were 6 males and 24 females in RSNA group, aged from 55 to 86 years old with an average of (68.06±8.23) years old;body mass index (BMI) ranged from 22.15 to 34.58 kg·m-2 with an average of (28.20±3.01) kg·m-2;the courses of disease ranged from 2 to 60 months with an average of (18.80±14.80) months;13 patients with grade Ⅲ and 17 patients with grade Ⅳ according to K-L grading. In traditional operation group, there were 8 males and 22 females, aged from 57 to 85 years old with an average of (67.26±6.32) years old;BMI ranged from 23.94 to 34.55 kg·m-2 with an average of (27.49±2.32) kg·m-2;the courses of disease ranged from 3 to 60 months with an average of (21.30±16.44) months;14 patients with grade Ⅲ and 16 patients with grade Ⅳ according to K-L grading. Western Ontario and McMaster Universities (WOMAC) osteoarthritis index and Knee Society score(KSS) were used to evaluate functional recovery of patients. Hip-knee-ankle angle (HKAA), distal femoral valgus angle (FVA) and distal fermoral flexion angle (DFFA) were measured before operation. HKAA and HKAA deviation angle were measured at 1 week after operation, and defective rate of lower limb force line, femur prosthesis valgus angle (FPVA) and femoral prosthesis flexion angle (FPFA), respectively, were calculated. RESULTS: There were no serious complications such as vascular and nerve injury during operation, and wound healed at stage Ⅰ. Both groups were followed up for 6 months. There were no significant difference in WOMAC index, KSS, HKAA, FVA and DFFA between two groups before operation (P>0.05). The force line defect rate, HKAA, HKAA deviation angle, FPVA deviation angle and FPFA of RSNA group were 6.7%, (178.74±1.56) °, (1.25±1.56) °, (1.84±0.16) ° and (4.85±2.46) °, respectively;while in traditional operation group were 20%, (176.73±3.46) °, (3.27±3.46) °, (2.44±0.26) °, (6.60±1.86) °;the difference between two groups were statistically significant (P<0.05). There were no significant difference in WOMAC index and KSS between two groups at 3 and 6 months after operation (P>0.05). CONCLUSION: RSNA system could reduce defective rate of lower limb force line, FPVA deviation angle and FPFA after TKA, which is more accurate and easy to operate than traditional intramedullary localization surgery while ensuring postoperative efficacy.

Controlled interconversion of macrocyclic atropisomers via defined intermediates.

Macrocyclic conformations play a crucial role in regulating their properties. Our understanding of the determinants to control macrocyclic conformation interconversion is still in its infancy. Here we present a macrocycle, octamethyl cyclo[4](1,3-(4,6)-dimethylbenzene)[4]((4,6-benzene)(1,3-dicarboxylate) (OC-4), that can exist at 298 K as two stable atropisomers with C2v and C4v symmetry denoted as C2v-OC-4 and C4v-OC-4, respectively. Heating induces the efficient stepwise conversion of C2v- to C4v-OC-4 via a Cs-symmetric intermediate (Cs-OC-4). It differs from the typical transition state-mediated processes of simple C-C single bond rotations. Hydrolysis and further esterification with a countercation dependence promote the generation of C2v- and Cs-OC-4 from C4v-OC-4. In contrast to C2v-OC-4, C4v-OC-4 can bind linear guests to form pseudo-rotaxans, or bind C60 or C70 efficiently. The present study highlights the differences in recognition behavior that can result from conformational interconversion, as well as providing insights into the basic parameters that govern coupled molecular rotations.

FABP3 Induces Mitochondrial Autophagy to Promote Neuronal Cell Apoptosis in Brain Ischemia-Reperfusion Injury.

This study elucidates the molecular mechanisms by which FABP3 regulates neuronal apoptosis via mitochondrial autophagy in the context of cerebral ischemia-reperfusion (I/R). Employing a transient mouse model of middle cerebral artery occlusion (MCAO) established using the filament method, brain tissue samples were procured from I/R mice. High-throughput transcriptome sequencing on the Illumina CN500 platform was performed to identify differentially expressed mRNAs. Critical genes were selected by intersecting I/R-related genes from the GeneCards database with the differentially expressed mRNAs. The in vivo mechanism was explored by infecting I/R mice with lentivirus. Brain tissue injury, infarct volume ratio in the ischemic penumbra, neurologic deficits, behavioral abilities, neuronal apoptosis, apoptotic factors, inflammatory factors, and lipid peroxidation markers were assessed using H&E staining, TTC staining, Longa scoring, rotation experiments, immunofluorescence staining, and Western blot. For in vitro validation, an OGD/R model was established using primary neuron cells. Cell viability, apoptosis rate, mitochondrial oxidative stress, morphology, autophagosome formation, membrane potential, LC3 protein levels, and colocalization of autophagosomes and mitochondria were evaluated using MTT assay, LDH release assay, flow cytometry, ROS/MDA/GSH-Px measurement, transmission electron microscopy, MitoTracker staining, JC-1 method, Western blot, and immunofluorescence staining. FABP3 was identified as a critical gene in I/R through integrated transcriptome sequencing and bioinformatics analysis. In vivo experiments revealed that FABP3 silencing mitigated brain tissue damage, reduced infarct volume ratio, improved neurologic deficits, restored behavioral abilities, and attenuated neuronal apoptosis, inflammation, and mitochondrial oxidative stress in I/R mice. In vitro experiments demonstrated that FABP3 silencing restored OGD/R cell viability, reduced neuronal apoptosis, and decreased mitochondrial oxidative stress. Moreover, FABP3 induced mitochondrial autophagy through ROS, which was inhibited by the free radical scavenger NAC. Blocking mitochondrial autophagy with sh-ATG5 lentivirus confirmed that FABP3 induces mitochondrial dysfunction and neuronal apoptosis by activating mitochondrial autophagy. In conclusion, FABP3 activates mitochondrial autophagy through ROS, leading to mitochondrial dysfunction and neuronal apoptosis, thereby promoting cerebral ischemia-reperfusion injury.

Trends in maternal and child health in China and its urban and rural areas from 1991 to 2020: a joinpoint regression model.

The long-term trends in maternal and child health (MCH) in China and the national-level factors that may be associated with these changes have been poorly explored. This study aimed to assess trends in MCH indicators nationally and separately in urban and rural areas and the impact of public policies over a 30‒year period. An ecological study was conducted using data on neonatal mortality rate (NMR), infant mortality rate (IMR), under-five mortality rate (U5MR), and maternal mortality ratio (MMR) nationally and separately in urban and rural areas in China from 1991 to 2020. Joinpoint regression models were used to estimate the annual percentage changes (APC), average annual percentage changes (AAPC) with 95% confidence intervals (CIs), and mortality differences between urban and rural areas. From 1991 to 2020, maternal and child mortalities in China gradually declined (national AAPC [95% CI]: NMRs - 7.7% [- 8.6%, - 6.8%], IMRs - 7.5% [- 8.4%, - 6.6%], U5MRs - 7.5% [- 8.5%, - 6.5%], MMRs - 5.0% [- 5.7%, - 4.4%]). However, the rate of decline nationally in child mortality slowed after 2005, and in maternal mortality after 2013. For all indicators, the decline in mortality was greater in rural areas than in urban areas. The AAPCs in rate differences between rural and urban areas were - 8.5% for NMRs, - 8.6% for IMRs, - 7.7% for U5MRs, and - 9.6% for MMRs. The AAPCs in rate ratios (rural vs. urban) were - 1.2 for NMRs, - 2.1 for IMRs, - 1.7 for U5MRs, and - 1.9 for MMRs. After 2010, urban‒rural disparity in MMR did not diminish and in NMR, IMR, and U5MR, it gradually narrowed but persisted. MCH indicators have declined at the national level as well as separately in urban and rural areas but may have reached a plateau. Urban‒rural disparities in MCH indicators have narrowed but still exist. Regular analyses of temporal trends in MCH are necessary to assess the effectiveness of measures for timely adjustments.

X-ray Structure-Guided Discovery of a Potent Benzimidazole Glutaminyl Cyclase Inhibitor That Shows Activity in a Parkinson's Disease Mouse Model.

The secretory glutaminyl cyclase (sQC) and Golgi-resident glutaminyl cyclase (gQC) are responsible for N-terminal protein pyroglutamation and associated with various human diseases. Although several sQC/gQC inhibitors have been reported, only one inhibitor, PQ912, is currently undergoing clinic trials for the treatment of Alzheimer's disease. We report an X-ray crystal structure of sQC complexed with PQ912, revealing that the benzimidazole makes "anchor" interactions with the active site zinc ion and catalytic triad. Structure-guided design and optimization led to a series of new benzimidazole derivatives exhibiting nanomolar inhibition for both sQC and gQC. In a MPTP-induced Parkinson's disease (PD) mouse model, BI-43 manifested efficacy in mitigating locomotor deficits through reversing dopaminergic neuronal loss, reducing microglia, and decreasing levels of the sQC/gQC substrates, α-synuclein, and CCL2. This study not only offers structural basis and new leads for drug discovery targeting sQC/gQC but also provides evidence supporting sQC/gQC as potential targets for PD treatment.

A potent new-scaffold androgen receptor antagonist discovered on the basis of a MIEC-SVM model.

Prostate cancer (PCa) is the second most prevalent malignancy among men worldwide. The aberrant activation of androgen receptor (AR) signaling has been recognized as a crucial oncogenic driver for PCa and AR antagonists are widely used in PCa therapy. To develop novel AR antagonist, a machine-learning MIEC-SVM model was established for the virtual screening and 51 candidates were selected and submitted for bioactivity evaluation. To our surprise, a new-scaffold AR antagonist C2 with comparable bioactivity with Enz was identified at the initial round of screening. C2 showed pronounced inhibition on the transcriptional function (IC50 = 0.63 µM) and nuclear translocation of AR and significant antiproliferative and antimetastatic activity on PCa cell line of LNCaP. In addition, C2 exhibited a stronger ability to block the cell cycle of LNCaP than Enz at lower dose and superior AR specificity. Our study highlights the success of MIEC-SVM in discovering AR antagonists, and compound C2 presents a promising new scaffold for the development of AR-targeted therapeutics.

[Research progress on chemical constituents from Kadsura genus and its pharmacological activities and clinical application].

The 29 plant species in the Kadsura genus of the Schisandraceae family are mainly distributed in eastern and southeas-tern Asia. Ten species of plants in this genus are distributed in China, some of which are folk medicinal plants with activating blood circulation, relieving pain, dispelling wind, and dehumidifying effects. Their main constituents are lignans and triterpenes. The current pharmacology and clinical studies have shown that their extracts and constituents have anti-rheumatoid arthritis, liver protection, antioxidation, anti-inflammatory, and other biological activities. The rheumatologic and liver diseases can also be treated with the plants in the clinic. The new chemical constituents reported in the last decade(2012 to date) from the plants of Kadsura genus in China, as well as their pharmacological effects and clinical applications in recent years were reviewed, so as to provide a theoretical basis for further research on the genus.

Advances in injectable hydrogels for radiation-induced heart disease.

Radiological heart damage (RIHD) is damage caused by unavoidable irradiation of the heart during chest radiotherapy, with a long latency period and a progressively increasing proportion of delayed cardiac damage due to conventional doses of chest radiotherapy. There is a risk of inducing diseases such as acute/chronic pericarditis, myocarditis, delayed myocardial fibrosis and damage to the cardiac conduction system in humans, which can lead to myocardial infarction or even death in severe cases. This paper details the pathogenesis of RIHD and gives potential targets for treatment at the molecular and cellular level, avoiding the drawbacks of high invasiveness and immune rejection due to drug therapy, medical device implantation and heart transplantation. Injectable hydrogel therapy has emerged as a minimally invasive tissue engineering therapy to provide necessary mechanical support to the infarcted myocardium and to act as a carrier for various bioactive factors and cells to improve the cellular microenvironment in the infarcted area and induce myocardial tissue regeneration. Therefore, this paper combines bioactive factors and cellular therapeutic mechanisms with injectable hydrogels, presents recent advances in the treatment of cardiac injury after RIHD with different injectable gels, and summarizes the therapeutic potential of various types of injectable hydrogels as a potential solution.

A publicly available newborn ear shape dataset for medical diagnosis of auricular deformities.

Early and accurate diagnosis of ear deformities in newborns is crucial for an effective non-surgical correction treatment, since this commonly seen ear anomalies would affect aesthetics and cause mental problems if untreated. It is not easy even for experienced physicians to diagnose the auricular deformities of newborns and the classification of the sub-types, because of the rich bio-metric features embedded in the ear shape. Machine learning has already been introduced to analyze the auricular shape. However, there is little publicly available datasets of ear images from newborns. We released a dataset that contains quality-controlled photos of 3,852 ears from 1,926 newborns. The dataset also contains medical diagnosis of the ear shape, and the health data of each newborn and its mother. Our aim is to provide a freely accessible dataset, which would facilitate researches related with ear anatomies, such as the AI-aided detection and classification of auricular deformities and medical risk analysis.

Cross-sectional imaging: current status and future potential in adult celiac disease.

Celiac disease (CD), triggered by exposure to gluten in genetically susceptible individuals, is an immune-mediated small bowel disease affecting about 1% of the population worldwide. But the prevalence of CD varies with age, sex, and location. A strict gluten-free diet remains the primary treatment for CD, currently. Most of patients with CD respond well to gluten-free diet with good prognosis, while some patients fail to get symptomatic relief or histological remission (e.g., nonresponsive or refractory CD). Because of heterogeneous clinical appearance, the diagnosis of CD is difficult. Moreover, malignant complications and poor outcomes accompanied with refractory CD present great challenges in disease management. Over the past three decades, cross-sectional imaging techniques (computed tomography [CT] and magnetic resonance imaging [MRI]) play an important role in small bowel inflammatory and neoplastic diseases. Compared with endoscopic techniques, cross-sectional imaging permits clearly presentation of both intraluminal and extraluminal abnormalities. It provides vascular and functional information, thus improving the possibility as diagnostic and follow-up tool. The value of cross-sectional imaging for patients with suspected or confirmed CD has been gradually demonstrated. Studies revealed that certain features suggested by cross-sectional imaging could help to establish the early diagnosis of CD. Besides, the potential contributions of cross-sectional imaging may lie in the evaluation of disease activity and severity, which helps guiding management strategies. The purpose of this review is to provide current overviews and future directions of cross-sectional imaging in adult CD, thus facilitating the understanding and application in clinical practice. CLINICAL RELEVANCE STATEMENT: In this review, we systematically summarized the existing knowledge of cross-sectional imaging in adult CD and analyzed their possible roles in clinical practice, including disease diagnosis, complication identification, treatment evaluation, and prognostic prediction. KEY POINTS: • Regarding a condition described as "celiac iceberg", celiac disease remains underdiagnosed and undertreated. • Cross-sectional imaging is helpful in clinical management of celiac disease, including disease diagnosis, complication identification, treatment evaluation, and prognostic prediction. • Cross-sectional imaging should be considered as the valuable examination in patients suspected from celiac disease.

Glycyrrhizin Protects Submandibular Gland Against Radiation Damage by Enhancing Antioxidant Defense and Preserving Mitochondrial Homeostasis.

Aims: Radiotherapy inevitably causes radiation damage to the salivary glands (SGs) in patients with head and neck cancers (HNCs). Excessive reactive oxygen species (ROS) levels and imbalanced mitochondrial homeostasis are serious consequences of ionizing radiation in SGs; however, there are few mitochondria-targeting therapeutic approaches. Glycyrrhizin is the main extract of licorice root and exhibits antioxidant activity to relieve mitochondrial damage in certain oxidative stress conditions. Herein, the effects of glycyrrhizin on irradiated submandibular glands (SMGs) and the related mechanisms were investigated. Results: Glycyrrhizin reduced radiation damage in rat SMGs at both the cell and tissue levels, and promoted saliva secretion in irradiated SMGs. Glycyrrhizin significantly downregulated high-mobility group box-1 protein (HMGB1) and toll-like receptor 5 (TLR5). Moreover, glycyrrhizin significantly suppressed the increases in malondialdehyde and glutathione disulfide (GSSG) levels; elevated the activity of some critical antioxidants, including superoxide dismutase, catalase, glutathione peroxidase, and glutathione (GSH); and increased the GSH/GSSG ratio in irradiated cells. Importantly, glycyrrhizin effectively enhanced thioredoxin-2 levels and scavenged mitochondrial ROS, inhibited the decline in mitochondrial membrane potential, improved adenosine triphosphate synthesis, preserved the mitochondrial ultrastructure, activated the proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α)/nuclear respiratory factor 1/2 (NRF1/2)/mitochondrial transcription factor A (TFAM) signaling pathway, and inhibited mitochondria-related apoptosis in irradiated SMG cells and tissues. Innovation: Radiotherapy causes radiation sialadenitis in HNC patients. Our data suggest that glycyrrhizin could be a mitochondria-targeted antioxidant for the prevention of radiation damage in SGs. Conclusion: These findings demonstrate that glycyrrhizin protects SMGs from radiation damage by downregulating HMGB1/TLR5 signaling, maintaining intracellular redox balance, eliminating mitochondrial ROS, preserving mitochondrial homeostasis, and inhibiting apoptosis.

Comparative Study of the Structural Characteristics and Bioactivity of Polysaccharides Extracted from Aspidopterys obcordata Hemsl. Using Different Solvents.

The polysaccharides extracted from Aspidopterys obcordata are thought to have anti-urolithiasis activity in Drosophila kidney stones. This study aimed to assess the effects of different extraction solvents on the yield, chemical composition, and bioactivity of polysaccharides from A. obcordata. A. obcordata polysaccharides were extracted by using four solutions: hot water, HCl solution, NaOH solution, and 0.1 M NaCl. The results revealed that the extraction solvents significantly influenced the extraction yields, molecular weight distribution, monosaccharide compositions, preliminary structural characteristics, and microstructures of polysaccharides. The NaOH solution's extraction yield was significantly higher than the other extraction methods. Vitro antioxidant activity assays revealed that the NaOH solution extracted exhibited superior scavenging abilities towards DPPH and ABTS radicals and higher FRAP values than other polysaccharides. The vitro assays conducted for calcium oxalate crystallization demonstrated that four polysaccharides exhibited inhibitory effects on the nucleation and aggregation of calcium oxalate crystals, impeded calcium oxalate monohydrate growth, and induced calcium oxalate dihydrate formation. The NaOH solution extracted exhibited the most pronounced inhibition of calcium oxalate crystal nucleation, while the hot water extracted demonstrated the most significant suppression of calcium oxalate crystal aggregation. Therefore, it can be inferred that polysaccharides extracted with NaOH solution exhibited significant potential as a viable approach for extracting polysaccharides from stems due to their superior yield and the remarkable bioactivity of the resulting products.

Proteomic characterization of epithelial ovarian cancer delineates molecular signatures and therapeutic targets in distinct histological subtypes.

Clear cell carcinoma (CCC), endometrioid carcinoma (EC), and serous carcinoma (SC) are the major histological subtypes of epithelial ovarian cancer (EOC), whose differences in carcinogenesis are still unclear. Here, we undertake comprehensive proteomic profiling of 80 CCC, 79 EC, 80 SC, and 30 control samples. Our analysis reveals the prognostic or diagnostic value of dysregulated proteins and phosphorylation sites in important pathways. Moreover, protein co-expression network not only provides comprehensive view of biological features of each histological subtype, but also indicates potential prognostic biomarkers and progression landmarks. Notably, EOC have strong inter-tumor heterogeneity, with significantly different clinical characteristics, proteomic patterns and signaling pathway disorders in CCC, EC, and SC. Finally, we infer MPP7 protein as potential therapeutic target for SC, whose biological functions are confirmed in SC cells. Our proteomic cohort provides valuable resources for understanding molecular mechanisms and developing treatment strategies of distinct histological subtypes.

Discovery of 2-Aminothiazole-4-carboxylic Acids as Broad-Spectrum Metallo-ß-lactamase Inhibitors by Mimicking Carbapenem Hydrolysate Binding.

Metallo-ß-lactamases (MBLs) are zinc-dependent enzymes capable of hydrolyzing all bicyclic ß-lactam antibiotics, posing a great threat to public health. However, there are currently no clinically approved MBL inhibitors. Despite variations in their active sites, MBLs share a common catalytic mechanism with carbapenems, forming similar reaction species and hydrolysates. We here report the development of 2-aminothiazole-4-carboxylic acids (AtCs) as broad-spectrum MBL inhibitors by mimicking the anchor pharmacophore features of carbapenem hydrolysate binding. Several AtCs manifested potent activity against B1, B2, and B3 MBLs. Crystallographic analyses revealed a common binding mode of AtCs with B1, B2, and B3 MBLs, resembling binding observed in the MBL-carbapenem product complexes. AtCs restored Meropenem activity against MBL-producing isolates. In the murine sepsis model, AtCs exhibited favorable synergistic efficacy with Meropenem, along with acceptable pharmacokinetics and safety profiles. This work offers promising lead compounds and a structural basis for the development of potential drug candidates to combat MBL-mediated antimicrobial resistance.

The thalamic reticular nucleus-lateral habenula circuit regulates depressive-like behaviors in chronic stress and chronic pain.

Chronic stress and chronic pain are two major predisposing factors to trigger depression. Enhanced excitatory input to the lateral habenula (LHb) has been implicated in the pathophysiology of depression. However, the contribution of inhibitory transmission remains unclear. Here, we dissect an inhibitory projection from the sensory thalamic reticular nucleus (sTRN) to the LHb, which is activated by acute aversive stimuli. However, chronic restraint stress (CRS) weakens sTRN-LHb synaptic strength, and this synaptic attenuation is indispensable for CRS-induced LHb neural hyperactivity and depression onset. Moreover, artificially inhibiting the sTRN-LHb circuit induces depressive-like behaviors in healthy mice, while enhancing this circuit relieves depression induced by both chronic stress and chronic pain. Intriguingly, neither neuropathic pain nor comorbid mechanical hypersensitivity in chronic stress is affected by this pathway. Altogether, our study demonstrates an sTRN-LHb circuit in establishing and modulating depression, thus shedding light on potential therapeutic targets for preventing or managing depression.

The Effects of BCDs in Unilateral Conductive Hearing Loss: A Systematic Review.

Bone conduction devices (BCDs) are widely used in the treatment of conductive hearing loss (CHL), but their applications on unilateral CHL (UCHL) patients remain controversial. To evaluate the effects of BCDs in UCHL, a systematic search was undertaken until May 2023 following the PRISMA guidelines. Among the 391 references, 21 studies met the inclusion criteria and were ultimately selected for review. Data on hearing thresholds, speech recognition, sound localization, and subjective questionnaire outcomes were collected and summarized. Moderate hearing threshold improvements were found in UCHL patients aided with BCDs. Their speech recognition abilities improved significantly. However, sound localization results showed wide individual variations. According to subjective questionnaires, BCDs had an overall positive influence on the daily life of UCHL patients, although several unfavorable experiences were reported by some of them. We concluded that the positive audiological benefits and subjective questionnaire results have made BCDs a credible intervention for UCHL patients. Before final implantations, UCHL patients should first go through a period of time when they were fitted with non-implantable BCDs as a trial.

A glutamatergic DRN-VTA pathway modulates neuropathic pain and comorbid anhedonia-like behavior in mice.

Chronic pain causes both physical suffering and comorbid mental symptoms such as anhedonia. However, the neural circuits and molecular mechanisms underlying these maladaptive behaviors remain elusive. Here using a mouse model, we report a pathway from vesicular glutamate transporter 3 neurons in the dorsal raphe nucleus to dopamine neurons in the ventral tegmental area (VGluT3DRN→DAVTA) wherein population-level activity in response to innocuous mechanical stimuli and sucrose consumption is inhibited by chronic neuropathic pain. Mechanistically, neuropathic pain dampens VGluT3DRN → DAVTA glutamatergic transmission and DAVTA neural excitability. VGluT3DRN → DAVTA activation alleviates neuropathic pain and comorbid anhedonia-like behavior (CAB) by releasing glutamate, which subsequently promotes DA release in the nucleus accumbens medial shell (NAcMed) and produces analgesic and anti-anhedonia effects via D2 and D1 receptors, respectively. In addition, VGluT3DRN → DAVTA inhibition produces pain-like reflexive hypersensitivity and anhedonia-like behavior in intact mice. These findings reveal a crucial role for VGluT3DRN → DAVTA → D2/D1NAcMed pathway in establishing and modulating chronic pain and CAB.