NLRP3-mediated autophagy dysfunction links gut microbiota dysbiosis to tau pathology in chronic sleep deprivation

Emerging evidence indicates that sleep deprivation(SD)can lead to Alzheimer’s disease(AD)-related pathological changes and cognitive decline.However,the underlying mechanisms remain obscure.In the present study,we identified the existence of a microbiota-gut-brain axis in cognitive deficits resulting from chronic SD and revealed a potential pathway by which gut microbiota affects cognitive functioning in chronic SD.Our findings demonstrated that chronic SD in mice not only led to cognitive decline but also induced gut microbiota dysbiosis,elevated NLRP3 inflammasome expression,GSK-3βactivation,autophagy dysfunction,and tau hyperphosphorylation in the hippocampus.Colonization with the“SD microbiota”replicated the pathological and behavioral abnormalities observed in chronic sleep-deprived mice.Remarkably,both the deletion of NLRP3 in NLRP3-/-mice and specific knockdown of NLRP3 in the hippocampus restored autophagic flux,suppressed tau hyperphosphorylation,and ameliorated cognitive deficits induced by chronic SD,while GSK-3βactivity was not regulated by the NLRP3 inflammasome in chronic SD.Notably,deletion of NLRP3 reversed NLRP3 inflammasome activation,autophagy deficits,and tau hyperphosphorylation induced by GSK-3βactivation in primary hippocampal neurons,suggesting that GSK-3β,as a regulator of NLRP3-mediated autophagy dysfunction,plays a significant role in promoting tau hyperphosphorylation.Thus,gut microbiota dysbiosis was identified as a contributor to chronic SD-induced tau pathology via NLRP3-mediated autophagy dysfunction,ultimately leading to cognitive deficits.Overall,these findings highlight GSK-3βas a regulator of NLRP3-mediated autophagy dysfunction,playing a critical role in promoting tau hyperphosphorylation.

Digital pathology-based artificial intelligence models for differential diagnosis and prognosis of sporadic odontogenic keratocysts

Odontogenic keratocyst(OKC)is a common jaw cyst with a high recurrence rate.OKC combined with basal cell carcinoma as well as skeletal and other developmental abnormalities is thought to be associated with Gorlin syndrome.Moreover,OKC needs to be differentiated from orthokeratinized odontogenic cyst and other jaw cysts.Because of the different prognosis,differential diagnosis of several cysts can contribute to clinical management.We collected 519 cases,comprising a total of 2157 hematoxylin and eosinstained images,to develop digital pathology-based artificial intelligence(AI)models for the diagnosis and prognosis of OKC.The Inception_v3 neural network was utilized to train and test models developed from patch-level images.Finally,whole slide imagelevel AI models were developed by integrating deep learning-generated pathology features with several machine learning algorithms.The AI models showed great performance in the diagnosis(AUC=0.935,95%CI:0.898–0.973)and prognosis(AUC=0.840,95%CI:0.751–0.930)of OKC.The advantages of multiple slides model for integrating of histopathological information are demonstrated through a comparison with the single slide model.Furthermore,the study investigates the correlation between AI features generated by deep learning and pathological findings,highlighting the interpretative potential of AI models in the pathology.Here,we have developed the robust diagnostic and prognostic models for OKC.The AI model that is based on digital pathology shows promise potential for applications in odontogenic diseases of the jaw.

Going straight for the gut:gut-brain axis pathology and treatment of Parkinson's disease

This perspective focuses on the recent literature regarding the role of the gut-brain axis(GBA) in fecal microbiota transplantation(FMT) and stem cell therapy(SCT) in Parkinson's disease(PD).PD is the second most common neurodegenerative disease in the United States,yet therapies remain limited.Current research suggests that the GBA may play a role in the pathogenesis of PD.GBAbased FMT as well as SCT offer promising new avenues for PD treatment.Pro bing the interactions between FMT and SCT with the GBA may reveal novel therapeutics for PD.

Amyloid-beta pathology-induced nanoscale synaptic disruption:the case of the GABA_B-GIRK assembly

Alzheimer's disease (AD) is characterized by an imbalance between excitatory and inhibitory brain networks,leading to aberrant homeostatic synaptic plasticity.AD has progressively been recognized as syna ptopathy and syna ptic dysfunction has been identified as a key component of its pathogenesis (Schirinzi et al.,2020).Syna ptic dysfunction is believed to precede synapse loss,a primary biological correlate of cognitive decline in AD,inevita bly associated with neuronal death.

Hysterectomies for Gynaecological Pathology: 56 Cases at the Segou Regional Hospital in Mali

Introduction: Hysterectomy is a surgical procedure involving partial or total removal of the uterus. It is the most common gynaecological surgery in the world. Objective: To describe the epidemio-clinical and prognostic aspects of gynaecological hysterectomies. Patients and methods: This was an 18-month retrospective prospective descriptive study with a six-month follow-up period from 1 December 2020 to 31 May 2022 carried out in the gynaecology department of the Segou regional hospital. Results: Fifty-six (56) hysterectomies were performed out of 118 gynaecological surgical procedures (47.45%). The mean age was 47 ± 11.77 years. Large multiparous women were the most common (50%), with an average parity of 4.58. The main indications were uterine fibroids (30.4%), precancerous lesions of the cervix (17.85%) and uterine prolapse (17.85%). The abdominal route was the most commonly used surgical route (82.14%). Hysterectomy was total in 100% of cases and associated with bilateral adnexectomy in 48.2% of cases. The intra- and post-operative prognosis was satisfactory in 94.6% of cases. No deaths were recorded. The average length of stay was 3.28 days, irrespective of the surgical approach. Three cases of dyspareunia were noted among those who had resumed sexual activity.

Using MsfNet to Predict the ISUP Grade of Renal Clear Cell Carcinoma in Digital Pathology Images

Clear cell renal cell carcinoma(ccRCC)represents the most frequent form of renal cell carcinoma(RCC),and accurate International Society of Urological Pathology(ISUP)grading is crucial for prognosis and treatment selection.This study presents a new deep network called Multi-scale Fusion Network(MsfNet),which aims to enhance the automatic ISUP grade of ccRCC with digital histopathology pathology images.The MsfNet overcomes the limitations of traditional ResNet50 by multi-scale information fusion and dynamic allocation of channel quantity.The model was trained and tested using 90 Hematoxylin and Eosin(H&E)stained whole slide images(WSIs),which were all cropped into 320×320-pixel patches at 40×magnification.MsfNet achieved a micro-averaged area under the curve(AUC)of 0.9807,a macro-averaged AUC of 0.9778 on the test dataset.The Gradient-weighted Class Activation Mapping(Grad-CAM)visually demonstrated MsfNet’s ability to distinguish and highlight abnormal areas more effectively than ResNet50.The t-Distributed Stochastic Neighbor Embedding(t-SNE)plot indicates our model can efficiently extract critical features from images,reducing the impact of noise and redundant information.The results suggest that MsfNet offers an accurate ISUP grade of ccRCC in digital images,emphasizing the potential of AI-assisted histopathological systems in clinical practice.

Microvascular structural changes in esophageal squamous cell carcinoma pathology according to intrapapillary capillary loop types under magnifying endoscopy

BACKGROUND The intrapapillary capillary loop(IPCL)characteristics,visualized using magnifying endoscopy,are commonly assessed for preoperative evaluation of the infiltration depth of esophageal squamous cell carcinoma(ESCC).Japan Esophageal Society(JES)classification is the most widely used classification.Microvascular structural changes are evaluated by magnifying endoscopy for the presence or absence of each morphological factor:tortuosity,dilatation,irregular caliber,and different shapes.However,the pathological characteristics of IPCLs have not been thoroughly investigated,especially the microvascular structures corresponding to the deepest parts of the lesions'infiltration.AIM To investigate differences in pathological microvascular structures of ESCC,which correspond to the deepest parts of the lesions'infiltration.METHODS Patients with ESCC and precancerous lesions diagnosed at Peking University Third Hospital were enrolled between January 2019 and April 2023.Patients first underwent magnified endoscopic examination,followed by endoscopic submucosal dissection or surgical treatment.Pathological images were scanned using a threedimensional slice scanner,and the pathological structural differences in different types,according to the JES classification,were analyzed using nonparametric tests and t-tests.RESULTS The 35 lesions were divided into four groups according to the JES classification:A,B1,B2,and B3.Statistical analyses revealed significant differences(aP<0.05)in the short and long calibers,area,location,and density between types A and B.Notably,there were no significant differences in these parameters between types B1 and B2 and between types B2 and B3(P>0.05).However,significant differences in the short calibers,long calibers,and area of IPCL were observed between types B1 and B3(aP<0.05);no significant differences were found in the density or location(P>0.05).CONCLUSION Pathological structures of IPCLs in the deepest infiltrating regions differ among various IPCL types classified by the JES classification under magnifying endoscopy,especially between the types A and B.

A Multi-Task Deep Learning Framework for Simultaneous Detection of Thoracic Pathology through Image Classification

Thoracic diseases pose significant risks to an individual's chest health and are among the most perilous medical diseases. They can impact either one or both lungs, which leads to a severe impairment of a person’s ability to breathe normally. Some notable examples of such diseases encompass pneumonia, lung cancer, coronavirus disease 2019 (COVID-19), tuberculosis, and chronic obstructive pulmonary disease (COPD). Consequently, early and precise detection of these diseases is paramount during the diagnostic process. Traditionally, the primary methods employed for the detection involve the use of X-ray imaging or computed tomography (CT) scans. Nevertheless, due to the scarcity of proficient radiologists and the inherent similarities between these diseases, the accuracy of detection can be compromised, leading to imprecise or erroneous results. To address this challenge, scientists have turned to computer-based solutions, aiming for swift and accurate diagnoses. The primary objective of this study is to develop two machine learning models, utilizing single-task and multi-task learning frameworks, to enhance classification accuracy. Within the multi-task learning architecture, two principal approaches exist soft parameter sharing and hard parameter sharing. Consequently, this research adopts a multi-task deep learning approach that leverages CNNs to achieve improved classification performance for the specified tasks. These tasks, focusing on pneumonia and COVID-19, are processed and learned simultaneously within a multi-task model. To assess the effectiveness of the trained model, it is rigorously validated using three different real-world datasets for training and testing.

Expanding role and scope of artificial intelligence in the field of gastrointestinal pathology

Digital pathology(DP)and its subsidiaries including artificial intelligence(AI)are rapidly making inroads into the area of diagnostic anatomic pathology(AP)including gastrointestinal(GI)pathology.It is poised to revolutionize the field of diagnostic AP.Historically,AP has been slow to adopt digital technology,but this is changing rapidly,with many centers worldwide transitioning to DP.Coupled with advanced techniques of AI such as deep learning and machine learning,DP is likely to transform histopathology from a subjective field to an objective,efficient,and transparent discipline.AI is increasingly integrated into GI pathology,offering numerous advancements and improvements in overall diagnostic accuracy,efficiency,and patient care.Specifically,AI in GI pathology enhances diagnostic accuracy,streamlines workflows,provides predictive insights,integrates multimodal data,supports research,and aids in education and training,ultimately improving patient care and outcomes.This review summarized the latest developments in the role and scope of AI in AP with a focus on GI pathology.The main aim was to provide updates and create awareness among the pathology community.

Axial length,vitreoretinal pathology,and anterior chamber depth can predict postoperative refractive outcomes in phacovitrectomy/silicone oil removal

AIM:To evaluate the postoperative refractive prediction error(PE)and determine the factors that af fect the refractive outcomes of combined pars plana vitrectomy(PPV)or silicone oil removal(SOR)with cataract surgery.METHODS:The study is a retrospective,case-series study.Totally 301 eyes of 301 patients undergoing combined PPV/SOR with cataract surgery were enrolled.Eligible individuals were separated into four groups according to their preoperative diagnoses:silicone oil-filled eyes after PPV(group 1),epiretinal membrane(group 2),macular hole(group 3),and primary retinal detachment(RD;group 4).The variables af fecting postoperative refractive outcomes were analyzed,including age,gender,preoperative best-corrected visual acuity(BCVA),axial length(AL),keratometry average,anterior chamber depth(ACD),intraocular tamponade,and vitreoretinal pathology.The outcome measurements include the mean refractive PE and the proportions of eyes with a PE within±0.50 diopter(D)and±1.00 D.RESULTS:For all patients,the mean PE was-0.04±1.17 D,and 50.17%of patients(eyes)had a PE within±0.50 D.There was a significant difference in refractive outcomes among the four groups(P=0.028),with RD(group 4)showing the least favorable refractive outcome.In multivariate regression analysis,only AL,vitreoretinal pathology,and ACD were strongly associated with PE(all P<0.01).Univariate analysis revealed that longer eyes(AL>26 mm)and a deeper ACD were correlated with hyperopic PE,and shorter eyes(AL<26 mm)and a shallower ACD were correlated with myopic PE.CONCLUSION:RD patients have the least favorable refractive outcome.AL,vitreoretinal pathology,and ACD are strongly associated with PE in the combined surgery.These three factors affect refractive outcomes and thus can be used to predict a better postoperative refractive outcome in clinical practice.

Aquaporin 5 in Alzheimer’s disease:a link between oral and brain pathology?

The involvement of aquaporins(AQPs)in the development of diseases has been widely described(Azad et al.,2021).AQP5 has been described in astrocytes changing after traumatic brain injuries(Chai et al.,2013),but the precise role of AQP5 in Alzheimer’s disease(AD)pathology is yet to be understood.We have recently reported that AQP5 expression changes during the development of AD(Antequera et al.,2022).The AQP5 expression in salivary glands is decreased in 6-month-old APP/PS1 mice and AD patients.This decrease in AQP5 expression could be involved in the mechanism of salivary gland dysfunction described in a previous study(Antequera et al.,2021).Now,we propose a new indirect role of AQP5 in the connection between infection-induced oral dysbiosis and AD(Sureda et al.,2020).Here,we suggest that the proinflammatory response induced by oral pathogen infection results in the downregulation of AQP5 contributing to the salivary gland secretory dysfunction.All these alterations destabilize the peripheral immune-inflammatory balance and exacerbate neuroinflammation and neurodegeneration leading to AD pathology.

Effects of alendronate on bone mass and organ pathology in ovariectomized mice

Objective:To investigate the effect of alendronate on bone mass and organ pathology of ovariectomized mice.Methods:Thirty SPF grade C57 female mice were randomly divided into three groups(n=10):Sham operation group(Sham),ovariectomized group(OVX)and ovariectomized+alendronate group(ALN).The sodium alendronate was injected subcutaneously at 400μg/kg twice a week in the ALN group.The equal volume of normal saline was injected subcutaneously twice a week in the SHAM group and OVX group.After 12 weeks of drug administration,the samples were taken.The organ coefficients,main organ pathological sections,and bone histopathological sections were observed,and the micro CT,L4 biomechanics and serum biochemical indicators were analyzed.Results:The uterine coefficient of Sham group was(0.0054±0.0007)significantly higher than that of OVX group(0.0026±0.0009)and ALN group(0.0025±0.0007),and the difference was statistically significant(P<0.05).No obvious lesions or toxic or side effects were observed in the main organs.Compared with the OVX group,the ALN group with decalcified sections of bone tissue had compact trabecular structure and fewer adipocytes.Micro-CT results showed that the Tb.BMD,Tb.N,Tb.Th and Tb.BV/TV values of the ALN group were significantly increased compared with those of the OVX group,but the Tb.Sp value was significantly decreased,and the difference was statistically significant(P<0.05).In L4 vertebral body biomechanics,the elastic modulus(50.29±13.43)and maximum load number(29.83±4.92)of ALN group were significantly higher than those of OVX group(14.77±3.12)and maximum load number(11.57±3.18),and the difference was statistically significant(P<0.05).Compared with the OVX group,the serum OCN and PINP indicators of bone formation in the ALN group were increased,while the bone resorption indicators TRACP-5b and CTX-I were decreased,with statistical significance(P<0.05).Conclusion:Alendronate sodium improves bone quality by increasing bone density,improving bone microstructure,increasing bone strength,promoting bone formation and inhibiting bone resorption,without obvious toxic and side effects on organs.

Evolution of human kidney allograft pathology diagnostics through 30 years of the Banff classification process

The second half of the previous century witnessed a tremendous rise in the number of clinical kidney transplants worldwide.This activity was,however,accompanied by many issues and challenges.An accurate diagnosis and appropriate management of causes of graft dysfunction were and still are,a big challenge.Kidney allograft biopsy played a vital role in addressing the above challenge.However,its interpretation was not standardized for many years until,in 1991,the Banff process was started to fill this void.Thereafter,regular Banff meetings took place every 2 years for the past 30 years.Marked changes have taken place in the interpretation of kidney allograft biopsies,diagnosis,and classification of rejection and other non-rejection pathologies from the original Banff 93 classification.This review attempts to summarize those changes for increasing the awareness and understanding of kidney allograft pathology through the eyes of the Banff process.It will interest the transplant surgeons,physicians,pathologists,and allied professionals associated with the care of kidney transplant patients.

Collision tumor of primary malignant lymphoma and adenocarcinoma in the colon diagnosed by molecular pathology:A case report and literature review

BACKGROUND Collision tumors of primary malignant lymphoma and adenocarcinoma in the colon are rare.Primary diffuse large B-cell lymphoma(DLBCL)–adenocarcinoma collision tumors are especially rare.CASE SUMMARY A 74-year-old woman presented with abdominal pain of 1 mo duration.Biopsy under colonoscopy revealed adenocarcinoma of the ascending colon.Subsequently,the patient underwent laparoscopic radical resection of right colon cancer with lymph node dissection.A collision tumor was found incidentally through postoperative pathological sampling.Genetic analysis showed a collision tumor of DLBCL with germinal center B-cell subtype and TP53 mutation,and adenocarcinoma arising in a tubulovillous adenoma in the colon,with BRAF mutation and mutL homolog 1 promoter methylation.The patient died 3 mo after surgery.To our knowledge,this is the 23rd reported case of collision tumor of colorectal adenocarcinoma and lymphoma.The mean age of the 23 patients was 73 years.The most common site was the cecum.There were 15 cases with followup data including 11 living and four dead with a 3-year overall survival rate of 71.5%.CONCLUSION Based on pathological and genetic analysis,surgery combined with chemotherapy or chemoradiotherapy may have good therapeutic effects for collision tumor.

Transitioning of renal transplant pathology from allograft to xenograft and tissue engineering pathology:Are we prepared?

Currently,the most feasible and widely practiced option for patients with endstage organ failure is the transplantation of part of or whole organs,either from deceased or living donors.However,organ shortage has posed and is still posing a big challenge in this field.Newer options being explored are xenografts and engineered/bioengineered tissues/organs.Already small steps have been taken in this direction and sooner or later,these will become a norm in this field.However,these developments will pose different challenges for the diagnosis and management of problems as compared with traditional allografts.The approach to pathologic diagnosis of dysfunction in these settings will likely be significantly different.Thus,there is a need to increase awareness and prepare transplant diagnosticians to meet this future challenge in the field of xenotransplantation/regenerative medicine.This review will focus on the current status of transplant pathology and how it will be changed in the future with the emerging scenario of routine xenotransplantation.

Preliminary Exploration of All-English Teaching in Pathology for International Students

With the development of medical education in China, the education of international students has gradually become an important part of China’s higher education. Pathology is a bridge course connecting basic medicine and clinical medicine, and is a compulsory course for international medical students. In order to improve the quality of all-English teaching in pathology, according to the characteristics of international students and the discipline characteristics of pathology, this paper discussed the problems existing in the pathology teaching of international students, such as language communication, teacher training, textbook selection, teaching content arrangement, etc., aiming at exploring ways to solve these problems and improve the learning effect of international students from teaching practice.

Effects of maternal methyl donor intake during pregnancy on ileum methylation and function in an intrauterine growth restriction pig model

Background Intrauterine growth retardation(IUGR)affects intestinal growth,morphology,and function,which leads to poor growth performance and high mortality.The present study explored whether maternal dietary methyl donor(MET)supplementation alleviates IUGR and enhances offspring’s growth performance by improving intestinal growth,function,and DNA methylation of the ileum in a porcine IUGR model.Methods Forty multiparous sows were allocated to the control or MET diet groups from mating until delivery.After farrowing,8 pairs of IUGR and normal birth weight piglets from 8 litters were selected for sampling before suckling colostrum.Results The results showed that maternal MET supplementation tended to decrease the IUGR incidence and increased the average weaning weight of piglets.Moreover,maternal MET supplementation significantly reduced the plasma concentrations of isoleucine,cysteine,urea,and total amino acids in sows and newborn pig-lets.It also increased lactase and sucrase activity in the jejunum of newborn piglets.MET addition resulted in lower ileal methionine synthase activity and increased betaine homocysteine S-methyltransferase activity in the ileum of newborn piglets.DNA methylation analysis of the ileum showed that MET supplementation increased the methyla-tion level of DNA CpG sites in the ileum of newborn piglets.Down-regulated differentially methylated genes were enriched in folic acid binding,insulin receptor signaling pathway,and endothelial cell proliferation.In contrast,up-regulated methylated genes were enriched in growth hormone receptor signaling pathway and nitric oxide biosyn-thetic process.Conclusions Maternal MET supplementation can reduce the incidence of IUGR and increase the weaning litter weight of piglets,which may be associated with better intestinal function and methylation status.

Self-assembly of tau fragments as a key pathologic event in tauopathies

Tau protein is encoded by the microtubuleassociated protein tau(MAPT)gene and stabilizes microtubules in the neurons.Tau has unique biophysical properties that make it both highly water-soluble and positively charged.Although tau is an intrinsically disordered protein lacking defined secondary structures,it can acquire highly organized-sheet structures and stack into a filamentous inclusion such as a paired helical filament(PHF).

Soluble alpha-synuclein post-translational modifications:unexpected regulators of pathological alpha-synuclein amplification

The build-up of misfoldedα-synuclein(α-syn)in the central nervous system is the pathological hallmark of a number of neurodegenerative diseases that are known asα-synucleinopathies.These include Parkinson’s disease(PD),Parkinson’s disease with dementia(PDD),dementia with Lewy body(LB),multiple system atrophy(MSA),and a subset of Alzheimer’s disease.Growing evidence underscores that the intercellular transmission and amplification of pathologicalα-syn are critical processes underlying the progression ofα-synucleinopathies(Peng et al.,2020),and as such,the study of these processes could lead to the identification of promising therapeutics to mitigate disease progression.Most previous studies have focused solely on pathological seeds in relation to disease progression.

Clinical Epidemiology and Surgical Treatment of Spontaneous Perforations of the Terminal Ileum: A Multicentre Study in Cameroon

Background: Perforations of the terminal ileum are a frequent clinical situation and a therapeutic challenge. Surgical treatment is controversial. Several surgical modalities have been proposed and postoperative morbidity and mortality remain high. The aim of this study was to review our experience in the surgical management of perforations of the terminal ileum. Patients and methods: This is a descriptive cross-sectional study with retrospective data collection from January 1, 2017 to December 31, 2021, in five hospitals in Cameroon. Patients’ demographic, clinical presentation, surgical findings and 30-days postoperative outcomes data were collected. Results: We collected 34 files. The sex ratio was 1.4 and the average age was 20.28 years. The average consultation time was 9.1 days. Abdominal pain was present in all our patients. Peritoneal irritation was present in 46 cases (88.5%). The mean time to treatment after admission was 17.5 hours. The perforation was unique in 40 cases (76.9%) and located between 6 and 10 cm from the ileocecal valve in 29 cases (55.8%). Typhoid was the most suspected etiology intraoperatively in 38 cases (73.1%). A simple suture was performed in 18 patients (34.6%), resection with anastomosis in 11 patients (21.2%) and an ileostomy in 5 patients (9.6%). The average length of hospitalization was 21.74 days. Postoperative morbidity and mortality were 32.7% and 17.3% respectively. Conclusion: Perforations of the terminal ileum are common and affect young people. Surgical procedures are varied. Reducing consultation and care times and respecting treatment principles could improve postoperative morbidity and mortality, which remain high.