New insights into the effects of APP gene dose on synapse in Down syndrome

Synaptic dysfunction:Alzheimer’s disease(AD)is a prevalent form of dementia,affecting over 35 million people worldwide(Tzioras et al.,2023).A synapse serves as the connection point between neurons,facilitating the transmission of information from one neuron to another.Dynamic alterations in synapses,known as synaptic plasticity,play a pivotal role in cognitive processes such as learning and memory.Synaptic loss has been identified as a key contributor to cognitive decline in AD patients.Studies have shown that the soluble forms of amyloid-beta(Aβ)and tau proteins are toxic to synapses,leading to cognitive impairment in animal models(Spires-Jones and Hyman,2014).Additionally,the formation of oligomers of tau and Aβcan spread pathology through synaptic connections in the brain,emphasizing the vital role of synapses in disease progression.

Genomic alterations in oral multiple primary cancers

Oral squamous cell carcinoma (OSCC) is the predominant type of oral cancer, while some patients may develop oral multiple primary cancers (MPCs) with unclear etiology. This study aimed to investigate the clinicopathological characteristics and genomic alterations of oral MPCs. Clinicopathological data from patients with oral single primary carcinoma (SPC, n=202) and oral MPCs (n=34) were collected and compared. Copy number alteration (CNA) analysis was conducted to identify chromosomal-instability differences among oral MPCs, recurrent OSCC cases, and OSCC patients with lymph node metastasis. Whole-exome sequencing was employed to identify potential unique gene mutations in oral MPCs patients. Additionally, CNA and phylogenetic tree analyses were used to gain preliminary insights into the molecular characteristics of different primary tumors within individual patients. Our findings revealed that, in contrast to oral SPC, females predominated the oral MPCs (70.59%), while smoking and alcohol use were not frequent in MPCs.Moreover, long-term survival outcomes were poorer in oral MPCs. From a CNA perspective, no significant differences were observed between oral MPCs patients and those with recurrence and lymph node metastasis. In addition to commonly mutated genes such as CASP8, TP53 and MUC16, in oral MPCs we also detected relatively rare mutations, such as HS3ST6 and RFPL4A. Furthermore, this study also demonstrated that most MPCs patients exhibited similarities in certain genomic regions within individuals, and distinct differences of the similarity degree were observed between synchronous and metachronous oral MPCs.

Activity-dependent mechanisms of neuroprotection:promising avenues against dementia

The study of the brain and its complex functions is highly fascinating and,at the same time,extremely important.Indeed,furthering our understanding of the biology of neurons and synapses is a prerequisite to uncover the mechanisms involved in memory formation and the coordination of movement as well as their alterations occurring in several neurological disorders.

Non-linear dynamic state-space network modeling for decoding neurodegeneration

Neurodegenerative disorders represent a pervasive global health challenge,yet therapeutic options remain conspicuously limited.These disorders are inherently dynamic processes within the central nervous system,unfolding across distinct sub-stages:initial structural neuronal alterations(sub-stage 1),functional impairment(sub-stage 2),and culminating in neuronal death(sub-stage 3).

A Blade Altering Toolbox for Automating Rotor Design Optimization

The Blade Altering Toolbox(BAT)described in this paper is a tool designed for fast reconstruction of an altered blade geometry for design optimization purposes.The BAT algorithm is capable of twisting a given rotor’s angle of attack and stretching the chord length along the span of the rotor.Several test cases were run using the BAT’s algorithm.The BAT code’s twisting,stretching,and mesh reconstruction capabilities proved to be able to handle reasonably large geometric alterations to a provided input rotor geometry.The test examples showed that the toolbox’s algorithm could handle any stretching of the blade’s chord as long as the blade remained within the original bounds of the unaltered mesh.The algorithm appears to fail when the net twist angle applied the geometry exceeds approximately 30 degrees,however this limitation is dependent on the initial geometry and other input parameters.Overall,the algorithm is a very powerful tool for automating a design optimization procedure.

Sex-dependent alterations in extracellular vesicles linking chronic spinal cord injury to brain neuroinflammation and neurodegeneration

Traumatic spinal cord injury(SCI)is a devastating exogenous injury with long-lasting consequences and a leading cause of death and disability worldwide.Advances in assistive technology,rehabilitative interventions,and the ability to identify and intervene in secondary conditions have significantly increased the long-term survival rate of SCI patients,with some people even living well into their seventh or eighth decade.These survival changes have led neurotrauma researchers to examine how SCI interacts with brain aging.Public health and epidemiological data showed that patients with long-term SCI can have a lower life expectancy and quality of life,along with a higher risk of comorbidities and complications.

Molecular features of gastroenteropancreatic neuroendocrine carcinoma: A comparative analysis with lung neuroendocrine carcinoma and digestive adenocarcinomas

Objective: There is an ongoing debate about whether the management of gastroenteropancreatic(GEP)neuroendocrine carcinoma(NEC) should follow the guidelines of small-cell lung cancer(SCLC). We aim to identify the genetic differences of GEPNEC and its counterpart.Methods: We recruited GEPNEC patients as the main cohort, with lung NEC and digestive adenocarcinomas as comparative cohorts. All patients undergone next-generation sequencing(NGS). Different gene alterations were compared and analyzed between GEPNEC and lung NEC(LNEC), GEPNEC and adenocarcinoma to yield the remarkable genes.Results: We recruited 257 patients, including 99 GEPNEC, 57 LNEC, and 101 digestive adenocarcinomas.Among the mutations, KRAS, RB1, TERT, IL7R, and CTNNB1 were found to have different gene alterations between GEPNEC and LNEC samples. Specific genes for each site were revealed: gastric NEC(TERT amplification),colorectal NEC(KRAS mutation), and bile tract NEC(ARID1A mutation). The gene disparities between small-cell NEC(SCNEC) and large-cell NEC(LCNEC) were KEAP1 and CDH1. Digestive adenocarcinoma was also compared with GEPNEC and suggested RB1, APC, and KRAS as significant genes. The TP53/RB1 mutation pattern was associated with first-line effectiveness. Putative targetable genes and biomarkers in GEPNEC were identified in22.2% of the patients, and they had longer progression-free survival(PFS) upon targetable treatment [12.5 months vs. 3.0 months, HR=0.40(0.21-0.75), P=0.006].Conclusions: This work demonstrated striking gene distinctions in GEPNEC compared with LNEC and adenocarcinoma and their clinical utility.

Advances in MET tyrosine kinase inhibitors in gastric cancer

Gastric cancer is among the most frequently occurring cancers and a leading cause of cancer-related deaths globally.Because gastric cancer is highly heterogenous and comprised of different subtypes with distinct molecular and clinical characteristics,the management of gastric cancer calls for better-defined,biomarker-guided,molecular-based treatment strategies.MET is a receptor tyrosine kinase mediating important physiologic processes,such as embryogenesis,tissue regeneration,and wound healing.However,mounting evidence suggests that aberrant MET pathway activation contributes to tumour proliferation and metastasis in multiple cancer types,including gastric cancer,and is associated with poor patient outcomes.As such,MET-targeting therapies are being actively developed and promising progress has been demonstrated,especially with MET tyrosine kinase inhibitors.This review aims to briefly introduce the role of MET alterations in gastric cancer and summarize in detail the current progress of MET tyrosine kinase inhibitors in this disease area with a focus on savolitinib,tepotinib,capmatinib,and crizotinib.Building on current knowledge,this review further discusses existing challenges in MET alterations testing,possible resistance mechanisms to MET inhibitors,and future directions of MET-targeting therapies.

Identifying Comprehensive Genomic Alterations and Potential Neoantigens for Cervical Cancer Immunotherapy in a Cohort of Chinese Squamous Cell Carcinoma of the Cervix

Objective Genomic alterations and potential neoantigens for cervical cancer immunotherapy were identified in a cohort of Chinese patients with cervical squamous cell carcinoma(CSCC).Methods Whole-exome sequencing was used to identify genomic alterations and potential neoantigens for CSCC immunotherapy.RNA Sequencing was performed to analyze neoantigen expression.Results Systematic bioinformatics analysis showed that C>T/G>A transitions/transversions were dominant in CSCCs.Missense mutations were the most frequent types of somatic mutation in the coding sequence regions.Mutational signature analysis detected signature 2,signature 6,and signature 7 in CSCC samples.PIK3CA,FBXW7,and BICRA were identified as potential driver genes,with BICRA as a newly reported gene.Genomic variation profiling identified 4,960 potential neoantigens,of which 114 were listed in two neoantigen-related databases.Conclusion The present findings contribute to our understanding of the genomic characteristics of CSCC and provide a foundation for the development of new biotechnology methods for individualized immunotherapy in CSCC.

How dopamine tunes parvalbumin interneurons in the hippocampus:new experimental observations in Alzheimer's disease

Despite decades of dedicated resea rch,Alzheimer's disease (AD) is an age-related and progressive neurodegenerative disorder for which the mechanisms of onset are sti unc ear.AD is cha racterized by featured histological alterations including amyloid-beta (AB) plaque deposition,accumulation of neurofibrillary to ngles of hyperphosphorylated-tau,and neuronal loss,accompanied by progressive cognitive decline and behavioral changes.

Endoscopic treatment of biliopancreatic pathology in patients with Whipple's pancreaticoduodenectomy surgical variants: Lessons learned from single-balloon enteroscopy-assisted ERCP

Background: Endoscopic treatment of biliopancreatic pathology is challenging due to surgically altered anatomy after Whipple's pancreaticoduodenectomy. This study aimed to evaluate the feasibility and safety of single-balloon enteroscopy-assisted endoscopic retrograde cholangiopancreatography(SBE-ERCP) to treat biliopancreatic pathology in patients with Whipple's pancreaticoduodenectomy surgical variants. Methods: We retrospectively analyzed 106 SBE-ERCP procedures in 46 patients with Whipple's variants. Technical and clinical success rates and adverse events were evaluated. Results: Biliary SBE-ERCP was performed in 34 patients and pancreatic SBE-ERCP in 17, including 5 with both indications. From a total of 106 SBE-ERCP procedures, 76 were biliary indication with technical success rate of 68/76(90%) procedures and clinical success rate of 30/34(88%) patients. Mild adverse event rate was 8/76(11%), without serious adverse events. From a total of 106 SBE-ERCP procedures, 30 were pancreatic indication with technical success rate of 24/30(80%) procedures( P = 0.194 vs. biliary SBEERCP) and clinical success rate of 11/17(65%) patients( P = 0.016 vs. biliary SBE-ERCP). Mild adverse event rate was 6/30(20%)( P = 0.194 vs. biliary SBE-ERCP), without serious adverse events. After SBE-ERCP failure, endoscopic ultrasound-guided drainage, percutaneous drainage and redo surgery were alternative therapeutic options. Conclusions: Biliopancreatic pathology after Whipple's pancreaticoduodenectomy variants can be treated using SBE-ERCP without serious adverse events. Technical and clinical success rates are high for biliary indications, whereas clinical success rate of pancreatic indications is significantly lower. SBE-ERCP can be considered as first-line treatment option in this patient group with surgically altered anatomy.

Plasma metabolites and risk of myocardial infarction:a bidirectional Mendelian randomization study

BACKGROUND Myocardial infarction(MI)is a critical cardiovascular event with multifaceted etiology,involving several genetic and environmental factors.It is essential to understand the function of plasma metabolites in the development of MI and unravel its complex pathogenesis.METHODS This study employed a bidirectional Mendelian randomization(MR)approach to investigate the causal relationships between plasma metabolites and MI risk.We used genetic instruments as proxies for plasma metabolites and MI and conducted MR analyses in both directions to assess the impact of metabolites on MI risk and vice versa.In addition,the large-scale genome-wide association studies datasets was used to identify genetic variants associated with plasma metabolite(1400 metabolites)and MI(20,917 individuals with MI and 440,906 individuals without MI)susceptibility.Inverse variance weighted was the primary method for estimating causal effects.MR estimates are expressed as beta coefficients or odds ratio(OR)with 95%CI.RESULTS We identified 14 plasma metabolites associated with the occurrence of MI(P<0.05),among which 8 plasma metabolites[propionylglycine levels(OR=0.922,95%CI:0.881–0.965,P<0.001),gamma-glutamylglycine levels(OR=0.903,95%CI:0.861–0.948,P<0.001),hexadecanedioate(C16-DC)levels(OR=0.941,95%CI:0.911–0.973,P<0.001),pentose acid levels(OR=0.923,95%CI:0.877–0.972,P=0.002),X-24546 levels(OR=0.936,95%CI:0.902–0.971,P<0.001),glycine levels(OR=0.936,95%CI:0.909–0.964,P<0.001),glycine to serine ratio(OR=0.930,95%CI:0.888–0.974,P=0.002),and mannose to trans-4-hydroxyproline ratio(OR=0.912,95%CI:0.869–0.958,P<0.001)]were correlated with a decreased risk of MI,whereas the remaining 6 plasma metabolites[1-palmitoyl-2-arachidonoyl-GPE(16:0/20:4)levels(OR=1.051,95%CI:1.018–1.084,P=0.002),behenoyl dihydrosphingomyelin(d18:0/22:0)levels(OR=1.076,95%CI:1.027–1.128,P=0.002),1-stearoyl-2-docosahexaenoyl-GPE(18:0/22:6)levels(OR=1.067,95%CI:1.027–1.109,P=0.001),alpha-ketobutyrate levels(OR=1.108,95%CI:1.041–1.180,P=0.001),5-acetylamino-6-formylamino-3-methyluracil levels(OR=1.047,95%CI:1.019–1.076,P<0.001),and N-acetylputrescine to(N(1)+N(8))-acetylspermidine ratio(OR=1.045,95%CI:1.018–1.073,P<0.001)]were associated with an increased risk of MI.Furthermore,we also observed that the mentioned relationships were unaffected by horizontal pleiotropy(P>0.05).On the contrary,MI did not lead to significant alterations in the levels of the aforementioned 14 plasma metabolites(P>0.05 for each comparison).CONCLUSIONS Our bidirectional MR study identified 14 plasma metabolites associated with the occurrence of MI,among which 13 plasma metabolites have not been reported previously.These findings provide valuable insights for the early diagnosis of MI and potential therapeutic targets.

Multi-scale data joint inversion of minerals and porosity in altered igneous reservoirs—A case study in the South China Sea

There are abundant igneous gas reservoirs in the South China Sea with significant value of research,and lithology classification,mineral analysis and porosity inversion are important links in reservoir evaluation.However,affected by the diverse lithology,complicated mineral and widespread alteration,conventional logging lithology classification and mineral inversion become considerably difficult.At the same time,owing to the limitation of the wireline log response equation,the quantity and accuracy of minerals can hardly meet the exploration requirements of igneous formations.To overcome those issues,this study takes the South China Sea as an example,and combines multi-scale data such as micro rock slices,petrophysical experiments,wireline log and element cutting log to establish a set of joint inversion methods for minerals and porosity of altered igneous rocks.Specifically,we define the lithology and mineral characteristics through core slices and mineral data,and establish an igneous multi-mineral volumetric model.Then we determine element cutting log correction method based on core element data,and combine wireline log and corrected element cutting log to perform the lithology classification and joint inversion of minerals and porosity.However,it is always difficult to determine the elemental eigenvalues of different minerals in inversion.This paper uses multiple linear regression methods to solve this problem.Finally,an integrated inversion technique for altered igneous formations was developed.The results show that the corrected element cutting log are in good agreement with the core element data,and the mineral and porosity results obtained from the joint inversion based on the wireline log and corrected element cutting log are also in good agreement with the core data from X-ray diffraction.The results demonstrate that the inversion technique is applicable and this study provides a new direction for the mineral inversion research of altered igneous formations.

Risk stratification for radioactive iodine refractoriness using molecular alterations in distant metastatic differentiated thyroid cancer

Objective: Patients with radioactive iodine-refractory differentiated thyroid cancer(RAIR-DTC) are often diagnosed with delay and constrained to limited treatment options. The correlation between RAI refractoriness and the underlying genetic characteristics has not been extensively studied.Methods: Adult patients with distant metastatic DTC were enrolled and assigned to undergo next-generation sequencing of a customized 26-gene panel(Thyro Lead). Patients were classified into RAIR-DTC or non-RAIR groups to determine the differences in clinicopathological and molecular characteristics. Molecular risk stratification(MRS) was constructed based on the association between molecular alterations identified and RAI refractoriness, and the results were classified as high, intermediate or low MRS.Results: A total of 220 patients with distant metastases were included, 63.2% of whom were identified as RAIRDTC. Genetic alterations were identified in 90% of all the patients, with BRAF(59.7% vs. 17.3%), TERT promoter(43.9% vs. 7.4%), and TP53 mutations(11.5% vs. 3.7%) being more prevalent in the RAIR-DTC group than in the non-RAIR group, except for RET fusions(15.8% vs. 39.5%), which had the opposite pattern. BRAF and TERT promoter are independent predictors of RAIR-DTC, accounting for 67.6% of patients with RAIR-DTC. MRS was strongly associated with RAI refractoriness(P<0.001), with an odds ratio(OR) of high to low MRS of 7.52 [95%confidence interval(95% CI), 3.96-14.28;P<0.001] and an OR of intermediate to low MRS of 3.20(95% CI,1.01-10.14;P=0.041).Conclusions: Molecular alterations were associated with RAI refractoriness, with BRAF and TERT promoter mutations being the predominant contributors, followed by TP53 and DICER1 mutations. MRS might serve as a valuable tool for both prognosticating clinical outcomes and directing precision-based therapeutic interventions.

Clinical and molecular significance of homologous recombination deficiency positive non-small cell lung cancer in Chinese population:An integrated genomic and transcriptional analysis

Objective:The clinical significance of homologous recombination deficiency(HRD)in breast cancer,ovarian cancer,and prostate cancer has been established,but the value of HRD in non-small cell lung cancer(NSCLC)has not been fully investigated.This study aimed to systematically analyze the HRD status of untreated NSCLC and its relationship with patient prognosis to further guide clinical care.Methods:A total of 355 treatment-naïve NSCLC patients were retrospectively enrolled.HRD status was assessed using the AmoyDx Genomic Scar Score(GSS),with a score of≥50 considered HRD-positive.Genomic,transcriptomic,tumor microenvironmental characteristics and prognosis between HRD-positive and HRDnegative patients were analyzed.Results:Of the patients,25.1%(89/355)were HRD-positive.Compared to HRD-negative patients,HRDpositive patients had more somatic pathogenic homologous recombination repair(HRR)mutations,higher tumor mutation burden(TMB)(P<0.001),and fewer driver gene mutations(P<0.001).Furthermore,HRD-positive NSCLC had more amplifications in PI3K pathway and cell cycle genes,MET and MYC in epidermal growth factor receptor(EGFR)/anaplastic lymphoma kinase(ALK)mutant NSCLC,and more PIK3CA and AURKA in EGFR/ALK wild-type NSCLC.HRD-positive NSCLC displayed higher tumor proliferation and immunosuppression activity.HRD-negative NSCLC showed activated signatures of major histocompatibility complex(MHC)-II,interferon(IFN)-γand effector memory CD8+T cells.HRD-positive patients had a worse prognosis and shorter progressionfree survival(PFS)to targeted therapy(first-and third-generation EGFR-TKIs)(P=0.042).Additionally,HRDpositive,EGFR/ALK wild-type patients showed a numerically lower response to platinum-free immunotherapy regimens.Conclusions:Unique genomic and transcriptional characteristics were found in HRD-positive NSCLC.Poor prognosis and poor response to EGFR-TKIs and immunotherapy were observed in HRD-positive NSCLC.This study highlights potential actionable alterations in HRD-positive NSCLC,suggesting possible combinational therapeutic strategies for these patients.

Clinicopathological alterations in wild mammals from the reservoir system of Trypanosoma cruzi:a scoping review

Trypanosoma cruzi is the etiologic agent of Chagas disease.This flagellated protozoan is transmitted to humans as well as different species of domestic and wild animals via vectors from the Reduviidae family(known as"kissing bugs").Despite the fact that hundreds of species of wild mammals are part of the reservoir system,the morphologi-cal changes and clinical manifestations resulting from the pathogenesis of the infection have been largely neglected.The aim of this review is to systematically compile the available information regarding clinicopathological altera-tions in wild mammals due to natural infection by T.cruzi.Information was obtained from six online bibliographic data search platforms,resulting in the identification of 29 publications that met the inclusion criteria.Mortality was the most common clinical manifestation,cardiac damage was the main finding at necropsy,and lymphoplas-macytic inflammation was the most frequent microscopic injury.Thus,regardless of its role as a reservoir,T.cruzi has the potential to affect the health status of wild mammals,a situation that highlights the need for further research to analyze,measure,and compare its effects at both the individual and population levels.

Gut microbiota-derived short-chain fatty acids and depression:deep insight into biological mechanisms and potential

The gut microbiota is a complex and dynamic ecosystem known as the second brain'.Composing the microbiota-gut-brain axis,the gut microbiota and its metabolites regulate the central nervous system through neural,endocrine and immune pathways to ensure the normal functioning of the organism,tuning individuals'health and disease status.Short-chain fatty acids(SCFAs),the main bioactive metabolites of the gut microbiota,are involved in several neuropsychiatric disorders,including depression.SCFAs have essential effects on each component of the microbiota-gut-brain axis in depression.In the present review,the roles of major SCFAs(acetate,propionate and butyrate)in the pathophysiology of depression are summarised with respect to chronic cerebral hypoperfusion,neuroinflammation,host epigenome and neuroendocrine alterations.Concluding remarks on the biological mechanisms related to gut microbiota will hopefully address the clinical value of microbiota-related treatments for depression.

Novel cyber-physical collaborative detection and localization method against dynamic load altering attacks in smart energy grids

Owing to the integration of energy digitization and artificial intelligence technology,smart energy grids can realize the stable,efficient and clean operation of power systems.However,the emergence of cyber-physical attacks,such as dynamic load-altering attacks(DLAAs)has introduced great challenges to the security of smart energy grids.Thus,this study developed a novel cyber-physical collaborative security framework for DLAAs in smart energy grids.The proposed framework integrates attack prediction in the cyber layer with the detection and localization of attacks in the physical layer.First,a data-driven method was proposed to predict the DLAA sequence in the cyber layer.By designing a double radial basis function network,the influence of disturbances on attack prediction can be eliminated.Based on the prediction results,an unknown input observer-based detection and localization method was further developed for the physical layer.In addition,an adaptive threshold was designed to replace the traditional precomputed threshold and improve the detection performance of the DLAAs.Consequently,through the collaborative work of the cyber-physics layer,injected DLAAs were effectively detected and located.Compared with existing methodologies,the simulation results on IEEE 14-bus and 118-bus power systems verified the superiority of the proposed cyber-physical collaborative detection and localization against DLAAs.

Modifying the progression of Parkinson's disease through movement interventions:multimodal quantification of underlying mechanisms

Introduction:Parkinson’s disease(PD)is the most common neurodegenerative movement disorder.The pathological hallmark is the progressive loss of dopaminergic neurons of the substantia nigra pars compacta,which is accompanied by widespread alterations in the structu re and function of distributed brain networks.Togethe r,these processes cause a variety of motor symptoms such as bradykinesia,rigidity,tremor,gait disorders,or difficulties in fine motor control(Bange et al.,2022).

Liver biopsy in the post-hepatitis C virus era in Japan

In Japan,liver biopsies were previously crucial in evaluating the severity of hepatitis caused by the hepatitis C virus(HCV)and diagnosing HCV-related hepatocellular carcinoma(HCC).However,due to the development of effective antiviral treatments and advanced imaging,the necessity for biopsies has significantly decreased.This change has resulted in fewer chances for diagnosing liver disease,causing many general pathologists to feel less confident in making liver biopsy diagnoses.This article provides a comprehensive overview of the challenges and potential solutions related to liver biopsies in Japan.First,it highlights the importance of considering steatotic liver diseases as independent conditions that can coexist with other liver diseases due to their increasing prevalence.Second,it emphasizes the need to avoid hasty assumptions of HCC in nodular lesions,because clinically diagnosable HCCs are not targets for biopsy.Third,the importance of diagnosing hepatic immune-related adverse events caused by immune checkpoint inhibitors is increasing due to the anticipated widespread use of these drugs.In conclusion,pathologists should be attuned to the changing landscape of liver diseases and approach liver biopsies with care and attention to detail.