Mucoadhesive chitosan-poly (lactic-co-glycolic acid) nanoparticles for intranasal delivery of quetiapine - Development & characterization in physiologically relevant 3D tissue models.

Quetiapine hemifumarate (QF) delivery to the CNS via conventional formulations is challenging due to poor solubility and lower oral bioavailability (9 %). Similarly, many other second-generation antipsychotics, such as olanzapine, clozapine, and paliperidone, have also shown low oral bioavailability of <50 %. Hence, the present work was intended to formulate QF-loaded biodegradable PLGA-NPs with appropriate surface charge modification through poloxamer-chitosan and investigate its targeting potential on RPMI-2650 cell lines to overcome the limitations of conventional therapies. QF-loaded poloxamer-chitosan-PLGA in-situ gel (QF-PLGA-ISG) was designed using emulsification and solvent evaporation techniques. Developed QF-PLGA-ISG were subjected to evaluation for particle size, PDI, zeta potential, ex-vivo mucoadhesion, entrapment efficiency (%EE), and drug loading, which revealed 162.2 nm, 0.124, +20.5 mV, 52.4 g, 77.5 %, and 9.7 %, respectively. Additionally, QF-PLGA formulation showed >90 % release within 12 h compared to 80 % of QF-suspension, demonstrating that the surfactant with chitosan-poloxamer polymers could sustainably release medicine across the membrane. Ex-vivo hemolysis study proved that developed PLGA nanoparticles did not cause any hemolysis compared to negative control. Further, in-vitro cellular uptake and transepithelial permeation were assessed using the RPMI-2650 nasal epithelial cell line. QF-PLGA-ISG not only improved intracellular uptake but also demonstrated a 1.5-2-fold increase in QF transport across RPMI-2650 epithelial monolayer. Further studies in the EpiNasal™ 3D nasal tissue model confirmed the safety and efficacy of the developed QF-PLGA-ISG formulation with up to a 4-fold increase in transport compared to plain QF after 4 h. Additionally, histological reports demonstrated the safety of optimized formulation. Finally, favorable outcomes of IN QF-PLGA-ISG formulation could provide a novel platform for safe and effective delivery of QF in schizophrenic patients.

Prevalence of Periodontal Disease among Patients Reporting to Tertiary Care Hospital in Ranchi.

Background: Despite a huge number of advancements in the medical field, periodontitis still remains one of the most prevalent oral diseases worldwide. Aim: Thus, the primary aim of our study was to evaluate the prevalence of periodontal diseases in patients reporting to the tertiary healthcare setup in Ranchi. Materials and Methods: Based on inclusion criteria, subjects aged 18-60 years were selected and a per forma was filled by the observer. The prevalence of periodontal disease was measured using the community periodontal index, simplified oral hygiene index, and stage of periodontitis. Results: Descriptive variables were assessed using frequency, percentage, mean, and standard deviations, while the categorical analysis was performed using the Chi-square tests. Conclusion: General awareness about periodontal health and regular dental visits should be given utmost importance among the rural populations of every developing country.

Effective cataract surgical coverage in India: Evidence from 31 districts.

BACKGROUND: Effective Cataract Surgical Coverage (eCSC) is a core outcomes domain indicator to assess accessibility and quality of eye care services with limited available information. PURPOSE: To generate baseline estimates of eCSC for India. METHODS: We performed the analysis of data pooled from Rapid Assessment of Avoidable Blindness surveys conducted in 31 districts of India during 2015-2019 among persons aged 50+ years. eCSC was calculated at various thresholds, the primary being operable cataract at best corrected visual acuity <6/12, good outcome at presenting visual acuity of 6/12. RESULTS: Age-sex standardized and weighed eCSC in India was 36.7% (95% CI: 33.6, 39.9), and cataract surgical coverage (CSC) was 57.3% (95% CI: 53.3, 61.2), a relative quality gap in cataract surgery being 36.0%. eCSC in males was higher at 38.0% than females (35.6%). eCSC increased with education from 31.0% in illiterate participants to 59.7% in class 10 educated. On multivariate analysis, rural setting, increasing age, and residence in eastern or northeastern zones of India continued to be associated with poor/worse eCSC, while female gender was associated with higher eCSC. District-wide variations in eCSC were observed. CONCLUSION: Developmental factors have an important bearing on eCSC in India. Geographical variations point toward the need for targeted, locally relevant strategies.

Biostimulatory effects of boar seminal gel, saliva and semen on sexual behavior of young boars, gilts and sows.

The present study aimed to identify novel biostimulatory compounds in boar seminal gel (SG), saliva and semen using Gas chromatography-mass spectrometry (GC-MS). The bio-stimulatory effect of SG, SG + saliva and SG + semen on young boar for semen collection as well were employed to study bio-stimulatory effects on gilts and sows. Distilled water (DW) exposure was kept as control. SG, saliva and semen were screened for total 105, 96 and 89 compounds. The highest concentration was of alkanes followed by sugar alcohols, then hydrocarbons, amino acids and fatty acids. Elaidic acid was the novel compound identified in pigs. Significantly higher (p < 0.05) number of males got trained in exposure to SG (80%), SG + saliva (75%) and SG + semen (75%) than control (0%). The time (hrs) taken by young boars to get trained on exposure to combination of SG + saliva (244 ± 22.19) and SG + semen (216 ± 13.14) was lesser (p < 0.05) than SG (356 ± 61.85) alone. Interval (hrs) from initiation of exposure for exhibition of different sexual behaviour by males on exposure to SG, saliva and semen was lesser (p < 0.05) than control. Significantly (p < 0.05) higher number of females showed estrus response to exposure of SG (72.72%), SG + saliva (69.23%) and SG + semen (76.92%) than control (0). Interval (hrs) taken to exhibit estrus was shorter (p < 0.05) in females exposed to SG + saliva (201.88 ± 12.66), SG + semen (198.20 ± 9.42) than SG (262.14 ± 20.06) alone. Interval (hrs) for exhibition of different sexual behaviour by females on exposure to SG + saliva and SG + semen was lesser (p < 0.05) than control. In conclusion, novel compounds were identified in boar seminal gel, saliva and semen with biostimulatory properties have been identified in boar SG, saliva and semen. The combined exposure of SG with saliva and semen has more intense biostimulation effect than SG alone for training of young boars and estrus induction in gilts and sows. Such compounds biostimulatory effects can be exploited for augmenting reproductive efficiency in pigs.

Molecular GBM versus Histopathological GBM: Radiology-Pathology-Genetic Correlation and the New WHO 2021 Definition of Glioblastoma.

Given the recent advances in molecular pathogenesis of tumors, with better correlation with tumor behavior and prognosis, major changes were made to the new 2021 WHO (CNS5) classification of CNS tumors, including updated criteria for diagnosis of glioblastoma. Diagnosis of GBM now requires absence of isocitrate dehydrogenase and histone 3 mutations (IDH-wildtype and H3-wildtype) as the basic cornerstone, with elimination of the IDH-mutated category. The requirements for diagnosis were conventionally histopathological, based on the presence of pathognomonic features such as microvascular proliferation and necrosis. However, even if these histological features are absent, many lower grade (WHO grade 2/3) diffuse astrocytic gliomas behave clinically similar to GBM (grade 4). The 2021 WHO classification introduced new molecular criteria that can be used to upgrade the diagnosis of such histologically lower-grade, IDH-wildtype, astrocytomas to GBM. The three molecular criteria include: concurrent gain of whole chromosome 7 and loss of whole chromosome 10 (+7/-10); TERT promoter mutation; epidermal growth factor receptor (EGFR) amplification. Given these changes, it is now strongly recommended to have molecular analysis of WHO grade 2/3 diffuse astrocytic, IDH-wildtype, gliomas in adult patients, as identification of any of the above mutations allows for upgrading the tumor to WHO grade 4 ("molecular GBM") with important prognostic implications. Despite at an early stage, there is active ongoing research on the unique MRI features of molecular GBM. This paper highlights the differences between "molecular" and "histopathological" GBM, with the aim of providing a basic understanding about these changes.ABBREVIATIONS: GBM=Glioblastoma; TERT=telomerase reverse transcriptase; EGFR=epidermal growth factor receptor; MGMT= methylguanine-DNA methyltransferase; NGS= next-generation sequencing; IDH= isocitrate dehydrogenase.

High-Grade Astrocytoma with Piloid Features: A Dual Institutional Review of Imaging Findings of a Novel Entity.

High-grade astrocytoma with piloid features (HGAP) is a recently identified brain tumor characterized by a distinct DNA methylation profile. Predominantly located in the posterior fossa of adults, HGAP is notably prevalent in individuals with neurofibromatosis type 1. We present an image-centric review of HGAP and explore the association between HGAP and neurofibromatosis type 1. Data were collected from 8 HGAP patients treated at two tertiary care institutions between January 2020 and October 2023. Demographic details, clinical records, management, and tumor molecular profiles were analyzed. Tumor characteristics, including location and imaging features on MR imaging, were reviewed. Clinical or imaging features suggestive of neurofibromatosis 1 or the presence of NF1 gene alteration were documented. The mean age at presentation was 45.5 years (male/female = 5:3). Tumors were midline, localized in the posterior fossa (n = 4), diencephalic/thalamic (n = 2), and spinal cord (n = 2). HGAP lesions were T1 hypointense, T2-hyperintense, mostly without diffusion restriction, predominantly peripheral irregular enhancement with central necrosis (n = 3) followed by mixed heterogeneous enhancement (n = 2). Two NF1 mutation carriers showed signs of neurofibromatosis type 1 before HGAP diagnosis, with one diagnosed during HGAP evaluation, strengthening the HGAP-NF1 link, particularly in patients with posterior fossa masses. All tumors were IDH1 wild-type, often with ATRX, CDKN2A/B, and NF1 gene alteration. Six patients underwent surgical resection followed by adjuvant chemoradiation. Six patients were alive, and two died during the last follow-up. Histone H3 mutations were not detected in our cohort, such as the common H3K27M typically seen in diffuse midline gliomas, linked to aggressive clinical behavior and poor prognosis. HGAP lesions may involve the brain or spine and tend to be midline or paramedian in location. Underlying neurofibromatosis type 1 diagnosis or imaging findings are important diagnostic cues.

Quantitative Proteomics Reveal Region-Specific Alterations in Neuroserpin-Deficient Mouse Brain and Retina: Insights into Serpini1 Function.

Neural regeneration and neuroprotection represent strategies for future management of neurodegenerative disorders such as Alzheimer's disease (AD) or glaucoma. However, the complex molecular mechanisms that are involved in neuroprotection are not clearly understood. A promising candidate that maintains neuroprotective signaling networks is neuroserpin (Serpini1), a serine protease inhibitor expressed in neurons which selectively inhibits extracellular tissue-type plasminogen activator (tPA)/plasmin and plays a neuroprotective role during ischemic brain injury. Abnormal function of this protein has been implicated in several conditions including stroke, glaucoma, AD, and familial encephalopathy with neuroserpin inclusion bodies (FENIB). Here, we explore the potential biochemical roles of Serpini1 by comparing proteome changes between neuroserpin-deficient (NS-/-) and control mice, in the retina (RE), optic nerve (ON), frontal cortex (FC), visual cortex (VC), and cerebellum (CB). To achieve this, a multiple-plex quantitative proteomics approach using isobaric tandem mass tag (TMT) technology was employed followed by functional enrichment and protein-protein interaction analysis. We detected around 5000 proteins in each tissue and a pool of 6432 quantified proteins across all regions, resulting in a pool of 1235 differentially expressed proteins (DEPs). Principal component analysis and hierarchical clustering highlighted similarities and differences in the retina compared to various brain regions, as well as differentiating NS-/- proteome signatures from control samples. The visual cortex revealed the highest number of DEPs, followed by cerebellar regions. Pathway analysis unveiled region-specific changes, including visual perception, focal adhesion, apoptosis, glutamate receptor activation, and supramolecular fiber organization in RE, ON, FC, VC, and CB, respectively. These novel findings provide comprehensive insights into the region-specific networking of Serpini1 in the central nervous system, further characterizing its potential role as a neuroprotective agent. Data are available via ProteomeXchange with identifier PXD046873.

Vaccination coverage against COVID-19 among rural population in Haryana, India: A cross-sectional study.

BACKGROUND: Conducting a study in rural pre-dominant areas will help to understand the penetration of the vaccination campaign during the COVID-19 health crisis. This study aimed to investigate vaccination coverage against COVID-19 among the rural adult population in India and to identify factors associated with vaccination coverage. METHODS: A population-based cross-sectional study was conducted among the rural population in one district of north India from January to February 2023. A semi-structured questionnaire was designed on the SurveyMonkey digital platform for interviewing the participants, which consisted of questions related to socio-demographic profile, health problems, vaccination status, types of vaccine, re-infection after vaccination, and functional difficulties. The data regarding infection with COVID-19 was collected based on self-reported positive testing for SARS-CoV 2 on RT-PCR. FINDINGS: A total of 3700 eligible individuals were enumerated for the survey, out of which 2954 (79.8%) were interviewed. The infection rate of past COVID-19 infection, based on self-report of testing positive, was 6.2% (95%CI: 5.3-7.1). Covishield vaccine was received by most participants (81.3%, 2380) followed by Covaxin (12.3%, 361) and Pfizer manufactured vaccine (0.03,1). The coverage for first, second, and booster doses of the vaccine was 98.2% (2902), 94.8% (2802), and 10.7% (315) respectively. The risk of reinfection at 12 months or more among participants with two doses of vaccine was 1.6% (46/2802, 95%CI: 1.2-2.1). The coverage among those with severe functional difficulties was lesser as compared to those with some or no difficulties. INTERPRETATION: Vaccination coverage against COVID-19 in rural Haryana, India is not dependent on factors like gender or occupation but is dependent on age and education. Although the full and partial vaccination coverage is high, the booster dose coverage is poor. In addition, the presence of severe disability was significantly associated with reduced vaccination coverage.

Transcriptome signatures of host tissue infected with African swine fever virus reveal differential expression of associated oncogenes.

African swine fever (ASF) has emerged as a threat to swine production worldwide. Evasion of host immunity by ASF virus (ASFV) is well understood. However, the role of ASFV in triggering oncogenesis is still unclear. In the present study, ASFV-infected kidney tissue samples were subjected to Illumina-based transcriptome analysis. A total of 2463 upregulated and 825 downregulated genes were differentially expressed (p < 0.05). A literature review revealed that the majority of the differentially expressed host genes were key molecules in signaling pathways involved in oncogenesis. Bioinformatic analysis indicated the activation of certain oncogenic KEGG pathways, including basal cell carcinoma, breast cancer, transcriptional deregulation in cancer, and hepatocellular carcinoma. Analysis of host-virus interactions revealed that the upregulated oncogenic RELA (p65 transcription factor) protein of Sus scrofa can interact with the A238L (hypothetical protein of unknown function) of ASFV. Differential expression of oncogenes was confirmed by qRT-PCR, using the H3 histone family 3A gene (H3F3A) as an internal control to confirm the RNA-Seq data. The levels of gene expression indicated by qRT-PCR matched closely to those determined through RNA-Seq. These findings open up new possibilities for investigation of the mechanisms underlying ASFV infection and offer insights into the dynamic interaction between viral infection and oncogenic processes. However, as these investigations were conducted on pigs that died from natural ASFV infection, the role of ASFV in oncogenesis still needs to be investigated in controlled experimental studies.

Clinical and Radiological Characterization of Central Nervous System Involvement in Nocardiosis: A 20-Year Experience.

Background This study aimed to present the clinical and radiological characteristics and the outcomes of patients with Nocardia infection of the central nervous system (CNS). Methodology We conducted a retrospective review of patients aged 18 and older admitted between August 1998 and November 2018 with culture-proven nocardiosis and CNS involvement. Results Out of 110 patients with nocardiosis, 14 (12.7%) patients had CNS involvement. The median age was 54.5 (27, 86) years, and 12 (85.7%) patients were male. Overall, 12 (85.7%) patients were immunosuppressed on high doses of glucocorticoids; seven (50%) patients were solid organ transplant recipients. Only eight (57.1%) patients had neurological symptoms at presentation, and the rest were diagnosed with CNS involvement after imaging surveillance. Three distinct radiologic patterns were identified, namely, single or multiple abscesses, focal cerebritis, and small, septic embolic infarcts. All isolates of Nocardia were susceptible to trimethoprim/sulfamethoxazole and amikacin, with susceptibility to linezolid and carbapenems being 90.9% and 79.5%, respectively. Despite receiving antibiotic therapy, six (42.8%) patients died, most of them within weeks of initial admission. All surviving patients underwent prolonged antimicrobial therapy until the resolution of MRI abnormalities. All solid organ transplant recipients recovered. Conclusions Nocardia CNS infection was a rare condition, even among a large, immunosuppressed patient population. CNS imaging surveillance is paramount for immunosuppressed patients with nocardiosis, as CNS involvement influences the choice and duration of therapy. Nocardia antibiotic susceptibility varied widely between strains and the empiric therapy should consist of multiple classes of antimicrobials with CNS penetration. Mortality was high, but all solid organ transplant recipients recovered.

Excipients for Novel Inhaled Dosage Forms: An Overview.

Pulmonary drug delivery is a form of local targeting to the lungs in patients with respiratory disorders like cystic fibrosis, pulmonary arterial hypertension (PAH), asthma, chronic pulmonary infections, and lung cancer. In addition, noninvasive pulmonary delivery also presents an attractive alternative to systemically administered therapeutics, not only for localized respiratory disorders but also for systemic absorption. Pulmonary delivery offers the advantages of a relatively low dose, low incidence of systemic side effects, and rapid onset of action for some drugs compared to other systemic administration routes. While promising, inhaled delivery of therapeutics is often complex owing to factors encompassing mechanical barriers, chemical barriers, selection of inhalation device, and limited choice of dosage form excipients. There are very few excipients that are approved by the FDA for use in developing inhaled drug products. Depending upon the dosage form, and inhalation devices such as pMDIs, DPIs, and nebulizers, different excipients can be used to provide physical and chemical stability and to deliver the dose efficiently to the lungs. This review article focuses on discussing a variety of excipients that have been used in novel inhaled dosage forms as well as inhalation devices.

Radiologic Classification of Hippocampal Sclerosis in Epilepsy.

Temporal lobe epilepsy is a common form of epilepsy that is often associated with hippocampal sclerosis (HS). Although HS is commonly considered a binary assessment in radiological evaluation, it is known that histopathological changes occur in distinct clusters. Some subtypes of HS only affect certain subfields, resulting in minimal changes to the overall volume of the hippocampus. This is likely a major reason why whole hippocampal volumetrics have underperformed versus expert readers. With recent advancements in MRI technology, it is now possible to characterize the substructure of the hippocampus more accurately. However, this is not consistently addressed in radiographic evaluations. The histological subtype of HS is critical for prognosis and treatment decision making, necessitating improved radiological classification of HS. The International League Against Epilepsy (ILAE) has issued a consensus classification scheme for subtyping HS histopathological changes. This review aims to explore how the ILAE subtypes of HS correlate with radiographic findings, introduce a grading system that integrates radiological and pathological reporting in HS, and outline an approach to detecting HS subtypes using MRI. This framework will not only benefit current clinical evaluations, but also enhance future studies involving high-resolution MRI in temporal lobe epilepsy.ABBREVIATIONS: CA = cornu ammonis; DG = dentate gyrus; HS = hippocampal sclerosis; ILAE = International League Against Epilepsy; SRLM = strata radiatum, lacunosum, and moleculare layers; TLE = temporal lobe epilepsy.

Incidences of Helicobacter infection in pigs and tracing occupational hazard in pig farmers.

Helicobacter species (spp.) is a gram-negative spiral-shaped motile bacterium that causes gastritis in pigs and also colonizes in the human stomach. The present study assessed the prevalence of Helicobacter spp. in pig gastric mucosa and the stool of pig farmers in Assam, India. A total of 403 stomach samples from pig slaughter points, 74 necropsy samples of pigs from pig farms, and 97 stool samples from pig farmers were collected. Among the pig stomach samples, 43 (20.09%) of those with gastritis showed the presence of Gram-negative, spiral-shaped organisms, while only 3.04% of stomach samples without lesions had these organisms. Scanning Electron Microscopy (SEM) of urease-positive stomach samples revealed tightly coiled Helicobacter bacteria in the mucus lining. Histopathological examination showed chronic gastritis with hemorrhagic necrosis, leucocytic infiltration, and lymphoid aggregates. PCR confirmed the presence of Helicobacter suis in 19.63% of pig stomach samples and 2.08% of pig farmer stool samples. Additionally, 3.12% of the stool samples from pig farmers were positive for Helicobacter pylori. Phylogenetic analysis revealed distinct clusters of Helicobacter suis with other Helicobacter spp. These findings highlight the prevalence of Helicobacter in both pig gastric mucosa and pig farmer stool. The findings highlight the need for improved sanitation and hygiene practices among pig farmers to minimize the risk of Helicobacter infection in humans.

Development of patient-specific finite element model for study of composite dental implants.

Traumatic dental injuries can occur due to various reasons such as accidents, sports injuries, fights, falls, and others. These injuries can affect the teeth, gums, and surrounding tissues, and can range from minor chips and cracks to severe fractures, dislocations, and avulsions (when the tooth is completely knocked out of the socket). The most common way to address this is by replacing affected teeth with dental implants. The purpose of this research is to evaluate the use of composite materials in dental implants and compare them with the traditionally used materials using a patient specific cone beam computed tomography (CBCT) based finite element model (FEM). To conduct this research, two different implant groups i.e., traditional implant and composite implant were designed using Titanium grade 4, zirconium oxide-reinforced lithium silicate (ZLS), and Zirconia (ZrO2). Six dental implants were designed namely Ti implant, ZLS implant, ZrO2implant, Ti-ZrO2composite, Ti-ZLS composite, and ZLS-ZrO2composite using 3D modelling software. Detailed full-scale 3D models of patient specific dental implant were developed and traumatic loading conditions were applied to the enamel of central incisor teeth or crown of dental implant, and maxilla was constrained in all directions. It was found that the use of composite materials for dental implants can reduce the stresses over the surface of abutment and implant as compared to traditional implants. The detailed models developed as a part of this study can advance the research on dental implants, and with further experimental validation allow the use of composite materials for fabrication of more stable dental implants.

CRISPR/Cas genome editing revealed non-angiogenic role of VEGFA gene in porcine luteal cells: a preliminary report.

BACKGROUND: The angiogenic cytokine vascular endothelial growth factor A (VEGFA) also exerts non-angiogenic effects on endocrine functionality of porcine luteal cells critical for progesterone (P4) production. METHOD AND RESULTS: The expression dynamics of VEGFA-FLT/KDR system were investigated using RT-qPCR during luteal stages and VEGFA gene knock out (KO) porcine luteal cells were generated using CRISPR/Cas9 technology. The downstream effects of VEGFA ablation were studied using RT-qPCR, Annexin V, MTT, ELISA for P4 estimation and scratch wound assay. Bioinformatics analysis of RNA-Seq data of porcine mid-luteal stage was conducted for exploring protein-protein interaction network, KEGG pathways, transcription factors and kinase mapping for VEGFA-FLT/KDR interactomes. The VEGFA-FLT/KDR system expressed throughout the luteal stages with highest expression during mid- luteal stage. Cellular morphology, structure and oil-red-o staining for lipid droplets did not differ significantly between VEGFA KO and wild type cells, however, VEGFA KO significantly decreased (p < 0.05) viability and proliferation efficiency of edited cells on subsequent passages. Expression of apoptotic gene, CASP3 and hypoxia related gene, HIF1A were significantly (p < 0.05) upregulated in KO cells. The relative mRNA expression of VEGFA and steroidogenic genes STAR, CYP11A1 and HSD3B1 decreased significantly (p < 0.05) upon KO, which was further validated by the significant (p < 0.05) decrease in P4 output from KO cells. Bioinformatics analysis mapped VEGFA-FLT/KDR system to signalling pathways associated with steroidogenic cell functionality and survival, which complemented the findings of the study. CONCLUSION: The ablation of VEGFA gene resulted in decreased steroidogenic capability of luteal cells, which suggests that VEGFA exerts additional non-angiogenic regulatory effects in luteal cell functionality.

Synthesis and evaluation of 2,5-substituted pyrimidines as small-molecule gankyrin binders.

Background: Gankyrin is an ankyrin-repeat protein that promotes cell proliferation, tumor development and cancer progression when overexpressed. Aim: To design and synthesize a novel series of gankyrin-binding small molecules predicated on a 2,5-pyrimidine scaffold. Materials & methods: The synthesized compounds were evaluated for their antiproliferative activity, ability to bind gankyrin and effects on cell cycle progression and the proteasomal degradation pathway. Results: Compounds 188 and 193 demonstrated the most potent antiproliferative activity against MCF7 and A549 cells, respectively. Both compounds also demonstrated the ability to effectively bind gankyrin, disrupt proteasomal degradation and inhibit cell cycle progression. Conclusion: The 2,5-pyrimidine scaffold exhibits a novel and promising strategy for binding gankyrin and inhibiting cancer cell proliferation.

7 T Lesion-Attenuated Magnetization-Prepared Gradient Echo Acquisition for Detection of Posterior Fossa Demyelinating Lesions in Multiple Sclerosis.

OBJECTIVES: Detection of infratentorial demyelinating lesions in multiple sclerosis (MS) presents a challenge in magnetic resonance imaging (MRI), a difficulty that is further heightened in 7 T MRI. This study aimed to assess the efficacy of a novel MRI approach, lesion-attenuated magnetization-prepared gradient echo acquisition (LAMA), for detecting demyelinating lesions within the posterior fossa and upper cervical spine on 7 T MRI and contrast its performance with conventional double-inversion recovery (DIR) and T2-weighted turbo spin echo sequences. MATERIALS AND METHODS: We conducted a retrospective cross-sectional study in 42 patients with a confirmed diagnosis of MS. All patients had 7 T MRI that incorporated LAMA, 3D DIR, and 2D T2-weighted turbo spin echo sequences. Three readers assessed lesion count in the brainstem, cerebellum, and upper cervical spinal cord using both DIR and T2-weighted images in one session. In a separate session, LAMA was analyzed alone. Contrast-to-noise ratio was also compared between LAMA and the conventional sequences. Lesion counts between methods were assessed using nonparametric Wilcoxon signed rank test. Interrater agreement in lesion detection was estimated by intraclass correlation coefficients. RESULTS: LAMA identified a significantly greater number of lesions than DIR + T2 (mean 6.4 vs 3.0; P < 0.001). LAMA also exhibited better interrater agreement (intraclass correlation coefficient [95% confidence interval], 0.75 [0.41-0.88] vs 0.61 [0.35-0.78]). The contrast-to-noise ratio for LAMA (3.7 ± 0.9) significantly exceeded that of DIR (1.94 ± 0.7) and T2 (1.2 ± 0.7) (all P's < 0.001). In cases with no lesions detected using DIR + T2, at least 1 lesion was identified in 83.3% with LAMA. Across all analyzed brain regions, LAMA consistently detected more lesions than DIR + T2. CONCLUSIONS: LAMA significantly improves the detection of infratentorial demyelinating lesions in MS patients compared with traditional methods. Integrating LAMA with standard magnetization-prepared 2 rapid acquisition gradient echo acquisition provides a valuable tool for accurately characterizing the extent of MS disease.

Transboundary hazard and downstream impact of glacial lakes in Hindu-Kush Karakoram Himalayas.

Glacial Lake Outburst Floods (GLOFs) can generate catastrophic flash floods when the damming structure is breached or overtopped. Some of these glacial lakes are located in transboundary regions where floods originating from the lake in one country could inundate a neighboring country, devastating the population and infrastructure of both nations and influencing socio-political relationships. Therefore, assessing the lakes' hazard is crucial. This study investigates transboundary glacial lakes, considering their GLOF hazard, including potential mass movement intrusion, moraine's stability, upstream and downstream process cascades, downstream flood extents, and the exposure and vulnerability of the downstream infrastructure and affected population. GLOF exposure assessments were carried out to identify exposed buildings, bridges, and hydropower systems in transboundary regions. China currently has the highest number of transboundary lakes, with most of them potentially impacting India and Nepal. Most of the transboundary lakes in China, and many in India and Nepal, are susceptible to mass movements. Among the 230 transboundary glacial lakes in the Hindu Kush Karakoram Himalaya, 55 lakes can potentially impact other glacial lakes along their flow path, creating a cascade of events. Five transboundary lakes could potentially impact over 1000 buildings, and 16 lakes could impact over 500 buildings. A total of 35 lakes can impact at least one hydropower station along their flow path, and 4 lakes can impact two hydropower stations. This research emphasizes the critical importance of conducting comprehensive risk analyses of GLOFs in transboundary regions to inform policy-makers. It calls for investing in broad-scale assessments and data-driven decision-making for mitigating and adapting to GLOF risks effectively. Finally, by raising awareness among policy-makers, the study aims to drive actions that safeguard communities and infrastructure vulnerable to GLOF.

Proteomics provides insights into the theranostic potential of extracellular vesicles.

Extracellular vesicles (EVs) encompass a diverse range of membranous structures derived from cells, including exosomes and microvesicles. These vesicles are present in biological fluids and play vital roles in various physiological and pathological processes. They facilitate intercellular communication by enabling the exchange of proteins, lipids, and genetic material between cells. Understanding the cellular processes that govern EV biology is essential for unraveling their physiological and pathological functions and their potential clinical applications. Despite significant advancements in EV research in recent years, there is still much to learn about these vesicles. The advent of improved mass spectrometry (MS)-based techniques has allowed for a deeper characterization of EV protein composition, providing valuable insights into their roles in different physiological and pathological conditions. In this chapter, we provide an overview of proteomics studies conducted to identify the protein contents of EVs, which contribute to their therapeutic and pathological features. We also provided evidence on the potential of EV proteome contents as biomarkers for early disease diagnosis, progression, and treatment response, as well as factors that influence their composition. Additionally, we discuss the available databases containing information on EV proteome contents, and finally, we highlight the need for further research to pave the way toward their utilization in clinical settings.