TOR2 plays the central role in rapamycin-induced lifespan extension in budding yeast.

The target of rapamycin (TOR) protein, renowned for its highly conserved nature across species, plays a pivotal role in modulating signaling pathways via its multiprotein complexes, TORC1 and TORC2. The relationship between TOR and its inhibitor, rapamycin, especially in the context of lifespan extension, has earned significant attention. Unlike mammals, which have a single TOR gene, the budding yeast Saccharomyces cerevisiae features two TOR paralogs: TOR1 and TOR2. Non-essential TOR1 gene has been the focus of extensive research, whereas the essential TOR2 gene has received relatively little attention in lifespan studies. In our research, we engineered a point mutation (Ser-1975-Ile) within the FKBP12-rapamycin-binding (FRB) domain of Tor2p to block rapamycin binding. Remarkably, this mutation negated the lifespan-extending benefits of rapamycin, irrespective of the TOR1 gene status. Our findings indicate that the TOR2 gene likely serves as the primary mammalian ortholog, playing a crucial role in mediating the effects of rapamycin on lifespan extension. This discovery opens a new avenue for the development of innovative anti-aging agents targeting the TOR. complex.

Enhancement of Electron Transport Characteristics Using MXene-MnFeO3 Nanocomposite Integration with Fullerene Derivatives for the Perovskite-Based Solar Cells and Detectors.

In this study, we prepared a hybrid film incorporating the MnFeO3-decorated conducting two-dimensional (2D) MXene sheet-suspended [6,6]-phenyl-C61-butyric acid methyl ester (PCBM) electron transfer layer (ETL) for the perovskite solar cells (PSCs) and detectors. The incorporation of MXene-MnFeO3 with the PCBM ETL could drive exceptional conducting features for the PSCs. Moreover, the presence of MXene-MnFeO3 facilitated superior charge transfer pathways, thereby enhancing the electron extraction and collection processes. This enhancement was directed to improve the electron mobility within the device, resulting in high photocurrents. The designed interface engineering with the MXene-MnFeO3 nanocomposite-tuned PCBM ETL has produced a remarkable power conversion efficiency of 17.79% ± 0.27. Moreover, X-ray detectors employing PCBM modulated with the MXene-MnFeO3 ETL achieved notable performance metrics including 18.47 µA/cm2 CCD-DCD, 5.53 mA/Gy·cm2 sensitivity, 7.64 × 10-4 cm2/V·s electron mobility, and 1.51 × 1015 cm2/V·s trap density.

Effect of increasing ß-mannanase supplementation in diets containing copra meal on growth performance, meat quality, liver health, intestinal morphology, and nutrient utilization in broiler chickens.

Objective: The current study aimed to investigate the effect of increasing ß-mannanase supplementation in diets containing copra meal (CM) on growth performance, meat quality, liver health, intestinal morphology, and nutrient utilization in broiler chickens. Methods: A total of 1,600 3-d-old Ross 308 broiler chickens (initial body weight [BW] ± SD = 43.3 ± 1.08 g) were randomly allotted to 1 of 5 treatment groups with 8 replicates. One group was fed a corn-soybean meal-based diet (control). Other 4 diets were prepared by inclusion of 10% commercial CM in the control diet with 0, 400, 800, and 1,600 U ß-mannanase/kg. Experiments lasted for 32 d. Results: Birds fed the control diet had less (p=0.001) feed conversion ratio (FCR) than those fed diets containing 10% CM without ß-mannanase supplementation. Increasing supplementation of ß-mannanase in diets containing 10% CM had no linear and quadratic effects on body weight gain, feed intake, and FCR in broiler chickens. The control diet had greater (p<0.01) apparent total tract retention (ATTR) of DM, GE, and N as compared to the diets containing 10% CM without ß-mannanase supplementation; however, no differences in the ATTR of Ca and P were identified between 2 diets. There were no linear and quadratic effects of increasing supplementation of ß-mannanase on the ATTR of DM, GE, N, Ca, and P in broiler diets containing 10% CM. Both inclusion of 10% CM and increasing supplementation of ß-mannanase in broiler diets did not affect apparent ME (AME) and N-corrected ME (AMEn) values in treatment diets. Conclusion: The use of 10% CM in broiler diets during growing and finishing period impairs growth performance by decreasing energy and nutrient utilization in diets. Increasing ß-mannanase supplementation in diets containing 10% CM has no positive effects on performance, meat quality, liver health, intestinal morphology, and nutrient utilization in broiler chickens.

Intranasal Administration of Recombinant Newcastle Disease Virus Expressing SARS-CoV-2 Spike Protein Protects hACE2 TG Mice against Lethal SARS-CoV-2 Infection.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), emerged as a global outbreak in 2019, profoundly affecting both human health and the global economy. Various vaccine modalities were developed and commercialized to overcome this challenge, including inactivated vaccines, mRNA vaccines, adenovirus vector-based vaccines, and subunit vaccines. While intramuscular vaccines induce high IgG levels, they often fail to stimulate significant mucosal immunity in the respiratory system. We employed the Newcastle disease virus (NDV) vector expressing the spike protein of the SARS-CoV-2 Beta variant (rK148/beta-S), and evaluated the efficacy of intranasal vaccination with rK148/beta-S in K18-hACE2 transgenic mice. Intranasal vaccination with a low dose (106.0 EID50) resulted in an 86% survival rate after challenge with the SARS-CoV-2 Beta variant. Administration at a high dose (107.0 EID50) led to a reduction in lung viral load and 100% survival against the SARS-CoV-2 Beta and Delta variants. A high level of the SARS-CoV-2 spike-specific IgA was also induced in vaccinated mice lungs following the SARS-CoV-2 challenge. Our findings suggest that rK148/beta-S holds promise as an intranasal vaccine candidate that effectively induces mucosal immunity against SARS-CoV-2.

Prevalence of KRAS amplification in patients with metastatic cancer: Real-world next-generation sequencing analysis.

BACKGROUND: The Kirsten rat sarcoma virus (KRAS) is a prominent proto-oncogene. Several treatments for KRAS mutations have been developed. However, KRAS amplification, a KRAS alteration, is poorly understood, and there is currently no appropriate treatment other than conventional chemotherapy. This study aimed to elucidate the role of KRAS amplification in different types of cancers. METHODS: From October 2019 to June 2023, we performed next-generation sequencing using Trusight Oncology 500 on 3895 patients with 37 different cancer types at the Samsung Medical Center. We analyzed the distribution of KRAS amplification according to cancer type and its correlation with tumor mutation burden (TMB). Concomitant KRAS mutations were also identified. RESULTS: Of the total 3895 patients, 99 (2.5 %) had KRAS amplification. The highest frequency of KRAS amplification was detected in 2 % (27/1350) of patients with colorectal cancer, followed by 3.48 % (32/920) of patients with gastric cancer and 3.88 % (9/232) patients with of pancreatic cancer. MSI-High was not detected in patients with KRAS amplification. There was no correlation between KRAS copy number variation and TMB status. Among patients with KRAS amplification, 27.3 % (27/99) had a concomitant KRAS mutation. More than 50 % of patients had G12D or G12V mutations. In gastric cancer, patients with both KRAS amplification and mutation were extremely rare at 3.1 % (1/32); however, in colorectal cancer, more than half of the patients had KRAS amplification and mutation (51.9 %, 14/27). KRAS amplification and mutations are associated with mutations in tumor suppressor genes TP53, BRCA2, ARID1B, and PTCH1. CONCLUSIONS: Of the 3895 patients with metastatic solid tumors, 99 (2.5 %) had KRAS amplification, and next-generation sequencing analysis provided a deeper understanding of KRAS amplification.

Real-world Comparison of P53 Immunohistochemistry and TP53 Mutation Analysis Using Next-generation Sequencing.

BACKGROUND/AIM: TP53 mutation in breast cancer (BC) is associated with chemoresistance, endocrine therapy resistance, and late recurrence, resulting in poor prognosis. Nuclear accumulation of p53 in immunohistochemistry (IHC) is a surrogate marker of TP53 mutation. This study analyzed the frequency, type, and distribution of TP53 mutations in BCs and assessed the efficacy of p53 IHC as a surrogate marker of TP53 mutation. PATIENTS AND METHODS: We collected data from 112 BC cases, including the results of p53 IHC and next-generation sequencing (NGS). RESULTS: Over-expression of p53 IHC was observed in 36 patients (32.1%), complete absence in 19 patients (17.0%), aberrant cytoplasmic staining in 1 patient (0.9%), and wild-type in 56 (50.0%) patients. The concordance rate between TP53 mutation and p53 IHC was 88.4% in all BCs, 89.9% in luminal BCs, and 86.0% in triple-negative BCs (TNBC). TNBC, abnormal p53 IHC pattern, p53 IHC over-expression, neoadjuvant chemotherapy (NAC) history, TP53 mutation, and high pre-treatment ki-67 labeling index (≥50%) were significantly associated with worse distant metastasis-free survival (DMFS) and overall survival (OS) (p<0.05). Pre-NAC clinical stage III was associated with worse DMFS but not OS. Multivariate analysis showed that NAC history, TNBC, and p53 IHC over-expression were independent predictors of worse DMFS. An abnormal p53 IHC pattern and NAC history were independent predictors of worse OS. CONCLUSION: P53 IHC is a valid surrogate marker of TP53 mutation in BC. Accumulation of abnormal p53 alone, regardless of TP53 mutation, was associated with worse DMFS and can be used as an easily accessible biomarker to predict chemoresistance.

Healthcare Seeking Behavior and Disease Perception Toward Cholera and Acute Diarrhea Among Populations Living in Cholera High-Priority Hotspots in Shashemene, Ethiopia.

BACKGROUND: Healthcare seeking behavior (HSB) and community perception on cholera can influence its management. We conducted a cross-sectional survey to generate evidence on cholera associated HSB and disease perception in populations living in cholera hotspots in Ethiopia. METHODS: A total of 870 randomly selected households (HHs) in Shashemene Town (ST) and Shashemene Woreda (SW) participated in our survey in January 2022. RESULTS: Predominant HHs (91.0%; 792/870) responded "primary health center" as the nearest healthcare facility (HCF). Around 57.4% (247/430) of ST HHs traveled <30 minutes to the nearest HCF. In SW, 60.2% (265/440) of HHs travelled over 30 minutes and 25.9% (114/440) over 4 km. Two-thirds of all HHs paid

Coverage of Two-Dose Preemptive Cholera Mass Vaccination Campaign in High-Priority Hotspots in Shashemene, Oromia Region, Ethiopia.

BACKGROUND: Cholera is a public health priority in Ethiopia. The Ethiopian National Cholera Plan elaborates a multi-year scheme of oral cholera vaccine (OCV) use. Aligned with this, a preemptive OCV campaign was conducted under our Ethiopia Cholera Control and Prevention project. Here, we present the OCV vaccination outcomes. METHOD: Cholera high-priority hotspots in the Oromia Region, Shashemene Town (ST) and Shashemene Woreda (SW), were selected. Four kebelles (Abosto, Alelu, Arada, and Awasho) in ST and 4 clusters (Faji Gole, Harabate, Toga, and Chabi) in SW were study sites with OCV areas nested within. A total of 40 000 and 60 000 people in ST and SW, respectively, were targeted for a 2-dose OCV (Euvichol-Plus) campaign in 11-15 May (first round [R1]) and 27-31 May (second round [R2]) 2022. Daily administrative OCV coverage and a coverage survey in 277 randomly selected households were conducted. RESULTS: The administrative OCV coverage was high: 102.0% for R1 and 100.5% for R2 in ST and 99.1% (R1) and 100.0% (R1) in SW. The coverage survey showed 78.0% (95% confidence interval [CI]: 73.1-82.9) of household members with 2-dose OCV and 16.8% (95% CI: 12.4-21.3) with no OCV in ST; and 83.1% (95% CI: 79.6-86.5) with 2-dose OCV and 11.8% (95% CI: 8.8-14.8) with no OCV in SW. The 2-dose coverages in 1-4-, 5-14-, and ≥15-year age groups were 88.3% (95% CI: 70.6-96.1), 88.9% (95% CI: 82.1-95.7), and 71.3% (95% CI: 64.2-78.3), respectively, in ST and 78.2% (95% CI: 68.8-87.7), 91.0% (95% CI: 86.6-95.3), and 78.7% (95% CI: 73.2-84.1) in SW. CONCLUSIONS: High 2-dose OCV coverage was achieved. Cholera surveillance is needed to assess the vaccine impact and effectiveness.

Dissecting Water, Sanitation, and Hygiene (WaSH) to Assess Risk Factors for Cholera in Shashemene, Oromia Region, Ethiopia.

BACKGROUND: Cholera outbreaks have afflicted Ethiopia, with nearly 100 000 cases and 1030 deaths reported from 2015 to 2023, emphasizing the critical need to understand water, sanitation, and hygiene (WaSH) risk factors. METHODS: We conducted a cross-sectional household (HH) survey among 870 HHs in Shashemene Town and Shashemene Woreda, alongside extracting retrospective cholera case data from the Ethiopian Public Health Institute database. Relationships between WaSH and sociodemographic/economic-levels of HHs were examined. WaSH status and cholera attack rates (ARs) were described at kebele-level using geospatial mapping, and their association was statistically analyzed. RESULTS: Access to basic drinking water, sanitation, and hygiene facilities was limited, with 67.5% (95% confidence interval, 64.4-70.6), 73.4% (70.3-76.3), and 30.3% (27.3-33.3) of HHs having access, respectively. Better WaSH practices were associated with urban residence (adjusted odds ratio, 1.7, [95% confidence interval, 1.1-2.7]), higher educational levels (2.7 [1.2-5.8]), and wealth (2.5 [1.6-4.0]). The association between cholera ARs and at least basic WaSH status was not statistically significant (multiple R2 = 0.13; P = .36), although localized effects were suggested for sanitation (Moran I = 0.22; P = .024). CONCLUSIONS: Addressing gaps in WaSH access and hygiene practices is crucial for reducing cholera risk. Further analyses with meaningful covariates and increased sample sizes are necessary to understand the association between cholera AR and specific WaSH components.

Retrospective Analysis of Cholera/Acute Watery Diarrhea Outbreaks in Ethiopia From 2001 To 2023: Incidence, Case Fatality Rate, and Seasonal and Multiyear Epidemic Patterns.

BACKGROUND: The Ethiopian government has developed the multisectoral cholera elimination plan (NCP) with an aim of reducing cholera incidence and case fatality rate (CFR). To better understand and monitor the progress of this plan, a comprehensive review of national cholera epidemiology is needed. METHODS: Reported data on cholera/acute watery diarrhea (AWD) cases in the past 20 years were extracted from the Ethiopian Public Health Institute and World Health Organization databases. Descriptive statistics, Pearson χ2, and logistic regression analyses were conducted. RESULTS: From January 2001 to November 2023, a total of 215 205 cholera/AWD cases, 2355 deaths with a cumulative CFR of 1.10% (95% confidence interval [CI], 1.092-1.095), and a mean annual incidence rate of 8.9/100 000 (95% CI, 6.5-11.3) were reported. Two major upsurges of cholera epidemics were found in the last two decades with mean attack rate (AR) of 20.57/100 000 in 2006-2010 and 14.83/100 000 in 2016-2020. Another resurgence of outbreaks occured in 2021-2023 (mean AR, 8.63/100 000). In 2015-2023, 54.0% (53 990/99 945) of cases were aged 15-44 years. National cholera CFR (3.13% [95% CI: 2.1-4.5]) was the highest in 2022. The 2015-2023 cumulative cholera CFR was different across regions: Benishangul Gumuz (6.07%), Gambela (1.89%), Sidama (1.42%), Southern Nation, Nationalities, and Peoples' (1.34%), Oromia (1.10%), and Amhara (1.09%). Cholera/AWD patients in older adults (≥45 years), severe dehydration, peak rainy season (June-August), and outpatients were associated with higher risk of death. CONCLUSIONS: Cholera has been a public health problem in Ethiopia with case fatalities still above the global target. Case management needs to be improved particularly in outpatients and older populations. Outbreak preparedness should be rolled out well in advance of the typical rainy seasons. Significant investments are essential to advance the cholera surveillance system at healthcare setting and community level. Underlying factors of cholera deaths per areas should be further investigated to guide appropriate interventions to meet the NCP target by 2028.

Generating 3D images of VMAT plans for predictive models and activation maps associated with plan deliverability.

BACKGROUND: Intensity modulation with dynamic multi-leaf collimator (MLC) and monitor unit (MU) changes across control points (CPs) characterizes volumetric modulated arc therapy (VMAT). The increased uncertainty in plan deliverability required patient-specific quality assurance (PSQA), which remained inefficient upon Quality Assurance (QA) failure. To prevent waste before QA, plan complexity metrics (PCMs) and machine learning models with the metrics were generated, which were lack of providing CP-specific information upon QA failures. PURPOSE: By generating 3D images from digital imaging and comminications in medicine in radiation therapy (DICOM RT) plan, we proposed a predictive model that can estimate the deliverability of VMAT plans and visualize CP-specific regions associated with plan deliverability. METHODS: The patient cohort consisted of 259 and 190 cases for left- and right-breast VMAT treatments, which were split into 235 and 166 cases for training and 24 cases from each treatment for testing the networks. Three-channel 3D images generated from DICOM RT plans were fed into a DenseNet-based deep learning network. To reflect VMAT plan complexity as an image, the first two channels described MLC and MU variations between two consecutive CPs, while the last channel assigned the beam field size. The network output was defined as binary classified PSQA results, indicating deliverability. The predictive performance was assessed by accuracy, sensitivity, specificity, F1-score, and area under the curve (AUC). The gradient-weighted class activation map (Grad-CAM) highlighted the regions of CPs in VMAT plans associated with deliverability, compared against PCMs by Spearman correlation. RESULTS: The DenseNet-based predictive model yielded AUCs of 92.2% and 93.8%, F1-scores of 97.0% and 93.8% and accuracies of 95.8% and 91.7% for the left- and right-breast VMAT cases. Additionally, the specificity of 87.5% for both cases indicated that the predictive model accurately detected QA failing cases. The activation maps significantly differentiated QA failing-labeled from passing-labeled classes for the non-deliverable cases. The PCM with the highest correlation to the Grad-CAM varied from patient cases, implying that plan deliverability would be considered patient-specific. CONCLUSION: This work demonstrated that the deep learning-based network based on visualization of dynamic VMAT plan information successfully predicted plan deliverability, which also provided control-point specific planning parameter information associated with plan deliverability in a patient-specific manner.

The Survival of Human Intervertebral Disc Nucleus Pulposus Cells under Oxidative Stress Relies on the Autophagy Triggered by Delphinidin.

Delphinidin (Delp), a natural antioxidant, has shown promise in treating age-related ailments such as osteoarthritis (OA). This study investigates the impact of delphinidin on intervertebral disc degeneration (IVDD) using human nucleus pulposus cells (hNPCs) subjected to hydrogen peroxide. Various molecular and cellular assays were employed to assess senescence, extracellular matrix (ECM) degradation markers, and the activation of AMPK and autophagy pathways. Initially, oxidative stress (OS)-induced hNPCs exhibited notably elevated levels of senescence markers like p53 and p21, which were mitigated by Delp treatment. Additionally, Delp attenuated IVDD characteristics including apoptosis and ECM degradation markers in OS-induced senescence (OSIS) hNPCs by downregulating MMP-13 and ADAMTS-5 while upregulating COL2A1 and aggrecans. Furthermore, Delp reversed the increased ROS production and reduced autophagy activation observed in OSIS hNPCs. Interestingly, the ability of Delp to regulate cellular senescence and ECM balance in OSIS hNPCs was hindered by autophagy inhibition using CQ. Remarkably, Delp upregulated SIRT1 and phosphorylated AMPK expression while downregulating mTOR phosphorylation in the presence of AICAR (AMPK activator), and this effect was reversed by Compound C, AMPK inhibitor. In summary, our findings suggest that Delp can safeguard hNPCs from oxidative stress by promoting autophagy through the SIRT1/AMPK/mTOR pathway.

Sex differences and role of lysyl oxidase-like 2 in angiotensin II-induced hypertension in mice.

Hypertension, a disease with known sexual dimorphism, accelerates aging-associated arterial stiffening, partly because of the activation of matrix remodeling caused by increased biomechanical load. In this study, we tested the effect of biological sex and the role of the matrix remodeling enzyme lysyl oxidase-like 2 (LOXL2) in hypertension-induced arterial stiffening. Hypertension was induced by angiotensin II (ANG II) infusion via osmotic minipumps in 12- to 14-wk-old male and female mice. Blood pressure and pulse wave velocity (PWV) were measured noninvasively. Wire myography and uniaxial tensile testing were used to test aortic vasoreactivity and mechanical properties. Aortic wall composition was examined by histology and Western blotting. Uniaxial stretch of cultured cells was used to evaluate the effect of biomechanical strain. LOXL2's catalytic function was examined using knockout and inhibition. ANG II infusion-induced hypertension in both genotypes and sexes. Wild-type (WT) males exhibited arterial stiffening in vivo and ex vivo. Aortic remodeling with increased wall thickness, intralamellar distance, higher LOXL2, and collagen I and IV content was noted in WT males. Female mice did not exhibit increased PWV despite the onset of hypertension. LOXL2 depletion improved vascular reactivity and mechanics in hypertensive males. LOXL2 depletion improved aortic mechanics but worsened hypercontractility in females. Hypertensive cyclic strain contributed to LOXL2 upregulation in the cell-derived matrix in vascular smooth muscle cells (VSMCs) but not endothelial cells. LOXL2's catalytic function facilitated VSMC alignment in response to biomechanical strain. In conclusion, in males, arterial stiffening in hypertension is driven both by VSMC response and matrix remodeling. Females are protected from PWV elevation in hypertension. LOXL2 depletion is protective in males with improved mechanical and functional aortic properties. VSMCs are the primary source of LOXL2 in the aorta, and hypertension increases LOXL2 processing and shifts to collagen I accumulation. Overall, LOXL2 depletion offers protection in young hypertensive males and females.NEW & NOTEWORTHY We examined the effect of sex on the evolution of angiotensin II (ANG II)-induced hypertension and the role of lysyl oxidase-like 2 (LOXL2), an enzyme that catalyzes matrix cross linking. While ANG II led to hypertension and worsening vascular reactivity in both sexes, aortic remodeling and stiffening occurred only in males. LOXL2 depletion improved outcomes in males but not females. Thus males and females exhibit a distinct etiology of hypertension and LOXL2 is an effective target in males.

The Mohawk homeobox gene represents a marker and osteo-inhibitory factor in calvarial suture osteoprogenitor cells.

The regeneration of the mammalian skeleton's craniofacial bones necessitates the action of intrinsic and extrinsic inductive factors from multiple cell types, which function hierarchically and temporally to control the differentiation of osteogenic progenitors. Single-cell transcriptomics of developing mouse calvarial suture recently identified a suture mesenchymal progenitor population with previously unappreciated tendon- or ligament-associated gene expression profile. Here, we developed a Mohawk homeobox (MkxCG; R26RtdT) reporter mouse and demonstrated that this reporter identifies an adult calvarial suture resident cell population that gives rise to calvarial osteoblasts and osteocytes during homeostatic conditions. Single-cell RNA sequencing (scRNA-Seq) data reveal that Mkx+ suture cells display a progenitor-like phenotype with expression of teno-ligamentous genes. Bone injury with Mkx+ cell ablation showed delayed bone healing. Remarkably, Mkx gene played a critical role as an osteo-inhibitory factor in calvarial suture cells, as knockdown or knockout resulted in increased osteogenic differentiation. Localized deletion of Mkx in vivo also resulted in robustly increased calvarial defect repair. We further showed that mechanical stretch dynamically regulates Mkx expression, in turn regulating calvarial cell osteogenesis. Together, we define Mkx+ cells within the suture mesenchyme as a progenitor population for adult craniofacial bone repair, and Mkx acts as a mechanoresponsive gene to prevent osteogenic differentiation within the stem cell niche.

Spatial and temporal clustering of typhoid fever in an urban slum of Dhaka City: Implications for targeted typhoid vaccination.

BACKGROUND: Salmonella enterica serotype Typhi (Salmonella Typhi) causes severe and occasionally life-threatening disease, transmitted through contaminated food and water. Humans are the only reservoir, inadequate water, sanitation, and hygiene infrastructure increases risk of typhoid. High-quality data to assess spatial and temporal relationships in disease dynamics are scarce. METHODS: We analyzed data from a prospective cohort conducted in an urban slum area of Dhaka City, Bangladesh. Passive surveillance at study centers identified typhoid cases by microbiological culture. Each incident case (index case) was matched to two randomly selected index controls, and we measured typhoid incidence in the population residing in a geographically defined region surrounding each case and control. Spatial clustering was evaluated by comparing the typhoid incidence in residents of geometric rings of increasing radii surrounding the index cases and controls over 28 days. Temporal clustering was evaluated by separately measuring incidence in the first and second 14-day periods following selection. Incidence rate ratios (IRRs) were calculated using Poisson regression models. RESULTS: We evaluated 141 typhoid index cases. The overall typhoid incidence was 0.44 per 100,000 person-days (PDs) (95% CI: 0.40, 0.49). In the 28 days following selection, the highest typhoid incidence (1.2 per 100,000 PDs [95% CI: 0.8, 1.6]) was in the innermost cluster surrounding index cases. The IRR in this innermost cluster was 4.9 (95% CI: 2.4, 10.3) relative to the innermost control clusters. Neither typhoid incidence rates nor relative IRR between index case and control populations showed substantive differences in the first and second 14-day periods after selection. CONCLUSION: In the absence of routine immunization programs, geographic clustering of typhoid cases suggests a higher intensity of typhoid risk in the population immediately surrounding identified cases. Further studies are needed to understand spatial and temporal trends and to evaluate the effectiveness of targeted vaccination in disrupting typhoid transmission.

2D Materials in Advanced Electronic Biosensors for Point-of-Care Devices.

Since two-dimensionalal (2D) materials have distinct chemical and physical properties, they are widely used in various sectors of modern technologies. In the domain of diagnostic biodevices, particularly for point-of-care (PoC) biomedical diagnostics, 2D-based field-effect transistor biosensors (bio-FETs) demonstrate substantial potential. Here, in this review article, the operational mechanisms and detection capabilities of biosensing devices utilizing graphene, transition metal dichalcogenides (TMDCs), black phosphorus, and other 2D materials are addressed in detail. The incorporation of these materials into FET-based biosensors offers significant advantages, including low detection limits (LOD), real-time monitoring, label-free diagnosis, and exceptional selectivity. The review also highlights the diverse applications of these biosensors, ranging from conventional to wearable devices, underscoring the versatility of 2D material-based FET devices. Additionally, the review provides a comprehensive assessment of the limitations and challenges faced by these devices, along with insights into future prospects and advancements. Notably, a detailed comparison of FET-based biosensors is tabulated along with various other biosensing platforms and their working mechanisms. Ultimately, this review aims to stimulate further research and innovation in this field while educating the scientific community about the latest advancements in 2D materials-based biosensors.

Using Dried Blood Spots to Quantitatively Detect Anti-SARS-CoV-2 IgG Antibodies by ELISA: A Validation Study.

SARS-CoV-2 serological testing is useful to determine seroprevalence, epidemiological trends, and the extent of transmission. The collection and transport of serum samples can be logistically challenging, especially in remote underserved areas. Dried blood spots (DBSs) would allow easier sample collection and logistical handling compared with standard serum collection, particularly for extensive and repeated SARS-CoV-2 serosurveys. We evaluated the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the IgG ELISA (Wantai, Beijing, China) using DBSs against sera for the quantitative detection of SARS-CoV-2 IgG antibody. The IgG ELISA was used to test paired sera and DBSs obtained from individuals with recent virologically confirmed COVID-19 illness and banked paired sera and DBSs collected before the COVID-19 pandemic. We found that 100/100 (100%) seropositive samples were positive using DBSs, and 193/194 (99%) seronegative samples were negative using DBSs. Compared with sera, the DBS method had a 100% sensitivity, 99% specificity, 99% PPV, and 100% NPV. Use of DBSs for SARS-CoV-2 household or population serosurveys may be considered in situations with limitations in sample collection, shipment, and storage.

Engineering extracellular vesicles for ROS scavenging and tissue regeneration.

Stem cell therapy holds promise for tissue regeneration, yet significant challenges persist. Emerging as a safer and potentially more effective alternative, extracellular vesicles (EVs) derived from stem cells exhibit remarkable abilities to activate critical signaling cascades, thereby facilitating tissue repair. EVs, nano-scale membrane vesicles, mediate intercellular communication by encapsulating a diverse cargo of proteins, lipids, and nucleic acids. Their therapeutic potential lies in delivering cargos, activating signaling pathways, and efficiently mitigating oxidative stress-an essential aspect of overcoming limitations in stem cell-based tissue repair. This review focuses on engineering and applying EVs in tissue regeneration, emphasizing their role in regulating reactive oxygen species (ROS) pathways. Additionally, we explore strategies to enhance EV therapeutic activity, including functionalization and incorporation of antioxidant defense proteins. Understanding these molecular mechanisms is crucial for optimizing EV-based regenerative therapies. Insights into EV and ROS signaling modulation pave the way for targeted and efficient regenerative therapies harnessing the potential of EVs.