53BP1 deficiency leads to hyperrecombination using break-induced replication (BIR).

Break-induced replication (BIR) is mutagenic, and thus its use requires tight regulation, yet the underlying mechanisms remain elusive. Here we uncover an important role of 53BP1 in suppressing BIR after end resection at double strand breaks (DSBs), distinct from its end protection activity, providing insight into the mechanisms governing BIR regulation and DSB repair pathway selection. We demonstrate that loss of 53BP1 induces BIR-like hyperrecombination, in a manner dependent on Polα-primase-mediated end fill-in DNA synthesis on single-stranded DNA (ssDNA) overhangs at DSBs, leading to PCNA ubiquitination and PIF1 recruitment to activate BIR. On broken replication forks, where BIR is required for repairing single-ended DSBs (seDSBs), SMARCAD1 displaces 53BP1 to facilitate the localization of ubiquitinated PCNA and PIF1 to DSBs for BIR activation. Hyper BIR associated with 53BP1 deficiency manifests template switching and large deletions, underscoring another aspect of 53BP1 in suppressing genome instability. The synthetic lethal interaction between the 53BP1 and BIR pathways provides opportunities for targeted cancer treatment.

Management of Postural Orthostatic Tachycardia Syndrome in Pediatric Patients: A Clinical Review.

Postural orthostatic tachycardia syndrome (POTS) is a chronic illness with unknown mortality and high morbidity, often diagnosed in the adolescent years. Published literature regarding POTS primarily focuses on the adult population, and guidance on treatment in pediatrics is sparse. The purpose of this clinical review is to evaluate the current literature on the management of POTS in pediatric patients. A search was conducted using the Cochrane database, Google Scholar, and PubMed. Studies were included if they evaluated the management of POTS, primarily in pediatric patients. Case reports and series were excluded. Eight published studies met the inclusion and exclusion criteria. To date, there are no US Food and Drug Administration-approved agents for the treatment of POTS. However, select pharmacological therapies have shown positive outcomes by addressing symptom origins, such as providing heart rate control, peripheral autonomic modulation, and targeting hypovolemia. Targeted pharmacological therapies studied in children and young adults include ivabradine, metoprolol, midodrine, pyridostigmine, intravenous crystalloid fluids, and fludrocortisone. Before adding pharmacotherapeutic interventions, non-pharmacologic interventions such as patient education, avoidance of symptom-triggering environments and medications, dietary fluid and sodium supplementation, exercise, and use of compression garments should be first attempted. Although the body of evidence for the management of POTS is expanding, additional research is needed to determine safe and efficacious dosing and establish clear guidelines for POTS in the pediatric population.

Microfluidic Modulation of Microvasculature in Microdissected Tumors.

The microvasculature within the tumor microenvironment (TME) plays an essential role in cancer signaling beyond nutrient delivery. However, it has been challenging to control the generation and/or maintenance of microvasculature in ex vivo systems, a critical step for establishing cancer models of high clinical biomimicry. There have been great successes in engineering tissues incorporating microvasculature de novo (e.g., organoids and organs-on-chip), but these reconstituted tissues are formed with non-native cellular and molecular components that can skew certain outcomes such as drug efficacy. Microdissected tumors, on the other hand, show promise in preserving the TME, which is key for creating cancer models that can bridge the gap between bench and bedside. However, microdissected tumors are challenging to perfuse. Here, we developed a microfluidic platform that allows for perfusing the microvasculature of microdissected tumors. We demonstrate that, compared to diffusive transport, microfluidically perfused tissues feature larger and longer microvascular structures, with a better expression of CD31, a marker for endothelial cells, as analyzed by 3D imaging. This study also explores the effects of nitric oxide pathway-related drugs on endothelial cells, which are sensitive to shear stress and can activate endothelial nitric oxide synthase, producing nitric oxide. Our findings highlight the critical role of controlled perfusion and biochemical modulation in preserving tumor microvasculature, offering valuable insights for developing more effective cancer treatments.

Importance of gap evaluation in the ossification of posterior longitudinal ligament lesions using 3-dimensional computed tomography.

BACKGROUND CONTEXT: Evaluating the gaps within the ossification of the posterior longitudinal ligament (OPLL) lesions, which may contribute to neurological symptoms, using conventional imaging techniques is challenging. OBJECTIVE: This study aimed to investigate the importance of evaluating gaps using 3-dimensional computed tomography (3D-CT) and their association with the occurrence of magnetic resonance imaging (MRI) T2 high intensity in the spinal cord. STUDY DESIGN/SETTING: Retrospective cohort study. PATIENT SAMPLE: Retrospective analysis of 116 patients diagnosed with cervical OPLL. OUTCOME MEASURES: Presence of gaps in OPLL, presence of T2 high intensity in the cervical spinal cord, and OPLL thickness were evaluated. METHODS: Lateral X-ray, CT, and reconstructed 3D-CT images were reviewed to assess lesion characteristics and the presence of gaps. MRI was used to evaluate the change in spinal cord signal intensity. The relationship among gap presence, lesion morphology, and MRI T2 high intensity in the spinal cord was examined. RESULTS: A significant difference in gap detection accuracy was observed between CT and 3D-CT (p=.0054). CT demonstrated false-positive results in the detection of gaps as compared with 3D-CT. The presence of gaps was significantly associated with an increased likelihood of MRI T2 high intensity in the spinal cord (p=.037). Patients with thicker lesions and smaller space available for the spinal cord (SAC) were more likely to exhibit T2 high intensity. Meanwhile, patients with gaps co-occurring with T2 high intensity exhibited significantly thinner lesions (p=.011) and larger SACs (p=.0002). Patients with gaps had a significantly lower JOA scores (p=.0035), which indicates that patient with gaps are likely to exhibit more severe clinical neurological symptoms. CONCLUSION: 3D-CT showed superiority in accurately identifying gaps within OPLL lesions, while CT demonstrated false-positive results in the detection of gaps. Furthermore, the gap presence was a risk factor for MRI T2 high intensity in the spinal cord, independent of lesion thickness. In addition, gaps are related to more severe clinical symptoms. This study highlighted the importance of evaluating gaps within OPLL lesions using 3D-CT to clarify neurological pathogenesis.

Recruitment and retention of pediatric participants for pandemic preparedness research: Experience from the PREMISE EV-D68 Pilot Study.

Recruitment and retention are challenges for prospective pediatric cohort studies, particularly those involving serial venipunctures. We investigated factors underlying enrollment and retention in the Pandemic Response Repository through Microbial and Immune Surveillance and Epidemiology (PREMISE) Enterovirus D68 (EV-D68) Pilot Study, a multicenter prospective longitudinal cohort study assessing the utility of immunologic surveillance for pandemic preparedness. This study enrolls children ≤10 years for two blood draws, pre- and post-EV-D68 season, separated by 6-18 months. Overall, 174 children were enrolled in Cohort 1 of the study and 120 (69 %) of children completed the study, with follow-up blood samples obtained from 101 (58 %) of participants. Families were primarily motivated to participate by a desire to help other children, advance science, and better prepare for the next pandemic. Adding research blood draws to clinically indicated blood draws improved enrollment, and multiple study touch points facilitated retention. These findings can be applied to improve recruitment and retention in future pandemic preparedness efforts and longitudinal pediatric cohort studies.

Diagnostic performances of the Ovarian Adnexal Reporting and Data System, the Risk of Ovarian Malignancy Algorithm, and the Copenhagen Index in the preoperative prediction of ovarian cancer: a prospective cohort study.

OBJECTIVE: This study aimed to assess the diagnostic performance of the Risk of Ovarian Malignancy Algorithm (ROMA), Copenhagen Index (CPH-I), and Ovarian Adnexal Reporting and Data System (O-RADS) for the preoperative prediction of ovarian cancer (OC). METHODS: A prospective cohort study was conducted on 462 patients diagnosed with ovarian tumors admitted to the Departments of Obstetrics and Gynecology, Hue University of Medicine and Pharmacy Hospital, and Hue Central Hospital from May 2020 to December 2022. ROMA and CPH-I were calculated using cancer antigen 125 (CA125), human epididymal protein 4 (HE4) levels, and patient characteristics (age and menopausal status). O-RADS criteria were applied to describe ovarian tumor characteristics from ultrasound findings. Compared with histopathological results, the predictive values of ROMA, CPH-I, and O-RADS alone or in combination with CA125/HE4 for OC were calculated. RESULTS: Among 462 patients, 381 had benign tumors, 11 had borderline tumors, and 50 had OC. At optimal cut-off points, ROMA's and CPH-I's areas under the curves (AUCs) were 0.880 (95% confidence interval [CI]=0.846-0.909) and 0.890 (95% CI=0.857-0.918), respectively, and ROMA and CPH-I sensitivities/specificities (Se/Sp) were 68.85%/95.01% and 77.05%/91.08%, respectively. O-RADS ≥3 yielded an AUCs of 0.949 (95% CI=0.924-0.968), with Se/Sp of 88.52%/88.98% (p<0.001). Combining O-RADS with CA125 demonstrated the highest predictive value, with AUCs of 0.969 (95% CI=0.949-0.983) and Se/Sp of 98.36%/86.09% (p<0.001). CONCLUSION: The ROMA, CPH-I, O-RADS, O-RADS + CA125, and O-RADS + HE4 models demonstrated good predictive values for OC; the combination of O-RADS and CA125 yielded the highest values.

Monitoring the Influence of Hand, Foot, and Mouth Disease: New Guidelines on Patient Care during the 2011-2012 Multiwaves and Multivariant Outbreak in Hai Phong City, Vietnam.

From 2011 to 2012, Northern Vietnam suffered its first large-scale hand, foot, and mouth disease (HFMD) epidemic. Two sets of official guidelines were issued during the outbreak to handle the HFMD crisis. The city of Hai Phong was used as a model to analyze the impact of the released guidelines. A total of 9621 HFMD cases were reported in Hai Phong city from April 2011 to December 2012. Three distinct waves of HFMD occurred. Enterovirus A71 and Coxsackievirus A16 were successively associated with the epidemics. Two periods, before and after the guidelines' release, could be distinguished and characterized by different patient patterns. The time to admission and severity changed notably. Guideline publications help the health system refocus on the 0.5-3 years age group with the highest incidence of the disease. The three waves showed different special distribution, but the main routes of infection were rivers and local secondary roads, most likely through local trade and occupational movements of people.

Characterization and molecular identification of the lumpy skin disease virus in cattle in the Mekong Delta of Vietnam.

Background: Lumpy skin disease (LSD) is caused by a virus belonging to the genus Capripoxvirus, exhibiting clinical symptoms ranging from mild signs to the development of nodules. LSD emerged in Asia and Southeast Asia, including Vietnam, in October 2020 and has since spread throughout the region, resulting in productivity and economic losses. Aim: This study aimed to investigate the virus-causing papular dermatitis in cattle from the Mekong Delta region of Vietnam by analyzing its GPCR gene and assessing its evolutionary relationship with sequences in the GenBank database. Methods: Blood samples (n = 180) were collected from cattle farms in Ben Tre, Tien Giang, and Tra Vinh provinces. PCR targeting the P32 antigen gene was utilized to detect LSDV presence, and GPCR gene amplification was performed to assess genetic variability. Results: LSDV was detected in 8.33% (15/180) of the samples using PCR targeting the P32 antigen gene. Each sample that tested positive for LSDV demonstrated complete amplification of the GPCR gene. Sequence alignments and phylogenetic analyses of the GPCR gene revealed that Mekong Delta LSDV isolates shared genetic similarities and possessed a 12-nucleotide insertion comparable to strains from China in 2019 and Northern Vietnam in 2020. Conclusion: This study provides preliminary insights into the molecular characteristics of LSDV in cattle from the Mekong Delta region of Vietnam. The observed genetic relatedness to other LSDV sequences from Asia and Southeast Asia underscores the importance of regional surveillance and control measures. These findings contribute to the development of effective strategies for LSDV control and prevention.

53BP1 deficiency leads to hyperrecombination using break-induced replication (BIR).

Break-induced replication (BIR) is mutagenic, and thus its use requires tight regulation, yet the underlying mechanisms remain elusive. Here we uncover an important role of 53BP1 in suppressing BIR after end resection at double strand breaks (DSBs), distinct from its end protection activity, providing insight into the mechanisms governing BIR regulation and DSB repair pathway selection. We demonstrate that loss of 53BP1 induces BIR-like hyperrecombination, in a manner dependent on Polα-primase-mediated end fill-in DNA synthesis on single-stranded DNA (ssDNA) overhangs at DSBs, leading to PCNA ubiquitination and PIF1 recruitment to activate BIR. On broken replication forks, where BIR is required for repairing single-ended DSBs (seDSBs), SMARCAD1 displaces 53BP1 to facilitate the localization of ubiquitinated PCNA and PIF1 to DSBs for BIR activation. Hyper BIR associated with 53BP1 deficiency manifests template switching and large deletions, underscoring another aspect of 53BP1 in suppressing genome instability. The synthetic lethal interaction between the 53BP1 and BIR pathways provides opportunities for targeted cancer treatment.

Assessment of physicochemical properties and radioactivity in groundwater at households living in bac Lieu province, vietnam.

This paper presents findings on groundwater physiochemical composition and radioactivity levels in households in Bac Lieu province, Vietnam. Through discriminant analysis, it was observed that groundwater quality exhibits spatial variations corresponding to saline intrusion zones. The paired-samples T-tests revealed significantly different ratios of Ra-224, Ra-226, and Ra-228 isotopes between Na-Cl and Ca-Na-HCO3 water types. All three water types had a ratio of Ra-226/Ra-228 of approximately one, indicating the presence of groundwater aquifers beneath the crust and fluvial marine sediment. Furthermore, strong associations between sulfate and calcium suggest that CO2 enrichment in groundwater aquifers indicates anoxic aquatic environments. Twenty-five of the thirty-three evaluated samples exceeded the national technical regulations for domestic water quality with parameters such as chloride, sulfate, sodium, gross alpha, or total dissolved solids. Fifteen samples exceeded gross alpha's allowable contamination threshold of 0.1 Bq/L. The combination of Ra-226 and Ra-228 did not surpass the U.S. Environmental Protection Agency's recommended limit of 0.185 Bq/L. However, nineteen samples exhibited annual committed effective doses of radium isotopes for infants that exceeded the WHO recommendation of 0.1 mSv/year.

Enhanced pollution removal from canal water by coupling aeration to floating treatment wetlands.

Floating treatment wetlands (FTWs) are natural solutions for purifying polluted water, providing a green surface area and improving city landscape. This study investigated if the efficiency of FTWs can be improved by aeration for treating contaminated canal water. The three used plant species were Canna generalis, Phragmites australis, and Cyperus alternifolius. The experiment was carried out in three FTWs with aeration and three without aeration to compare the removal for COD, NH4+-N, E. coli, PO43--P, and Fe. In the aerated FTWs, air blowers were installed to run at two different air flow rates of 2.5 L min-1 (Batch 1) and 1.0 L min-1 (Batch 2). Aeration increased the dissolved oxygen concentrations in each tank, which came over 6.5 mg L-1 in both batches. This study sheds light on the positive impact of aeration has on COD and NH4+-N removal: these are nearly three-fold higher compared to non-aeration conditions and reached approximately 99% (1.7-log reduction) for E. coli removal. Additionally, the plant growth rate in the aerated FTWs was higher than in the non-aerated ones. The average shoot growth rate of Phragmites australis was 0.76 cm d-1 for the aerated FTW which was two-fold higher compared to the non-aerated one.

This article investigates the treatment performance of Floating Treatment Wetlands (FTWs) coupled with aeration to reduce the diffuse pollution in canal water. The results showed that the aeration enhanced the treatment of organics and nutrients, and the plant growth of the aerated FTWs was two-fold higher than that of non-aerated FTWs, which has a phytoremediation potential for treating canal water in Ho Chi Minh city.

Label-free, real-time monitoring of cytochrome C drug responses in microdissected tumor biopsies with a multi-well aptasensor platform.

Functional assays on intact tumor biopsies can complement genomics-based approaches for precision oncology, drug testing, and organs-on-chips cancer disease models by capturing key therapeutic response determinants, such as tissue architecture, tumor heterogeneity, and the tumor microenvironment. Most of these assays rely on fluorescent labeling, a semiquantitative method best suited for single-time-point assays or labor-intensive immunostaining analysis. Here, we report integrated aptamer electrochemical sensors for on-chip, real-time monitoring of cytochrome C, a cell death indicator, from intact microdissected tissues with high affinity and specificity. The platform features a multi-well sensor layout and a multiplexed electronic setup. The aptasensors measure increases in cytochrome C in the supernatant of mouse or human microdissected tumors after exposure to various drug treatments. Because of the sensor's high affinity, it primarily tracks rising concentrations of cytochrome C, capturing dynamic changes during apoptosis. This approach could help develop more advanced cancer disease models and apply to other complex in vitro disease models, such as organs-on-chips and organoids.

Left ventricular thrombus in patient with nonischemic cardiomyopathy: A case report.

Left ventricular thrombus (LVT) is a severe consequence that typically follows acute myocardial infarction (MI) and can occur in nonischemic cardiomyopathies. In patients who have experienced an ST-segment elevation acute myocardial infarction (STEMI), LVT is seen up to 15% of the time; for patients without an ischemic cardiomyopathy, it is only 2% to 36% of the time. According to Virchow's triad, the cornerstone of LVT formation includes endothelial injury, blood stasis, and hypercoagulability. However, LVT increases morbidity and mortality in patients with both ischemic and nonischemic cardiomyopathies by increasing the risk of stroke or systemic embolism. Studies on nonischemic etiology are limited, and the majority of LVT case series concentrate on ischemic cardiomyopathies. We present this case with the nonischemic cardiomyopathies caused by LVT. Specifically, the patient underwent coronary artery assessment using photon-counting computed tomography, which is among the most advanced systems worldwide.

Prominin 1 and Tweety Homology 1 both induce extracellular vesicle formation.

Prominin-1 (Prom1) is a five-transmembrane-pass integral membrane protein that associates with curved regions of the plasma membrane. Prom1 interacts with membrane cholesterol and actively remodels the plasma membrane. Membrane bending activity is particularly evident in photoreceptors, where Prom1 loss-of-function mutations cause failure of outer segment homeostasis, leading to cone-rod retinal dystrophy (CRRD). The Tweety Homology (Ttyh) protein family has been proposed to be homologous to Prominin, but it is not known whether Ttyh proteins have an analogous membrane-bending function. Here, we characterize the membrane-bending activity of human Prom1 and Ttyh1 in native bilayer membranes. We find that Prom1 and Ttyh1 both induce formation of extracellular vesicles (EVs) in cultured mammalian cells and that the EVs produced are physically similar. Ttyh1 is more abundant in EV membranes than Prom1 and produces EVs with membranes that are more tubulated than Prom1 EVs. We further show that Prom1 interacts more stably with membrane cholesterol than Ttyh1 and that this may contribute to membrane bending inhibition in Prom1 EVs. Intriguingly, a loss-of-function mutation in Prom1 associated with CRRD induces particularly stable cholesterol binding. These experiments provide mechanistic insight into Prominin function in CRRD and suggest that Prom and Ttyh belong to a single family of functionally related membrane-bending, EV-generating proteins.

Enpp1 mutations promote upregulation of hedgehog signaling in heterotopic ossification with aging.

INTRODUCTION: Heterotopic ossification of the tendon and ligament (HOTL) is a chronic progressive disease that is usually accompanied by thickening and ossification of ligaments and high osteogenic activity of the surrounding ligament tissue. However, the molecular mechanism of maintaining the cellular phenotype of HOTL remains unclear. MATERIALS AND METHODS: We first constructed a model of HOTL, Enpp1flox/flox/EIIa-Cre mice, a novel genetic mouse system. Imaging, histological, and cell-level analyses were performed to investigate the progressive ossification of the posterior longitudinal ligament, Achilles tendons, and degeneration joints caused by Enpp1 deficiency. RESULTS: The results indicate that Enpp1 deficiency led to markedly progressive heterotopic ossification (HO), especially spine, and Achilles tendons, and was associated with progressive degeneration of the knees. The bone mass was decreased in the long bone. Furthermore, fibroblasts from Enpp1flox/flox/EIIa-Cre mice had greater osteogenic differentiation potential following induction by osteogenesis, accompanied by enhanced hedgehog (Hh) signaling. In addition, fibroblast cells show senescence, and aggravation of the senescence phenotype by further osteogenic induction. CONCLUSION: Our study indicated that with increasing age, mutations in Enpp1 promote ectopic ossification of spinal ligaments and endochondral ossification in tendons and further aggravate knee degeneration by upregulating hedgehog signaling.

Modeling the Dynamic of Multiwave Diseases: The Model of Hand, Foot and Mouth Disease.

An HFMD outbreak spread over the city of Hai Phòng from summer 2011 to autumn 2012. This epidemic was chosen because it was the very first HFMD epidemic in North Vietnam, eliminating thus interferences with previous outbreaks. This epidemic displayed three separate waves. A complete dataset was collected for more than 9500 patients during this period, which enabled us to analyze this epidemic at different scales. Access to the healthcare system was crucial during this period, which was possible due to a reorganization of the system in February-March 2012. An analysis at the commune level enabled us to track the epidemic along certain communication routes. The three-waves structure reveals a wide disparity at the district level. We developed a mathematical model showing high accuracy at the adjustment of data for both the total number of cases and for the number of cases per week. As a consequence, the model was able to accurately determine the dates of the beginning and end of each wave and to show that they overlapped. Using mathematical functions associated with this model, it was possible to calculate the probability for a patient to belong to a specific wave.