Synthetic polyubiquitinated α-Synuclein reveals important insights into the roles of the ubiquitin chain in regulating its pathophysiology

Ubiquitination regulates, via different modes of modifications, a variety of biological processes, and aberrations in the process have been implicated in the pathogenesis of several neurodegenerative diseases. However, our ability to dissect the pathophysiological relevance of the ubiquitination code has been hampered due to the lack of methods that allow site-specific introduction of ubiquitin (Ub) chains to a specific substrate. Here, we describe chemical and semisynthetic strategies for site-specific incorporation of K48-linked di- or tetra-Ub chains onto the side chain of Lys12 of α-Synuclein (α-Syn). These advances provided unique opportunities to elucidate the role of ubiquitination and Ub chain length in regulating α-Syn stability, aggregation, phosphorylation, and clearance. In addition, we investigated the cross-talk between phosphorylation and ubiquitination, the two most common α-Syn pathological modifications identified within Lewy bodies and Parkinson disease. Our results suggest that α-Syn functions under complex regulatory mechanisms involving cross-talk among different posttranslational modifications

Early Life Child Micronutrient Status, Maternal Reasoning, and a Nurturing Household Environment have Persistent Influences on Child Cognitive Development at Age 5 years : Results from MAL-ED

Funding Information: The Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development Project (MAL-ED) is carried out as a collaborative project supported by the Bill & Melinda Gates Foundation, the Foundation for the NIH, and the National Institutes of Health/Fogarty International Center. This work was also supported by the Fogarty International Center, National Institutes of Health (D43-TW009359 to ETR). Author disclosures: BJJM, SAR, LEC, LLP, JCS, BK, RR, RS, ES, LB, ZR, AM, RS, BN, SH, MR, RO, ETR, and LEM-K, no conflicts of interest. Supplemental Tables 1–5 and Supplemental Figures 1–3 are available from the “Supplementary data” link in the online posting of the article and from the same link in the online table of contents at https://academic.oup.com/jn/. Address correspondence to LEM-K (e-mail: [email protected]). Abbreviations used: HOME, Home Observation for Measurement of the Environment inventory; MAL-ED, The Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development Project; TfR, transferrin receptor; WPPSI, Wechsler Preschool Primary Scales of Intelligence.Peer reviewe

Early life child micronutrient status, maternal reasoning, and a nurturing household environment have persistent influences on child cognitive development at age 5 years: Results from MAL-ED

Background: Child cognitive development is influenced by early-life insults and protective factors. To what extent these factors have a long-term legacy on child development and hence fulfillment of cognitive potential is unknown. Objective: The aim of this study was to examine the relation between early-life factors (birth to 2 y) and cognitive development at 5 y. Methods: Observational follow-up visits were made of children at 5 y, previously enrolled in the community-based MAL-ED longitudinal cohort. The burden of enteropathogens, prevalence of illness, complementary diet intake, micronutrient status, and household and maternal factors from birth to 2 y were extensively measured and their relation with the Wechsler Preschool Primary Scales of Intelligence at 5 y was examined through use of linear regression. Results: Cognitive T-scores from 813 of 1198 (68%) children were examined and 5 variables had significant associations in multivariable models: mean child plasma transferrin receptor concentration (β: −1.81, 95% CI: −2.75, −0.86), number of years of maternal education (β: 0.27, 95% CI: 0.08, 0.45), maternal cognitive reasoning score (β: 0.09, 95% CI: 0.03, 0.15), household assets score (β: 0.64, 95% CI: 0.24, 1.04), and HOME child cleanliness factor (β: 0.60, 95% CI: 0.05, 1.15). In multivariable models, the mean rate of enteropathogen detections, burden of illness, and complementary food intakes between birth and 2 y were not significantly related to 5-y cognition. Conclusions: A nurturing home context in terms of a healthy/clean environment and household wealth, provision of adequate micronutrients, maternal education, and cognitive reasoning have a strong and persistent influence on child cognitive development. Efforts addressing aspects of poverty around micronutrient status, nurturing caregiving, and enabling home environments are likely to have lasting positive impacts on child cognitive development.publishedVersio

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

Delineation of spring recharge zones using environmental isotopes to support climate-resilient interventions in two mountainous catchments in Far-Western Nepal

Though springs are the primary source of water for communities in the mid-hills of Nepal, an in-depth scientific understanding of spring systems is missing, preventing the design of effective climate-resilient interventions for long-term sustainability of springs. This study marks the first attempt to combine environmental isotopes analysis with hydrometric and hydrogeological measurements to identify dominant recharge zones for springs in two mountainous catchments—Banlek and Shikarpur—in Far-Western Nepal. In total, 422 water samples collected from rainfall, springs and streams between March 2016 and March 2017 were analyzed for their isotopic composition (δ18O and δD). Isotopic composition of rainwater shows seasonality, suggesting that different sources of water vapor cause rains in monsoon and in dry season. Rainfall responses of individual springs were used to identify connections to unconfined and deeper groundwater strata. The isotopic composition of springs in the two catchments ranges from −9.55 to −8.06‰ for δ18O and −67.58 to −53.51‰ for δD. The isotopic signature of the spring sources falls close to the local meteoric water line for the corresponding season, indicating strong rainfall contribution to springs. Altitudinal isotopic gradients suggest mean recharge elevation of 2,600–2,700 m asl for springs in Shikarpur, which lies beyond the surface-water catchment, and a recharge elevation of 1,000–1,100 m asl for Banlek, which partially extends beyond the surface-water catchment. The demarcated recharge zones will be used by government agencies to implement recharge interventions to increase the resiliency and reliability of springs in Far-Western Nepal.Peer reviewe

Complementation of Human Papillomavirus Type 16 E6 and E7 by Jagged1-Specific Notch1-Phosphatidylinositol 3-Kinase Signaling Involves Pleiotropic Oncogenic Functions Independent of CBF1;Su(H);Lag-1 Activation

We have analyzed the induction and role of phosphatidylinositol 3-kinase (PI3K) by Notch signaling in human papillomavirus (HPV)-derived cancers. Jagged1, in contrast to Delta1, is preferentially upregulated in human cervical tumors. Jagged1 and not Delta1 expression sustained in vivo tumors by HPV16 oncogenes in HaCaT cells. Further, Jagged1 expression correlates with the rapid induction of PI3K-mediated epithelial-mesenchymal transition in both HaCaT cells and a human cervical tumor-derived cell line, suggestive of Delta1;Serrate/Jagged;Lag2 ligand-specific roles. Microarray analysis and dominant-negatives reveal that Notch-PI3K oncogenic functions can be independent of CBF1;Su(H);Lag-1 activation and instead relies on Deltex1, an alternative Notch effector

Human Papillomavirus Type 16 E6 Amino Acid 83 Variants Enhance E6-Mediated MAPK Signaling and Differentially Regulate Tumorigenesis by Notch Signaling and Oncogenic Ras

Oncogenically high-risk human papillomaviruses (HPVs) are causally associated with the progression of major human neoplasia-like cancers of the cervix. Several studies have defined functions of the key E6 and E7 oncoproteins in epithelial cell immortalization. The roles of these oncogenes in the progression of immortalized epithelial cells to invasive tumors are still poorly understood. Here, we establish a novel link between the E6 oncoprotein and activation of mitogen-activated protein kinase (MAPK) signaling and show that this signaling involves Rap1. We find that activated MAPK signaling cooperates with deregulated Notch1 signaling to recreate features of HPV-driven invasive cervical carcinomas. We extend our analysis to evaluate an E6 (amino acid [aa] 83) variant that has been linked to invasive tumors. The variant enhances MAPK signaling and cooperative transformation with deregulated Notch1 signaling. Unlike E6, this variant surprisingly inhibits oncogenic Ras-mediated transformation. Our data reveal that the quantitative differences in activation of MAPK signaling by E6 and its variant correlate with differences in cooperative transformation with other signaling pathways, thus suggesting that thresholds of MAPK activation may define permissive conditions for other signaling pathways in tumorigenesis. Epidemiological studies have suggested the importance of E6 aa 83 variants in invasive carcinomas; our data support a key deterministic role for this variant in human cervical tumorigenesis. These observations, along with our recent data showing that deregulated Notch signaling activates phosphatidylinositol 3-kinase signaling, strengthen the possibility of the existence of Ras-independent mechanisms to recreate signaling through classical Ras effector pathways

NiFeOOH-Co₉S₈‑Intercalated Nanostructure Arrays for Energy-Efficient H₂ Production and Sulfion Oxidation at High Current Density

Though electrocatalysts displaying efficacy for the hydrogen evolution reaction (HER) or sulfion oxidation reaction (SOR) individually are available in the literature, systems exhibiting proficiency toward the HER and SOR together are desirable to produce H2 in a robustly energy-efficient manner. Furthermore, simultaneous facile growth and intercalation of multiple nanocatalyst systems to achieve the above objective are synthetically challenging. Herewith, the reactivity preferences of Lewis acid (FeCl3) and salt [Co­(NO3)2] are utilized to longitudinally grow NiFeOOH-Co9S8-n intercalated nanostructure arrays of varied Fe:Co ratios on Nickel foam using a one-step procedure at low temperature (50 °C). The NiFeOOH-Co9S8-n exhibit bifunctionality and H2 production at a relatively high j value of 1000 mA/cm2 is realized at a low overall potential (SOR + HER) value of 0.84 V in NaOH (1.0 M)-Na2S (1.0 M). The efficiency of the electrode enabled the SOR j value to reach 1000 mA/cm2 at 0.72 V in 1.0 M Na2S solution in the absence of NaOH. The density functional theory analysis revealed that the oxide doping of the Co9S8 facilitated by the FeOOH-Co9S8 intercalation promoted the electrocatalytic activity. The nanocatalyst promotes highly energy-efficient and sustainable H2 production, where a j value of 100 mA/cm2 under the electrolyzer mode is realized at an unprecedented potential of 0.44 V (iR-uncorrected) and ultralow power consumption (11.8 kW h/kg H2), which is minimum among reported systems suggesting its viability toward commercial production of H2 in future

Cardio-embolic stroke due to valve tissue embolization during Percutaneous Transseptal Mitral Commissurotomy (PTMC)

Percutaneous Transseptal Mitral Commissurotomy (PTMC) has replaced surgical commissurotomy as a treatment of choice in selected patients of rheumatic mitral stenosis. Various randomized trials have shown PTMC to be equal or superior to surgical commissurotomy in terms of hemodynamic improvement as well as long term survival. Systemic embolism is one of the dreaded complications of PTMC, which is reported in 0.5–5% of cases and involves cerebral circulation in 1% of cases. Most of the time, periprocedural embolism during PTMC is caused by the mobilization of preexisting thrombus in the left atrial appendage. We report an unusual case of acute stroke due embolization of mitral valve tissue during PTMC