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Objective: Brain somatic mutations in mTOR pathway genes are a major genetic etiology of focal cortical dysplasia type II (FCDII). Despite a greater ability to detect low‐level somatic mutations in the brain by deep sequencing and analytics, about 40% of cases remain genetically unexplained. Methods: We included 2 independent cohorts consisting of 21 patients with mutation‐negative FCDII without apparent mutations on conventional deep sequencing of bulk brain. To find ultra‐low level somatic variants or structural variants, we isolated cells exhibiting phosphorylation of the S6 ribosomal protein (p‐S6) in frozen brain tissues using fluorescence‐activated cell sorting (FACS). We then performed deep whole‐genome sequencing (WGS; >90×) in p‐S6+ cells in a cohort of 11 patients with mutation‐negative. Then, we simplified the method to whole‐genome amplification and target gene sequencing of p‐S6+ cells in independent cohort of 10 patients with mutation‐negative followed by low‐read depth WGS (10×). Results: We found that 28.6% (6 of 21) of mutation‐negative FCDII carries ultra‐low level somatic mutations (less than 0.2% of variant allele frequency [VAF]) in mTOR pathway genes. Our method showed ~34 times increase of the average mutational burden in FACS mediated enrichment of p‐S6+ cells (average VAF = 5.84%) than in bulky brain tissues (average VAF = 0.17%). We found that 19% (4 of 21) carried germline structural variations in GATOR1 complex undetectable in whole exome or targeted gene sequencing. Conclusions: Our method facilitates the detection of ultra‐low level somatic mutations, in specifically p‐S6+ cells, and germline structural variations and increases the genetic diagnostic rate up to ~80% for the entire FCDII cohort. ANN NEUROL 2023;93:1082–1093 [ABSTRACT FROM AUTHOR]

High‐frequency, paired measurements of the partial pressure of CO2 (pCO2) and dissolved O2 were combined with dissolved organic matter (DOM) characterization to investigate diurnal (7:00–19:00) and seasonal variations in CO2 dynamics in the lower Ganges River. Diurnal variations in pCO2 shifted seasonally, concurring with changes in DOM optical properties, biodegradable DOM, and O2 departures from atmospheric equilibrium (ΔO2). Increased pCO2 and CO2 flux (FCO2) in August–September corresponded to monsoonal floods carrying more terrestrial materials. Lower dry‐season pCO2 and FCO2 concurred with higher ΔO2, and exhibited strong relationships with DO and pH, indicating a dominant influence of phytoplankton production. Despite large variations in pCO2, the year‐long positive FCO2 implied that the lower Ganges acted as a CO2 source, reaching 122 mmol m−2 d−1. Increasing hydrologic variability and pollution in the Ganges Basin can amplify pCO2 variations linked to seasonal shifts in terrestrial inputs and phytoplankton production. [ABSTRACT FROM AUTHOR]

Summary: Background: NUDT15 polymorphisms are associated with leukopenia during treatment with thiopurines. However, data regarding its effect on treatment outcomes are scarce. Aims: To investigate the outcomes between NUDT15 normal and intermediate metabolisers in paediatric patients with Crohn's disease (CD) treated with a combination therapy of infliximab (IFX) and azathioprine (AZA). Methods: In this retrospective observational study, 143 patients categorised into the NUDT15 normal and intermediate metaboliser groups were compared based on clinical remission (CR), biochemical remission (BR), mucosal healing (MH) at 1 year treatment, IFX trough levels (TLs), antibodies to IFX (ATIs), 6‐thioguanine nucleotide (6‐TGN) levels, loss of response (LOR) and IFX durability. Results: No significant differences were observed between the groups in CR, BR, MH at 1 year, whereas IFX TLs and ATIs and 6‐TGN levels were comparable. However, LOR (6.5% vs 27.7%, P = 0.025) was significantly lower and IFX durability significantly higher (96.8% vs 80.4% P = 0.027) in the intermediate group. Multivariable Cox proportional hazard regression analysis showed that ATI positivity (hazard ratio (HR): 4.76, 95% CI: 2.25‐10.07, P < 0.001) and the NUDT15 metaboliser group was associated with LOR (HR: 0.18, 95% CI: 0.04‐0.76, P = 0.019). The Kaplan‐Meier survival curves showed that the LOR‐free survival rate was significantly lower in normal metabolisers (log‐rank test P = 0.009). Conclusion: NUDT15 intermediate metabolisers were associated with lower LOR in paediatric patients with CD treated with IFX and AZA combination therapy. This finding may partially explain the longer durability of IFX in Korean children than their counterparts in Western countries. [ABSTRACT FROM AUTHOR]

Despite growing research on greenhouse gas (GHG) emissions from inland waters, few systematic efforts have been made to assess the regional‐scale GHG emissions from Asian rivers under increasing anthropogenic stress. We examined factors controlling longitudinal and seasonal variations in the partial pressure of CO2 (pCO2), and CH4 and N2O concentrations in the Ganges, Mekong, and Yellow River by simultaneously measuring gas concentrations and stable C isotopes, and optical properties of dissolved organic matter (DOM) from 2016 to 2019. The levels of pCO2 and CH4 were distinctively higher in polluted tributaries and affected reaches of the Ganges and Mekong than in the Yellow River. The highest levels of N2O were found in the Ganges, followed by the Yellow River and Mekong. Across these basins, dry‐season mean concentrations of CO2, CH4, and N2O were 1.6, 2, and 7 times higher than those measured in the monsoon season, respectively. This seasonality was consistent with that of δ13C‐CO2, while δ13C‐CH4 showed an opposite pattern. GHG concentrations exhibited significant positive relationships with DOM concentrations and optical properties including fluorescence index and protein‐like fluorescence, implying the contribution of anthropogenic, labile DOM to production of GHGs in the polluted reaches. Graphical mixing models of δ13C‐CO2 and δ13C‐CH4 support the stronger impact of wastewater on the Ganges and Mekong than on the Yellow River. The overall results suggest that neglecting localized pollution impacts on GHG emissions from increasingly urbanized river basins can result in a substantial underestimation of global riverine GHG emissions. Plain Language Summary: Rapid urbanization and poor wastewater infrastructure are turning many large rivers in Asia into significant sources of greenhouse gases (GHGs). We examined controlling factors for the concentrations of CO2, CH4, and N2O in the Ganges, Mekong, and Yellow River by simultaneously measuring gas concentrations and stable carbon isotopes, and optical properties of dissolved organic matter (DOM). The concentrations of CO2 and CH4 were distinctively higher in polluted tributaries and affected sections of the Ganges and Mekong than in the Yellow River. N2O concentration was highest in the Ganges, followed by the Yellow River and Mekong. Across these basins, the concentrations of the three gases were generally higher during dry periods than in the monsoon season. GHG concentrations were positively related to DOM optical properties indicating the contribution of easily degradable DOM from pollution sources. The stable carbon isotope ratios of CO2 and CH4 support the stronger impact of wastewater on the Ganges and Mekong than on the Yellow River. The overall results suggest that neglecting local pollution impacts on GHG emissions from increasingly urbanized river basins can result in a substantial underestimation of global riverine GHG emissions. Key Points: High CO2, CH4, and N2O concentrations in urbanized river reaches reflect influences from local tributaries carrying wastewaterSeasonality in stable C isotopes and dissolved organic matter properties corresponds to higher dry‐season greenhouse gas concentrations than in the monsoonStable C isotopes and their relationships with CO2 and CH4 concentrations support localized wastewater effects on urbanized rivers [ABSTRACT FROM AUTHOR]

Background: Mupirocin is a topical antibacterial drug used for the treatment of staphylococcal infections, including meticillin‐resistant Staphylococcus pseudintermedius (MRSP). The recent emergence of resistance to mupirocin is a major concern in many countries. Objectives: This study investigated the prevalence and genotype of mupirocin‐resistant S. pseudintermedius isolated from pet dogs with pyoderma. Samples: A total of 110 clinical isolates of S. pseudintermedius were collected from dogs with pyoderma (n = 110) between July 2010 and September 2016. All animals were client‐owned dogs. Methods: Low‐ and high‐level mupirocin resistance were evaluated with both the broth microdilution and disk diffusion tests. Mupirocin resistance in S. pseudintermedius isolates was confirmed by genetic analysis of the ileS‐2 and naïve ileS genes. Results: MRSP and meticillin‐susceptible S. pseudintermedius were detected in 69 and 41 dogs, respectively. One MRSP strain was highly resistant to mupirocin and contained the high‐level mupirocin resistance gene ileS‐2. There were no low‐level mupirocin‐resistant isolates. Conclusion and clinical importance: Mupirocin is a useful topical antibacterial for MRSP, but a clinical MRSP isolate that had not previously been exposed to mupirocin exhibited the high‐level mupirocin resistance in phenotype and genotype. Therefore, continuous monitoring for mupirocin resistance is important in small animal practice. [ABSTRACT FROM AUTHOR]

We examined the influence of warming and supplemental precipitation on plant production and abundance of the dominant microarthropod, the springtail Cryptopygus antarcticus (Collembola), in tundra dominated by the vascular plants Colobanthus quitensis and Deschampsia antarctica along the Antarctic Peninsula. Tundra cores were placed in plots near Palmer Station where they were warmed with infrared heaters in combination with receiving supplemental precipitation. Diel canopy air and soil temperatures and air vapor pressure deficits in warmed plots were elevated 0.8 °C, 2.2 °C and 0.13 kPa, respectively. After two growing seasons, total aboveground plant production was greater under warming as a result of enhanced production by C. quitensis, which more than offset declines in moss biomass. Total aboveground plant production was also greater under supplemental precipitation primarily as a result of enhanced moss production. Total aboveground plant production was greatest under the combination of warming and supplemental precipitation, primarily as a result of enhanced C. quitensis production. C. antarcticus were more abundant in cores receiving supplemental precipitation and there was a strong treatment interaction; these springtails were most abundant in warmed cores receiving supplemental precipitation. Over 50% of the variability in the abundance of C. antarcticus could be explained by differences in aboveground plant biomass. However, plant production did not appear directly responsible for differences in C. antarcticus abundance; when we examined C. antarcticus abundance per unit of aboveground plant biomass, differences in its abundance among treatments were still apparent implying these differences were not the direct result of plant biomass. The responses of C. antarcticus were consistent with its known moisture and thermal preferences, suggesting that abiotic factors played a dominant role in controlling its abundance. Precipitation regime had large impacts on warming responses and these were species specific, illustrating the importance of future precipitation regimes in predicting system responses to warming. [ABSTRACT FROM AUTHOR]

Biogeochemical responses to changing climate and atmospheric deposition were investigated using nitrogen (N) and sulfur (S) mass balances, including dry deposition and organic solutes in the Arbutus Lake watershed in the Adirondack Mountains, New York State. Long-term monitoring of wet-only precipitation (NADP/NTN, 1983–2001) and dry deposition (AIRMoN, 1990–2001) at sites adjacent to the watershed showed that concentrations of SO42− in precipitation, SO42− in particles,and SO2 vapor all declined substantially ( P<0.005) in contrast to no marked temporal changes observed for most N constituents (NH4+ in precipitation, HNO3 vapor, and particulate NO3−), except for NO3− in precipitation, which showed a small decrease in the late 1990s. From 1983 to 2001, concentrations of SO42− in the lake outlet significantly decreased (−2.1 μeq L−1 yr−1, P<0.0001), whereas NO3− and dissolved organic N (DON) concentrations showed no consistent temporal trends. With the inclusion of dry deposition and DON fluxes into the mass balance, the retained portion of atmospheric N inputs within the main subcatchment increased from 37% to 60%. Sulfur outputs greatly exceeded inputs even with the inclusion of dry S deposition, while organic S flux represented another source of S output, implying substantial internal S sources. A significant relationship between the annual mean concentrations of SO42− in lake discharge and wet deposition over the last two decades ( r=0.64, P<0.01) suggested a considerable influence of declining S deposition on surface water SO42− concentrations, despite substantial internal S sources. By contrast, interannual variations in both NO3− concentrations and fluxes in lake discharge were significantly related to year-to-year changes in air temperature and runoff. Snowmelt responses to winter temperature fluctuations were crucial in explaining large portions of interannual variations in watershed NO3− export during the months preceding spring snowmelt (especially, January–March). Distinctive response patterns of monthly mean concentrations of NO3− and DON in the major lake inlet to seasonal changes in air temperature also suggested climatic regulation of seasonal patterns in watershed release of both N forms. The sensitive response of N drainage losses to climatic variability might explain the synchronous patterns of decadal variations in watershed NO3− export across the northeastern USA. [ABSTRACT FROM AUTHOR]

Objectives: In screening studies of Western patients with cerebellar dysfunction, FMR1 premutations have been detected. A screening study of East Asian patients with presumed essential tremor (ET) did not detect these mutations, possibly because the ET patients did not closely mimic the phenotype of fragile X‐associated tremor/ataxia syndrome (FXTAS). The aim of this study was to estimate the prevalence of FMR1 premutations in a carefully recruited group of ET patients with additional phenotypic features of FXTAS. Materials and Methods: From April 2014 to April 2018, we prospectively recruited patients with ET diagnoses from three tertiary care centers. Demographic and clinical data were collected, as well as data on presence of cerebellar signs and extrapyramidal signs (EPS). Tremor, cerebellar signs, and EPS were evaluated using appropriate clinical rating scales. For ET patients with additional cerebellar signs or EPS, FMR1 mutation analysis and brain magnetic resonance imaging were performed. Results: Six hundred and three ET patients were recruited. Cerebellar signs or EPS were present in 168 (27.9%) of 603. FMR1 CGG repeat analysis was performed in 74 of 168 patients. Fifty‐two of 74 had cerebellar signs only, three had EPS only, and 19 had both neurologic abnormalities. Two patients had a FMR1 premutation and fulfiled both clinical and radiological criteria of FXTAS. Conclusions: Two (2.7%) of 74 patients with presumed ET and additional neurological features were discovered to have FXTAS. The possibility of FXTAS should be considered in patients with ET who exhibit mild cerebellar signs or EPS. [ABSTRACT FROM AUTHOR]