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We construct non-linear machine learning (ML) prediction models for systolic and diastolic blood pressure (SBP, DBP) using demographic and clinical variables and polygenic risk scores (PRSs). We developed a two-model ensemble, consisting of a baseline model, where prediction is based on demographic and clinical variables only, and a genetic model, where we also include PRSs. We evaluate the use of a linear versus a non-linear model at both the baseline and the genetic model levels and assess the improvement in performance when incorporating multiple PRSs. We report the ensemble models performance as percentage variance explained (PVE) on a held-out test dataset. A non-linear baseline model improved the PVEs from 28.1 to 30.1% (SBP) and 14.3% to 17.4% (DBP) compared with a linear baseline model. Including seven PRSs in the genetic model computed based on the largest available GWAS of SBP/DBP improved the genetic model PVE from 4.8 to 5.1% (SBP) and 4.7 to 5% (DBP) compared to using a single PRS. Adding additional 14 PRSs computed based on two independent GWASs further increased the genetic model PVE to 6.3% (SBP) and 5.7% (DBP). PVE differed across self-reported race/ethnicity groups, with primarily all non-White groups benefitting from the inclusion of additional PRSs. In summary, non-linear ML models improves BP prediction in models incorporating diverse populations.

Abstract This study investigates the state of inclusivity in Ukrainian universities, focusing on the perceptions of university staff amid the country's ongoing sociopolitical transformations. Here we report on the perceptions of 820 staff members from various professional roles, including academic, management, and support positions, this research explored inclusivity through diverse lenses, encompassing work experience, interactions with students with disabilities, and self-identification with vulnerable groups. Most respondents assessed a moderate to high level of inclusivity, indicating a positive overall outlook on inclusive practices within these institutions. Notably, perceptions of inclusivity vary slightly across different professional roles, with academic staff expressing a marginally lower level of perceived inclusivity than their counterparts. However, these variations are not statistically significant, suggesting a uniform perception across staff categories. Furthermore, the study revealed that personal experience in working with students with disabilities does not substantially alter staff perceptions of inclusivity. Similarly, self-identification with vulnerable groups only marginally influences these perceptions. This suggests that while individual experiences and identities are factors in inclusivity perceptions, their impact is not profoundly different. This research contributes to understanding inclusivity in higher education, particularly within environments undergoing significant social and political changes.

Abstract We construct non-linear machine learning (ML) prediction models for systolic and diastolic blood pressure (SBP, DBP) using demographic and clinical variables and polygenic risk scores (PRSs). We developed a two-model ensemble, consisting of a baseline model, where prediction is based on demographic and clinical variables only, and a genetic model, where we also include PRSs. We evaluate the use of a linear versus a non-linear model at both the baseline and the genetic model levels and assess the improvement in performance when incorporating multiple PRSs. We report the ensemble model’s performance as percentage variance explained (PVE) on a held-out test dataset. A non-linear baseline model improved the PVEs from 28.1 to 30.1% (SBP) and 14.3% to 17.4% (DBP) compared with a linear baseline model. Including seven PRSs in the genetic model computed based on the largest available GWAS of SBP/DBP improved the genetic model PVE from 4.8 to 5.1% (SBP) and 4.7 to 5% (DBP) compared to using a single PRS. Adding additional 14 PRSs computed based on two independent GWASs further increased the genetic model PVE to 6.3% (SBP) and 5.7% (DBP). PVE differed across self-reported race/ethnicity groups, with primarily all non-White groups benefitting from the inclusion of additional PRSs. In summary, non-linear ML models improves BP prediction in models incorporating diverse populations.

Abstract Structural variations are a pervasive feature of human genomes, and there is growing recognition of their role in disease development through their impact on spatial chromatin architecture. This understanding has led us to investigate the clinical significance of CNVs in noncoding regions that influence TAD structures. In this study, we focused on the Epb41l4a locus, which contains a highly conserved TAD boundary present in both human chromosome 5 and mouse chromosome 18, and its association with neurodevelopmental phenotypes. Analysis of human data from the DECIPHER database indicates that CNVs within this locus, including both deletions and duplications, are often observed alongside neurological abnormalities, such as dyslexia and intellectual disability, although there is not enough evidence of a direct correlation or causative relationship. To investigate these possible associations, we generated mouse models with deletion and inversion mutations at this locus and carried out RNA-seq analysis to elucidate gene expression changes. We found that modifications in the Epb41l4a TAD boundary led to dysregulation of the Nrep gene, which plays a crucial role in nervous system development. These findings underscore the potential pathogenicity of these CNVs and highlight the crucial role of spatial genome architecture in gene expression regulation.

Abstract When traditional EEG signals are collected based on the Nyquist theorem, long-time recordings of EEG signals will produce a large amount of data. At the same time, limited bandwidth, end-to-end delay, and memory space will bring great pressure on the effective transmission of data. The birth of compressed sensing alleviates this transmission pressure. However, using an iterative compressed sensing reconstruction algorithm for EEG signal reconstruction faces complex calculation problems and slow data processing speed, limiting the application of compressed sensing in EEG signal rapid monitoring systems. As such, this paper presents a non-iterative and fast algorithm for reconstructing EEG signals using compressed sensing and deep learning techniques. This algorithm uses the improved residual network model, extracts the feature information of the EEG signal by one-dimensional dilated convolution, directly learns the nonlinear mapping relationship between the measured value and the original signal, and can quickly and accurately reconstruct the EEG signal. The method proposed in this paper has been verified by simulation on the open BCI contest dataset. Overall, it is proved that the proposed method has higher reconstruction accuracy and faster reconstruction speed than the traditional CS reconstruction algorithm and the existing deep learning reconstruction algorithm. In addition, it can realize the rapid reconstruction of EEG signals.

Abstract This study examined burnout dynamics among Ukrainian academic staff during the full-scale war. A cross-sectional study was conducted twice: the first wave in July 2022 and the second in January 2023. To assess the burnout syndrome as the final outcome, the self-reported Maslach Burnout Inventory-Human Services adapted for socioeconomic professions by Vodopyanova was used and correlated with different characteristics. The results showed a significant positive trend in emotional exhaustion among Ukrainian academic staff, with females being more sensitive to war-related factors. The results demonstrate that prolonged stressful situations associated with the ongoing war and constant changes in professional conditions lead to significant depersonalization dynamics among academic staff of both sexes. For male academic staff, factors such as age and academic position become less significant for depersonalization. However, university relocation and migration processes were significant factors affecting female academic staff’s' perception of effectiveness and accomplishment in their professional activities. The alarming dynamic of burnout levels detected among Ukrainian academic staff urges the national and institutional levels to take prompt actions to enhance the academic staff’s mental health in the workplace for preserving not only the quality of higher education, but also human capital in war times for postwar recovery in Ukraine.

Abstract Resina Draconis (RD) is known as the "holy medicine for promoting blood circulation" and possesses antitumor properties against various types of cancer, including breast cancer (BC); however, the underlying mechanism is not well understood. To explore the potential mechanism of RD against BC using network pharmacology and experimental validation, data on bioactive compounds, potential targets of RD, and related genes of BC were obtained from multiple public databases. Gene Ontology (GO) and KEGG pathway analyses were performed via the DAVID database. Protein interactions were downloaded from the STRING database. The mRNA and protein expression levels and survival analysis of the hub targets were analyzed using the UALCAN, HPA, Kaplan‒Meier mapper, and cBioPortal databases. Subsequently, molecular docking was used to verify the selected key ingredients and hub targets. Finally, the predicted results of network pharmacology methods were verified by cell experiments. In total, 160 active ingredients were obtained, and 148 RD target genes for the treatment of BC were identified. KEGG pathway analysis indicated that RD exerted its therapeutic effects on BC by regulating multiple pathways. Of these, the PI3K-AKT pathway was indicated to play an important role. In addition, RD treatment of BC seemed to involve the regulation of hub targets that were identified based on PPI interaction network analysis. Validation in different databases showed that AKT1, ESR1, HSP90AA1, CASP3, SRC and MDM2 may be involved in the carcinogenesis and progression of BC and that ESR1, IGF1 and HSP90AA1 were correlated with worse overall survival (OS) in BC patients. Molecular docking results showed that 103 active compounds have good binding activity with the hub targets, among which flavonoid compounds were the most important active components. Therefore, the sanguis draconis flavones (SDF) were selected for subsequent cell experiments. The experimental results showed that SDF significantly inhibited the cell cycle and cell proliferation of MCF-7 cells through the PI3K/AKT pathway and induced MCF-7 cell apoptosis. This study has preliminarily reported on the active ingredients, potential targets, and molecular mechanism of RD against BC, and RD was shown to exert its therapeutic effects on BC by regulating the PI3K/AKT pathway and related gene targets. Importantly, our work could provide a theoretical basis for further study of the complex anti-BC mechanism of RD.

The potential role of enteric viral infections and the developing infant virome in affecting immune responses to the oral poliovirus vaccine (OPV) is unknown. Here we performed viral metagenomic sequencing on 3 serially collected stool samples from 30 Bangladeshi infants following OPV vaccination and compared findings to stool samples from 16 age-matched infants in the United States (US). In 14 Bangladeshi infants, available post-vaccination serum samples were tested for polio-neutralizing antibodies. The abundance (p = 0.006) and richness (p = 0.013) of the eukaryotic virome increased with age and were higher than seen in age-matched US infants (p

Abstract Oral mucositis (OM) is a complex acute cytotoxicity of antineoplastic treatment that affects 40–85% of patients undergoing hematopoietic stem-cell transplantation. OM is associated with prolonged hospitalization, increased extensive pharmacotherapy, need for parenteral nutrition, and elevated treatment costs. As OM onset relates to the mucosal microenvironment status, with a particular role for microbiota-driven inflammation, we aimed to investigate whether the oral mucosa microbiota was associated with the clinical course of OM in patients undergoing allogeneic hematopoietic stem-cell transplantation. We collected oral mucosa samples from 30 patients and analyzed the oral mucosa microbiota by 16S rRNA sequencing. A total of 13 patients (43%) developed ulcerative OM. We observed that specific taxa were associated with oral mucositis grade and time to oral mucositis healing. Porphyromonas relative abundance at preconditioning was positively correlated with ulcerative OM grade (Spearman ρ = 0.61, P = 0.028) and higher Lactobacillus relative abundance at ulcerative OM onset was associated with shortened ulcerative OM duration (P = 0.032). Additionally, we generated a machine-learning-based bacterial signature that uses pre-treatment microbial profiles to predict whether a patient will develop OM during treatment. Our findings suggest that further research should focus on host-microbiome interactions to better prevent and treat OM.

Abstract Although speech declines rapidly in some individuals with amyotrophic lateral sclerosis (ALS), longitudinal changes in speech have rarely been characterized. The study objectives were to model the rate of decline in speaking rate and speech intelligibility as a function of disease onset site, sex, and age at onset in 166 individuals with ALS; and estimate time to speech loss from symptom onset. We also examined the association between clinical (speaking rate/intelligibility) measures and patient-reported measures of ALS progression (ALSFRS-R). Speech measures declined faster in the bulbar-onset group than in the spinal-onset group. The rate of decline was not significantly affected by sex and age. Functional speech was still maintained at 60 months since disease onset for most patients with spinal onset. However, the time to speech loss was 23 months based on speaking rate

Abstract Nowadays, Transit-Oriented Development (TOD) plays a vital role for public transport planners in developing potential city facilities. Knowing the necessity of this concept indicates that TOD effective parameters such as network accessibility (node value) and station-area land use (place value) should be considered in city development projects. To manage the coordination between these two factors, we need to consider ridership and peak and off-peak hours as essential enablers in our investigations. To aim this, we conducted our research on Chengdu rail-transit stations as a case study to propose our Node-Place-Ridership-Time (NPRT) model. We applied the Multiple Linear Regression (MLR) to examine the impacts of node value and place value on ridership. Finally, K-Means and Cube Methods were used to classify the stations based on the NPRT model results. This research indicates that our NPRT model could provide accurate results compared with the previous models to evaluate rail-transit stations.

Abstract Following the COVID-19 outbreak, psychological stress was particularly pronounced in the student population due to prolonged home isolation, online study, closed management, graduation, and employment pressures. The objective of this study is to identify the incidence of psychological stress reactions in student populations following a global outbreak and the associated influencing factors. Four English databases (Pubmed, Embase, Cochrane Library, Web of Science) and four Chinese biomedical databases (Chinese Biomedical Literature Database, VIP Database for Chinese Technical Periodicals, China National Knowledge Infrastructure, Wanfang) were searched in this study. We also retrieved other search engines manually. The search period was from the time of database creation to 10 March 2022. This study included cross-sectional studies related to psychological stress reactions in student populations during the COVID-19 epidemic. Three groups of researchers screened the retrieved studies and assessed the quality of the included studies using the Agency for Healthcare Research and Quality Cross-Sectional Study Quality Assessment Checklist. A random-effects model was used to analyze the prevalence of depression, anxiety, stress, and fear symptoms in the student population during the COVID-19 epidemic. Of the 146,330 records retrieved, we included 104 studies (n = 2,088,032). The quality of included studies was moderate. The prevalence of depressive symptoms in the student population during the epidemic was 32.0% (95% CI [28.0–37.0%]); anxiety symptoms was 28.0% (95% CI [24.0–32.0%]); stress symptoms was 31.0% (95% CI [23.0–39.0%]); and fear symptoms was 33.0% (95% CI [20.0–49.0%]). The prevalence differed by gender, epidemic stage, region, education stage, student major and assessment tool. The prevalence of psychological stress in the student population during the COVID-19 epidemic may be higher compared to the global prevalence of psychological stress. We need to alleviate psychological stress in the student population in a targeted manner to provide mental health services to safeguard the student population.

Abstract Bariatric surgery (BS) improves outcomes in patients with myocardial infarction (MI). Here we tested the hypothesis that BS-mediated reduction in fatal MI could be attributed to its infarct-limiting effect. Wistar rats were randomized into five groups: control (CON), sham (SHAM), Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), and ileotransposition (IT). Ten weeks later, animals were subjected to 30-min myocardial ischemia plus 120-min reperfusion. Infarct size (IS) and no-reflow area were determined histochemically. Fasting plasma levels of glucagon-like peptide-1 (GLP-1), leptin, ghrelin, and insulin were measured using ELISA. Compared with SHAM, RYGB and SG reduced IS by 22% (p = 0.011) and 10% (p = 0.027), and no-reflow by 38% (p = 0.01) and 32% (p = 0.004), respectively. IT failed to reduce IS and no-reflow. GLP-1 level was increased in the SG and RYGB groups compared with CON. In both the SG and RYGB, leptin level was decreased compared with CON and SHAM. In the SG group, ghrelin level was lower than that in the CON and SHAM. Insulin levels were not different between groups. In conclusion, RYGB and SG increased myocardial tolerance to ischemia–reperfusion injury of non-obese, non-diabetic rats, and their infarct-limiting effect is associated with decreased leptin and ghrelin levels and increased GLP-1 level.

Abstract Zero-dimensional Perovskite Magic-size Clusters play crucial roles in understanding and controlling nucleation and growth of semiconductor nanoparticles. However, their metastability behavior is a critical hindrance for reliable characterizations. Here, we report the first demonstration of using an excess amount of surface ligand and SiO2 as novel passivation for synthesizing the magic-sized clusters (MSCs) by the Ligand-assisted reprecipitation method. A synergetic effect between an excessed surface ligand and SiO2 inhibits the protonation and deprotonation reaction between amine-based and acid-based ligand, leading to enhanced PL stability. The obtained CH3NH3PbBr3 PMSCs/SiO2 retain 70% of its initial emission intensity in ambient conditions for 20 days. This passivation approach opens an entirely new avenue for the reliable characterizations of CH3NH3PbBr3 PMSCs, which will significantly broaden their application for understanding and controlling nucleation and growth of semiconductor nanoparticles.

Abstract Intestinal microbiota (IM) diversity and composition regulates host immunity and affects outcomes after allogeneic stem cell transplantation (allo-HSCT). We evaluated if the oral mucosa microbiota (OM) could impact the outcomes in patients who underwent allo-HSCT. Samples from the oral mucosa of 30 patients were collected at three time points: before the conditioning regimen, at aplasia, and at engraftment. We analyzed the associations of OM diversity and composition with allo-HSCT outcomes. Lower OM diversity at preconditioning was associated with a higher risk of relapse at 3 years (68% versus 33%, respectively; P = 0.04). Dominance (relative abundance ≥ 30%) by a single genus at preconditioning was also associated with a higher risk of relapse (63% versus 36% at 3 years, respectively; P = 0.04), as well as worse progression-free survival (PFS; 19% versus 55%, respectively; P = 0.01), and overall survival (OS) at 3 years (38% versus 81%, respectively; P = 0.02). In our study we observed that OM dysbiosis is associated with a higher risk of relapse and worse survival after allo-HSCT.

Abstract Treatment of multiple myeloma (MM) aims at inducing cell apoptosis by surpassing the limited capacity of MM cells to cope with oxidative stress. MM cell survival may further be suppressed by limiting cellular cholesterol. Long-chain fatty acid analogs of the MEDICA series promote mitochondrial stress and inhibit cholesterol biosynthesis, thus prompting us to verify their efficacy and mode-of-action in suppressing MM cell survival, in comparison to bortezomib. MEDICA analog is shown here to effectively suppress survival of MM cells, and to inhibit growth of MM xenograft. Suppression of MM cell survival by MEDICA is accompanied by inhibition of the STAT3, MAPK and the mTORC1 transduction pathways due to mitochondrial oxidative stress. MEDICA-induced oxidative stress is abrogated by added exogenous cholesterol. Suppression of MM cell survival by bortezomib is similarly driven by bortezomib-induced oxidative stress, being abrogated by added cholesterol. In line with that, the time-to-best-response of MM patients to bortezomib-based treatment protocols is shown to be positively correlated with their plasma cholesterol level. MEDICA profile may indicate novel therapeutic potential in the management of MM.

Abstract Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by brain-specific loss of UBE3A, an E3 ubiquitin protein ligase. A substantial number of possible ubiquitination targets of UBE3A have been identified, although evidence of being direct UBE3A substrates is often lacking. Here we identified the synaptic protein Rabphilin-3a (RPH3A), an effector of the RAB3A small GTPase involved in axonal vesicle priming and docking, as a ubiquitination target of UBE3A. We found that the UBE3A and RAB3A binding sites on RPH3A partially overlap, and that RAB3A binding to RPH3A interferes with UBE3A binding. We confirmed previous observations that RPH3A levels are critically dependent on RAB3A binding but, rather surprisingly, we found that the reduced RPH3A levels in the absence of RAB3A are not mediated by UBE3A. Indeed, while we found that RPH3A is ubiquitinated in a UBE3A-dependent manner in mouse brain, UBE3A mono-ubiquitinates RPH3A and does not facilitate RPH3A degradation. Moreover, we found that an AS-linked UBE3A missense mutation in the UBE3A region that interacts with RPH3A, abrogates the interaction with RPH3A. In conclusion, our results identify RPH3A as a novel target of UBE3A and suggest that UBE3A-dependent ubiquitination of RPH3A serves a non-degradative function.

Abstract Cat eye syndrome (CES), a human genetic disorder caused by the inverted duplication of a region on chromosome 22, has been known since the late 1890s. Despite the significant impact this disorder has on affected individuals, models for CES have not been produced due to the difficulty of effectively duplicating the corresponding chromosome region in an animal model. However, the study of phenotypes associated with individual genes in this region such as CECR2 may shed light on the etiology of CES. In this study we have shown that deleterious loss of function mutations in mouse Cecr2 effectively demonstrate many of the abnormal features present in human patients with CES, including coloboma and specific skeletal, kidney and heart defects. Beyond phenotypic analyses we have demonstrated the importance of utilizing multiple genetic backgrounds to study disease models, as we see major differences in penetrance of Cecr2-related abnormal phenotype between mouse strains, reminiscent of the variability in the human syndrome. These findings suggest that Cecr2 is involved in the abnormal features of CES and that Cecr2 mice can be used as a model system to study the wide range of phenotypes present in CES.

Abstract Fungal infections and toxicoses caused by insecticides may alter microbial communities and immune responses in the insect gut. We investigated the effects of Metarhizium robertsii fungus and avermectins on the midgut physiology of Colorado potato beetle larvae. We analyzed changes in the bacterial community, immunity- and stress-related gene expression, reactive oxygen species (ROS) production, and detoxification enzyme activity in response to topical infection with the M. robertsii fungus, oral administration of avermectins, and a combination of the two treatments. Avermectin treatment led to a reduction in microbiota diversity and an enhancement in the abundance of enterobacteria, and these changes were followed by the downregulation of Stat and Hsp90, upregulation of transcription factors for the Toll and IMD pathways and activation of detoxification enzymes. Fungal infection also led to a decrease in microbiota diversity, although the changes in community structure were not significant, except for the enhancement of Serratia. Fungal infection decreased the production of ROS but did not affect the gene expression of the immune pathways. In the combined treatment, fungal infection inhibited the activation of detoxification enzymes and prevented the downregulation of the JAK-STAT pathway caused by avermectins. The results of this study suggest that fungal infection modulates physiological responses to avermectins and that fungal infection may increase avermectin toxicosis by blocking detoxification enzymes in the gut.

Anthropogenic emissions of carbon dioxide (CO2) are causing ocean acidification, lowering seawater aragonite (CaCO3) saturation state (Ω arag), with potentially substantial impacts on marine ecosystems over the 21(st) Century. Calcifying organisms have exhibited reduced calcification under lower saturation state conditions in aquaria. However, the in situ sensitivity of calcifying ecosystems to future ocean acidification remains unknown. Here we assess the community level sensitivity of calcification to local CO2-induced acidification caused by natural respiration in an unperturbed, biodiverse, temperate intertidal ecosystem. We find that on hourly timescales nighttime community calcification is strongly influenced by Ω arag, with greater net calcium carbonate dissolution under more acidic conditions. Daytime calcification however, is not detectably affected by Ω arag. If the short-term sensitivity of community calcification to Ω arag is representative of the long-term sensitivity to ocean acidification, nighttime dissolution in these intertidal ecosystems could more than double by 2050, with significant ecological and economic consequences.

Abstract The FDA-approved DNA hypomethylating agents (DHAs) like 5-azacytidine (5AC) and decitabine (DAC) demonstrate efficacy in the treatment of hematologic malignancies. Despite previous reports that showed histone acetylation changes upon using these agents, the exact mechanism underpinning these changes is unknown. In this study, we investigated the relative potency of the nucleoside analogs and non-nucleoside analogs DHAs on DNA methylation reversal using DNA pyrosequencing. Additionally, we screened their effect on the enzymatic activity of the histone deacetylase sirtuin family (SIRT1, SIRT2, SIRT3, SIRT5 and SIRT6) using both recombinant enzymes and nuclear lysates from leukemia cells. The nucleoside analogs (DAC, 5AC and zebularine) were the most potent DHAs and increased the enzymatic activity of SIRT6 without showing any significant increase in other sirtuin isoforms. ChIP-Seq analysis of bone marrow cells derived from six acute myeloid leukemia (AML) patients and treated with the nucleoside analog DAC induced genome-wide acetylation changes in H3K9, the physiological substrate for SIRT6. Data pooling from the six patients showed significant acetylation changes in 187 gene loci at different chromosomal regions including promoters, coding exons, introns and distal intergenic regions. Signaling pathway analysis showed that H3K9 acetylation changes are linked to AML-relevant signaling pathways like EGF/EGFR and Wnt/Hedgehog/Notch. To our knowledge, this is the first report to identify the nucleoside analogs DHAs as activators of SIRT6. Our findings provide a rationale against the combination of the nucleoside analogs DHAs with SIRT6 inhibitors or chemotherapeutic agents in AML due to the role of SIRT6 in maintaining genome integrity and DNA repair.

Abstract This study aimed to investigate the pattern of gestational weight gain (GWG) among Chinese women. We included pregnant women, who delivered at a referral medical center in China and had no pre-specified adverse pregnancy outcomes. We collected weight data across all pregnancy visits, and used the two-level spline linear model to fit for the pattern of GWG according to pre-pregnancy BMI categories. In total, 4,567 pregnant women with 47,699 repeated measures were eligible. For those who were underweight, normal and overweight before pregnancy, the interquartile ranges (25th to 75th quartiles) of GWG between 14 and 36 gestational weeks were 12.9–17.7 kg, 12.6–17.3 kg and 11.7–16.8 kg, and the corresponding rates of GWG were 2.62 kg/month, 2.56 kg/month and 2.37 kg/month. For underweight and normal women, the rates of GWG were similar before 14 weeks (0.57 and 0.58 kg/month) and after 36 weeks (1.69 and 1.70 kg/month); however, the rates of GWG were higher for overweight women (0.66 kg/month before 14 weeks and 1.89 kg/month after 36 weeks). In summary, the pattern of GWG among Chinese pregnant women is generally consistent with the IOM recommendation, particularly for those who are normal or underweight. Modifications are, however, warranted for overweight pregnant women.

Abstract Despite striking advances in the treatment of metastasized melanoma, the disease is often still fatal. Attention is therefore paid towards combinational regimens. Oxidants endogenously produced in mitochondria are currently targeted in pre-clinical and clinical studies. Cytotoxic synergism of mitochondrial cytochrome c oxidase (CcO) inhibition in conjunction with addition of exogenous oxidants in 2D and 3D melanoma cell culture models were examined. Murine (B16) and human SK-MEL-28 melanoma cells exposed to low-dose CcO inhibitors (potassium cyanide or sodium azide) or exogenous oxidants alone were non-toxic. However, we identified a potent cytotoxic synergism upon CcO inhibition and plasma-derived oxidants that led to rapid onset of caspase-independent melanoma cell death. This was mediated by mitochondrial dysfunction induced by superoxide elevation and ATP depletion. This observation was validated by siRNA-mediated knockdown of COX4I1 in SK-MEL-28 cells with cytotoxicity in the presence of exogenous oxidants. Similar effects were obtained with ADDA 5, a recently identified specific inhibitor of CcO activity showing low toxicity in vivo. Human keratinocytes were not affected by this combinational treatment, suggesting selective effects on melanoma cells. Hence, targeting mitochondrial CcO activity in conjunction with exogenous pro oxidant therapies may constitute a new and effective melanoma treatment modality.

Abstract Mammalian SIRT6 is a well-studied histone deacetylase that was recently shown to exhibit high protein deacylation activity enabling the removal of long chain fatty acyl groups from proteins. SIRT6 was shown to play key roles in cellular homeostasis by regulating a variety of cellular processes including DNA repair and glucose metabolism. However, the link between SIRT6 enzymatic activities and its cellular functions is not clear. Here, we utilized a directed enzyme evolution approach to generate SIRT6 mutants with improved deacylation activity. We found that while two mutants show increased deacylation activity at high substrate concentration and improved glucose metabolism they exhibit no improvement and even abolished deacetylation activity on H3K9Ac and H3K56Ac in cells. Our results demonstrate the separation of function between SIRT6 catalytic activities and suggest that SIRT6 deacylation activity in cells is important for glucose metabolism and can be mediated by still unknown acylated cellular proteins.

Abstract After strong fertilization in the 20th century, many deep lakes in Central Europe are again nutrient poor due to long-lasting restoration (re-oligotrophication). In line with reduced phosphorus and nitrogen loadings, total organismic productivity decreased and lakes have now historically low nutrient and biomass concentrations. This caused speculations that restoration was overdone and intended fertilizations are needed to ensure ecological functionality. Here we show that recent re-oligotrophication processes indeed accelerated, however caused by lake warming. Rising air temperatures strengthen thermal stabilization of water columns which prevents thorough turnover (holomixis). Reduced mixis impedes down-welling of oxygen rich epilimnetic (surface) and up-welling of phosphorus and nitrogen rich hypolimnetic (deep) water. However, nutrient inputs are essential for algal spring blooms acting as boost for annual food web successions. We show that repeated lack (since 1977) and complete stop (since 2013) of holomixis caused drastic epilimnetic phosphorus depletions and an absence of phytoplankton spring blooms in Lake Zurich (Switzerland). By simulating holomixis in experiments, we could induce significant vernal algal blooms, confirming that there would be sufficient hypolimnetic phosphorus which presently accumulates due to reduced export. Thus, intended fertilizations are highly questionable, as hypolimnetic nutrients will become available during future natural or artificial turnovers.

Abstract L-Cysteine functionalized magnetite nanoparticles (L-Cyst-Fe3O4 NPs) were synthesized by chemical co-precipitation using Fe2+ and Fe3+ as iron precursors, sodium hydroxide as a base and L-Cysteine as functionalized agent. The structural and morphological studies were carried out using X-ray powder diffraction, transmission electron microscopy, dynamic light scattering, scanning electron microscopy and energy dispersive X-ray spectroscopy, Fourier transform infrared spectroscopy, and UV-Vis spectrophotometric techniques. The zeta potential of bare Fe3O4 and functionalized L-Cyst-Fe3O4 NPs were +28 mV and −30.2 mV (pH 7.0), respectively. The positive surface charge changes to negative imply the presence of L-Cyst monolayer at particle interface. Band gap energy of 2.12 eV [bare Fe3O4NPs] and 1.4 eV [L-Cyst-Fe3O4 NPs] were obtained. Lead and chromium removal were investigated at different initial pHs, contact time, temperatures and adsorbate-adsorbent concentrations. Maximum Cr6+ and Pb2+ removal occurred at pH 2.0 and 6.0, respectively. Sorption dynamics data were best described by pseudo-second order rate equation. Pb2+ and Cr6+ sorption equilibrium data were best fitted to Langmuir equation. Langmuir adsorption capacities of 18.8 mg/g (Pb2+) and 34.5 mg/g (Cr6+) at 45 °C were obtained. Regeneration of exhausted L-Cyst-Fe3O4 NPs and recovery of Pb2+/Cr6+ were demonstrated using 0.01 M HNO3 and NaOH. L-Cyst-Fe3O4 NPs stability and reusability were also demonstrated.

Abstract Herein, we report energy storage devices, which are based on densely packed, vertically aligned MoS2 (VA-MoS2) or planar oriented MoS2 (PO-MoS2) and compare their electrochemical performances. The VA-MoS2 films have been processed by chemical vapor deposition (CVD) to reach unprecedented micron-scale thick films while maintaining the vertical alignment for the whole thickness. The VA-MoS2 and the PO-MoS2 films form a high-performance Li-ion electrode, reaching the theoretical limits of reversible capacity for this material (800 mAh/g; twice the specific capacity of graphite). The vertical alignment allows faster charge-discharge rates while maintaining a high specific capacity (C-rate measurements). Noteworthy, the reversible cycling of the Li-ion electrode also benefits from the vertical alignment. In this article, we present the full synthesis, structural and electrochemical characterization of VA-MoS2 along with the properties of PO-MoS2 to deconvolute the intrinsic properties of MoS2 from the influence of the layers’ orientation.

Abstract Any two unrelated individuals differ by about 10,000 single amino acid variants (SAVs). Do these impact molecular function? Experimental answers cannot answer comprehensively, while state-of-the-art prediction methods can. We predicted the functional impacts of SAVs within human and for variants between human and other species. Several surprising results stood out. Firstly, four methods (CADD, PolyPhen-2, SIFT, and SNAP2) agreed within 10 percentage points on the percentage of rare SAVs predicted with effect. However, they differed substantially for the common SAVs: SNAP2 predicted, on average, more effect for common than for rare SAVs. Given the large ExAC data sets sampling 60,706 individuals, the differences were extremely significant (p-value