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Dominant X-linked diseases are uncommon due to female X chromosome inactivation (XCI). While random XCI usually protects females against X-linked mutations, Rett syndrome (RTT) is a female neurodevelopmental disorder caused by heterozygous MECP2 mutation. After 6-18 months of typical neurodevelopment, RTT girls undergo a poorly understood regression. We performed longitudinal snRNA-seq on cerebral cortex in a construct-relevant Mecp2e1 mutant mouse model of RTT, revealing transcriptional effects of cell type, mosaicism, and sex on progressive disease phenotypes. Across cell types, we observed sex differences in the number of differentially expressed genes (DEGs) with 6x more DEGs in mutant females than males. Unlike males, female DEGs emerged prior to symptoms, were enriched for homeostatic gene pathways in distinct cell types over time and correlated with disease phenotypes and human RTT cortical cell transcriptomes. Non-cell-autonomous effects were prominent and dynamic across disease progression of Mecp2e1 mutant females, indicating that wild-type-expressing cells normalize transcriptional homeostasis. These results advance our understanding of RTT progression and treatment.

Background Neurodevelopmental disorders have a strong male bias that is poorly understood. Placenta is a rich source of molecular information about environmental interactions with genetics (including biological sex), that affect the developing brain. We investigated placental-brain transcriptional responses in an established mouse model of prenatal exposure to a human-relevant mixture of polychlorinated biphenyls (PCBs). Results To understand sex, tissue, and dosage effects in embryonic (E18) brain and placenta by RNAseq, we used weighted gene correlation network analysis (WGCNA) to create correlated gene networks that could be compared across sex or tissue. WGCNA revealed that expression within most correlated gene networks was significantly and strongly associated with PCB exposures, but frequently in opposite directions between male-female and placenta-brain comparisons. In both WGCNA and differentially expressed gene analyses, male brain showed more PCB-induced transcriptional changes than male placenta, but the reverse pattern was seen in females. Furthermore, non-monotonic dose responses to PCBs were observed in most gene networks but were most prominent in male brain. The transcriptomic effects of low dose PCB exposure were significantly reversed by dietary folic acid supplementation across both sexes, but these effects were strongest in female placenta. PCB-dysregulated and folic acid-reversed gene networks were commonly enriched in functions in metabolic pathways involved in energy usage and translation, with female-specific protective effects enriched in PPAR, thermogenesis, glycerolipids, and O-glycan biosynthesis, as opposed to toxicant responses in male brain. Conclusions The female protective effect in prenatal PCB exposures appears to be mediated by dose-dependent sex differences in transcriptional modulation of metabolism in placenta. Graphical Abstract

Abstract Dominant X-linked diseases are uncommon due to female X chromosome inactivation (XCI). While random XCI usually protects females against X-linked mutations, Rett syndrome (RTT) is a female neurodevelopmental disorder caused by heterozygous MECP2 mutation. After 6-18 months of typical neurodevelopment, RTT girls undergo a poorly understood regression. We performed longitudinal snRNA-seq on cerebral cortex in a construct-relevant Mecp2e1 mutant mouse model of RTT, revealing transcriptional effects of cell type, mosaicism, and sex on progressive disease phenotypes. Across cell types, we observed sex differences in the number of differentially expressed genes (DEGs) with 6x more DEGs in mutant females than males. Unlike males, female DEGs emerged prior to symptoms, were enriched for homeostatic gene pathways in distinct cell types over time and correlated with disease phenotypes and human RTT cortical cell transcriptomes. Non-cell-autonomous effects were prominent and dynamic across disease progression of Mecp2e1 mutant females, indicating that wild-type-expressing cells normalize transcriptional homeostasis. These results advance our understanding of RTT progression and treatment.

Abstract The use of beach-cast macroalgae as a fertilizer (F) or soil amendment (SA) is coming back into focus, due to its highly efficient transformation of CO2, nutrients, salts and minerals from its aqueous surroundings into biomass. This research studied the hydrothermal carbonization (HTC) of Fucus vesiculosus macroalgae to hydrochar and evaluated its feasibility for use in soil applications. F. vesiculosus was submitted to HTC following a full factorial design of experiments with three HTC process parameters varied to assess their impact on the hydrochars: temperature (T: 160, 190, 220 °C), solid content (%So: 20, 35%), and process water recirculation (PWrec: yes and no). In general, F. vesiculosus and its hydrochars were rich in nutrients, but also contained regulated heavy metals. Investigation of the partitioning behavior of inorganic elements between the hydrochars and process water showed that heavy metals like Cr, Pb, Co and Cu tended to accumulate in the hydrochar, unaffected by HTC conditions. Nutrients such as P, N, B, and Mn were primarily found in the hydrochar and could be partially influenced to transfer to process water by changing %So and T. The correlation between the mass fractions of 22 elements in the hydrochar and HTC process parameters was studied. T was the most influential parameter, showing a significant positive correlation for eleven elements. %So and PWrec showed inconsistent effects on different elements. When process water was recirculated, some elements decreased (Ca, Cd, Fe) while others increased (K, Na, B, N) in the hydrochar. Assessment against various regulations and standards for F and SA revealed that F. vesiculosus complied with Cd limit values for most rules including the EURF and B, and was regulated only in the RAL for SA, over the limit value. In contrast, the limit value of Cd for both F and SA applications was surpassed in the 13 hydrochars. The contents of N, P, K, S, and Na in the feedstock and hydrochars complied with European F and SA rules, while they were too high for German rules on SA. The other limits for F rules were achieved (under certain HTC process parameters) except for P (lower than the requirements in F for F. vesiculosus and its hydrochars). Graphical Abstract

Abstract Neurofibromatosis Type 1 (NF1) is caused by loss of function variants in the NF1 gene. Most patients with NF1 develop skin lesions called cutaneous neurofibromas (cNFs). Currently the only approved therapeutic for NF1 is selumetinib, a mitogen -activated protein kinase (MEK) inhibitor. The purpose of this study was to analyze the transcriptome of cNF tumors before and on selumetinib treatment to understand both tumor composition and response. We obtained biopsy sets of tumors both pre- and on- selumetinib treatment from the same individuals and were able to collect sets from four separate individuals. We sequenced mRNA from 5844 nuclei and identified 30,442 genes in the untreated group and sequenced 5701 nuclei and identified 30,127 genes in the selumetinib treated group. We identified and quantified distinct populations of cells (Schwann cells, fibroblasts, pericytes, myeloid cells, melanocytes, keratinocytes, and two populations of endothelial cells). While we anticipated that cell proportions might change with treatment, we did not identify any one cell population that changed significantly, likely due to an inherent level of variability between tumors. We also evaluated differential gene expression based on drug treatment in each cell type. Ingenuity pathway analysis (IPA) was also used to identify pathways that differ on treatment. As anticipated, we identified a significant decrease in ERK/MAPK signaling in cells including Schwann cells but most specifically in myeloid cells. Interestingly, there is a significant decrease in opioid signaling in myeloid and endothelial cells; this downward trend is also observed in Schwann cells and fibroblasts. Cell communication was assessed by RNA velocity, Scriabin, and CellChat analyses which indicated that Schwann cells and fibroblasts have dramatically altered cell states defined by specific gene expression signatures following treatment (RNA velocity). There are dramatic changes in receptor-ligand pairs following treatment (Scriabin), and robust intercellular signaling between virtually all cell types associated with extracellular matrix (ECM) pathways (Collagen, Laminin, Fibronectin, and Nectin) is downregulated after treatment. These response specific gene signatures and interaction pathways could provide clues for understanding treatment outcomes or inform future therapies.

Purpose Vertebral compression fractures (VCFs) are common and associated with high morbidity including severe, debilitating pain. Percutaneous vertebroplasty/kyphoplasty is a demonstrated effective treatment for VCF. Sarcopenia has been implicated as a risk factor for VCF and refracture following cement augmentation, and as a risk factor for procedural complications in some populations; however, the effect of sarcopenia on VCF patients undergoing these procedures is unknown. This study aims to improve outcomes and patient selection by investigating the effects of highly common VCF comorbidities.

O presente estudo foi realizado buscando comparar a eficiência dos tratamentos de coagulação/floculação e eletrocoagulação aplicados a um efluente têxtil sintético contendo o corante azul marinho (AM-16). Para o processo de coagulação/floculação, utilizou-se policloreto de alumínio (PAC-18%) e sulfato de alumínio (Al2(SO4)3) como coagulantes e o polímero catiônico (PC) como auxiliar de coagulação. Os tratamentos de coagulação/floculação foram avaliados nas concentrações do corante na faixa de 150–350 mg L-1, concentração do PAC-18% (faixa de 10–50 mg L-1), concentração do PC (faixa de 0,1–0,5 mg L-1), pH inicial (faixa de 5–9). Para os ensaios com o Al2(SO4)3 as mesmas faixas de estudo foram aplicadas, com exceção apenas do pH inicial, para o qual a faixa utilizada foi de 4 a 8. Para o processo de eletrocoagulação, utilizaram-se eletrodos de alumínio, que foi conduzido utilizando-se a faixa de concentração para o corante de 150 a 350 mg L-1 e a corrente aplicada de 0,3 a 0,9 A. As variáveis de resposta foram remoção do contaminante (AM-16), remoção de cor, demanda química de oxigênio, carbono orgânico total e redução de toxicidade empregando-se o microcrustáceo Artemia salina como bioindicador. O objetivo foi comparar o desempenho dos diferentes métodos de tratamento (coagulação/floculação e eletrocoagulação), bem como avaliar como todas as variáveis independentes e suas interações afetaram a eficiência dos processos. Os resultados encontrados por meio da análise estatística demonstraram que fator de maior influência no processo de coagulação/floculação para a remoção da concentração do corante AM-16 foi o pH inicial, tanto para o PAC-18% quanto para o sulfato de alumínio (Al2(SO4)3). No entanto, para este último a concentração do corante também teve influência, mostrando que o aumento no pH e na concentração do corante favorecem a remoção. Quanto à toxicidade do efluente após os tratamentos, houve redução média máxima de aproximadamente 11% para o tratamento com o Al2(SO4)3. A eletrocoagulação não apresentou nenhuma variável significante nos níveis estudados, entretanto apresentou bom desempenho médio na remoção da concentração do corante (83,68%) e da cor (95,1%) do efluente. Os dois processos de tratamento avaliados (coagulação/floculação e eletrocoagulação) demonstraram eficiência para as variáveis estudadas e seus níveis. Entretanto, os processos de coagulação/floculação tiveram melhor desempenho se levarmos em consideração as remoções obtidas no conjunto das variáveis de resposta avaliadas.

NMR is a valuable experimental tool in the structural biologist's toolkit to elucidate the structures, functions, and motions of biomolecules. The progress of machine learning, particularly in structural biology, reveals the critical importance of large, diverse, and reliable datasets in developing new methods and understanding in structural biology and science more broadly. Biomolecular NMR research groups produce large amounts of data, and there is renewed interest in organizing these data to train new, sophisticated machine learning architectures and to improve biomolecular NMR analysis pipelines. The foundational data type in NMR is the free-induction decay (FID). There are opportunities to build sophisticated machine learning methods to tackle long-standing problems in NMR data processing, resonance assignment, dynamics analysis, and structure determination using NMR FIDs. Our goal in this study is to provide a lightweight, broadly available tool for archiving FID data as it is generated at the spectrometer, and grow a new resource of FID data and associated metadata. This study presents a relational schema for storing and organizing the metadata items that describe an NMR sample and FID data, which we call Spectral Database (SpecDB). SpecDB is implemented in SQLite and includes a Python software library providing a command-line application to create, organize, query, backup, share, and maintain the database. This set of software tools and database schema allow users to store, organize, share, and learn from NMR time domain data. SpecDB is freely available under an open source license at https://github.rpi.edu/RPIBioinformatics/SpecDB.

Abstract Inadequate disposal of hazardous waste results risks to the environment and human health. Although the use of hazardous waste in new processes and/or products has received limited attention in the literature, there is still significant potential to be investigated. Reducing the usage of natural resources and waste management are important for sustainable practices during concrete production. This study investigated the mechanical and leaching behavior of paint booth waste (PBW) as a partial substitute (10, 20, 30 and 40%) of coarse aggregate in concrete mixtures for the manufacture of interlocking blocks. A sample of PBW used in this research differs from those in the literature due to its granulometry characterized by aggregates of different sizes. Concrete consistency, compressive strength, water absorption, X-ray diffraction, scanning electron microscopy, and leaching tests were carried out. The PBW did not influence the consistency in the fresh state of the concrete. The blocks with smaller substitutions (10 and 20%) presented denser structures and with greater strengths, surpassing 35 MPa after 28 days. Higher levels of PBW resulted in more porous concrete blocks with greater water absorption. The concrete-PBW mixtures showed no metal toxicity, i.e., the incorporation of this waste in the construction material avoided metal leaching. Concrete blocks with up to 20% PBW demonstrated satisfactory mechanical and environmental performance.

Abstract Human African trypanosomiasis or sleeping sickness, caused by the protozoan parasite Trypanosoma brucei, is characterized by the manipulation of the host’s immune response to ensure parasite invasion and persistence. Uncovering key molecules that support parasite establishment is a prerequisite to interfere with this process. We identified Q586B2 as a T. brucei protein that induces IL-10 in myeloid cells, which promotes parasite infection invasiveness. Q586B2 is expressed during all T. brucei life stages and is conserved in all Trypanosomatidae. Deleting the Q586B2-encoding Tb927.6.4140 gene in T. brucei results in a decreased peak parasitemia and prolonged survival, without affecting parasite fitness in vitro, yet promoting short stumpy differentiation in vivo. Accordingly, neutralization of Q586B2 with newly generated nanobodies could hamper myeloid-derived IL-10 production and reduce parasitemia. In addition, immunization with Q586B2 delays mortality upon a challenge with various trypanosomes, including Trypanosoma cruzi. Collectively, we uncovered a conserved protein playing an important regulatory role in Trypanosomatid infection establishment.

Abstract Recently, we have shown that after partial hepatectomy (PHx), an increased hepatic blood flow initiates liver growth in mice by vasodilation and mechanically-triggered release of angiocrine signals. Here, we use mass spectrometry to identify a mechanically-induced angiocrine signal in human hepatic endothelial cells, that is, myeloid-derived growth factor (MYDGF). We show that it induces proliferation and promotes survival of primary human hepatocytes derived from different donors in two-dimensional cell culture, via activation of mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3). MYDGF also enhances proliferation of human hepatocytes in three-dimensional organoids. In vivo, genetic deletion of MYDGF decreases hepatocyte proliferation in the regenerating mouse liver after PHx; conversely, adeno-associated viral delivery of MYDGF increases hepatocyte proliferation and MAPK signaling after PHx. We conclude that MYDGF represents a mechanically-induced angiocrine signal and that it triggers growth of, and provides protection to, primary mouse and human hepatocytes.

Background: Chronic liver diseases such as hepatic tumors can affect the brain through the liver–brain axis, leading to neurotransmitter dysregulation and behavioral changes. Cancer patients suffer from fatigue, which can be associated with sleep disturbances. Sleep is regulated via two interlocked mechanisms: homeostatic regulation and the circadian system. In mammals, the hypothalamic suprachiasmatic nucleus (SCN) is the key component of the circadian system. It generates circadian rhythms in physiology and behavior and controls their entrainment to the surrounding light/dark cycle. Neuron–glia interactions are crucial for the functional integrity of the SCN. Under pathological conditions, oxidative stress can compromise these interactions and thus circadian timekeeping and entrainment. To date, little is known about the impact of peripheral pathologies such as hepatocellular carcinoma (HCC) on SCN. Materials and Methods: In this study, HCC was induced in adult male mice. The key neuropeptides (vasoactive intestinal peptide: VIP, arginine vasopressin: AVP), an essential component of the molecular clockwork (Bmal1), markers for activity of neurons (c-Fos), astrocytes (GFAP), microglia (IBA1), as well as oxidative stress (8-OHdG) in the SCN were analyzed by immunohistochemistry at four different time points in HCC-bearing compared to control mice. Results: The immunoreactions for VIP, Bmal1, GFAP, IBA1, and 8-OHdG were increased in HCC mice compared to control mice, especially during the activity phase. In contrast, c-Fos was decreased in HCC mice, especially during the late inactive phase. Conclusions: Our data suggest that HCC affects the circadian system at the level of SCN. This involves an alteration of neuropeptides, neuronal activity, Bmal1, activation of glia cells, and oxidative stress in the SCN.

The All of Us Research Program seeks to engage at least one million diverse participants to advance precision medicine and improve human health. We describe here the cloud-based Researcher Workbench that uses a data passport model to democratize access to analytical tools and participant information including survey, physical measurement, and electronic health record (EHR) data. We also present validation study findings for several common complex diseases to demonstrate use of this novel platform in 315,000 participants, 78% of whom are from groups historically underrepresented in biomedical research, including 49% self-reporting non-White races. Replication findings include medication usage pattern differences by race in depression and type 2 diabetes, validation of known cancer associations with smoking, and calculation of cardiovascular risk scores by reported race effects. The cloud-based Researcher Workbench represents an important advance in enabling secure access for a broad range of researchers to this large resource and analytical tools.

Antimicrobial resistance (AMR) represents a significant source of morbidity and mortality worldwide, with expectations that AMR-associated consequences will continue to worsen throughout the coming decades. Since resistance to antibiotics is encoded in the microbiome, interventions aimed at altering the taxonomic composition of the gut might allow us to prophylactically engineer microbiomes that harbor fewer antibiotic resistant genes (ARGs). Diet is one method of intervention, and yet little is known about the association between diet and antimicrobial resistance. To address this knowledge gap, we examined diet using the food frequency questionnaire (FFQ; habitual diet) and 24-h dietary recalls (Automated Self-Administered 24-h [ASA24®] tool) coupled with an analysis of the microbiome using shotgun metagenome sequencing in 290 healthy adult participants of the United States Department of Agriculture (USDA) Nutritional Phenotyping Study. We found that aminoglycosides were the most abundant and prevalent mechanism of AMR in these healthy adults and that aminoglycoside-O-phosphotransferases (aph3-dprime) correlated negatively with total calories and soluble fiber intake. Individuals in the lowest quartile of ARGs (low-ARG) consumed significantly more fiber in their diets than medium- and high-ARG individuals, which was concomitant with increased abundances of obligate anaerobes, especially from the family Clostridiaceae, in their gut microbiota. Finally, we applied machine learning to examine 387 dietary, physiological, and lifestyle features for associations with antimicrobial resistance, finding that increased phylogenetic diversity of diet was associated with low-ARG individuals. These data suggest diet may be a potential method for reducing the burden of AMR. IMPORTANCE Antimicrobial resistance (AMR) represents a considerable burden to health care systems, with the public health community largely in consensus that AMR will be a major cause of death worldwide in the coming decades. Humans carry antibiotic resistance in the microbes that live in and on us, collectively known as the human microbiome. Diet is a powerful method for shaping the human gut microbiome and may be a tractable method for lessening antibiotic resistance, and yet little is known about the relationship between diet and AMR. We examined this relationship in healthy individuals who contained various abundances of antibiotic resistance genes and found that individuals who consumed diverse diets that were high in fiber and low in animal protein had fewer antibiotic resistance genes. Dietary interventions may be useful for lessening the burden of antimicrobial resistance and might ultimately motivate dietary guidelines which will consider how nutrition can reduce the impact of infectious disease.

RASopathies are a group of genetic disorders that are caused by genes that affect the canonical Ras/mitogen-activated protein kinase (MAPK) signaling pathway. Despite tremendous progress in understanding the molecular consequences of these genetic anomalies, little movement has been made in translating these findings to the clinic. This year, the seventh International RASopathies Symposium focused on expanding the research knowledge that we have gained over the years to enhance new discoveries in the field, ones that we hope can lead to effective therapeutic treatments. Indeed, for the first time, research efforts are finally being translated to the clinic, with compassionate use of Ras/MAPK pathway inhibitors for the treatment of RASopathies. This biannual meeting, organized by the RASopathies Network, brought together basic scientists, clinicians, clinician scientists, patients, advocates, and their families, as well as representatives from pharmaceutical companies and the National Institutes of Health. A history of RASopathy gene discovery, identification of new disease genes, and the latest research, both at the bench and in the clinic, were discussed.