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Rimbawan (foresters) is one of the human resources owned by the Ministry of Environment and Forestry. They need to enhance their performance in decreasing forest fire areas. It will affect future public health, economic development, ecological balance, social stability, and land aesthetics. Accordingly, scenario planning helps in contemplating how the future may develop and is especially important when needing to make sense of uncertainty in the forest sustainability management sector. Scenario planning can be narrative-based and represented quantitatively to ensure Rimbawan’s performance level. On the other hand, promoting a more controllable forest fire area has not been fully anticipated. Therefore, this study aims to help environmental policymakers by offering a discovery of basic data for forest fire precautions, forest firefighting, and post-forest fire handling. This study has conducted a descriptively quantitative method. The results suggest that the average forest fire area in South Sumatra Province based on their KPH from 2015-to 2019 is 30.71 percent of those 2,265,457.34 hectares of KPH. Whereas the 1 level of an increase in forest fire prevention activities will reduce the probability of forest fire insight into the upscaled Rimbawan’s performance level through conversation quality and engagement, learning, decision-making style, mental models, and leadership support.

Objectives: Urinary tract infection (UTI) is one of the most frequent reasons for prescribing antibiotics. Escherichia coli implicated in 75-90 % cases of UTI is becoming increasingly resistant to antibiotics. Finding alternative therapeutic agent for this infection is critical, for which herbal drugs may be an option. In Unani medicine, urinary tract infection (Ṭa'diya Majra-i-Bawl) is treated with herbal drugs possessing Da'fe Ufoonat (antiseptic), Muhallilat (anti-inflammatory) and Mudirrat (diuretic) properties. Polyherbal formulations of such drugs are expected to be beneficial in treating Escherichia coli infection. The aim of the study was to assess the efficacy and safety of a Unani polyherbal formulation aimed to develop a safe and efficacious drug for the treatment of urinary tract infection (Ṭa'diya Majra-i-Bawl) caused by Escherichia coli ., Methods: This open-label, single armed clinical study was conducted on patients with clinical signs and symptoms of UTI and positive urine culture for E. coli . Patients were treated with the polyherbal formulation consisting of 50 % hydro-alcoholic extracts of Khar Khasak (Tribulus terrestris), Bhui Amla (Phyllanthus niruri), Kabab Cheeni (Piper cubeba), Beekh -i-Kasni (Cichorium intybus), Beekh-i-Karafs (Apium graveolens), Asl-us-Soos (Glycyrrhiza glabra), and Giloy (Tinospora cordifolia) in a dose of one capsule (500 mg) thrice a day orally with plain water for 42 days., Results: Maximum (83 %) urine cultures turned out negative for E. coli after the completion of therapy., Conclusions: Polyherbal Unani formulation was found to be very effective for the treatment of Urinary tract infection. Clinical and microbiological cure was achieved in maximum number of patients and drug was very well tolerated without any adverse/side effect., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Background: Variable benefits have been reported from the adjunctive use of simvastatin and the 5HT3 receptor antagonist, ondansetron, in patients with schizophrenia. We investigated their independent efficacy and possible synergy to improve negative symptoms of schizophrenia within a single trial., Methods: A 6-month, randomised, double-blind, placebo-controlled trial with a 4-arm, 2 × 2 factorial design, in three centres in Pakistan. In total, 303 people with stable treated schizophrenia aged 18-65 were randomly allocated to add-on ondansetron, simvastatin, both or neither. The primary outcome was a Positive and Negative Syndrome Scale (PANSS) negative score at 3 and 6 months., Results: Mixed model analysis and analysis of covariance revealed no main effects of simvastatin or ondansetron but a significant negative interaction between them ( p  = 0.03); when given alone, both drugs significantly reduced negative symptoms compared to placebo but they were ineffective in combination. Individual treatment effects versus placebo were -1.9 points (95%CIs -3.23, -0.49; p  = 0.01) for simvastatin and -1.6 points for ondansetron (95%CIs -3.00, -0.14; p  = 0.03). Combined treatment significantly increased depression and side effects. In those with less than the median 5 years of treatment, ondansetron improved all PANSS subscales, global functioning measures and verbal learning and fluency, whereas simvastatin did not., Conclusion: Small improvement in negative symptoms on simvastatin and ondansetron individually are not synergistic in combination in treating negative symptoms of schizophrenia. Ondansetron showed broad efficacy in patients on stable antipsychotic treatment within 5 years of illness. The findings suggest that ondansetron should be evaluated in patients at risk of psychosis or early in treatment., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: I.B.C. and N.H. have given lectures and advice to Eli Lilly, Bristol Myers Squibb, Lundbeck, Astra Zeneca and Janssen pharmaceuticals for which they or their employing institution have been reimbursed. M.I.H. has served as an advisor to MindSet Pharma, Psyched Therapeutics and Wake Network and reports grants from the Brain and Behavior Research Foundation, Canadian Institutes of Health Research, CAMH Foundation, Physician’s Services Incorporated Foundation and University of Toronto. M.I.H., I.B.C. and N.H. were previously trustees of the Pakistan Institute of Learning and Living. B.D. has share options in P1vital.com and is a PI on MRC grant MRC grant MR/S037675/1.

The mosquito Aedes aegypti is distributed worldwide and is recognized as the primary vector for dengue in numerous countries. To investigate whether the fitness cost of a single DENV-1 isolate varies among populations, we selected four Ae. aegypti populations from distinct localities: Australia (AUS), Brazil (BRA), Pakistan (PAK), and Peru (PER). Utilizing simple methodologies, we concurrently assessed survival rates and fecundity. Overall, DENV-1 infection led to a significant decrease in mosquito survival rates, with the exception of the PER population. Furthermore, infected Ae. aegypti from PAK, the population with the lowest infection rate among those tested, exhibited a noteworthy reduction in egg laying. These findings collectively suggest that local mosquito-virus adaptations may influence dengue transmission in endemic settings.

Background and Aims: Fibrosis is the common end point for all forms of chronic liver injury, and the progression of fibrosis leads to the development of end-stage liver disease. Activation of HSCs and their transdifferentiation into myofibroblasts results in the accumulation of extracellular matrix proteins that form the fibrotic scar. Long noncoding RNAs regulate the activity of HSCs and provide targets for fibrotic therapies., Approach and Results: We identified long noncoding RNA TILAM located near COL1A1 , expressed in HSCs, and induced with liver fibrosis in humans and mice. Loss-of-function studies in human HSCs and human liver organoids revealed that TILAM regulates the expression of COL1A1 and other extracellular matrix genes. To determine the role of TILAM in vivo, we annotated the mouse ortholog ( Tilam ), generated Tilam- deficient green fluorescent protein-reporter mice, and challenged these mice in 2 different models of liver fibrosis. Single-cell data and analysis of single-data and analysis of Tilam-deficient reporter mice revealed that Tilam is induced in murine HSCs with the development of fibrosis in vivo. Tilam -deficient reporter mice revealed that Tilam is induced in murine HSCs with the development of fibrosis in vivo. Furthermore, loss of Tilam expression attenuated the development of fibrosis in the setting of in vivo liver injury. Finally, we found that TILAM interacts with promyelocytic leukemia nuclear body scaffold protein to regulate a feedback loop by which TGF-β2 reinforces TILAM expression and nuclear localization of promyelocytic leukemia nuclear body scaffold protein to promote the fibrotic activity of HSCs., Conclusions: TILAM is activated in HSCs with liver injury and interacts with promyelocytic leukemia nuclear body scaffold protein to drive the development of fibrosis. Depletion of TILAM may serve as a therapeutic approach to combat the development of end-stage liver disease., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Cancer prediction in the early stage is a topic of major interest in medicine since it allows accurate and efficient actions for successful medical treatments of cancer. Mostly cancer datasets contain various gene expression levels as features with less samples, so firstly there is a need to eliminate similar features to permit faster convergence rate of classification algorithms. These features (genes) enable us to identify cancer disease, choose the best prescription to prevent cancer and discover deviations amid different techniques. To resolve this problem, we proposed a hybrid novel technique CSSMO-based gene selection for cancer classification. First, we made alteration of the fitness of spider monkey optimization (SMO) with cuckoo search algorithm (CSA) algorithm viz., CSSMO for feature selection, which helps to combine the benefit of both metaheuristic algorithms to discover a subset of genes which helps to predict a cancer disease in early stage. Further, to enhance the accuracy of the CSSMO algorithm, we choose a cleaning process, minimum redundancy maximum relevance (mRMR) to lessen the gene expression of cancer datasets. Next, these subsets of genes are classified using deep learning (DL) to identify different groups or classes related to a particular cancer disease. Eight different benchmark microarray gene expression datasets of cancer have been utilized to analyze the performance of the proposed approach with different evaluation matrix such as recall, precision, F1-score, and confusion matrix. The proposed gene selection method with DL achieves much better classification accuracy than other existing DL and machine learning classification models with all large gene expression dataset of cancer., (© 2023. The Author(s).)

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing cause of morbidity with limited treatment options. Thus, accurate in vitro systems to test new therapies are indispensable. While recently, human liver organoid models have emerged to assess steatotic liver disease, a systematic evaluation of their translational potential is still missing. Here, we evaluated human liver organoid models of MASLD, comparatively testing disease induction in three conditions: oleic acid, palmitic acid, and TGF-β1. Through single-cell analyses, we find that all three models induce inflammatory signatures, but only TGF-β1 promotes collagen production, fibrosis, and hepatic stellate cell expansion. In striking contrast, oleic acid ameliorates fibrotic signatures and reduces the hepatic stellate cell population. Linking data from each model to gene expression signatures associated with MASLD disease progression further demonstrates that palmitic acid and TGF-β1 more robustly model inflammation and fibrosis. Our findings highlight the importance of stratifying MASLD organoid models by signatures of clinical disease progression, provide a single-cell reference to benchmark future organoid injury models, and allow us to study evolving steatohepatitis, fibrosis, and HSC susceptibility to injury in a dynamic, multi-lineage human in vitro system., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)

Vector control has been an essential strategy in Brazil to manage vector-borne diseases, and the use of insecticides plays an important role in this effort. Pyriproxyfen (PPF) has become a common insect growth regulator used to control juvenile stages of mosquitoes by disturbing their growth and development. This study assesses the susceptibility and resistance status of Brazilian Ae. aegypti populations that previously showed low resistance levels to PPF. Eggs of Ae. aegypti were collected from six cities located in the northeast states of Ceará (Quixadá, Icó, and Juazeiro do Norte), and Bahia (Itabuna, Brumado, and Serrinha). We used the Ae. aegypti Rockefeller strain as an experimental control and a strain known to be susceptible to insecticides. Inhibition of emergence rates by 50% of Ae. aegypti populations varied from 0.0098-0.046 µg/L. Mosquitoes from Icó, Serrinha, and Brumado showed low resistance levels [resistance ratio (RR 50 ) = 2.33, 4.52, and 4.83, respectively], whereas moderate levels of resistance were detected in populations from Juazeiro do Norte (RR 50 =5.83) and Itabuna (RR 50 =7.88). Aedes aegypti collected from the Quixadá population showed a high resistance level to pyriproxyfen (RR 50 =11). The evolution of resistance in Brazilian Ae. aegypti populations to PPF can compromise vector control efforts. Continuous monitoring of insecticide resistance in Ae. aegypti is essential for making timely management decisions for effective vector control and management.

Inflammatory bowel disease (IBD) is driven by host genetics and environmental factors, including commensal microorganisms. Speckled Protein 140 (SP140) is an immune-restricted chromatin "reader" that is associated with Crohn's disease (CD), multiple sclerosis (MS), and chronic lymphocytic leukemia (CLL). However, the disease-causing mechanisms of SP140 remain undefined. Here, we identify an immune-intrinsic role for SP140 in regulating phagocytic defense responses to prevent the expansion of inflammatory bacteria. Mice harboring altered microbiota due to hematopoietic Sp140 deficiency exhibited severe colitis that was transmissible upon cohousing and ameliorated with antibiotics. Loss of SP140 results in blooms of Proteobacteria, including Helicobacter in Sp140 -/- mice and Enterobacteriaceae in humans bearing the CD-associated SP140 loss-of-function variant. Phagocytes from patients with the SP140 loss-of-function variant and Sp140 -/- mice exhibited altered antimicrobial defense programs required for control of pathobionts. Thus, mutations within this epigenetic reader may constitute a predisposing event in human diseases provoked by microbiota., Competing Interests: Declaration of interests K.L.J. is a shareholder and employee of Moderna Inc., 200 Technology Square, Cambridge, MA 02138, since November 2021. K.L.J. is a member of the scientific advisory board for Ancilia Biosciences. None of these relationships influenced the work in this study., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Chronic liver injury causes fibrosis, characterized by the formation of scar tissue resulting from excessive accumulation of extracellular matrix (ECM) proteins. Hepatic stellate cell (HSC) myofibroblasts are the primary cell type responsible for liver fibrosis, yet there are currently no therapies directed at inhibiting the activity of HSC myofibroblasts. To search for potential anti-fibrotic compounds, we performed a high-throughput compound screen in primary human HSC myofibroblasts and identified 19 small molecules that induce HSC inactivation, including the polyether ionophore nanchangmycin (NCMC). NCMC induces lipid re-accumulation while reducing collagen expression, deposition of collagen in the extracellular matrix, cell proliferation, and migration. We find that NCMC increases cytosolic Ca 2+ and reduces the phosphorylated protein levels of FYN, PTK2 (FAK), MAPK1/3 (ERK2/1), HSPB1 (HSP27), and STAT5B. Further, depletion of each of these kinases suppress COL1A1 expression. These studies reveal a signaling network triggered by NCMC to inactivate HSC myofibroblasts and reduce expression of proteins that compose the fibrotic scar. Identification of the antifibrotic effects of NCMC and the elucidation of pathways by which NCMC inhibits fibrosis provide new tools and therapeutic targets that could potentially be utilized to combat the development and progression of liver fibrosis., Competing Interests: WL, JC, CS, RS, LP, RR, SM, JP, RK, DW, SH No competing interests declared, MB MB is an employee of Boehringer Ingelheim, AS AS is an employee of Boehringer Ingelheim, JD JFD is an employee of Boehringer Ingelheim, JR JFR is an employee of Boehringer Ingelheim, AM ACM receives funding from Bristol-Myers Squibb and GlaxoSmithKline for unrelated projects and is a consultant for Circ Bio and Third Rock Ventures, (© 2022, Li et al.)

Altered enteric microorganisms in concert with host genetics shape inflammatory bowel disease (IBD) phenotypes. However, insight is limited to bacteria and fungi. We found that eukaryotic viruses and bacteriophages (collectively, the virome), enriched from non-IBD, noninflamed human colon resections, actively elicited atypical anti-inflammatory innate immune programs. Conversely, ulcerative colitis or Crohn's disease colon resection viromes provoked inflammation, which was successfully dampened by non-IBD viromes. The IBD colon tissue virome was perturbed, including an increase in the enterovirus B species of eukaryotic picornaviruses, not previously detected in fecal virome studies. Mice humanized with non-IBD colon tissue viromes were protected from intestinal inflammation, whereas IBD virome mice exhibited exacerbated inflammation in a nucleic acid sensing-dependent fashion. Furthermore, there were detrimental consequences for IBD patient-derived intestinal epithelial cells bearing loss-of-function mutations within virus sensor MDA5 when exposed to viromes. Our results demonstrate that innate recognition of IBD or non-IBD human viromes autonomously influences intestinal homeostasis and disease phenotypes. Thus, perturbations in the intestinal virome, or an altered ability to sense the virome due to genetic variation, contribute to the induction of IBD. Harnessing the virome may offer therapeutic and biomarker potential.

The present study aimed to use a comprehensive approach for evaluating 12 factors related to embryo quality (shape, size and transparency), donors (age, ET type, number of recovered embryos and day of uterine flushing), recipients (age), males (age and individual variations) and environment (season and year) which could affect the outcome of ET in terms of pregnancy (PR) and pregnancy losses in dromedary camels. During three breeding seasons, 116 donor females were mated repeatedly at 12- to 14-day intervals by fertile male camels (n = 33) without stimulation of the ovaries (WSPO). Superovulation (SPO ET) regimen was applied for each donor female twice or thrice per season. In the occasions of applying superovulation regimen, donor females having an ovulatory follicle were mated instead of GnRH administration and superovulation regimen was applied 4 days post-mating (MIX ET). The uteri of all donor females were flushed at Day 8 or 9 post-mating, and a total of 2,095 embryos were recovered and transferred individually to 924 recipient females. Pregnancy diagnoses were conducted at Day 10 after ET (Days 18-19 of gestation) by using progesterone assay and by transrectal ultrasonography (TRU) at Days 30 and 60 of gestation. By using logistic regression analysis, transparency of embryos and age of recipient females had significant effects on PR at Days 18-19 (p < .01), 30 (p < .01) and 60 (p < .01; p < .05, respectively) of gestation. The shape of embryos had significant effects on the PR at Days 30 (p < .05) and 60 (p < .01) of gestation. Type of ET and the breeding season (year) had significant (p < .05) effects on the PR at Day 30, while day of flushing had the same effect on PR at Day 60. Regarding the pregnancy losses, transparency and shape of the embryo, type of ET, breeding season had significant (p < .05) effect on the late embryonic mortalities (LEM) and shape and season of year had significant (p < .01 and p < .05, respectively) effect on LEM/early foetal mortalities (EFM). Regarding male individual factor, there was a tendency for a significant (p = .055) effect of male camels on the PR at Days 18-19 and rate of LEM. In conclusion, transferring a spherical, transparent or a large-sized embryo (>750 µm) into recipient females ageing between 8 and 11 y could greatly improve the PR from Days 18 to 60 of gestation. Also, embryo recovered from donor females with Mix ET type or embryos sired by certain male camel or at Day 8 post-mating of the donor could improve the 2-month PR. In addition, transferring a transparent or spherical-shaped embryo or embryos recovered from donor females with SPO or Mix ET could reduce the pregnancy losses during the first 2 months of pregnancy., (© 2021 Wiley-VCH GmbH.)

In this review, the disease and immunogenicity affected by COVID-19 vaccination at the metabolic level are described considering the use of nuclear magnetic resonance (NMR) spectroscopy for the analysis of different biological samples. Consistently, we explain how different biomarkers can be examined in the saliva, blood plasma/serum, bronchoalveolar-lavage fluid (BALF), semen, feces, urine, cerebrospinal fluid (CSF) and breast milk. For example, the proposed approach for the given samples can allow one to detect molecular biomarkers that can be relevant to disease and/or vaccine interference in a system metabolome. The analysis of the given biomaterials by NMR often produces complex chemical data which can be elucidated by multivariate statistical tools, such as PCA and PLS-DA/OPLS-DA methods. Moreover, this approach may aid to improve strategies that can be helpful in disease control and treatment management in the future., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Insecticide resistant Aedes populations have recently been reported in Pakistan, imposing a threat to their control. We aimed to evaluate the susceptibility of Aedes aegypti and Aedes albopictus populations from Lahore to WHO-recommended insecticides and to investigate metabolic and target-site resistance mechanisms. For this purpose, we first carried out bioassays with the larvicides temephos and pyriproxyfen, and the adulticides malathion, permethrin, deltamethrin, alpha-cypermethrin, and etofenprox. We looked for Knockdown resistance mutations (kdr) by qPCR, High-Resolution Melt (HRM), and sequencing. In order to explore the role of detoxifying enzymes in resistance, we carried out synergist bioassay with both species and then checked the expression of CYP9M6, CYP9J10, CYP9J28, CYP6BB2, CCAe3a, and SAP2 genes in Ae. aegypti. Both species were susceptible to organophosphates and the insect growth regulator, however resistant to all pyrethroids. We are reporting the kdr haplotypes 1520Ile + 1534Cys and T1520 + 1534Cys in high frequencies in Ae. aegypti while Ae. albopictus only exhibited the alteration L882M. PBO increased the sensitivity to permethrin in Ae. aegypti, suggesting the participation of P450 genes in conferring resistance, and indeed, CYP928 was highly expressed. We presume that dengue vectors in Lahore city are resistant to pyrethroids, probably due to multiple mechanisms, such as kdr mutations and P450 overexpression.

Vector control largely relies on neurotoxic chemicals, and insecticide resistance (IR) directly threatens their effectiveness. In some cases, specific alleles cause IR, and knowledge of the genetic diversity and gene flow among mosquito populations is crucial to track their arrival, rise, and spread. Here we evaluated Aedes aegypti populations' susceptibility status, collected in 2016 from six different municipalities of Rio de Janeiro state (RJ), to temephos, pyriproxyfen, malathion, and deltamethrin. We collected eggs of Ae. aegypti in Campos dos Goytacazes (Cgy), Itaperuna (Ipn), Iguaba Grande (Igg), Itaboraí (Ibr), Mangaratiba (Mgr), and Vassouras (Vsr). We followed the World Health Organization (WHO) guidelines and investigated the degree of susceptibility/resistance of mosquitoes to these insecticides. We used the Rockefeller strain as a susceptible positive control. We genotyped the V1016I and F1534C knockdown resistance (kdr) alleles using qPCR TaqMan SNP genotyping assay. Besides, with the use of Ae. aegypti SNP-chip, we performed genomic population analyses by genotyping more than 15,000 biallelic SNPs in mosquitoes from each population. We added previous data from populations from other countries to evaluate the ancestry of RJ populations. All RJ Ae. aegypti populations were susceptible to pyriproxyfen and malathion and highly resistant to deltamethrin. The resistance ratios for temephos was below 3,0 in Cgy, Ibr, and Igg populations, representing the lowest rates since IR monitoring started in this Brazilian region. We found the kdr alleles in high frequencies in all populations, partially justifying the observed resistance to pyrethroid. Population genetics analysis showed that Ae. aegypti revealed potential higher migration among some RJ localities and low genetic structure for most of them. Future population genetic studies, together with IR data in Ae aegypti on a broader scale, can help us predict the gene flow within and among the Brazilian States, allowing us to track the dynamics of arrival and changes in the frequency of IR alleles, and providing critical information to improving vector control program., Competing Interests: The authors have declared that no competing interests exist.

We present the Small RNA Expression Atlas (SEAweb), a web application that allows for the interactive querying, visualization and analysis of known and novel small RNAs across 10 organisms. It contains sRNA and pathogen expression information for over 4200 published samples with standardized search terms and ontologies. In addition, SEAweb allows for the interactive visualization and re-analysis of 879 differential expression and 514 classification comparisons. SEAweb's user model enables sRNA researchers to compare and re-analyze user-specific and published datasets, highlighting common and distinct sRNA expression patterns. We provide evidence for SEAweb's fidelity by (i) generating a set of 591 tissue specific miRNAs across 29 tissues, (ii) finding known and novel bacterial and viral infections across diseases and (iii) determining a Parkinson's disease-specific blood biomarker signature using novel data. We believe that SEAweb's simple semantic search interface, the flexible interactive reports and the user model with rich analysis capabilities will enable researchers to better understand the potential function and diagnostic value of sRNAs or pathogens across tissues, diseases and organisms., (© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.)

A deep understanding of how regulation of the multiple levels of gene expression in mammalian tissues give rise to complex phenotypes has been impeded by cellular diversity. A handful of techniques were developed to tag-select nucleic acids of interest in specific cell types, thereby enabling their capture. We expanded this strategy by developing the Tagger knock-in mouse line bearing a quad-cistronic transgene combining enrichment tools for nuclei, nascent RNA, translating mRNA, and mature microRNA (miRNA). We demonstrate that Tagger can capture the desired nucleic acids, enabling multiple omics approaches to be applied to specific cell types in vivo using a single transgenic mouse line., Competing Interests: The authors have declared that no competing interests exist.

Background: Nephron number is a major determinant of long-term renal function and cardiovascular risk. Observational studies suggest that maternal nutritional and metabolic factors during gestation contribute to the high variability of nephron endowment. However, the underlying molecular mechanisms have been unclear., Methods: We used mouse models, including DNA methyltransferase ( Dnmt1, Dnmt3a, and Dnmt3b ) knockout mice, optical projection tomography, three-dimensional reconstructions of the nephrogenic niche, and transcriptome and DNA methylation analysis to characterize the role of DNA methylation for kidney development., Results: We demonstrate that DNA hypomethylation is a key feature of nutritional kidney growth restriction in vitro and in vivo, and that DNA methyltransferases Dnmt1 and Dnmt3a are highly enriched in the nephrogenic zone of the developing kidneys. Deletion of Dnmt1 in nephron progenitor cells (in contrast to deletion of Dnmt3a or Dnm3b ) mimics nutritional models of kidney growth restriction and results in a substantial reduction of nephron number as well as renal hypoplasia at birth. In Dnmt1 -deficient mice, optical projection tomography and three-dimensional reconstructions uncovered a significant reduction of stem cell niches and progenitor cells. RNA sequencing analysis revealed that global DNA hypomethylation interferes in the progenitor cell regulatory network, leading to downregulation of genes crucial for initiation of nephrogenesis, Wt1 and its target Wnt4. Derepression of germline genes, protocadherins, Rhox genes, and endogenous retroviral elements resulted in the upregulation of IFN targets and inhibitors of cell cycle progression., Conclusions: These findings establish DNA methylation as a key regulatory event of prenatal renal programming, which possibly represents a fundamental link between maternal nutritional factors during gestation and reduced nephron number., (Copyright © 2019 by the American Society of Nephrology.)

The homeostasis of the proteome depends on the tight regulation of the mRNA and protein abundances, of the translation rates, and of the protein lifetimes. Results from several studies on prokaryotes or eukaryotic cell cultures have suggested that protein homeostasis is connected to, and perhaps regulated by, the protein and the codon sequences. However, this has been little investigated for mammals in vivo. Moreover, the link between the coding sequences and one critical parameter, the protein lifetime, has remained largely unexplored, both in vivo and in vitro. We tested this in the mouse brain, and found that the percentages of amino acids and codons in the sequences could predict all of the homeostasis parameters with a precision approaching experimental measurements. A key predictive element was the wobble nucleotide. G-/C-ending codons correlated with higher protein lifetimes, protein abundances, mRNA abundances and translation rates than A-/U-ending codons. Modifying the proportions of G-/C-ending codons could tune these parameters in cell cultures, in a proof-of-principle experiment. We suggest that the coding sequences are strongly linked to protein homeostasis in vivo, albeit it still remains to be determined whether this relation is causal in nature.

The turnover of brain proteins is critical for organism survival, and its perturbations are linked to pathology. Nevertheless, protein lifetimes have been difficult to obtain in vivo. They are readily measured in vitro by feeding cells with isotopically labeled amino acids, followed by mass spectrometry analyses. In vivo proteins are generated from at least two sources: labeled amino acids from the diet, and non-labeled amino acids from the degradation of pre-existing proteins. This renders measurements difficult. Here we solved this problem rigorously with a workflow that combines mouse in vivo isotopic labeling, mass spectrometry, and mathematical modeling. We also established several independent approaches to test and validate the results. This enabled us to measure the accurate lifetimes of ~3500 brain proteins. The high precision of our data provided a large set of biologically significant observations, including pathway-, organelle-, organ-, or cell-specific effects, along with a comprehensive catalog of extremely long-lived proteins (ELLPs).

In patients with Charcot-Marie-Tooth disease 1A (CMT1A), peripheral nerves display aberrant myelination during postnatal development, followed by slowly progressive demyelination and axonal loss during adult life. Here, we show that myelinating Schwann cells in a rat model of CMT1A exhibit a developmental defect that includes reduced transcription of genes required for myelin lipid biosynthesis. Consequently, lipid incorporation into myelin is reduced, leading to an overall distorted stoichiometry of myelin proteins and lipids with ultrastructural changes of the myelin sheath. Substitution of phosphatidylcholine and phosphatidylethanolamine in the diet is sufficient to overcome the myelination deficit of affected Schwann cells in vivo. This treatment rescues the number of myelinated axons in the peripheral nerves of the CMT rats and leads to a marked amelioration of neuropathic symptoms. We propose that lipid supplementation is an easily translatable potential therapeutic approach in CMT1A and possibly other dysmyelinating neuropathies.

Background: Small RNA molecules play important roles in many biological processes and their dysregulation or dysfunction can cause disease. The current method of choice for genome-wide sRNA expression profiling is deep sequencing., Results: Here we present Oasis 2, which is a new main release of the Oasis web application for the detection, differential expression, and classification of small RNAs in deep sequencing data. Compared to its predecessor Oasis, Oasis 2 features a novel and speed-optimized sRNA detection module that supports the identification of small RNAs in any organism with higher accuracy. Next to the improved detection of small RNAs in a target organism, the software now also recognizes potential cross-species miRNAs and viral and bacterial sRNAs in infected samples. In addition, novel miRNAs can now be queried and visualized interactively, providing essential information for over 700 high-quality miRNA predictions across 14 organisms. Robust biomarker signatures can now be obtained using the novel enhanced classification module., Conclusions: Oasis 2 enables biologists and medical researchers to rapidly analyze and query small RNA deep sequencing data with improved precision, recall, and speed, in an interactive and user-friendly environment., Availability and Implementation: Oasis 2 is implemented in Java, J2EE, mysql, Python, R, PHP and JavaScript. It is freely available at https://oasis.dzne.de.

Mutually exclusive splicing of exons is a mechanism of functional gene and protein diversification with pivotal roles in organismal development and diseases such as Timothy syndrome, cardiomyopathy and cancer in humans. In order to obtain a first genomewide estimate of the extent and biological role of mutually exclusive splicing in humans, we predicted and subsequently validated mutually exclusive exons (MXEs) using 515 publically available RNA-Seq datasets. Here, we provide evidence for the expression of over 855 MXEs, 42% of which represent novel exons, increasing the annotated human mutually exclusive exome more than fivefold. The data provide strong evidence for the existence of large and multi-cluster MXEs in higher vertebrates and offer new insights into MXE evolution. More than 82% of the MXE clusters are conserved in mammals, and five clusters have homologous clusters in Drosophila Finally, MXEs are significantly enriched in pathogenic mutations and their spatio-temporal expression might predict human disease pathology., (© 2017 The Authors. Published under the terms of the CC BY 4.0 license.)

Aim: To understand the experience of maternal depression, the factors implicated in accessing health, and the acceptability of the psychosocial intervention., Methods: The participants were recruited from the paediatrics outpatient department of Civil Hospital Karachi, Pakistan. The study started in December 2009 and completed in December 2010. Women with maternal depression, aged 18-44 years with children aged 0-30 mo who had received nutritional supplements, and participated in the intervention programme [called Learning through Play (LTP) plus] were included in the study. Qualitative interviews were conducted with 8 participants before the intervention and 7 participants after the intervention. A semi structured topic guide was used to conduct the interviews., Results: Framework analysis procedures were used to analyse the qualitative data. Four themes emerged: (1) the women's contextual environment: Interpersonal conflicts, lack of social support and financial issues being the major barriers in assessing healthcare; (2) women's isolation and powerlessness within the environment: Sense of loneliness was identified as a restricting factor to access healthcare; (3) the impact of the intervention (LTP-Plus): Women felt "listened to" and seemed empowered; and (4) empowered transformed women within the same contextual environment: The facilitator provided a "gardening role" in nurturing the women resulting in a positive transformation within the same environment. The women's homes seemed to be more happy homes and there was a positive change in their behaviour towards their children., Conclusion: Findings informed the further development and testing of culturally-appropriate psychosocial intervention (LTP + ) for addressing maternal depression., Competing Interests: Conflict-of-interest statement: None.

Recent evidence suggests that the formation and maintenance of memory requires epigenetic changes. In an effort to understand the spatio-temporal extent of learning and memory-related epigenetic changes we have charted genome-wide histone and DNA methylation profiles, in two different brain regions, two cell types, and three time-points, before and after learning. In this data descriptor we provide detailed information on data generation, give insights into the rationale of experiments, highlight necessary steps to assess data quality, offer guidelines for future use of the data and supply ready-to-use code to replicate the analysis results. The data provides a blueprint of the gene regulatory network underlying short- and long-term memory formation and maintenance. This 'healthy' gene regulatory network of learning can now be compared to changes in neurological or psychiatric diseases, providing mechanistic insights into brain disorders and highlighting potential therapeutic avenues., Competing Interests: The authors declare no competing financial interests.

The Medaka Expression Pattern Database (MEPD; http://mepd.cos.uni-heidelberg.de/) is designed as a repository of medaka expression data for the scientific community. In this update we present two main improvements. First, we have changed the previous clone-centric view for in situ data to a gene-centric view. This is possible because now we have linked all the data present in MEPD to the medaka gene annotation in ENSEMBL. In addition, we have also connected the medaka genes in MEPD to their corresponding orthologous gene in zebrafish, again using the ENSEMBL database. Based on this, we provide a link to the Zebrafish Model Organism Database (ZFIN) to allow researches to compare expression data between these two fish model organisms. As a second major improvement, we have modified the design of the database to enable it to host regulatory elements, promoters or enhancers, expression patterns in addition to gene expression. The combination of gene expression, by traditional in situ, and regulatory element expression, typically by fluorescence reporter gene, within the same platform assures consistency in terms of annotation. In our opinion, this will allow researchers to uncover new insights between the expression domain of genes and their regulatory landscape., (© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The ability to form memories is a prerequisite for an organism's behavioral adaptation to environmental changes. At the molecular level, the acquisition and maintenance of memory requires changes in chromatin modifications. In an effort to unravel the epigenetic network underlying both short- and long-term memory, we examined chromatin modification changes in two distinct mouse brain regions, two cell types and three time points before and after contextual learning. We found that histone modifications predominantly changed during memory acquisition and correlated surprisingly little with changes in gene expression. Although long-lasting changes were almost exclusive to neurons, learning-related histone modification and DNA methylation changes also occurred in non-neuronal cell types, suggesting a functional role for non-neuronal cells in epigenetic learning. Finally, our data provide evidence for a molecular framework of memory acquisition and maintenance, wherein DNA methylation could alter the expression and splicing of genes involved in functional plasticity and synaptic wiring.

Unlabelled: Oasis is a web application that allows for the fast and flexible online analysis of small-RNA-seq (sRNA-seq) data. It was designed for the end user in the lab, providing an easy-to-use web frontend including video tutorials, demo data and best practice step-by-step guidelines on how to analyze sRNA-seq data. Oasis' exclusive selling points are a differential expression module that allows for the multivariate analysis of samples, a classification module for robust biomarker detection and an advanced programming interface that supports the batch submission of jobs. Both modules include the analysis of novel miRNAs, miRNA targets and functional analyses including GO and pathway enrichment. Oasis generates downloadable interactive web reports for easy visualization, exploration and analysis of data on a local system. Finally, Oasis' modular workflow enables for the rapid (re-) analysis of data., Availability and Implementation: Oasis is implemented in Python, R, Java, PHP, C++ and JavaScript. It is freely available at http://oasis.dzne.de., Contact: stefan.bonn@dzne.de, Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author 2015. Published by Oxford University Press.)

Background: Self-harm is a major risk factor for completed suicide., Aims: To determine the efficacy of a brief psychological intervention - culturally adapted manual-assisted problem-solving training (C-MAP) - delivered following an episode of self-harm compared with treatment as usual (TAU)., Method: The study was a randomised controlled assessor-masked clinical trial (trial registration: ClinicalTrials.gov NCT01308151). All patients admitted after an episode of self-harm during the previous 7 days to the participating medical units of three university hospitals in Karachi, Pakistan, were included in the study. A total of 250 patients were screened and 221 were randomly allocated to C-MAP plus treatment as usual (TAU) or to TAU alone. All patients were assessed at baseline, at 3 months (end of intervention) and at 6 months after baseline. The primary outcome measure was reduction in suicidal ideation at 3 months. The secondary outcome measures included hopelessness, depression, coping resources and healthcare utilisation., Results: A total of 108 patients were randomised to the C-MAP group and 113 to the TAU group. Patients in the C-MAP group showed statistically significant improvement on the Beck Scale for Suicide Ideation and Beck Hopelessness Inventory, which was sustained at 3 months after the completion of C-MAP. There was also a significant reduction in symptoms of depression compared with patients receiving TAU., Conclusions: The positive outcomes of this brief psychological intervention in patients attempting self-harm are promising and suggest that C-MAP may have a role in suicide prevention., (Royal College of Psychiatrists.)

The hepatoprotective activity of flavonoid rhamnocitrin 4'-β-D-galactopyranoside (RGP) obtained from leaves of Astragalus hamosus L. against N-diethylnitrosamine (DENA)-induced hepatic cancer in Wistar albino rats was evaluated. Hepatic cancer in rats was induced by single-dose intraperitoneal administration of DENA (200 mg/kg). Induction of hepatic cancer was confirmed after 7 days of DENA administration by measurement of elevated level of serum α-feto protein (AFP). Administration of DENA in a single dose lofted the levels of serum biochemical parameters like alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, total protein and AFP. Antioxidant enzymes like superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and lipid per oxidation (LPO) were annealed significantly by administration of RGP in a dose-dependant manner. The histopathological examination of rat liver section was found to reinforce the biochemical observations significantly. It was observed that a substantial and dose-dependent reversal of DENA-diminished activity of antioxidant enzymes like SOD, CAT, GPx, GST and the reduced DENA-elevated level of LPO with a marked change. Any elevation in the levels of serum markers along with suppression of free radical formation by scavenging the hydroxyl radicals is significantly prevented by RGP. It also modulates the levels of LPO and perceptibly increases the endogenous antioxidant enzymes level in DENA-induced hepatocellular carcinogenesis. The findings suggest that RGP prevents hepatocellular carcinoma by suppressing the marked increase in the levels of serum marker enzymes, and suppresses the free radical by scavenging hydroxyl radicals.

Background: Negative symptoms and cognitive deficits are two partially-related features of schizophrenia which have a major negative impact on social function and objective quality of life. Standard drug treatments have little impact on either. There is some evidence that anti-inflammatory treatment may have beneficial effects in schizophrenia and major depression. Statins are cholesterol-lowering agents that have been found to be anti-inflammatory agents and are also known to decrease C-reactive protein (CRP). Ondansetron is a serotonin (5-HT3) receptor antagonist widely used to prevent nausea and vomiting in patients receiving chemotherapy for cancer. Small studies have suggested that ondansetron is effective as an adjunct drug in improving the symptoms of schizophrenia., Methods/design: This is a two center, six-month, double-blind placebo controlled, factorial design study of ondansetron and/or simvastatin added to treatment as usual for patients suffering from schizophrenia, schizoaffective disorder, psychosis not otherwise specified or schizophreniform disorder. This will be a 2 × 2 design, with 54 patients in each cell, giving a total of 216 patients over three years. There will be a screening, a randomization and seven follow-up visits. Full clinical and neurocognitive assessments will be carried out at baseline (randomization), 14 weeks and at 26 weeks, while the positive and negative syndrome scale (PANSS), pill count and side effects checklist will be carried out at every visit. Simvastatin will be started at 20 mg once daily (OD), this will be increased to 40 mg after four weeks. Ondansetron will be administered in an 8 mg dose., Discussion: Anti-inflammatory treatments have been shown to have some beneficial effects in schizophrenia. Both simvastatin and ondansetron provide some evidence of a reduction in symptoms compared to treatment as usual. The aim of this study is to establish the degree of improvement in negative symptoms with the addition of ondansetron and/or simvastatin to treatment as usual., Trial Registration: [corrected] ClinicalTrials.gov NCT01602029.