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Abstract Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is a heterogeneous group of malignancies with poor outcome. Here, we identify a subgroup, PTCL-NOS SMARCB1- , which is characterized by the lack of the SMARCB1 protein and occurs more frequently in young patients. Human and murine PTCL-NOS SMARCB1- show similar DNA methylation profiles, with hypermethylation of T-cell-related genes and hypomethylation of genes involved in myeloid development. Single-cell analyses of human and murine tumors revealed a rich and complex network of interactions between tumor cells and an immunosuppressive and exhausted tumor microenvironment (TME). In a drug screen, we identified histone deacetylase inhibitors (HDACi) as a class of drugs effective against PTCL-NOS Smarcb1- . In vivo treatment of mouse tumors with SAHA, a pan-HDACi, triggered remodeling of the TME, promoting replenishment of lymphoid compartments and reversal of the exhaustion phenotype. These results provide a rationale for further exploration of HDACi combination therapies targeting PTCL-NOS SMARCB1- within the TME.

Abstract The government of Serdang Bedagai Regency initiated a supplementation program to reduce the high prevalence of stunting in the area by delivering extra supplementation, which were nutritious biscuits from national government and fish-based supplement produced from local resources. A 6-month study from April 2022 to September 2022 was conducted to monitor and evaluate the government program that involved 219 under-5-year-old children with height-for-age Z-score (HAZ-score) below − 2. We observed the stunting prevalence reduction by 37.00%, where 81 children recovered from stunting (HAZ-score ≥ − 2). Furthermore, the mean HAZ-score and WHZ-score (Weight-for-Height Z-score) were monitored to significantly improve by 0.97 ± 1.45 (P-value = 1.74e−14) and 1.00 ± 2.18 (P-value = and 2.40e−8), subsequently. The most significant improvement in HAZ-score was monitored among children receiving fish-based supplements with 1.04 ± 1.44 improvement (P-value = 6.59e−17). Then, a significant WHZ-score improvement was reported from children consuming fish-based supplements and a combination of fish-based supplements with nutritious biscuits (P-value = 2.32e−8 and 5.48e−5) by 1.04 ± 2.29 and 0.83 ± 1.84, respectively. The results of the observation become evidence that the program could effectively reduce the prevalence of stunting in children below five years old, especially among children who received locally produced fish-based supplements.

Pleuronectiformes are flatfishes with high commercial value and a prominent example of successful marine adaptation through chromosomal evolution. Hence, the aim of this study was to analyze the 14 relative abundance of repetitive elements (satellite DNA and transposable elements (TE)) in the 15 genome of 10 fish species (8 flatfish) delving into the study of the species of special relevance, 16 Senegalese sole, Solea senegalensis. The results showed differences in the abundance of repetitive elements, with S. senegalensis exhibiting the highest frequency and coverage of these elements reaching the 40% of the genome and not at random distribution. It is noteworthy the presence of relevant peaks of Helitrons in centromeric/pericentromeric positions mainly in the bi-armed chromosomes 1, 2, 4, 6, 7, and 9. The position of the centromeres of this species determined through the genomic localization of the family of satellite DNA PvuII, and other repetitive sequences was obtained de novo. This allowed us to know the genomic position of the centromeres in 19 out of the 21 chromosomes of S. senegalensis. Helitrons showed an accumulation of tandem copies mainly in the pericentromeric positions of chromosomes 1 and 2, occupying a region, in the first case, of 600Kb of tandem repeats. That has only been previously described in mammals and plants. Divergence and copy number studies indicated the presence of active families in the species’ genome and the existence of two important events of transposon activity (burst) in the genome of S. senegalensis, mainly accentuated in Helitrons. The results showed that only the families of DNA transposons exhibited a landscape with symmetrical bell-shaped distribution. The phylogenetic analysis of Helitron families revealed the presence of two large groups of families and the presence of four groups of sequences with heterogeneous distribution among chromosomes. Finally, the phylogenomic analysis of 8615 sequences belonging to Helitron insertions from 5 families of flatfish and two external species, allowed to classify the copies into nine groups of sequences with different levels of divergence and clusters, including some branches with distant phylogenetically species. The implications of this study will help to expand the knowledge of chromosome structure and evolution of these species.

Summary: Glucocorticoid (GC) signaling is essential for mounting a stress response, however, chronic stress or prolonged GC therapy downregulates the GC receptor (GR), leading to GC resistance. Regulatory mechanisms that refine this equilibrium are not well understood. Here, we identify seven lysine acetylation sites in the amino terminal domain of GR, with lysine 154 (Lys154) in the AF-1 region being the dominant acetyl-acceptor. GR-Lys154 acetylation is mediated by p300/CBP in the nucleus in an agonist-dependent manner and correlates with transcriptional activity. Deacetylation by NAD+-dependent SIRT1 facilitates dynamic regulation of this mark. Notably, agonist-binding to both wild-type GR and an acetylation-deficient mutant elicits similar short-term target gene expression. In contrast, upon extended treatment, the polyubiquitination of the acetylation-deficient GR mutant is impaired resulting in higher protein stability, increased chromatin association and prolonged transactivation. Taken together, reversible acetylation fine-tunes duration of the GC response by regulating proteasomal degradation of activated GR.

Abstract Brain injury and cerebral vasospasm during the 14 days after the subarachnoid hemorrhage (SAH) are considered the leading causes of poor outcomes. The primary injury induces a cascade of events, including increased intracranial pressure, cerebral vasospasm and ischemia, glutamate excitotoxicity, and neuronal cell death. The objective of this study was to monitor the time course of glutamate, and associated enzymes, such as glutamate–oxaloacetate transaminase (GOT1), glutamate-pyruvate transaminase (GPT) in cerebrospinal fluid (CSF) and serum, shortly after SAH, and to assess their prognostic value. A total of 74 participants participated in this study: 45 participants with SAH and 29 controls. Serum and CSF were sampled up to 14 days after SAH. SAH participants' clinical and neurological status were assessed at hospitalization, at discharge from the hospital, and 3 months after SAH. Furthermore, a logistic regression analysis was carried out to evaluate the ability of GOT1 and glutamate levels to predict neurological outcomes. Our results demonstrated consistently elevated serum and CSF glutamate levels after SAH. Furthermore, serum glutamate level was significantly higher in patients with cerebral ischemia and poor neurological outcome. CSF GOT1 was significantly higher in patients with uncontrolled intracranial hypertension and cerebral ischemia post-SAH, and independently predicted poor neurological outcomes.

Abstract As the fourth most populous country in the world, Indonesia must increase the annual rice production rate to achieve national food security by 2050. One possible solution comes from the nanoscopic level: a genetic variant called Single Nucleotide Polymorphism (SNP), which can express significant yield-associated genes. The prior benchmark of this study utilized a statistical genetics model where no SNP position information and attention mechanism were involved. Hence, we developed a novel deep polygenic neural network, named the NucleoNet model, to address these obstacles. The NucleoNets were constructed with the combination of prominent components that include positional SNP encoding, the context vector, wide models, Elastic Net, and Shannon’s entropy loss. This polygenic modeling obtained up to 2.779 of Mean Squared Error (MSE) with 47.156% of Symmetric Mean Absolute Percentage Error (SMAPE), while revealing 15 new important SNPs. Furthermore, the NucleoNets reduced the MSE score up to 32.28% compared to the Ordinary Least Squares (OLS) model. Through the ablation study, we learned that the combination of Xavier distribution for weights initialization and Normal distribution for biases initialization sparked more various important SNPs throughout 12 chromosomes. Our findings confirmed that the NucleoNet model was successfully outperformed the OLS model and identified important SNPs to Indonesian rice yields.

Summary: Cell surface receptor internalization can either terminate signaling or activate alternative endosomal signaling pathways. We investigated here whether endosomal signaling is involved in the function of the human receptors for Fc immunoglobulin fragments (FcRs): FcαRI, FcγRIIA, and FcγRI. All these receptors were internalized after their cross-linking with receptor-specific antibodies, but their intracellular trafficking was different. FcαRI was targeted directly to lysosomes, while FcγRIIA and FcγRI were internalized in particular endosomal compartments described by the insulin responsive aminopeptidase (IRAP), where they recruited signaling molecules, such as the active form of the kinase Syk, PLCγ and the adaptor LAT. Destabilization of FcγR endosomal signaling in the absence of IRAP compromised cytokine secretion downstream FcγR activation and macrophage ability to kill tumor cells by antibody-dependent cell-mediated cytotoxicity (ADCC). Our results indicate that FcγR endosomal signaling is required for the FcγR-driven inflammatory reaction and possibly for the therapeutic action of monoclonal antibodies.

Abstract Colorectal cancer is a common cancer in Indonesia, yet it has been understudied in this resource-constrained setting. We conducted a genome-wide association study focused on evaluation and preliminary discovery of colorectal cancer risk factors in Indonesians. We administered detailed questionnaires and collecting blood samples from 162 colorectal cancer cases throughout Makassar, Indonesia. We also established a control set of 193 healthy individuals frequency matched by age, sex, and ethnicity. A genome-wide association analysis was performed on 84 cases and 89 controls passing quality control. We evaluated known colorectal cancer genetic variants using logistic regression and established a genome-wide polygenic risk model using a Bayesian variable selection technique. We replicate associations for rs9497673, rs6936461 and rs7758229 on chromosome 6; rs11255841 on chromosome 10; and rs4779584, rs11632715, and rs73376930 on chromosome 15. Polygenic modeling identified 10 SNP associated with colorectal cancer risk. This work helps characterize the relationship between variants in the SCL22A3, SCG5, GREM1, and STXBP5-AS1 genes and colorectal cancer in a diverse Indonesian population. With further biobanking and international research collaborations, variants specific to colorectal cancer risk in Indonesians will be identified.

T cell receptors (TCR) are internalized when activated by their ligands. Here the authors show that the internalized TCRs are localized to endosomes expressing IRAP and Syntaxin 6 to maintain intracellular signalling capacity, whose importance is shown by the absence of efficient polyclonal anti-tumour response in mice with T-specific conditional deletion of IRAP.

Sexual activity and/or reproduction are associated with a doubling of life expectancy in the long-lived rodent genus Fukomys. To investigate the molecular mechanisms underlying this phenomenon, we analyzed 636 RNA-seq samples across 15 tissues. This analysis suggests that changes in the regulation of the hypothalamic–pituitary–adrenal stress axis play a key role regarding the extended life expectancy of reproductive vs. non-reproductive mole-rats. This is substantiated by a corpus of independent evidence. In accordance with previous studies, the up-regulation of the proteasome and so-called ‘anti-aging molecules’, for example, dehydroepiandrosterone, is linked with enhanced lifespan. On the other hand, several of our results are not consistent with knowledge about aging of short-lived model organisms. For example, we found the up-regulation of the insulin-like growth factor 1/growth hormone axis and several other anabolic processes to be compatible with a considerable lifespan prolongation. These contradictions question the extent to which findings from short-lived species can be transferred to longer-lived ones.

Knowing the factors responsible for sex determination in a species has significant theoretical and practical implications; the dmrt1 gene (Doublesex and Mab-3 (DM)-related Transcription factor 1) plays this role in diverse animal species. Solea senegalensis is a commercially important flat fish in which females grow 30% faster than males. It has 2n = 42 chromosomes and an XX / XY chromosome system for sex determination, without heteromorph chromosomes but with sex proto-chromosome. In the present study, we are providing the genomic structure and nucleotide sequence of dmrt1 gene obtained from cDNA from male and female adult gonads. A cDNA of 2027 containing an open-reading frame (ORF) of 1206 bp and encoding a 402 aa protein it is described for dmrt1 gene of S. senegalensis. Multiple mRNA isoforms indicating a high variable system of alternative splicing in the expression of dmrt1 of the sole in gonads were studied. None isoforms could be related to sex of individuals. The genomic structure of the dmrt1 of S. senegalensis showed a gene of 31400 bp composed of 7 exons and 6 introns. It contains an unexpected duplication of more than 10399 bp, involving part of the exon I, exons II and III and a SINE element found in the sequence that it is proposed as responsible for the duplication. A mature miRNA of 21 bp in length was localized at 336 bp from exon V. Protein-protein interacting networks of the dmrt1 gene showed matches with dmrt1 protein from Cynoglossus semilaevis and a protein interaction network with 11 nodes (dmrt1 plus 10 other proteins). The phylogenetic relationship of the dmrt1 gene in S. senegalensis is consistent with the evolutionary position of its species. The molecular characterization of this gene will enhance its functional analysis and the understanding of sex differentiation in Solea senegalensis and other flatfish.

Triportheus (Characiformes, Triportheidae) is a freshwater fish genus with 18 valid species. These fishes are widely distributed in the major river drainages of South America, having commercial importance in the fishing market, mainly in the Amazon basin. This genus has diverged recently in a complex process of speciation carried out in different river basins. The use of repetitive sequences is suitable to trace the genomic reorganizations occured along the speciation process. In this work, the 5S rDNA multigene family has been characterized at molecular and phylogenetic level. The results showed that other multigene family has been found within the non-transcribed spacer (NTS): the U1 snRNA gene. Double-FISH with 5S and U1 probes were also performed, confirming the close linkage between these two multigene families. Moreover, evidences of different transposable elements (TE) were detected within the spacer, thus suggesting a transposon-mediated mechanism of 5S-U1 evolutionary pathway in this genus. Phylogenetic analysis demonstrated a species-specific grouping, except for Triportheus pantanensis, Triportheus aff. rotundatus and Triportheus trifurcatus. The evolutionary model of the 5S rDNA in Triportheus species has been discussed. In addition, the results suggest new clues for the speciation and evolutionary trend in these species, which could be suitable to use in other Characiformes species.

One of company’s occupational health programs is disease management which is a part of preventive health care. In its realization, it was discovered that there some challenges in data collection, monitoring of catering and sport activity, employee health reports, and medical costs. The purpose of this study is to design an IT solution for the disease management program at PT. Panasonic Manufacturing Indonesia (PMI). The diseases in focus are diabetes, hypertension, and tuberculosis. Methodology starts with survey on PT. PMI requirements, research parameters, problem analysis, literature study, and system design. Solution is focused on designing a registry system that includes Alert Management System, Food Tracking, EHR, Sport Tracking, Guidelines, and Report System. The results of this study is a web-based information system that can assist health care workers in seeking data, monitoring food intake and sport activity, and reporting systems for upper-level management.

Treatment with recombinant human growth hormone (rhGH) has been consistently reported to induce transcriptional changes in various human tissues including peripheral blood. For other hormones it has been shown that the induction of such transcriptional effects is conferred or at least accompanied by DNA-methylation changes. To analyse effects of short term rhGH treatment on the DNA-methylome we investigated a total of 24 patients at baseline and after 4-day rhGH stimulation. We performed array-based DNA-methylation profiling of paired peripheral blood mononuclear cell samples followed by targeted validation using bisulfite pyrosequencing. Unsupervised analysis of DNA-methylation in this short-term treated cohort revealed clustering according to individuals rather than treatment. Supervised analysis identified 239 CpGs as significantly differentially methylated between baseline and rhGH-stimulated samples (p

Ansell's mole-rats (Fukomys anselli) are subterranean, long-lived rodents, which live in eusocial families, where the maximum lifespan of breeders is twice as long as that of non-breeders. Their metabolic rate is significantly lower than expected based on allometry, and their retinae show a high density of S-cone opsins. Both features may indicate naturally low thyroid hormone levels. In the present study, we sequenced several major components of the thyroid hormone pathways and analyzed free and total thyroxine and triiodothyronine in serum samples of breeding and non-breeding F. anselli to examine whether a) their thyroid hormone system shows any peculiarities on the genetic level, b) these animals have lower hormone levels compared to euthyroid rodents (rats and guinea pigs), and c) reproductive status, lifespan and free hormone levels are correlated. Genetic analyses confirmed that Ansell's mole-rats have a conserved thyroid hormone system as known from other mammalian species. Interspecific comparisons revealed that free thyroxine levels of F. anselli were about ten times lower than of guinea pigs and rats, whereas the free triiodothyronine levels, the main biologically active form, did not differ significantly amongst species. The resulting fT4:fT3 ratio is unusual for a mammal and potentially represents a case of natural hypothyroxinemia. Comparisons with total thyroxine levels suggest that mole-rats seem to possess two distinct mechanisms that work hand in hand to downregulate fT4 levels reliably. We could not find any correlation between free hormone levels and reproductive status, gender or weight. Free thyroxine may slightly increase with age, based on sub-significant evidence. Hence, thyroid hormones do not seem to explain the different ageing rates of breeders and non-breeders. Further research is required to investigate the regulatory mechanisms responsible for the unusual proportion of free thyroxine and free triiodothyronine.

Sex differences are well known to be determinants of development, health and disease. Epigenetic mechanisms are also known to differ between men and women through X-inactivation in females. We hypothesized that epigenetic sex differences may also result from sex hormone functions, in particular from long-lasting androgen programming. We aimed at investigating whether inactivation of the androgen receptor, the key regulator of normal male sex development, is associated with differences of the patterns of DNA methylation marks in genital tissues. To this end, we performed large scale array-based analysis of gene methylation profiles on genomic DNA from labioscrotal skin fibroblasts of 8 males and 26 individuals with androgen insensitivity syndrome (AIS) due to inactivating androgen receptor gene mutations. By this approach we identified differential methylation of 167 CpG loci representing 162 unique human genes. These were significantly enriched for androgen target genes and low CpG content promoter genes. Additional 75 genes showed a significant increase of heterogeneity of methylation in AIS compared to a high homogeneity in normal male controls. Our data show that normal and aberrant androgen receptor function is associated with distinct patterns of DNA-methylation marks in genital tissues. These findings support the concept that transcription factor binding to the DNA has an impact on the shape of the DNA methylome. These data which derived from a rare human model suggest that androgen programming of methylation marks contributes to sexual dimorphism in the human which might have considerable impact on the manifestation of sex-associated phenotypes and diseases.

Epigenetic mechanisms including DNA methylation are supposed to play a key role in fetal development. Here we have investigated fetal DNA-methylation levels of 27,578 CpG loci in 47 chorionic villi (CVS) and 16 amniotic cell (AC) samples. Methylation levels differed significantly between karyotypically normal AC and CVS for 2,014 genes. AC showed more extreme DNA-methylation levels of these genes than CVS and the differentially methylated genes are significantly enriched for processes characteristic for the different cell types sampled. Furthermore, we identified 404 genes differentially methylated in CVS with trisomy 21. These genes were significantly enriched for high CG dinucleotid (CpG) content and developmental processes associated with Down syndrome. Our study points to major tissue-specific differences of fetal DNA-methylation and gives rise to the hypothesis that part of the Down syndrome phenotype is epigenetically programmed in the first trimester of pregnancy.

Increasing numbers of pyelonephritis-associated uropathogenic Escherichia coli (UPEC) are exhibiting high resistance to antibiotic therapy. They include a particular clonal group, the CTX-M-15-producing O25b:H4-ST131 clone, which has been shown to have a high dissemination potential. Here we show that a representative isolate of this E. coli clone, referred to as TN03, has enhanced metabolic capacities, acts as a potent intestine- colonizing strain, and displays the typical features of UPEC strains. In a modified streptomycin-treated mouse model of intestinal colonization where streptomycin was stopped 5 days before inoculation, we show that TN03 outcompetes the commensal E. coli strains K-12 MG1655, IAI1, and ED1a at days 1 and 7. Using an experimental model of ascending UTI in C3H/HeN mice, we then show that TN03 colonized the urinary tract. One week after the transurethral inoculation of the TN03 isolates, the bacterial loads in the bladder and kidneys were significantly greater than those of two other UPEC strains (CFT073 and HT7) belonging to the same B2 phylogenetic group. The differences in bacterial loads did not seem to be directly linked to differences in the inflammatory response, since the intrarenal expression of chemokines and cytokines and the number of polymorphonuclear neutrophils attracted to the site of inflammation was the same in kidneys colonized by TN03, CFT073, or HT7. Lastly, we show that in vitro TN03 has a high maximum growth rate in both complex (Luria-Bertani and human urine) and minimum media. In conclusion, our findings indicate that TN03 is a potent UPEC strain that colonizes the intestinal tract and may persist in the kidneys of infected hosts.