Divergent Profiles Research Articles

Expanding diversity in developmental profiles of very-low-birth-weight infants during 6 years after birth

Very-low-birth-weight infants (VLBWIs) are at high risk for neurodevelopmental problems after age 3 years. We investigated the association between the developmental quotient (DQ) of VLBWIs and their growth profiles during 6 years after birth. Participants were VLBWIs born at Kokura Medical Center (the first cohort) and Kyushu University Hospital (the second cohort) between 2012 and 2017. Recorded charts were used to collect growth profiles and developmental quotients (DQ) of the participants until age 6 years. In the first cohort (n = 64), the DQ values at age 6 years were correlated with those at age 3 years. VLBWIs with DQ ≥ 85 at age 6 years had a higher body weight and height at age 3 years than those with DQ < 85. The second cohort (n = 69) validated these findings. A comparative analysis of the two cohorts revealed that the DQ of VLBWIs was dissociated from their growth profiles after age 3 years. Clustering analyses indicated that DQ values at age 3 years predicted better the prognosis of VLBWIs with DQ ≥ 85 at age 6 years than their growth profiles. This study demonstrates that VLBWIs gain divergent profiles in growth, development, and growth-and-development correlation during postnatal 6 years.

P-2237. Mortality and Causative Pathogens of Sepsis Differ by Molecular Phenotype in a Secondary Analysis of MARS

Abstract Background Heterogeneity of host response has been a barrier to identifying novel therapies in sepsis. Two molecular phenotypes of critical illness, called the Hyperinflammatory and Hypoinflammatory, have been identified in multiple cohorts of sepsis and ARDS ( &amp;gt;12,000 patients), with divergent biology, clinical course, and responses to therapy1. We evaluated whether these phenotypes were identifiable in MARS-- a large observational cohort of critically ill patients-- and whether the pathogens present in each phenotype differed. Methods MARS recruited critically ill patients from two Dutch ICUs. Only patients meeting sepsis or ARDS diagnostic criteria were included for this analysis. We applied latent class analysis (LCA) to vital signs, clinical laboratory values, and protein biomarkers from Day 1 of ICU admission in 1,485 patients. LCA models with 1-5 classes were fitted. We assigned class membership using the best fitting model and compared characteristics between classes. The present classes’ overlap with prior phenotypes was evaluated by comparison to an extensively validated parsimonious model,2 trained previously to classify molecular phenotypes. Results A two-class model best fit the cohort (VLMR p&amp;lt; .001), and the parsimonious model and multivariate profiles suggested high overlap (AUC=.929) with previously described ‘Hypoinflammatory’ (Class 1; n=895) and ‘Hyperinflammatory’ (Class 2; n=590) phenotypes (Figure 1). Bacteremia was more prevalent in the Hyperinflammatory phenotype (27.2% vs 7.8%; p&amp;lt; .001), with Enterobacteriaceae as the most prevalent species. For primary infection sites, lower respiratory tract was more common in the Hypoinflammatory (56% vs 36%) and abdomen more common in the Hyperinflammatory phenotype (26% vs 9%). Mortality was significantly higher in the Hyperinflammatory phenotype at both 30 days (OR=2.54, CI95%= 2.003—3.235 ) and 90 days (OR=2.41, CI95% = 1.925—3.016; both p&amp;lt; .001). Conclusion In MARS, we identified the previously described Hypo- and Hyperinflammatory phenotypes with divergent host response, pathogen profiles, and outcomes. These findings suggest that host phenotype signatures in part may be driven by sites of infection and pathogen species. Disclosures Lieuwe D.J. Bos, MD-PhD, Astra Zeneca: Advisor/Consultant|CSL Behring: Advisor/Consultant|Impentri: Advisor/Consultant|Novartis: Advisor/Consultant|Scailyte: Advisor/Consultant|Sobi: Advisor/Consultant Pratik Sinha, MBChB/PhD, AstraZeneca: Advisor/Consultant|Prenosis Inc: Board Member Carolyn S. Calfee, MD, Cellenkos: Advisor/Consultant|Gen1e Life Sciences: Advisor/Consultant|Janssen: Advisor/Consultant|NGMBio: Advisor/Consultant|Santhera: Advisor/Consultant|Vasomune: Advisor/Consultant

Distinct CD8+ T-cell types Associated with COVID-19 Severity in Unvaccinated HLA-A2+ Patients.

Although emerging data have revealed the critical role of memory CD8+ T cells in preventing and controlling SARS-CoV-2 infection, virus-specific CD8+ T-cell responses against SARS-CoV-2 and its memory and innate-like subsets in unvaccinated COVID-19 patients with various disease manifestations in an HLA-restricted fashion remain to be understood. Here, we show the strong association of protective cellular immunity with mild COVID-19 and unique cell types against SARS-CoV-2 virus in an HLA-A2 restricted manner. ELISpot assays reveal that SARS-CoV-2-specific CD8+ T-cell responses in mild COVID-19 patients are significantly higher than in severe patients, whereas neutralizing antibody responses against SARS-CoV-2 virus significantly correlate with disease severity. Single-cell analyses of HLA-A2-restricted CD8+ T cells, which recognize highly conserved immunodominant SARS-CoV-2-specific epitopes, demonstrate divergent profiles in unvaccinated patients with mild versus severe disease. CD8+ T-cell types including cytotoxic KLRB1 + CD8αα cells with innate-like T-cell signatures, IFNG hi ID3 hi memory cells and IL7R + proliferative stem cell-like memory cells are preferentially observed in mild COVID-19, whereas distinct terminally-differentiated T-cell subsets are predominantly detected in severe COVID-19: highly activated FASL hi T-cell subsets and early-terminated or dysfunctional IL4R + GATA3 + stem cell-like memory T-cell subset. In conclusion, our findings suggest that unique and contrasting SARS-CoV-2-specific CD8+ T-cell profiles may dictate COVID-19 severity.

Spiny mice (Acomys) have evolved cellular features to support regenerative healing.

Spiny mice (Acomys spp.) are warm-blooded (homeothermic) vertebrates whose ability to restore missing tissue through regenerative healing has coincided with the evolution of unique cellular and physiological adaptations across different tissue types. This review seeks to explore how these bizarre rodents deploy unique or altered injury response mechanisms to either enhance tissue repair or fully regenerate excised tissue compared to closely related, scar-forming mammals. First, we examine overall trends in healing Acomys tissues, including the cellular stress response, the ability to activate and maintain cell cycle progression, and the expression of certain features in reproductive adults that are normally associated with embryos. Second, we focus on specific cell types that exhibit precisely regulated proliferation to restore missing tissue. While Acomys utilize many of the same cell types involved in scar formation, these cells exhibit divergent activation profiles during regenerative healing. Considered together, current lines of evidence support sustained deployment of proregenerative pathways in conjunction with transient activation of fibrotic pathways to facilitate regeneration and improve tissue repair in Acomys.

Altered Connectome Topology in Newborns at Risk for Cognitive Developmental Delay: A Cross-Etiologic Study.

The human brain connectome is characterized by the duality of highly modular structure and efficient integration, supporting information processing. Newborns with congenital heart disease (CHD), prematurity, or spina bifida aperta (SBA) constitute a population at risk for altered brain development and developmental delay (DD). We hypothesize that, independent of etiology, alterations of connectomic organization reflect neural circuitry impairments in cognitive DD. Our study aim is to address this knowledge gap by using a multi-etiologic neonatal dataset to reveal potential commonalities and distinctions in the structural brain connectome and their associations with DD. We used diffusion tensor imaging of 187 newborns (42 controls, 51 with CHD, 51 with prematurity, and 43 with SBA). Structural weighted connectomes were constructed using constrained spherical deconvolution-based probabilistic tractography and the Edinburgh Neonatal Atlas. Assessment of brain network topology encompassed the analysis of global graph features, network-based statistics, and low-dimensional representation of global and local graph features. The Cognitive Composite Score of the Bayley scales of Infant and Toddler Development 3rd edition was used as outcome measure at corrected 2 years for the preterm born individuals and SBA patients, and at 1 year for the healthy controls and CHD. We detected differences in the connectomic structure of newborns across the four groups after visualizing the connectomes in a two-dimensional space defined by network integration and segregation. Further, analysis of covariance analyses revealed differences in global efficiency (p < 0.0001), modularity (p < 0.0001), mean rich club coefficient (p = 0.017), and small-worldness (p = 0.016) between groups after adjustment for postmenstrual age at scan and gestational age at birth. Moreover, small-worldness was significantly associated with poorer cognitive outcome, specifically in the CHD cohort (r = -0.41, p = 0.005). Our cross-etiologic study identified divergent structural brain connectome profiles linked to deviations from optimal network integration and segregation in newborns at risk for DD. Small-worldness emerges as a key feature, associating with early cognitive outcomes, especially within the CHD cohort, emphasizing small-worldness' crucial role in shaping neurodevelopmental trajectories. Neonatal connectomic alterations associated with DD may serve as a marker identifying newborns at-risk for DD and provide early therapeutic interventions. Trial Registration: ClinicalTrials.gov identifier: NCT00313946.

An antisense-long-noncoding-RNA modulates p75NTR expression levels during neuronal polarization.

Proper polarization of newly generated neurons is a critical process for neural network formation and brain development. The pan-neurotrophin p75NTR receptor plays a key role in this process localizing asymmetrically in one of the differentiating neurites and specifying its axonal identity in response to neurotrophins. During axonal specification, p75NTR levels are transiently modulated, yet the molecular mechanisms underlying this process are not known. Here, we identified a previously uncharacterized natural antisense transcript, AS-p75, encoded within the p75NGFR mouse gene. Using an invitro model of polarizing murine neurons, we found that AS-p75 and p75NTR display divergent expression profiles and that p75NTR expression levels increase upon competition or depletion of AS-p75, indicating that AS-p75 is a negative regulator of p75NTR expression. Depletion of AS-p75 also results in altered p75NTR subcellular distribution and affects the polarization process. Overall, our data uncovered AS-p75 as a modulator of p75NTR expression, offering new insights into the regulation of this neurotrophin receptor during invitro neuronal polarization.

The Bacterial Cell Wall Components Lipopolysaccharide and Peptidoglycan Initiate Divergent Local Tissue and Systemic Inflammatory Response Profiles in the Chicken Model.

The innate immune system plays an important role in the defense against pathogens, whereby the ability to rapidly mount an effective inflammatory response is critical in the elimination/containment of the infection. To better understand the nature of the inflammatory responses to bacterial components in chickens, we used the growing feather (GF) cutaneous bioassay together with blood sampling to examine the local and systemic inflammatory responses initiated by intradermal (i.d.) GF-pulp injection of lipopolysaccharide (LPS) from Salmonella Typhimurium or peptidoglycan (PGN) from Staphylococcus aureus. Three studies were conducted in egg-type chickens between 9 and 15 weeks of age; Study 1 and 2 examined the leukocyte response profiles to a 100-fold dose range of LPS or PGN over 24 h or 7 d, respectively; Study 3 examined the leukocyte- and cytokine mRNA-profiles in pulps in response to LPS and PGN concurrently over 72 h. I.d. injection of LPS stimulated a heterophil and monocyte/macrophage dominated response in both GF-pulps and blood that was resolved by 48-72 h and differed based on dose administered. The inflammatory response stimulated by PGN was characterized by rapid infiltration of lymphocytes in GF-pulps with sustained high levels of T and B cells over 5-7 d and was neither affected by PGN dose nor reflected in the blood. Limited cytokine transcriptome analyses did not reveal differences that could explain the divergent response profiles to LPS versus PGN. More research is needed to understand the mechanisms underlying the divergent inflammatory responses to LPS and PGN in chickens.

Acute tear versus chronic-degenerated rotator cuff pathologies are associated with divergent tendon metabolite profiles

ABSTRACT Purpose/Aim Metabolic disorders are risk factors for rotator cuff injuries, which suggests that the rotator cuff is sensitive to local metabolic fluctuations. However, the link between the metabolic microenvironment and pathologic features of acute tear versus chronic degeneration is currently unknown. The overarching goal of this study was to evaluate alterations in tendon metabolite profiles following acute tear or chronic degeneration of the rotator cuff. We hypothesized that injury types (acute tear vs. chronic degeneration) would result in distinct metabolite profiles relative to clinically unaffected tendon controls. Materials and Methods We utilized untargeted metabolomics to identify pathways that were altered at the time of rotator cuff repair (RCR; acute tear) or reverse total shoulder arthroplasty (rTSA; chronic degeneration) relative to total shoulder arthroplasty controls (TSA; tendon clinically unaffected). Results Acute tears to the rotator cuff were associated with an overall decrease in tendon metabolites. This global decrease was primarily associated with glycolic acid and decreased tricarboxylic acid (TCA) cycle activity. Conversely, chronic tendon specimens from patients undergoing rTSA showed an overall increase in metabolites. Most notably, chronic injury was associated with increased levels of multiple amino acids including alanine, aspartate, lysine, and proline. Conclusions Overall, this study demonstrates that distinct metabolite profiles are associated with injury types, and that therapeutic strategies should address both cellular and matrix components regardless of injury induction. The specific pathways identified paired with validated, established, treatment methods may serve as novel therapeutic targets for patients who suffer from rotator cuff injuries.

Hepatic Transcriptomics of Broilers with Low and High Feed Conversion in Response to Caloric Restriction.

In broiler chickens, the efficient utilization of macro- and micronutrients is influenced by various metabolic pathways that are closely linked to feed efficiency (FE), a critical metric in poultry industry, with residual feed intake (RFI) as the preferred proxy. Feed restriction is considered an approach to address the underlying molecular mechanisms of feed conversion. We hypothesized that broiler chickens with divergent RFI subjected to quantitative feed restriction differ in their pattern of molecular pathways for efficient nutrient utilization in liver as post-absorptive tissue. Cobb 500FF broiler chickens divergent for RFI (n = 112) were feed-restricted from day 9 until market weight at day 33-37 post-hatch. Based on a previous trial, feed restriction levels were set at 92% (low-RFI birds) and 80% (high-RFI birds) relative to the control groups. Transcriptomic analyses of the liver were conducted. Due to the interaction of the RFI group and feeding regimen, a total of 140 to 507 differentially expressed genes were identified for the respective contrasts, with implications for hepatic metabolism and cellular stress response. Although the broilers did not realize their full growth potential under restrictive feeding (12.4% reduced body weight vs. controls, p = 0.094), the gene expression patterns indicate a lower susceptibility to blood coagulation (KNG1, FGG, and FGB), suggesting that controlled and mild feed restriction could lead to health benefits in less feed-efficient broilers. Moreover, FE traits are shown to be linked to cellular detoxification processes (MGST3 and CYP2AC2) and triacylglycerol syntheses (MOGAT1 and LPIN1). Divergent transcriptional profiles between broiler groups under varied caloric conditions indicate potential for optimizing nutritional management strategies.

Divergent Proteomic Profiles and Uptake Mechanisms of Exosomes Derived from Human Dental Pulp Stem Cells, Endothelial Cells, and Fibroblasts.

Effective intercellular communication is crucial for tissue repair and regeneration, with exosomes playing a key role in mediating these processes by transferring proteins, lipids, and nucleic acids between cells. This study explored the mechanisms underlying the uptake of exosomes derived from human dental pulp stem cells (hDPSCs), human umbilical vein endothelial cells (HUVECs), and human fibroblasts (HFBs). Our findings revealed that hDPSCs exhibited the greatest capacity for exosome uptake across all three cell types. Moreover, exosomes originating from hDPSCs were also taken up in the highest amounts by all three cell types. Proteomic analysis uncovered significant differences in protein expression among exosomes from these different cell types, particularly in proteins related to endocytosis. Clathrin-dependent endocytosis emerged as the primary pathway for exosome uptake in hDPSCs and HUVECs, while HFBs appeared to use a different mechanism. Additionally, proteins such as fibronectin and tetraspanins were found to be highly expressed in hDPSC-derived exosomes, suggesting their potential involvement in exosome-cell interactions. This study offers new insights into exosome uptake mechanisms and highlights the potential of exosomes in advancing tissue engineering and regenerative medicine.

Non-Hermitian phase-biased Josephson junctions

We study non-Hermitian Josephson junctions formed by superconductors with a finite phase difference under non-Hermiticity, which naturally appears due to coupling to normal reservoirs. Depending on the structure of non-Hermiticity, captured in terms of retarded self-energies, the low-energy spectrum hosts topologically stable exceptional points either at zero or finite real energies as a function of the superconducting phase difference. Interestingly, the corresponding phase-biased supercurrents may acquire divergent profiles at such exceptional points. This instance is a natural and unique non-Hermitian effect that signals a possible way to enhance the sensitivity of Josephson junctions. Our work opens a way for realizing unique non-Hermitian phenomena due to the interplay between non-Hermitian topology and the Josephson effect. Published by the American Physical Society 2024

RNA sequencing analysis reveals distinct gene expression patterns in infrapatellar fat pads of patients with end-stage osteoarthritis or rheumatoid arthritis

Osteoarthritis (OA) and autoimmune-driven rheumatoid arthritis (RA) are inflammatory joint diseases that share partly similar symptoms but have different, inadequately understood pathogeneses. Adipose tissues, including intra-articular infrapatellar fat pad (IFP), may contribute to their development. Analysis of differentially expressed genes (DEGs) in IFPs could improve the diagnostics of these conditions and help to develop novel treatment strategies. The aim was to identify potentially crucial genes and pathways discriminating OA and RA IFPs using RNA sequencing analysis. We aimed to distinguish genetically distinct patient groups as a starting point for further translational studies with the eventual goal of personalized medicine. Samples were collected from arthritic knees during total knee arthroplasty of sex- and age-matched OA and seropositive RA patients (n = 5–6/group). Metabolic pathways of interest were investigated by whole transcriptome sequencing, and DEGs were analyzed with univariate tests, hierarchical clustering (HC), and pathway analyses. There was significant interindividual variation in mRNA expression patterns, but distinct subgroups of OA and RA patients emerged that reacted similarly to their disease states based on HC. Compared to OA, RA samples showed 703 genes to be upregulated and 691 genes to be downregulated. Signaling pathway analyses indicated that these DEGs had common pathways in lipid metabolism, fatty acid biosynthesis and degradation, adipocytokine and insulin signaling, inflammatory response, and extracellular matrix organization. The divergent mRNA expression profiles in RA and OA suggest contribution of IFP to the regulation of synovial inflammatory processes and articular cartilage degradation and could provide novel diagnostic and therapeutic targets.

Using machine learning to derive neurobiological subtypes of general psychopathology in late childhood.

Traditional mental health diagnoses rely on symptom-based classifications. Yet this approach can oversimplify clinical presentations as diagnoses often do not adequately map onto neurobiological features. Alternatively, our study used structural imaging data and a semisupervised machine learning technique, heterogeneity through discriminative analysis, to identify neurobiological subtypes in 9- to 10-year-olds with high psychopathology endorsements (n = 9,027). Our model revealed two stable neurobiological subtypes (adjusted Rand index = 0.38). Subtype 1 showed smaller structural properties, elevated conduct problems and attention-deficit/hyperactivity disorder symptoms, and impaired cognitive performance compared to Subtype 2 and typically developing youth. Subtype 2 had larger structural properties, cognitive abilities comparable to typically developing youth, and elevated internalizing symptoms relative to Subtype 1 and typically developing youth. These subtypes remained stable in their neurobiological characteristics, cognitive ability, and associated psychopathology traits over time. Taken together, our data-driven approach uncovered evidence of neural heterogeneity as demonstrated by structural patterns that map onto divergent profiles of psychopathology symptoms and cognitive performance in youth. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Human iPSC-derived neural stem cells displaying radial glia signature exhibit long-term safety in mice

Human induced pluripotent stem cell-derived neural stem/progenitor cells (hiPSC-NSCs) hold promise for treating neurodegenerative and demyelinating disorders. However, comprehensive studies on their identity and safety remain limited. In this study, we demonstrate that hiPSC-NSCs adopt a radial glia-associated signature, sharing key epigenetic and transcriptional characteristics with human fetal neural stem cells (hfNSCs) while exhibiting divergent profiles from glioblastoma stem cells. Long-term transplantation studies in mice showed robust and stable engraftment of hiPSC-NSCs, with predominant differentiation into glial cells and no evidence of tumor formation. Additionally, we identified the Sterol Regulatory Element Binding Transcription Factor 1 (SREBF1) as a regulator of astroglial differentiation in hiPSC-NSCs. These findings provide valuable transcriptional and epigenetic reference datasets to prospectively define the maturation stage of NSCs derived from different hiPSC sources and demonstrate the long-term safety of hiPSC-NSCs, reinforcing their potential as a viable alternative to hfNSCs for clinical applications.

Longitudinal transcriptional changes reveal genes from the natural killer cell-mediated cytotoxicity pathway as critical players underlying COVID-19 progression

Patients present a wide range of clinical severities in response severe acute respiratory syndrome coronavirus 2 infection, but the underlying molecular and cellular reasons why clinical outcomes vary so greatly within the population remains unknown. Here, we report that negative clinical outcomes in severely ill patients were associated with divergent RNA transcriptome profiles in peripheral immune cells compared with mild cases during the first weeks after disease onset. Protein–protein interaction analysis indicated that early-responding cytotoxic natural killer cells were associated with an effective clearance of the virus and a less severe outcome. This innate immune response was associated with the activation of select cytokine–cytokine receptor pathways and robust Th1/Th2 cell differentiation profiles. In contrast, severely ill patients exhibited a dysregulation between innate and adaptive responses affiliated with divergent Th1/Th2 profiles and negative outcomes. This knowledge forms the basis of clinical triage that may be used to preemptively detect high-risk patients before life-threatening outcomes ensue.

Longitudinal transcriptional changes reveal genes from the natural killer cell-mediated cytotoxicity pathway as critical players underlying COVID-19 progression.

Patients present a wide range of clinical severities in response severe acute respiratory syndrome coronavirus 2 infection, but the underlying molecular and cellular reasons why clinical outcomes vary so greatly within the population remains unknown. Here, we report that negative clinical outcomes in severely ill patients were associated with divergent RNA transcriptome profiles in peripheral immune cells compared with mild cases during the first weeks after disease onset. Protein-protein interaction analysis indicated that early-responding cytotoxic natural killer cells were associated with an effective clearance of the virus and a less severe outcome. This innate immune response was associated with the activation of select cytokine-cytokine receptor pathways and robust Th1/Th2 cell differentiation profiles. In contrast, severely ill patients exhibited a dysregulation between innate and adaptive responses affiliated with divergent Th1/Th2 profiles and negative outcomes. This knowledge forms the basis of clinical triage that may be used to preemptively detect high-risk patients before life-threatening outcomes ensue.

Genomic and metabolomic insights into the selection and differentiation of bioactive compounds in citrus

Bioactive compounds play an increasingly prominent role in breeding functional and nutritive fruit crops such as citrus. However, the genomic and metabolic bases for the selection and differentiation underlying bioactive compound variations in citrus remain poorly understood. In this study, we constructed a species-level variation atlas of genomes and metabolomes using 299 citrus accessions. A total of 19 829 significant SNPs were targeted to 653 annotated metabolites, among which multiple significant signals were identified for secondary metabolites, especially flavonoids. Significant differential accumulation of bioactive compounds in the phenylpropane pathway, mainly flavonoids and coumarins, was unveiled across ancestral citrus species during differentiation, which is likely associated with the divergent haplotype distribution and/or expression profiles of relevant genes, including p-coumaroyl coenzyme A 2′-hydroxylases, flavone synthases, cytochrome P450 enzymes, prenyltransferases, and UDP-glycosyltransferases. Moreover, we systematically evaluated the beneficial bioactivities such as the antioxidant and anticancer capacities of 219 citrus varieties, and identified robust associations between distinct bioactivities and specific metabolites. Collectively, these findings provide citrus breeding options for enrichment of beneficial flavonoids and avoidance of potential risk of coumarins. Our study will accelerate the application of genomic and metabolic engineering strategies in developing modern healthy citrus cultivars.

Interaction of CTCF and CTCFL in genome regulation through chromatin architecture during the spermatogenesis and carcinogenesis.

The zinc finger protein CTCF is ubiquitously expressed and is integral to the regulation of chromatin architecture through its interaction with cohesin. Conversely, CTCFL expression is predominantly restricted to the adult male testis but is aberrantly expressed in certain cancers. Despite their distinct expression patterns, the cooperative and competitive mechanisms by which CTCF and CTCFL regulate target gene expression in spermatocytes and cancer cells remain inadequately understood. In this review, we comprehensively examine the literature on the divergent amino acid sequences, target sites, expression profiles and functions of CTCF and CTCFL in normal tissues and cancers. We further elucidate the mechanisms by which CTCFL competitively or cooperatively binds to CTCF target sites during spermatogenesis and carcinogenesis to modulate chromatin architecture. We mainly focus on the role of CTCFL in testicular and cancer development, highlighting its interaction with CTCF at CTCF binding sites to regulate target genes. In the testis, CTCF and CTCFL cooperate to regulate the expression of testis-specific genes, essential for proper germ cell progression. In cancers, CTCFL overexpression competes with CTCF for DNA binding, leading to aberrant gene expression, a more relaxed chromatin state, and altered chromatin loops. By uncovering the roles of CTCF and CTCFL in spermatogenesis and carcinogenesis, we can better understand the implications of aberrant CTCFL expression in altering chromatin loops and its contribution to disease pathogenesis.

Highly divergent satellitomes of two barley species of agronomic importance, Hordeum chilense and H. vulgare

In this paper, we have performed an in-depth study of the complete set of the satellite DNA (satDNA) families (i.e. the satellitomes) in the genome of two barley species of agronomic value in a breeding framework, H. chilense (H1 and H7 accessions) and H. vulgare (H106 accession), which can be useful tools for studying chromosome associations during meiosis. The study has led to the analysis of a total of 18 satDNA families in H. vulgare, 25 satDNA families in H. chilense (accession H1) and 27 satDNA families in H. chilense (accession H7) that constitute 46 different satDNA families forming 36 homology groups. Our study highlights different important contributions of evolutionary and applied interests. Thus, both barley species show very divergent satDNA profiles, which could be partly explained by the differential effects of domestication versus wildlife. Divergence derives from the differential amplification of different common ancestral satellites and the emergence of new satellites in H. chilense, usually from pre-existing ones but also random sequences. There are also differences between the two H. chilense accessions, which support genetically distinct groups. The fluorescence in situ hybridization (FISH) patterns of some satDNAs yield distinctive genetic markers for the identification of specific H. chilense or H. vulgare chromosomes. Some of the satellites have peculiar structures or are related to transposable elements which provide information about their origin and expansion. Among these, we discuss the existence of different (peri)centromeric satellites that supply this region with some plasticity important for centromere evolution. These peri(centromeric) satDNAs and the set of subtelomeric satDNAs (a total of 38 different families) are analyzed in the framework of breeding as the high diversity found in the subtelomeric regions might support their putative implication in chromosome recognition and pairing during meiosis, a key point in the production of addition/substitution lines and hybrids.

Divergent transcriptomic profiles in depressed individuals with hyper- and hypophagia implicating inflammatory status

BackgroundMajor Depressive Disorder (MDD) is a heterogenous and etiologically complex disease often presenting with divergent appetitive phenotypes including Hyperphagic MDD (characterized by an increased appetite) and Hypophagic MDD (characterized by a decrease in appetite) which are closely related to comorbidities, including cardiometabolic disorders. Hyperphagia is associated with atypical depression, decreased stress-hormone signaling, a pro-inflammatory status, hypersomnia, and poorer clinical outcomes. Yet, our understanding of associated biological correlates of Hyperphagic and Hypophagic MDD remain fragmented. MethodsWe performed an exploratory study on peripheral blood RNA profiling using bulk RNAseq in unmedicated individuals with Hyperphagic and Hypophagic MDD (n = 7 and n = 13, respectively). ResultsAt baseline, we discovered an increased expression of TADA2B in hyperphagic MDD with the significant enrichment of 72 gene ontology pathways mainly related to inflammation. In addition, we used the Maastricht Acute Stress Task to uncover stress-related transcriptomic profiles in Hyper- and Hypophagic MDD and discovered the upregulation of CCDC196 and the downregulation of SPATA33 in hyperphagic MDD. Gene ontology enrichment analysis after stress exposure showed pathways related to ribosomal activity. Limitations: The present findings are tempered primarily by the limited sample size, which requires independent replication of this exploratory study. However, stringent methods controlling for false positive findings mitigate the risk associated with sample size limitations. DiscussionLimitations notwithstanding, findings suggest that hyper- and hypophagic MDD is associated with divergent RNA expression profiles in peripheral blood that are amplified by exposure to a controlled stress test. Our findings in a well-controlled study provide evidence for peripheral markers of a relevant endophenotype of MDD.