Distinct Phenotypes Research Articles

Decoding transcriptional identity in developing human sensory neurons and organoid modeling.

Dorsal root ganglia (DRGs) play a crucial role in processing sensory information, making it essential to understand their development. Here, we construct a single-cell spatiotemporal transcriptomic atlas of human embryonic DRG. This atlas reveals the diversity of cell types and highlights the extrinsic signaling cascades and intrinsic regulatory hierarchies that guide cell fate decisions, including neuronal/glial lineage restriction, sensory neuron differentiation and specification, and the formation of neuron-satellite glial cell (SGC) units. Additionally, we identify a human-enriched NTRK3+/DCC+ nociceptor subtype, which is involved in multimodal nociceptive processing. Mimicking the programmed activation of signaling pathways invivo, we successfully establish functional human DRG organoids and underscore the critical roles of transcriptional regulators in the fate commitment of unspecialized sensory neurons (uSNs). Overall, our research elucidates the multilevel signaling pathways and transcription factor (TF) regulatory hierarchies that underpin the diversity of somatosensory neurons, emphasizing the phenotypic distinctions in human nociceptor subtypes.

Distinct Cutibacterium acnes subspecies defendens strains classified by multi-omics dissection alleviate inflammatory skin lesions of a rosacea-like mouse model

IntroductionCutibacterium acnes (C. acnes) resides in various organs such as the skin, prostate, eye, nose, stomach, and intestine, indicating the possibility of extensive crosstalk between this bacterium and the human body. C. acnes strains are classified into three subspecies based on phylogenetics and distinguishable phenotypes. Among them, C. acnes subsp. defendens strains are characterized by anti-inflammatory features, raising expectations for their potential as future microbiome therapeutics. However, the heterogeneity of C. acnes subsp. defendens and its corresponding immunological functions have not been clearly addressed.MethodsThe genetic diversity of the strains was assessed using single- and multi-locus sequence typing. Their immune-modulatory functions were evaluated in vitro using 2D and 3D assays with immune and epithelial cells. The anti-inflammatory effects were further confirmed in vivo using a rosacea-like mouse model. Comparative genomic and transcriptomic analyses were conducted to uncover mechanisms underlying the immunosuppressive activity of the strains.ResultsWe demonstrated that the newly isolated C. acnes subsp. defendens strains, exhibiting phenotypic heterogeneity, are distinctly clustered using single- and multi-locus sequence typing methods. These strains showed strong immune-regulatory functions in immune and epithelial cell-based 2D and 3D in vitro assays. Furthermore, their anti-inflammatory role was functionally confirmed in vivo using a rosacea-like mouse model, where they alleviated skin lesions characterized by hyperplasia and dermal inflammation. Comparative transcriptomics revealed that these strains may exert their immunosuppressive effects through the enhanced expression of acnecins and transcriptional variation in envelope stress regulators (specifically the two-component systems, CesSR homologs). Additionally, we propose that these C. acnes type II strains produce anti-inflammatory metabolites or peptides smaller than 3 kDa, which are associated with elevated pyrimidine and reduced L-arginine biosynthesis.DiscussionThe newly isolated C. acnes subsp. defendens strains demonstrate significant anti-inflammatory properties both in vitro and in vivo, suggesting their potential as microbiome-based therapeutics. Their unique genomic and transcriptomic profiles, including the production of small bioactive compounds and specific transcriptomic patterns, underpin their immunosuppressive capabilities. These findings provide a foundation for developing novel treatments for inflammatory skin conditions, such as rosacea.

Absent, but not glucocorticoid-modulated, corticotropin-releasing hormone (Crh) regulates anxiety-like behaviors in mice.

The hypothalamic-pituitary-adrenal (HPA) axis is a well characterized endocrine response system. Hypothalamic Crh in the paraventricular nucleus of the hypothalamus (PVH) initiates HPA axis signaling to cause the release of cortisol (or corticosterone in rodents) from the adrenal gland. PVH-specific deletion of Crh reduces anxiety-like behaviors in mice. Here we report that manipulation of PVH Crh expression in primary adrenal insufficiency or by dexamethasone (DEX) treatment do not alter mouse anxiety behaviors. In Experiment 1, we compared wildtype (WT) mice to those with primary adrenal insufficiency ( Mrap KO) or global deletion of Crh ( Crh KO). We analyzed behaviors using open field (OF) and elevated plus maze (EPM), PVH Crh mRNA expression by spatial transcriptomics, and plasma ACTH and corticosterone after a 15-minute restraint test with ELISAs. EPM analysis showed Crh KO mice were less anxious than WT and Mrap KO mice, and Mrap KO mice had no distinguishing behavioral phenotype. In Experiment 2, we evaluated HPA axis habituation to chronically elevated Crh expression by comparing mice treated with 5-8 weeks of DEX with those similarly treated followed by DEX withdrawal for 1 week. All mice regardless of genotype and treatment showed no significant behavioral differences. Our findings suggest that reduced anxiety associated with low Crh expression requires extreme deficiency, perhaps outside of those PVH Crh neurons negatively regulated by glucocorticoids. If these findings extend to humans, they suggest that increases in Crh expression with primary adrenal insufficiency, or decreases with exogenous glucocorticoid therapy, may not alter anxiety behaviors via modulation of Crh expression.

Phenotypic and Molecular-Markers-Based Assessment of Jamun (Syzygium cumini) Genotypes from Pakistan

Jamun plant displays enormous diversity throughout Pakistan, which necessitates its screening, evaluation, and validation to document elite genotypes having better traits for the benefit of the fruit industry and farmers. Surveys were made in natural Jamun habitats across Punjab, Pakistan, and genotypes were marked based on visual diversity of trees and fruits. In total, 60 Jamun genotypes were selected for characterization based on phenotypic and genetic markers. Phenotypic characters related to trees, leaf, and flower along with fruit qualitative traits were assessed in situ. Results revealed significant diversity with high (>25%) coefficient of variance values and the first two components of correspondence analysis exhibited 41.71% variation among genotypes. A strong association was observed among traits like upright tree and round fruit shape (0.74), bluish-colored fruit and pinkish pulp (0.85), and elliptic-shaped fruit with low fruit waxiness (−0.72). Leaves of phenotypically characterized plants were brought to Wheat Biotechnology Lab., University of Agriculture, Faisalabad, Pakistan, where Jamun genotypes were investigated genetically using Random Amplified Polymorphic DNA (RAPD) and Inter Simple Sequence Repeat (ISSR) markers. A total of 132 bands were scored, of which 108 were polymorphic, corresponding to almost 81% polymorphism among collected genotypes. High polymorphism information content values were observed against RAPD (0.389) and ISSR (0.457) markers. Genotypes were compared in relation to genetic markers, which exhibited that almost 86% of genetic variability was attributed to differences among accessions, while 14% of variation was due to differences between collections of different areas. Findings of this study confirmed wide phenotypic and genetic distinctness of Jamun in Pakistan that can aid breeders for marker-assisted selection and germplasm enhancement for future crop improvement programs.

A genotype–phenotype approach to discriminate Central European spelt landraces from modern wheat-spelt intercrosses in the Swiss context

Marketed as a healthier alternative to bread wheat, spelt (Triticum aestivum ssp. spelta) is in increasing demand from consumers and bakers in Switzerland. The Swiss spelt landscape is currently dominated by two varieties—Ostro and Oberkulmer Rotkorn—considered as references for Swiss “typical” spelt. However, these two varieties are rather old and deliver low yields; the market therefore needs improved spelt varieties with higher agronomic potential while keeping the essential attributes of typical spelt. As spelt and winter wheat can be interbred, modern spelt varieties often result from crosses between the two. It has therefore become increasingly difficult to distinguish between typical spelt and modern wheat-spelt intercrosses. This project aims to clarify the phenotypic distinction between typical spelt and modern wheat-spelt intercrosses in the Swiss context. To do this, we performed field trials with 50 spelt varieties, including typical and modern cultivars from Switzerland and Central Europe. We measured agronomic, rheological and nutritional parameters of each variety. In addition, these cultivars were genotyped using a 25 K Illumina Wheat SNP array. This allowed us to identify which phenotypic parameters were associated with genetic proximity to typical spelt. Swiss typical spelt varieties were characterized by highly extensible doughs, later phenology, low harvest index, high thousand kernel weights, and lower Zeleny/protein ratio. By linking phenotypic characteristics, easily measurable in fields, to the underlying genetic information of each variety, these results will help to better classify spelt varieties in Switzerland and pave the way for more clarity and transparency on the Swiss spelt market.

Streptomyces odontomachi sp. nov., a novel actinobacterium with antimicrobial potential isolated from ants (Odontomachus simillimus Smith, 1858).

A new actinomycete strain, ODS25T, exhibited antimicrobial activity against Bacillus subtilis, Kocuria rhizophila, Staphylococcus aureus, Staphylococcus epidermidis, Candida albicans, Candida tropicalis, was isolated from the ants, Odontomachus simillimus, collected from National Science Museum Thailand, Pathum Thani, Thailand. A polyphasic technique was used to characterize the taxonomic position. The morphological and chemotaxonomic properties of the strain are typical of members of the genus Streptomyces. Strain ODS25T contained ll-diaminopimelic and glucose in the whole-cell hydrolysate. The major cellular fatty acids were iso-C16:0, iso-C15:0, and anteiso-C15:0. The polar lipids were phosphatidylethanolamine, phosphatidylinositol mannosides, phosphatidylinositol, diphosphatidylglycerol, phosphatidylglycerol, three unidentified phospholipids, three unidentified amino lipids and two unidentified lipids. The menaquinones were MK-9(H6), MK-9(H8), and MK-9(H4). The G + C content of the genomic DNA was 71.3%. The 16 S rRNA gene sequence analysis demonstrated that the strain had the highest similarity to Streptomyces lusitanus NBRC 13464T (98.07%) but shared the phylogenetic neighbour with Streptomyces sulfonofaciens JCM 5069T. Both digital DNA-DNA hybridization and average nucleotide identity values among strain ODS25T and its associated Streptomyces type strains fell within the values lower than the threshold for differentiate the strain to the same species. Based on the phenotypic characteristics and genotypic distinctiveness, strain ODS25T is considered a novel species within the genus Streptomyces, for which the name Streptomyces odontomachi sp. nov. is proposed. The type strain is ODS25T (=TBRC 16204T=NBRC 115862T).

Anatomical and behavioral correlates of auditory perception in developmental dyslexia.

Developmental dyslexia is typically associated with difficulties in basic auditory processing and in manipulating speech sounds. However, the neuroanatomical correlates of auditory difficulties in developmental dyslexia (DD) and their contribution to individual clinical phenotypes are still unknown. Recent intracranial electrocorticography findings associated processing of sound amplitude rises and speech sounds with posterior and middle superior temporal gyrus (STG), respectively. We hypothesize that regional STG anatomy will relate to specific auditory abilities in DD, and that auditory processing abilities will relate to behavioral difficulties with speech and reading. One hundred and ten children (78 DD, 32 typically developing, age 7-15 years) completed amplitude rise time and speech in noise discrimination tasks. They also underwent a battery of cognitive tests. Anatomical MRI scans were used to identify regions in which local cortical gyrification complexity correlated with auditory behavior. Behaviorally, amplitude rise time but not speech in noise performance was impaired in DD. Neurally, amplitude rise time and speech in noise performance correlated with gyrification in posterior and middle STG, respectively. Furthermore, amplitude rise time significantly contributed to reading impairments in DD, while speech in noise only explained variance in phonological awareness. Finally, amplitude rise time and speech in noise performance were not correlated, and each task was correlated with distinct neuropsychological measures, emphasizing their unique contributions to DD. Overall, we provide a direct link between the neurodevelopment of the left STG and individual variability in auditory processing abilities in neurotypical and dyslexic populations.

Methylobacterium amylolyticum sp. nov. and Methylobacterium ligniniphilum sp. nov., isolated from soil.

Two pink-pigmented bacteria, designated strains NEAU-140T and NEAU-KT, were isolated from field soil collected from Linyi, Shandong Province, PR China. Both isolates were aerobic, Gram-stain-negative, rod-shaped, and facultatively methylotrophic. 16S rRNA gene sequences analysis showed that these two strains belong to the genus Methylobacterium. Strain NEAU-140T exhibited high 16S rRNA gene sequence similarities to Methylobacterium radiotolerans NBRC 15690T (97.43 %) and Methylobacterium phyllostachyos NBRC 105206T (97.36 %). Strain NEAU-KT exhibited high 16S rRNA gene sequence similarities to M. phyllostachyos NBRC 105206T (99.00 %) and Methylobacterium longum DSM 23933T (98.72 %). A phylogenetic tree based on 16S rRNA gene sequences showed that strain NEAU-140T formed a clade with Methylobacterium aerolatum (95.94 %), Methylobacterium persicinum (95.66 %) and Methylobacterium komagatae (96.87 %), and strain NEAU-KT formed a cluster with M. phyllostachyos and M. longum. The predominant fatty acid in both strains was C18 : 1 ω7c. Both strains contained ubiquinone Q-10 as the only respiratory quinone. The polar lipid profiles of both strains contained diphosphatidylglycerol, phosphatidylethanolamine, and phosphatidylcholine. Whole-genome phylogeny showed that strains NEAU-140T and NEAU-KT formed a phyletic line with M. aerolatum, M. persicinum, Methylobacterium radiotolerans, Methylobacterium fujisawaense, Methylobacterium oryzae, Methylobacterium tardum, M. longum and M. phyllostachyos. The orthologous average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values between strain NEAU-140T and its closely related strains were lower than 82.62 and 25.90 %, respectively. The ANI and dDDH values between strain NEAU-KT and its closely related strains were lower than 86.29 and 31.7 %, respectively. The genomic DNA G+C contents were 71.63 mol% for strain NEAU-140T and 69.08 mol% for strain NEAU-KT. On the basis of their phenotypic and phylogenetic distinctiveness and the results of dDDH and ANI hybridization, these two isolates represent two novel species within the genus Methylobacterium, for which the names Methylobacterium amylolyticum sp. nov. (type strain NEAU-140T=MCCC 1K08801T=DSM 110568T) and Methylobacterium ligniniphilum sp. nov. (type strain NEAU-KT=MCCC 1K08800T=DSM 110567T) are proposed.

Variability analysis of the Phenotypic Characteristics of some Grapefruit and Pomelo under Moroccan Conditions

Citrus is an economically important fruit crop with a long history of cultivation worldwide, and many citrus varieties are grown extensively in Morocco, both for domestic consumption and export. Nevertheless, the genetic diversity of this genus in Morocco has not been reported upon. Our objective was to explore phenotypic variations in grapefruit and pomelo genotypes for targeted breeding, enhancing key traits, and identifying opportunities for genetic improvement. We emphasize practical implications and outline future research directions for developing improved citrus varieties. This present study physiochemically analyzes eight grapefruit (Citrus paradisi) and two pomelo (Citrus maxima) cultivars to assess the genetic variability of these fruits’ physicochemical characteristics. The results revealed significant variance among the genotypes for all traits. For example, the phenotypic coefficient of variation (PCV) was higher than genotypic coefficient of variation (GCV) for all the traits. Moreover, a high degree of heritability was recorded for seed number, β-carotene, vitamin C, juice yield (%), total soluble solids, titratable acidity, maturity index, fruit diameter, and fruit weight, whereas limited heritability was observed for fruit length, peel thickness, and segment number per fruit. The high genetic advance scores corresponded to the high degree of heritability estimates for seed number per fruit, β-carotene, juice yield, and vitamin C, suggesting the existence of additive genetic effects. Our principal component analysis (PCA) identified four components with cumulative variance of 93.20%, while hierarchical cluster analysis grouped the collection into five clusters. In conclusion, phenotypic distinctions among grapefruit and pomelo genotypes reveal opportunities for genetic enhancement through selection or hybridization. Varied traits, including seed count, vitamin C, beta-carotene, and juice yield, across genotypes suggest potential avenues for targeted breeding and practical applications in diverse citrus varieties.

Predicting changes in brain metabolism and progression from mild cognitive impairment to dementia using multitask Deep Learning models and explainable AI

Background:The prediction of Alzheimer’s disease (AD) progression from its early stages is a research priority. In this context, the use of Artificial Intelligence (AI) in AD has experienced a notable surge in recent years. However, existing investigations predominantly concentrate on distinguishing clinical phenotypes through cross-sectional approaches. This study aims to investigate the potential of modeling additional dimensions of the disease, such as variations in brain metabolism assessed via [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET), and utilize this information to identify patients with mild cognitive impairment (MCI) who will progress to dementia (pMCI). Methods:We analyzed data from 1,617 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) who had undergone at least one FDG-PET scan. We identified the brain regions with the most significant hypometabolism in AD and used Deep Learning (DL) models to predict future changes in brain metabolism. The best-performing model was then adapted under a multi-task learning framework to identify pMCI individuals. Finally, this model underwent further analysis using eXplainable AI (XAI) techniques. Results:Our results confirm a strong association between hypometabolism, disease progression, and cognitive decline. Furthermore, we demonstrated that integrating data on changes in brain metabolism during training enhanced the models’ ability to detect pMCI individuals (sensitivity=88.4%, specificity=86.9%). Lastly, the application of XAI techniques enabled us to delve into the brain regions with the most significant impact on model predictions, highlighting the importance of the hippocampus, cingulate cortex, and some subcortical structures. Conclusion:This study introduces a novel dimension to predictive modeling in AD, emphasizing the importance of projecting variations in brain metabolism under a multi-task learning paradigm.

Integrative systematic revision of the Montseny brook newt (Calotriton arnoldi), with the description of a new subspecies.

The Montseny brook newt (Calotriton arnoldi), a glacial relict endemic to a small, isolated massif in northeast Spain, is considered the only Critically Endangered urodele in Europe. Its restricted range is divided by a deep valley that acts as an impassable barrier to dispersal, separating two isolated metapopulations (Western and Eastern) that correspond to independent lineages with different evolutionary trajectories, based on genetic and genomic data. Here, we address the ecological differentiation between lineages and discuss its potential effect on the phenotypic distinctness of each lineage. Based on multiple lines of evidence, we formally describe the Western Montseny brook newt as a new subspecies: Calotriton arnoldi laietanus ssp. nov. Finally, our study underscores the importance of considering taxonomic progress in the conservation policies of endangered species, ensuring appropriate management and protection of the newly described taxa.

Isoptericola haloaureus sp. nov., a dimorphic actinobacterium isolated from mangrove sediments of southeast India, implicating biosaline agricultural significance through nitrogen fixation and salt tolerance genes.

Strain MP-1014T, an obligate halophilic actinobacterium, was isolated from the mangrove soil of Thandavarayancholanganpettai, Tamil Nadu, India. A polyphasic approach was utilized to explore its phylogenetic position completely. The isolate was Gram-positive, filamentous, non-motile, and coccoid in older cultures. Ideal growth conditions were seen at 30°C and pH 7.0, with 5% NaCl (W/V), and the DNA G + C content was 73.3%. The phylogenic analysis of this strain based upon 16S rRNA gene sequence revealed 97-99.8% similarity to the recognized species of the genus Isoptericola. Strain MP-1014T exhibits the highest similarity to I. sediminis JC619T (99.7%), I. chiayiensis KCTC19740T (98.9%), and subsequently to I. halotolerans KCTC19646T (98.6%), when compared with other members within the Isoptericola genus (< 98%). ANI scores of strain MP-1014T are 86.4%, 84.2%, and 81.5% and dDDH values are 59.7%, 53.6%, and 34.8% with I. sediminis JC619T, I. chiayiensis KCTC19740T and I. halotolerans KCTC19646T respectively. The major polar lipids of the strain MP-1014T were phosphatidylinositol, phosphatidylglycerol, diphosphotidylglycerol, two unknown phospholipids, and glycolipids. The predominant respiratory menaquinones were MK9 (H4) and MK9 (H2). The major fatty acids were anteiso-C15:0, anteiso-C17:0, iso-C14:0, C15:0, and C16:0. Also, initial genome analysis of the organism suggests it as a biostimulant for enhancing agriculture in saline environments. Based on phenotypic and genetic distinctiveness, the strain MP-1014 T represents the novel species of the genus Isoptericola assigned Isoptericola haloaureus sp. nov., is addressed by the strain MP-1014 T, given its phenotypic, phylogenetic, and hereditary uniqueness. The type strain is MP-1014T [(NCBI = OP672482.1 = GCA_036689775.1) ATCC = BAA 2646T; DSMZ = 29325T; MTCC = 13246T].

Explainable Multimodal Graph Isomorphism Network for Interpreting Sex Differences in Adolescent Neurodevelopment

Explainable Multimodal Graph Isomorphism Network for Interpreting Sex Differences in Adolescent Neurodevelopment

Advances of NOTCH2NLC Repeat Expansions and Associated Diseases: A Bibliometric and Meta-analysis.

The unclear pathogenic mechanisms of neurodegenerative disorders stemming from NOTCH2NLC GGC repeat expansions drive focused research. Thus, a bibliometric and meta-analysis was conducted to uncover research trends and positivity rates in NOTCH2NLC. We conducted systematic searches in the Web of Science, PubMed, Embase, and Scopus databases for studies related to NOTCH2NLC up until August 2, 2023. Information regarding countries, institutions, authors, journals, and keywords of studies included in the Web of Science was analyzed and visualized. The positivity rates of NOTCH2NLC GGC repeat expansions across all screened patients and patients' families were pooled under the random-effects model. Publication bias and its impact were examined using funnel plots, Egger's linear regression, and trim-and-fill method. The bibliometric analysis, revealing pronounced publication growth, comprised 119 studies, which came from China and Japan particularly. "Neuronal intranuclear inclusion disease" emerged as a frequently used keyword. The meta-analysis comprised 36 studies, indicating global positivity rates of 1.79% (95% CI, 0.75-3.17) for all patients and 2.00% (95% CI, 0.26-4.78) for patients' families. Subgroup analyses based on region and phenotype suggested the highest NOTCH2NLC positivity rates in Taiwan population (5.42%, 95% CI 0.08-16.89) and in leukoencephalopathy-dominant patients (8.25%, 95% CI, 3.01-15.60). Sensitivity analysis affirmed the robustness of results. In conclusion, NOTCH2NLC GGC repeat expansions exhibit rare globally, primarily in East Asia, and leukoencephalopathy-dominant patients, emphasizing regional and phenotypic distinctions. Emerging focal points in NOTCH2NLC researches underscore the need for collaborative exploration.

MiR-21, miR-221, miR-29 and miR-34 are distinguishable molecular features of a metabolically unhealthy phenotype in young adults.

Discrepancies between the measurement of body mass index (BMI) and metabolic health status have been described for the onset of metabolic diseases. Studying novel biomarkers, some of which are associated with metabolic syndrome, can help us to understand the differences between metabolic health (MetH) and BMI. A group of 1469 young adults with pre-specified anthropometric and blood biochemical parameters were selected. Of these, 80 subjects were included in the downstream analysis that considered their BMI and MetH parameters for selection as follows: norm weight metabolically healthy (MHNW) or metabolically unhealthy (MUNW); overweight/obese metabolically healthy (MHOW) or metabolically unhealthy (MUOW). Our results showed for the first time the differences when the MetH status and the BMI are considered as global MetH statures. First, all the evaluated miRNAs presented a higher expression in the metabolically unhealthy group than the metabolically healthy group. The higher levels of leptin, IL-1b, IL-8, IL-17A, miR-221, miR-21, and miR-29 are directly associated with metabolic unhealthy and OW/OB phenotypes (MUOW group). In contrast, high levels of miR34 were detected only in the MUNW group. We found differences in the SIRT1-PGC1α pathway with increased levels of SIRT1+ cells and diminished mRNA levels of PGCa in the metabolically unhealthy compared to metabolically healthy subjects. Our results demonstrate that even when metabolic diseases are not apparent in young adult populations, MetH and BMI have a distinguishable phenotype print that signals the potential to develop major metabolic diseases.

Identification of Distinct Brain MRI Phenotypes and Their Association With Long-Term Dementia Risk in Community-Dwelling Older Adults.

Individual brain MRI markers only show at best a modest association with long-term occurrence of dementia. Therefore, it is challenging to accurately identify individuals at increased risk for dementia. We aimed to identify different brain MRI phenotypes by hierarchical clustering analysis based on combined neurovascular and neurodegenerative brain MRI markers and to determine the long-term dementia risk within the brain MRI phenotype subgroups. Hierarchical clustering analysis based on 32 combined neurovascular and neurodegenerative brain MRI markers in community-dwelling individuals of the Age-Gene/Environment Susceptibility Reykjavik Study was applied to identify brain MRI phenotypes. A Cox proportional hazards regression model was used to determine the long-term risk for dementia per subgroup. We included 3,056 participants and identified 15 subgroups with distinct brain MRI phenotypes. The phenotypes ranged from limited burden, mostly irregular white matter hyperintensity (WMH) shape and cerebral atrophy, mostly irregularly WMHs and microbleeds, mostly cortical infarcts and atrophy, mostly irregularly shaped WMH and cerebral atrophy to multiburden subgroups. Each subgroup showed different long-term risks for dementia (min-max range hazard ratios [HRs] 1.01-6.18; mean time to follow-up 9.9 ± 2.6 years); especially the brain MRI phenotype with mainly WMHs and atrophy showed a large increased risk (HR 6.18, 95% CI 3.37-11.32). Distinct brain MRI phenotypes can be identified in community-dwelling older adults. Our results indicate that distinct brain MRI phenotypes are related to varying long-term risks of developing dementia. Brain MRI phenotypes may in the future assist in an improved understanding of the structural correlates of dementia predisposition.

Modulating the phenotype and function of bone marrow-derived macrophages via mandible and femur osteoblasts

Various studies have been investigated the phenotypic and functional distinctions of craniofacial and long bone cells involved in bone regeneration. However, the process of bone tissue regeneration after bone grafting involves complicated interactions between different cell types at the donor-recipient site. Additionally, differences in alterations of the immune microenvironment at the recipient site remained to be explored. Osteoblasts (OBs) and macrophages (MØ) play essential roles in the bone restoration and regeneration processes in the bone and immune systems, respectively. The modulation of MØ on OBs has been extensively explored in the literature, whereas limited research has been conducted on the influence of OBs on the MØ phenotype and function. In the present study, OBs from the mandible and femur (MOBs and FOBs, respectively) promoted cranial defect regeneration in rats, with better outcomes noted in the MOBs-treated group. After MOBs transplantation, a significant inflammatory response was induced, accompanied by an early increase in IL-10 secretion. And then, there was an upregulation in M2-MØ-related cell markers and inflammatory factor expression. Condition media (CM) of OBs mildly inhibited apoptosis in MØ, enhanced their migration and phagocytic functions, and concurrently increased iNOS and Arg1 expression, with MOB-CM demonstrating more pronounced effects compared to FOB-CM.In conclusion, our investigation showed that MOBs and FOBs have the ability to modulate MØ phenotype and function, with MOBs exhibiting a stronger regulatory potential. These findings provide a new direction for improving therapeutic strategies for bone regeneration in autologous bone grafts from the perspective of the immune microenvironment.

Intimate Partner Violence-Related Brain Injury: Unmasking and Addressing the Gaps.

Intimate partner violence (IPV) is a significant, global public health concern. Women, individuals with historically underrepresented identities, and disabilities are at high risk for IPV and tend to experience severe injuries. There has been growing concern about the risk of exposure to IPV-related head trauma, resulting in IPV-related brain injury (IPV-BI), and its health consequences. Past work suggests that a significant proportion of women exposed to IPV experience IPV-BI, likely representing a distinct phenotype compared with BI of other etiologies. An IPV-BI often co-occurs with psychological trauma and mental health complaints, leading to unique issues related to identifying, prognosticating, and managing IPV-BI outcomes. The goal of this review is to identify important gaps in research and clinical practice in IPV-BI and suggest potential solutions to address them. We summarize IPV research in five key priority areas: (1) unique considerations for IPV-BI study design; (2) understanding non-fatal strangulation as a form of BI; (3) identifying objective biomarkers of IPV-BI; (4) consideration of the chronicity, cumulative and late effects of IPV-BI; and (5) BI as a risk factor for IPV engagement. Our review concludes with a call to action to help investigators develop ecologically valid research studies addressing the identified clinical-research knowledge gaps and strategies to improve care in individuals exposed to IPV-BI. By reducing the current gaps and answering these calls to action, we will approach IPV-BI in a trauma-informed manner, ultimately improving outcomes and quality of life for those impacted by IPV-BI.

Reclassification of a reveromycin-producer and the proposals of Actinacidiphila reveromycinica sp. nov. and Actinacidiphila acidipaludis comb. nov.

Streptomyces sp. SN-593, a reveromycin producer, was previously thought to belong to the genus Streptomyces based on its morphological and chemotaxonomic characteristics. In this paper, we re-considered its taxonomic position according to the current criteria. Phylogenetic analysis using 16S rRNA gene sequences showed that the strain belongs to the genus Actinacidiphila. In multilocus sequence and phylogenomic analyses, the strain SN-593 represented a distinct evolutionary lineage within this genus, and its closest neighbor was A. yanglinensis. Digital DNA-DNA hybridization indicated that the strain shares less than 32% DNA-DNA relatedness with the type strains of closely related species, confirming this strain is a novel genomospecies. According to its phenotypic distinctiveness from the closest neighbor, we propose Actinacidiphila reveromycinica sp. nov. for the strain SN-593T. Additionally, as Streptomyces acidipaludis belonged to the genus Actinacidiphila in these analyses, it should be transferred to the genus, for which Actinacidiphila acidipaludis comb. nov. is proposed.

Abstract 2961: Investigating the role of aging and treatment-induced senescence in the metastatic liver cancer tumor microenvironment

Abstract Liver senescence, marked by the progressive decline in hepatic cell function and regenerative capacity, plays a vital role in the context of aging, chronic liver diseases, and cancer progression, particularly when influenced by anti-cancer therapies. This study is designed to extensively characterize liver senescence under two specific conditions: replicative aging and therapy-induced changes. We examined liver samples from 20 individuals, covering a wide age range (young, &amp;lt;40 years; old, &amp;gt;60 years), and 16 cases of colorectal cancer (CRC) liver metastasis (ages 37-66). Our integrative approach melds single-nucleus RNA-sequencing (snRNA-seq) and ATAC-sequencing (snATAC-seq) to investigate the transcriptomic and epigenetic landscapes across a spectrum of liver cell types, including hepatocytes, cholangiocytes, stellate cells, liver sinusoidal endothelial cells, and diverse immune cells. Key findings include an upregulation of senescence markers such as CDKN1A, CDKN2A, and HMGB1, particularly in specific hepatocytes from older individuals and various cell types in the CRC liver metastasis group. Furthermore, we noted a distinctive senescence-associated secretory phenotype (SASP) across multiple immune cell types in our treated CRC liver metastasis group and upregulation of treatment-induced senescence gene signatures, such as SenCan. Moreover, hepatic stellate cells from older subjects exhibited augmented senescence-related gene signatures (SenSig) and transcription factors (SenMayo), with myofibroblast-like and FAP+ stellate cells showing a marked senescence phenotype, evidenced by elevated SASP molecule expression (CCL2, SERPINE1, GLB1, IGFBP7, IGFBP3).Incorporating advanced high-resolution imaging techniques, our study delves into the detailed morphological characteristics and spatial distribution of senescence markers within the liver in the setting of replicative aging and treatment-induced senescence. This study sheds light on the heterogeneity and intricacies of senescence-associated gene expression within liver cell populations. By combining comprehensive multiomic data with advanced high-resolution spatial profiling, we aim to decipher unique senescence phenotypes in the context of both replicative and treatment-induced senescence. Our work highlights the significance of cellular senescence in liver pathologies and cancer progression, suggesting new directions for therapeutic interventions that target these complex dynamics. Citation Format: Kelsey Gallant, Alla Karpova, Xiang Li, Michael Iglesia, Andrew Houston, Daniel Rapp, Chien-Wei Peng, Clara Liu, John Herdon, Feng Chen, Ryan Fields, Li Ding. Investigating the role of aging and treatment-induced senescence in the metastatic liver cancer tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2961.