Genetic Factors Research Articles

Comparative Hypothalamic Proteomic Analysis Between Diet-Induced Obesity and Diet-Resistant Rats

Obesity arises from a complex interplay of genetic and environmental factors. Even among individuals with the same genetic predisposition, diet-induced obesity (DIO) exhibits varying degrees of susceptibility, which are categorized as DIO and diet-induced obesity resistance (DR). The hypothalamus plays a pivotal role in regulating energy homeostasis. This study performed a comparative hypothalamic proteomic analysis in DIO and DR rats to identify differentially expressed proteins (DEPs) associated with alterations in body weight. Male Sprague Dawley rats were fed either a standard chow diet or a high-fat diet for 12 weeks. DIO rats exhibited the most rapid weight gain compared to both the control and DR rats. Despite consuming similar caloric intake, DR rats exhibited less weight gain relative to DIO rats. Proteomic analysis revealed 31 DEPs in the hypothalamus of DR rats compared to DIO rats (with a false discovery rate (FDR) < 1%). Notably, 14 proteins were upregulated and 17 proteins were downregulated in DR rats. Gene ontology analysis revealed an enrichment of ion-binding proteins, such as those binding to Fe2+, Zn2+, Ca2+, and Se, as well as proteins involved in neuronal activity and function, potentially enhancing neuronal development and cognition in DR rats. The DEPs pathway analysis via the Kyoto Encyclopedia of Genes and Genomes (KEGG) implicated starch and sucrose metabolism, antigen processing and presentation, and the regulation of inflammatory mediator affecting TRP channels. Western blotting confirmed the proteomic findings for TRPV4, CaMKV, RSBN1, and BASP1, which were consistent with those obtained from Tandem Mass tag (TMT) proteomic analysis. In conclusion, our study highlights the hypothalamic proteome as a critical determinant in the susceptibility to DIO and provides novel targets for obesity prevention and treatment.

Management of anophthalmia, microphthalmia and coloboma in the newborn, shared care between neonatologist and ophthalmologist: a literature review.

Congenital ocular anomalies significantly contribute to global disability, with 15-20% of infant blindness attributed to these anomalies. This study examined anophthalmia, microphthalmia, and coloboma (AMC) through collaborative neonatology and ophthalmology care.The global prevalence of AMC varies: anophthalmia at 0.6-4.2 per 100,000 births and microphthalmia at 2-17 per 100,000 births, with a combined prevalence of up to 30 per 100,000. The prevalence of coloboma, alone or associate with other eye defects is 2-19 per 100,000 live births. Anophthalmia and microphthalmia may present as isolated or genetic syndromes, necessitating comprehensive evaluation. AMC etiology encompasses genetic and environmental factors. Chromosomal aberrations and mutations in genes such as PAX6, SOX2, OTX2, and CHD7 are contributors. Syndromic associations, such as CHARGE (heart defect, atresia choanae, retarded growth and development, genital hypoplasia, ear anomalies/deafness) syndrome, underscore the complexity of this syndrome. Early AMC diagnosis is pivotal for timely intervention. This work provides a literature review offering insights for effective management and genetic counseling in a pediatric context.

Alexithymia may explain the genetic relationship between autism and sensory sensitivity

Sensory symptoms are highly prevalent amongst autistic individuals and are now considered in the diagnostic criteria. Whilst evidence suggests a genetic relationship between autism and sensory symptoms, sensory symptoms are neither universal within autism nor unique to autism. One explanation for the heterogeneity within autism and commonality across conditions with respect to sensory symptoms, is that it is alexithymia (a condition associated with difficulties identifying and describing one’s own emotions) that has a genetic relationship with sensory symptoms, and that alexithymia commonly co-occurs with autism and with several other conditions. Using parent-reports of symptoms in a sample of adolescent twins, we sought to examine the genetic association between autism, alexithymia and sensory symptoms. Results showed that the genetic correlation between autism and sensory symptoms was not significant after controlling for alexithymia. In contrast, after controlling for variance in alexithymia explained by autism, the genetic correlation between alexithymia and sensory symptoms was significant (and the proportion of variance explained by genetic factors remained consistent after controlling for autism). These results suggest that 1) alexithymia and sensory symptoms share aetiology that is not accounted for by their association with autism and 2) that the genetic association between sensory symptoms and autism may be, in part or wholly, a product of alexithymia. Future research should seek to examine the contribution of alexithymia to sensory symptoms across other conditions.

Association of fine particulate matter constituents with chronic obstructive pulmonary disease and the effect modification of genetic susceptibility

This study investigated the link between long-term exposure to PM2.5 components and the risk of developing chronic obstructive pulmonary disease (COPD) using UK Biobank data. The exposure dataset, derived from the European Monitoring and Evaluation Program (EMEP) model, included elemental carbon (EC), organic matter (OM), ammonium (NH4+), nitrate (NO3−), and sulfate (SO42−). The risk of COPD was assessed using the Cox proportional hazards model, and the contribution of each component was evaluated with quantile g-computation. A polygenic risk score for COPD was used to explore genetic interactions with PM2.5 constituents. Adjusted hazard ratios showed an increased risk for each component and the mixed exposure, with SO42− (40.8%) contributing the most. We observed synergistic effects between genetic risk and exposure to PM2.5, EC, NH4+, and SO42−, accounting for 10–18% of total COPD risk. Prolonged exposure to PM2.5, especially SO42−, increased the risk of COPD, with genetic factors modifying the effect.

Regeneration following tissue necrosis is mediated by non-apoptotic caspase activity.

Tissue necrosis is a devastating complication for many human diseases and injuries. Unfortunately, our understanding of necrosis and how it impacts surrounding healthy tissue - an essential consideration when developing effective methods to treat such injuries - has been limited by a lack of robust genetically tractable models. Our lab previously established a method to study necrosis-induced regeneration in the Drosophila wing imaginal disc, which revealed a unique phenomenon whereby cells at a distance from the injury upregulate caspase activity in a process called Necrosis-induced Apoptosis (NiA) that is vital for regeneration. Here, we have further investigated this phenomenon, showing that NiA is predominantly associated with the highly regenerative pouch region of the disc, shaped by genetic factors present in the presumptive hinge. Furthermore, we find that a proportion of NiA fail to undergo apoptosis, instead surviving effector caspase activation to persist within the tissue and stimulate reparative proliferation late in regeneration. This proliferation relies on the initiator caspase Dronc, and occurs independent of JNK, ROS or mitogens associated with the previously characterized Apoptosis-induced Proliferation (AiP) mechanism. These data reveal a new means by which non-apoptotic Dronc signaling promotes regenerative proliferation in response to necrotic damage.

Regeneration following tissue necrosis is mediated by non-apoptotic caspase activity

Tissue necrosis is a devastating complication for many human diseases and injuries. Unfortunately, our understanding of necrosis and how it impacts surrounding healthy tissue – an essential consideration when developing effective methods to treat such injuries – has been limited by a lack of robust genetically tractable models. Our lab previously established a method to study necrosis-induced regeneration in the Drosophila wing imaginal disc, which revealed a unique phenomenon whereby cells at a distance from the injury upregulate caspase activity in a process called Necrosis-induced Apoptosis (NiA) that is vital for regeneration. Here, we have further investigated this phenomenon, showing that NiA is predominantly associated with the highly regenerative pouch region of the disc, shaped by genetic factors present in the presumptive hinge. Furthermore, we find that a proportion of NiA fail to undergo apoptosis, instead surviving effector caspase activation to persist within the tissue and stimulate reparative proliferation late in regeneration. This proliferation relies on the initiator caspase Dronc, and occurs independent of JNK, ROS or mitogens associated with the previously characterized Apoptosis-induced Proliferation (AiP) mechanism. These data reveal a new means by which non-apoptotic Dronc signaling promotes regenerative proliferation in response to necrotic damage.

Exploring proinsulin proteostasis: insights into beta cell health and diabetes

Proinsulin misfolding is central to diabetes. This review examines the cellular mechanisms regulating proinsulin proteostasis in pancreatic β-cells, encompassing genetic factors such as insulin gene mutations, and exploring the roles of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), ER redox balance, mitochondrial function, and the influence of extrinsic factors. Mutations in the INS gene, particularly those affecting cysteine residues, impair folding and disulfide bond formation, often exhibiting dominant-negative effects on the wild-type proinsulin. The importance of ER quality control mechanisms, including chaperones and oxidoreductases, in facilitating proper folding and degradation of misfolded proinsulin is emphasized. Disruptions in these systems, due to genetic mutations, ER stress, or impaired ER-to-Golgi trafficking, lead to proinsulin accumulation and β-cell dysfunction. The unfolded protein response (UPR), especially the PERK and IRE1α-XBP1 pathways, emerges as a central regulator of protein synthesis and ER stress management. The review also discusses the role of mitochondrial health, ER redox state, and extrinsic factors such as diet and medications in influencing proinsulin proteostasis. Finally, the structural insights from NMR and molecular dynamics simulations are discussedhighlighting the dynamics of misfolding and underscoring the importance of disulfide bonds. These mechanistic insights suggest innovative strategies targeting thiol/disulfide redox systems in cells to mitigate protein misfolding diseases including diabetes.

X-Linked Deafness Type 2 and Poor Response to Cochlear Implantation: A Case Report

Purpose: Hearing loss (HL) affects about one of every five children by the age of 18 years, and up to 60% can be related to genetic factors. The aim of this study is to present an unusual case of poor response to cochlear implantation in a child with X-linked deafness type 2. Method: This case report follows the “CARE” checklist. Results: The following report presents a 2-year-old child with bilateral nonsyndromic sensorineural HL with incomplete cochlear partition type III. The child has had a cochlear implant since 14 months of age. Genetic studies were performed after surgery. Next-generation sequencing analysis revealed two variants in GJB2ka and POU3F4 genes. Conclusion: This case study enables us to suggest auditory-verbal therapy and hearing aid trials before CI surgery in the absence of auditory dyssynchrony.

Impact of POU3F4 mutation on cochlear development and auditory function

BackgroundHearing loss, a major public health issue, affects 1.33 per 1,000 live births worldwide. Genetic factors contribute to over half of congenital cases, with X-linked inheritance accounting for 1–5%. POU3F4 mutations are associated with approximately 50% of X-linked non-syndrome hearing loss cases. POU3F4 plays a critical role in cochlear development by regulating otic mesenchyme cell differentiation. The study investigates the impact of a novel POU3F4 p.E294G mutation on cochlear structure and function using cellular and animal model.MethodsThe study utilized immortalized lymphoblastoid cell lines, POU3F4 overexpressed HEK293 cells and generated Pou3f4 knock-in (Pou3f4KI) mice via CRISPR/Cas9 to introduce the p.E294G mutation. Alterations in expression and subcellular localization of POU3F4 were detected at the cellular level. Auditory function was assessed using auditory brainstem response testing. Cochlear structure was analyzed through histology, immunohistochemistry, scanning electron microscopy, and transmission electron microscopy. RNA sequencing, qPCR and Western blot were conducted to evaluate gene expression and mitochondrial function.ResultsThe transcription of POU3F4 was abnormal and the expression was normal in lymphoblastoid cell lines. Abnormal nuclear localization of POU3F4 p.E294G was found in overexpressed HEK293 cells. Pou3f4KI mice exhibited cochlear malformations, including modiolus hypoplasia and reduced stria vascularis cell populations. Auditory testing revealed progressive hearing loss. Pou3f4 affect mitochondrial protein expression by affecting the expression of TFAM. Mitochondrial dysfunction was evident, with reduced oxidative phosphorylation (OXPHOS) complex assembly and activity, decreased ATP levels. The level of reactive oxygen species, mitochondrial fission and apoptosis in cochlea were elevated.ConclusionsThe POU3F4 p.E294G resulted in abnormal nuclear localization. Pou3f4 mutant disrupts cochlear development and function, impairs mitochondrial integrity, induces oxidative stress, and promotes apoptosis, leading to progressive hearing loss. The findings enhance the understanding of POU3F4-related hearing loss mechanisms and highlight the importance of early genetic screening and audiological monitoring.

Genetic factors contributing to the development of metabolic syndrome

Recently, the role of metabolic syndrome (MS) has become crucial. There is a tendency for this disease to increase not only in the Russian Federation and throughout the world. According to World Health Organization data for 2022, approximately 60% of the European population is overweight or obese. The United States and Russia have the largest numbers of obese individuals. MS often occurs in developed countries, mainly in the adult population, and is a comorbid pathology. MS increases the risk of future disability and mortality. Despite the environmental factors that increase the risk of MS, genetic factors are also involved in the development of this pathology. The genes involved in the development of MS: MC4R, LEP, LEPR, PCSK1, ADCY3, POMC, and MRAP2, were identified. These genes and MRAP2 were identified and involved in the leptin-melanocortin signaling pathway, namely, they regulate energy metabolism, which, when a mutation occurs, leads to nonsyndromic monogenic obesity. MS is a multifactorial pathological condition that includes four independent sub-syndromes: obesity or overweight, hypertension, dyslipidemia, and insulin resistance. This article describes the features of genes contributing to the development of MS as well as the clinical features of the MS course.

Mediterranean diet and breast cancer: A narrative review.

Breast cancer is the second most common neoplasm and the deadliest among women worldwide. Its incidence varies according to human development and is associated with several risk factors, including age, genetic factors, obesity, and dietary habits. Recent research has revealed a significant influence of dietary habits on the onset and progression of this disease, which is why this review aims to comprehensively analyze the available literature to understand better the role played by the mediterranean diet in the development and management of breast cancer. The mediterranean diet has anti-inflammatory and antioxidant effects, may influence gene regulation, and produce hormonal and intestinal microbiota changes, resulting in improved quality of life for breast cancer patients by alleviating symptoms such as pain, inflammation, and reducing the risk and mortality from this disease. Evidence suggests that greater adherence to the mediterranean diet reduces the risk of breast cancer, as well as an improvement in patients' quality of life and mortality. These findings underscore its potential relevance in the context of dietary patterns associated with breast cancer prevention and management, which could inform considerations for public health policies. Further research is needed to confirm these observations and to understand the underlying mechanisms better.

The effect of near work on the anterior eye and associations with myopia: a narrative review.

The global prevalence of myopia has increased significantly in recent decades, and it is anticipated that half the population of the world will be myopic by 2050. The dramatic increase in myopia cannot be explained solely by genetic factors; hence, environmental factors such as near work may play an important role in myopia development. Near work activities involve accommodation, convergence, and pupil constriction, which lead to various mechanical changes that alter the structural and optical properties of the anterior eye. Mechanical changes associated with near work activities include ciliary body contraction, medial rectus contraction, lateral rectus relaxation, changes in the eyelid-cornea interaction, pupil size, and crystalline lens shape and position. These structural variations lead to optical changes including a change in spherical refractive power, astigmatism, accommodative convergence, higher order aberrations, and retinal image quality. Several differences in near work-related optical and structural changes have been observed between myopes and non-myopes. These differences elucidate mechanisms that potentially underpin near work-associated axial elongation and myopia development. This narrative review explores anterior segment structural and optical changes during near work and their potential mechanistic contribution to myopia development, while highlighting literature gaps that require further research.

Sequential prenatal diagnosis of fetal skeletal dysplasia: A cohort study.

Genetic factors are considered to be the main factors leading to fetal skeletal dysplasia (SD), and chromosomal microarray analysis (CMA) has been used clinically for the detection of SD fetuses. At present, whole exome sequencing (WES) has been applied in SD fetuses, but there is still a lack of data accumulation. The aim of this study is to perform sequential prenatal diagnosis for fetuses with SD indicated by ultrasound and to explore the clinical value of CMA followed by WES. From January 2019 to May 2024, 147 fetuses with SD were detected by prenatal ultrasound screening. After the collection of amniotic fluid or abortive tissue, CMA was performed first, then WES was performed in the cases with a negative CMA result. 147 cases accepted the prenatal CMA test, and 23 cases were reported to have chromosomal abnormalities, including 9 cases of chromosomal aneuploidies, 11 cases of pathogenic copy number variants, and 3 cases of likely pathogenic copy number variants. The detection rate of chromosomal abnormalities by the prenatal CMA test was 15.6% (23/147). 58 cases with negative results of CMA underwent WES, and 21 genes with pathogenic/likely pathogenic variants were detected in 21 cases, including FGFR3, COL2A1, COL1A1, COL1A2, RUNX2, LMX1B, GLI3, SHOX, ALPL, and DYNC2H1. The rate of abnormal prenatal WES was 36.2% (21/58). In the subgroup analysis of the SD phenotype, the detection rate of chromosomal abnormalities in isolated SD fetuses was 7.7% (7/91), which was significantly lower than that in SD fetuses combined with other system abnormalities (28.6%, 16/56) (p = 0.001). The detection rate of monogenic abnormalities in short long bones with other skeletal abnormalities was 62.5% (10/16), which was higher than that in short long bones with non-skeletal abnormalities 10.5% (2/19), and the difference was statistically significant (p = 0.003). SD is mostly caused by monogenic abnormalities, and prenatal WES has significantly improved the detection rate of SD fetuses. The prenatal WES can be used as an important molecular genetic testing method combined with CMA in the sequential prenatal diagnosis of SD fetuses.

When Proteins Go Berserk: The Unfolded Protein Response and ER stress.

Background The cellular proteostasis machinery is essential for maintaining protein homeostasis by employing quality control systems that identify, sequester, and eliminate damaged or misfolded proteins. However, the accumulation of misfolded proteins can overwhelm these protective mechanisms, disrupting proteostasis. This phenomenon is a hallmark of numerous pathologies, including a variety of genetic disorders. In the secretory pathway, the buildup of misfolded proteins triggers endoplasmic reticulum (ER) stress, which activates the unfolded protein response (UPR). The UPR serves as an adaptive mechanism, aiming to alleviate stress and restore cellular homeostasis. However, if ER stress is prolonged or severe, the UPR may fail to restore balance and apoptosis is induced. Summary This review introduces the intricate signaling pathways activated by the three UPR transmembrane sensors: protein-kinase R-like endoplasmic reticulum kinase (PERK), inositol requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6). We briefly present the roles of the distinct transcriptional programs activated by each sensor in modulating the cellular response to protein stress and in determining cell fate. We discuss how genetic variants and environmental factors contribute to the heterogeneity observed in protein misfolding diseases. Finally, we critically evaluate select therapeutic strategies, specifically protein stabilization, trafficking modulation, and UPR sensor targeting approaches. Key message This review introduces the potential consequences of protein misfolding, which may not only impair protein function, but can also lead to toxic protein accumulation and stress induction. Using Fabry disease as a compelling example, we suggest that future therapeutic intervention may require nuanced, combination approaches that address both loss and gain of protein function.

Differential Association of Schizotypy Dimensions With Brain Structural Connectivity and Moderation by Schizophrenia Polygenic Risk.

Schizotypy as a psychosis proneness marker has facilitated the study of schizophrenia spectrum models, linking phenotypic psychosis risk to brain structural and functional variation. However, association studies to structural connectome markers are limited and often do not consider relations to genetic risk. We tested the hypothesis that dimensions of schizotypy (rather than overall phenotype risk burden) are related to fiber tract integrity and that this is moderated by polygenic schizophrenia risk (or resilience). In a cohort of 346 psychiatrically healthy subjects, we obtained diffusion tensor imaging, schizotypy using O-LIFE (Oxford-Liverpool Inventory of Feelings and Experiences), and polygenic risk scores (PRS) for schizophrenia risk and resilience to schizophrenia. Using FSL and TBSS (tract-based spatial statistics), we first analyzed the association between O-LIFE and fractional anisotropy (FA) for the anterior thalamic radiation, uncinate fascicle, and cingulum bundle, as well as moderation analyses with PRS scores. O-LIFE dimensions were differentially associated with structural connectivity, in particular, negative schizotypy positively to right uncinate FA, positive schizotypy negatively to right cingulum and disorganized schizotypy negatively to left cingulum. In disorganized schizotypy the association was moderated by schizophrenia PRS. Our results support a neurobiological continuum model of structural connectivity across psychosis proneness, emphasizing differential association with different schizotypy facets. Genetic schizophrenia risk, however, appears to impact only some of these associations, highlighting the need for further studies to understand the contribution of other genetic and/or environmental factors.

The combined effect between environmental exposure and oxidative stress-related susceptible gene polymorphisms on human semen quality.

The aim of the current study was to investigate the relationship between environmental factors and metabolic gene genotypes related to semen quality. A total of 341 men were recruited and classified into normal or abnormal semen quality groups according to the World Health Organization's 2010 criteria. Alcohol and tobacco use among men was self-reported. Pb (lead), As (arsenic), Ti (titanium), and Zn (zinc) metal elements in seminal plasma were measured using inductively coupled plasma mass spectrometry (ICP-MS). The ALDH2 rs671 and GSTP1 rs1695 polymorphism were detected using high-resolution melting (HRM) PCR. Individual environmental factors, including smoking, drinking, and exposure to Pb, As, Ti, or Zn, did not significantly associate with the risk of semen abnormalities. The ALDH2 GA/AA mutation genotype increased the risk of semen abnormalities in smoking males (AOR = 1.27; 95% CI, 1.01-1.62) and in males with high seminal Ti levels (AOR = 1.36; 95% CI, 1.00-1.90). The GSTP1 rs1695 gene (GG/AG) mutation genotype exhibited a protective effect on semen quality in males who did not consume alcohol (AOR = 0.65; 95% CI, 0.51-0.85) or smoke (AOR = 0.79; 95% CI, 0.61-1.00), as well as in those with low Pb (AOR = 0.63; 95% CI, 0.46-0.88) and Ti (AOR = 0.64; 95% CI, 0.47-0.90) exposure. The current study demonstrated that genetic and environmental factors interact with semen quality, and that men with the ALDH2 rs671A or GSTP1 rs1695A allele are susceptible to Ti-, alcohol-, and tobacco-induced semen quality abnormalities.

Unveiling thermosensitive genetic male sterility in rice - molecular insights and approaches

The application of male sterility has facilitated the commercialization of heterosis in rice, resulting in an enhanced yield and output of this staple food crop. The application of three-line hybrid rice technology is decreasing due to limited heterosis, lack of good combiner in cytoplasmic male sterile lines, poor reproducibility of hybrid seeds and limited commercial acceptance. Two-line heterosis breeding can overcome these issues. Two-line breeding allows for more diverse germplasm as parents, including any line as female and 97% of germplasm as male. Moreover, two-line breeding can lead to lower production costs. Systematic research can enable the widespread deployment of two-line hybrid rice technology. Identifying the novel genetic, molecular, and cellular factors and understanding the regulatory networks regulating male sterility in rice is vital for maximizing heterosis and ensuring global food security. In this review, we have briefly discussed the types of environment-sensitive genetic male sterility systems for two-line hybrid seed production. Furthermore, we have discussed the genetic, molecular and cellular basis for the thermosensitive genetic male sterility (TGMS) mechanism. We have provided insights on molecular and biotechnological interventions such as CRISPR and omics techniques in the TGMS system to address the existing concerns and to overcome the problems related to two-line rice breeding.

RNF213 Variant and Infectious Burden Associated With Intracranial Artery Stenosis in Moyamoya Disease.

The mechanisms driving the progression of moyamoya disease (MMD) remain unrecognized. There is evidence suggesting that genetic and environmental factors may be associated with intracranial artery stenosis. Here, we aimed to investigate the characteristics of infectious exposure and the association of the RNF213 (RING finger protein 213) variant and infectious burden (IB) with intracranial artery stenosis of MMD. We prospectively recruited 275 patients with MMD. Participants underwent RNF213p.R4810K sequencing. Serum antibody titers of herpes simplex virus, cytomegalovirus, toxoplasma, rubella virus, and Epstein-Barr virus were assessed and combined into an IB score. The degree of intracranial artery stenosis was measured by using the Willis narrowing score (WNS), which was then dichotomized as mild and severe. Multivariate regression analyses were performed to analyze variables associated with severe WNS. Patients with the RNF213 variant had a higher risk of severe WNS than wild-type individuals (P=0.003). Patients with MMD with severe WNS showed an increased level of IB score (P<0.001). The RNF213 variant (odds ratio [OR], 2.832 [95% CI, 1.347-5.955]; P=0.006) and IB score (OR, 1.771 [95% CI, 1.286-2.439]; P<0.001) were significantly associated with severe WNS after adjusting for covariates. Furthermore, the associations between IB score and severe WNS were more prominent among patients with modifiable risk factors of elevated body mass index (Pinteraction<0.001), triglycerides (Pinteraction=0.011), and homocysteine (Pinteraction=0.016). This study outlined a perspective of the genetic-environmental interactions in the progression of MMD. The RNF213 variant and increased IB were associated with intracranial artery stenosis in MMD. The study will provide novel insights into the mechanism of disease progression, which may offer opportunities for early intervention of infectious exposure in MMD.

Frontal Fibrosing Alopecia (FFA)

Frontal fibrosing alopecia (FFA) is a progressive cicatricial alopecia primarily affecting the frontal and temporal hairlines, often accompanied by eyebrow loss. First described by Steven Kossard in 1994, FFA has since emerged as a globally recognised condition, predominantly affecting postmenopausal women, though cases in men, premenopausal women, and adolescents are reported. Its pathogenesis remains unclear, involving autoimmune, hormonal, genetic, and environmental factors. Histopathological similarities to lichen planopilaris (LPP) suggest a potential overlap. FFA progresses slowly and is challenging to diagnose early, with symptoms such as hairline recession, perifollicular erythema, and scalp fibrosis. The condition is often associated with thyroid disorders, rosacea, and other autoimmune diseases. FFA’s multifactorial aetiology includes immune dysfunction, PPAR- γ dysregulation, and hormonal influences, with oestrogen depletion being significant in postmenopausal women. Environmental factors, such as certain skincare products and surgeries, may trigger the disease in genetically predisposed individuals. Treatments aim to halt disease progression and alleviate symptoms, as hair regrowth is typically unattainable once scarring occurs. Topical corticosteroids, calcineurin inhibitors, 5α-reductase inhibitors, and systemic agents like hydroxychloroquine are commonly used, but no standardised treatment exists. Ongoing research seeks to clarify its pathogenesis and improve therapeutic options. Early diagnosis and tailored management are essential to mitigate FFA’s impact.

Bioenergetic-related gene expression in the hippocampus predicts internalizing vs. externalizing behavior in an animal model of temperament

Externalizing and internalizing behavioral tendencies underlie many psychiatric and substance use disorders. These tendencies are associated with differences in temperament that emerge early in development via the interplay of genetic and environmental factors. To better understand the neurobiology of temperament, we have selectively bred rats for generations to produce two lines with highly divergent behavior: bred Low Responders (bLRs) are highly inhibited and anxious in novel environments, whereas bred High Responders (bHRs) are highly exploratory, sensation-seeking, and prone to drug-seeking behavior. Recently, we delineated these heritable differences by intercrossing bHRs and bLRs (F0-F1-F2) to produce a heterogeneous F2 sample with well-characterized lineage and behavior (exploratory locomotion, anxiety-like behavior, Pavlovian conditioning). The identified genetic loci encompassed variants that could influence behavior via many mechanisms, including proximal effects on gene expression. Here we measured gene expression in male and female F0s (n = 12 bHRs, 12 bLRs) and in a large sample of heterogeneous F2s (n = 250) using hippocampal RNA-Seq. This enabled triangulation of behavior with both genetic and functional genomic data to implicate specific genes and biological pathways. Our results show that bHR/bLR differential gene expression is robust, surpassing sex differences in expression, and predicts expression associated with F2 behavior. In F0 and F2 samples, gene sets related to growth/proliferation are upregulated with bHR-like behavior, whereas gene sets related to mitochondrial function, oxidative stress, and microglial activation are upregulated with bLR-like behavior. Integrating our F2 RNA-Seq data with previously-collected whole genome sequencing data identified genes with hippocampal expression correlated with proximal genetic variation (cis-expression quantitative trait loci or cis-eQTLs). These cis-eQTLs successfully predict bHR/bLR differential gene expression based on F0 genotype. Sixteen of these genes are associated with cis-eQTLs colocalized within loci we previously linked to behavior and are strong candidates for mediating the influence of genetic variation on behavioral temperament. Eight of these genes are related to bioenergetics. Convergence between our study and others targeting similar behavioral traits revealed five more genes consistently related to temperament. Overall, our results implicate hippocampal bioenergetic regulation of oxidative stress, microglial activation, and growth-related processes in shaping behavioral temperament, thereby modulating vulnerability to psychiatric and addictive disorders.