Biological Underpinnings Research Articles

The pollutome-connectome axis: a putative mechanism to explain pollution effects on neurodegeneration.

The study of pollutant effects is extremely important to address the epochal challenges we are facing, where world populations are increasingly moving from rural to urban centers, revolutionizing our world into an urban world. These transformations will exacerbate pollution, thus highlighting the necessity to unravel its effect on human health. Epidemiological studies have reported that pollution increases the risk of neurological diseases, with growing evidence on the risk of neurodegenerative disorders. Air pollution and water pollutants are the main chemicals driving this risk. These chemicals can promote inflammation, acting in synergy with genotype vulnerability. However, the biological underpinnings of this association are unknown. In this review, we focus on the link between pollution and brain network connectivity at the macro-scale level. We provide an updated overview of epidemiological findings and studies investigating brain network changes associated with pollution exposure, and discuss the mechanistic insights of pollution-induced brain changes through neural networks. We explain, in detail, the pollutome-connectome axis that might provide the functional substrate for pollution-induced processes leading to cognitive impairment and neurodegeneration. We describe this model within the framework of two pollutants, air pollution, a widely recognized threat, and polyfluoroalkyl substances, a large class of synthetic chemicals which are currently emerging as new neurotoxic source.

Tumoral Densities of T-Cells and Mast Cells Are Associated With Recurrence in Early-Stage Lung Adenocarcinoma

IntroductionLung cancer is the deadliest cancer in the United States and worldwide, and lung adenocarcinoma (LUAD) is the most prevalent histologic subtype in the United States. LUAD exhibits a wide range of aggressiveness and risk of recurrence, but the biological underpinnings of this behavior are poorly understood. Past studies have focused on the biological characteristics of the tumor itself, but the ability of the immune response to contain tumor growth represents an alternative or complementary hypothesis. Emerging technologies enable us to investigate the spatial distribution of specific cell types within the tumor nest and characterize this immune response. This study aimed to investigate the association between immune cell density within the primary tumor and recurrence-free survival (RFS) in stage I and II LUAD. MethodsThis study is a prospective collection with retrospective evaluation. A total of 100 patients with surgically resected LUAD and at least 5-year follow-ups, including 69 stage I and 31 stages II tumors, were enrolled. Multiplexed immunohistochemistry panels for immune markers were used for measurement. ResultsCox regression models adjusted for sex and EGFR mutation status revealed that the risk of recurrence was reduced by 50% for the unit of one interquartile range (IQR) change in the tumoral T-cell (adjusted hazard ratio per IQR increase = 0.50, 95% confidence interval: 0.27–0.93) and decreased by 64% in mast cell density (adjusted hazard ratio per IQR increase = 0.36, confidence interval: 0.15–0.84). The analyses were reported without the type I error correction for the multiple types of immune cell testing. ConclusionsAnalysis of the density of immune cells within the tumor and surrounding stroma reveals an association between the density of T-cells and RFS and between mast cells and RFS in early-stage LUAD. This preliminary result is a limited study with a small sample size and a lack of an independent validation set.

Neurological Dysfunction in Long COVID Should Not Be Labelled as Functional Neurological Disorder.

There have been suggestions that Long COVID might be purely functional (meaning psychological) in origin. Labelling patients with neurological dysfunction in Long COVID as having functional neurological disorder (FND) in the absence of proper testing may be symptomatic of that line of thought. This practice is problematic for Long COVID patients, as motor and balance symptoms have been reported to occur in Long COVID frequently. FND is characterized by the presentation of symptoms that seem neurological but lack compatibility of the symptom with a neurological substrate. Although diagnostic classification according to the ICD-11 and DSM-5-TR is dependent predominantly on the exclusion of any other medical condition that could account for the symptoms, current neurological practice of FND classification allows for such comorbidity. As a consequence, Long COVID patients with motor and balance symptoms mislabeled as FND have no longer access to Long COVID care, whereas treatment for FND is seldom provided and is ineffective. Research into underlying mechanisms and diagnostic methods should explore how to determine whether motor and balance symptoms currently diagnosed as FND should be considered one part of Long COVID symptoms, in other words, one component of symptomatology, and in which cases they correctly represent FND. Research into rehabilitation models, treatment and integrated care are needed, which should take into account biological underpinnings as well as possible psychological mechanisms and the patient perspective.

The Association between Infant Colic and the Multi-Omic Composition of Human Milk

Infant colic is a common condition with unclear biologic underpinnings and limited treatment options. We hypothesized that complex molecular networks within human milk (i.e., microbes, micro-ribonucleic acids (miRNAs), cytokines) would contribute to colic risk, while controlling for medical, social, and nutritional variables. This hypothesis was tested in a cohort of 182 breastfed infants, assessed with a modified Infant Colic Scale at 1 month. RNA sequencing was used to interrogate microbial and miRNA features. Luminex assays were used to measure growth factors and cytokines. Milk from mothers of infants with colic (n = 28) displayed higher levels of Staphylococcus (adj. p = 0.038, d = 0.30), miR-224-3p (adj. p = 0.023, d = 0.33), miR-125b-5p (adj. p = 0.028, d = 0.29), let-7a-5p (adj. p = 0.028, d = 0.27), and miR-205-5p (adj. p = 0.029, d = 0.26) compared to milk from non-colic mother-infant dyads (n = 154). Colic symptom severity was directly associated with milk hepatocyte growth factor levels (R = 0.21, p = 0.025). A regression model involving let-7a-5p, miR-29a-3p, and Lactobacillus accurately modeled colic risk (X2 = 16.7, p = 0.001). Molecular factors within human milk may impact colic risk, and provide support for a dysbiotic/inflammatory model of colic pathophysiology.

Dopamine Dynamics and Neurobiology of Non-Response to Antipsychotics, Relevance for Treatment Resistant Schizophrenia: A Systematic Review and Critical Appraisal

Treatment resistant schizophrenia (TRS) is characterized by a lack of, or suboptimal response to, antipsychotic agents. The biological underpinnings of this clinical condition are still scarcely understood. Since all antipsychotics block dopamine D2 receptors (D2R), dopamine-related mechanisms should be considered the main candidates in the neurobiology of antipsychotic non-response, although other neurotransmitter systems play a role. The aims of this review are: (i) to recapitulate and critically appraise the relevant literature on dopamine-related mechanisms of TRS; (ii) to discuss the methodological limitations of the studies so far conducted and delineate a theoretical framework on dopamine mechanisms of TRS; and (iii) to highlight future perspectives of research and unmet needs. Dopamine-related neurobiological mechanisms of TRS may be multiple and putatively subdivided into three biological points: (1) D2R-related, including increased D2R levels; increased density of D2Rs in the high-affinity state; aberrant D2R dimer or heteromer formation; imbalance between D2R short and long variants; extrastriatal D2Rs; (2) presynaptic dopamine, including low or normal dopamine synthesis and/or release compared to responder patients; and (3) exaggerated postsynaptic D2R-mediated neurotransmission. Future points to be addressed are: (i) a more neurobiologically-oriented phenotypic categorization of TRS; (ii) implementation of neurobiological studies by directly comparing treatment resistant vs. treatment responder patients; (iii) development of a reliable animal model of non-response to antipsychotics.

Depression Predicts Cardiac Cachexia in Heart Failure Patients.

Cardiac cachexia (CC) is associated with increased morbidity and mortality in persons with heart failure (HF). Compared to the biological underpinning of CC, little is known about the psychological factors. Thus, the overarching objective of this study was to determine whether depression predicts the onset of cachexia at 6 months in patients with chronic HF. 114 participants with a mean age of 56.7 ± 13.0 years, LVEF of 33.13 ± 12.30% and NYHA class III (48.0%) were assessed for depression using the PHQ-9. Body weight was measured at baseline and at 6 months. Patients who had ≥6% non-edematous unintentional weight loss were classified as cachectic. Univariate and logistic multivariate regression were used to examine the relationship between CC and depression, controlling for clinical and demographic variables. Cachectic patients (11.4%) had significantly higher baseline BMI levels (31.35 ± 5.70 vs. 28.31 ± 4.73; p = .038), lower LVEF (mean = 24.50 ± 9.48 vs. 34.22 ± 12.18, p = .009), and depression scores (mean = 7.17 ± 6.44 vs. 4.27 ± 3.98, p = .049) when compared to their non-cachectic counterparts. In multivariate regression analysis, depression scores (β = 1.193, p = .035) and LVEF (β = .835, p = .031) predicted cachexia after controlling for age, gender, body mass index, VO2 max, and New York Heart Association class and accounted for 49% of the variance in Cardiac cachexia. When depression was dichotomized, depression and LVEF predicted 52.6% of the variance in CC. Depression predicts CC in patients with HF. Additional studies are needed to expand the knowledge of the role of the psychological determinants of this devastating syndrome.

Host-Related Factors in the Interplay among Inflammation, Immunity and Dormancy in Breast Cancer Recurrence and Prognosis: An Overview for Clinicians.

A significant proportion of patients treated for early breast cancer develop medium-term and late distant recurrence. The delayed manifestation of metastatic disease is defined as "dormancy". This model describes the aspects of the clinical latency of isolated metastatic cancer cells. Dormancy is regulated by extremely complex interactions between disseminated cancer cells and the microenvironment where they reside, the latter in turn influenced directly by the host. Among these entangled mechanisms, inflammation and immunity may play leading roles. This review is divided into two parts: the first describes the biological underpinnings of cancer dormancy and the role of the immune response, in particular, for breast cancer; the second provides an overview of the host-related factors that may influence systemic inflammation and immune response, subsequently impacting the dynamics of breast cancer dormancy. The aim of this review is to provide physicians and medical oncologists a useful tool to understand the clinical implications of this relevant topic.

What does the immunometabolic status tell us about depression?

AbstractDespite being a clinical identifiable entity, major depressive disorder (MDD) is an heterogenous clinical syndrome, with a variety of clinical presentations which likely reflects different biological underpinnings. The identification of biologically-based depression symptoms profiles would be of great importance to unravel different pathophysiological pathways in MDD and therefore to achieve more precise and personalized therapeutical approaches as well as preventive strategies.Converging evidence from epidemiological and clinical studies, points to the importance of inflammation in MDD, shown by increased levels of pro-inflammatory proteins and increased inflammation-related comorbidities, including metabolic diseases. In fact, there exists a bidirectional relationship between inflammation and metabolic dysfunction that could be linked to multiple factors, including life style, stress and genetic predisposition. MDD patients exhibit several metabolic disturbances such as overweight, insuline resistance and dyslipidemia, among others, which are not always fully explained by life style factors. These findings have led to the formulation of an immunometabolic hypothesis, which could be present in a subgroup of MDD patients, associated to specific symptoms and clinical features.In this presentation, data reflecting the complex relationships and interactions between immune and metabolic disturbances in MDD will be shown. In particular, it will be shown how machine learning approaches can be useful to disentangle the clinical and biological heterogeneity of MDD, using immunometabolic biomarkers.Disclosure of InterestP. Lopez-Garcia Grant / Research support from: Grant from Carlos III Health Institute ref PI15/00204 and FEDER funding from the EU

Gender differences in the risk of developing obesity related disease can be explained by sex‐specific molecular signatures that regulates adipose endothelial cell growth

Obesity is the excessive growth of adipose tissue resulting from the chronic consumption of excess calories and is a recognised risk factor for developing cardio-metabolic diseases. There is however a significant variation in the size and expandibility of different adipose tissue in humans. The inability of adipose tissue to expand “safely” leads to ectopic fat deposition, causing insulin resistance, type 2 diabetes and cardiovascular conditions – which are more prevalent in men than women. Thus, the mechanisms that control the expandability of adipose tissue are key factors in determining diabetes risk in obesity. An interesting study from York University have provided new insights on the biological underpinning in gender differences in the risk of developing obesity-related diseases. Previous study from this group has observed that when mice become obese, females grow more new blood vessels to supply the expanding fat tissue with oxygen and nutrients, whereas males grow a lot less. To understand the mechanism regulating this, the team used software to help sift through thousands of genes to zero in on the ones that would be associated with blood vessel growth. They discovered that processes associated with the proliferation of new blood vessels were high in the female mice, whereas the males had a high level of processes associated with inflammation. Thereafter, the investigators examined the behaviour of the endothelial cells ex-vivo. Interestingly, they observed that even when these cells were studied ex-vivo, male and female endothelial cells still behave very differently from each other - female endothelial cells replicated faster, while male endothelial cells displayed greater sensitivity to an inflammatory stimulus. Further studies to investigate the effects of specific genes in humans that regulate endothelial cells growth will provide potential therapeutic target to manage and treat obesity related cardio-metabolic diseases. The study was funded by a grant through the Canadian Institutes of Health Research, as well as the Natural Science and Engineering Research Council of Canada and York's Faculty of Health.

Contributions of eudaimonic well-being to mental health practice

PurposeThe purpose of this article is to examine synergies between a eudaimonic model of psychological well-being (Ryff, 1989) and mental health practice. The model grew out of clinical, developmental, existential and humanistic perspectives that emphasized psychological strengths and capacities, in contrast to the focus on emotional distress and dysfunction in clinical psychology.Design/methodology/approachConceptual foundations of the eudaimonic approach are described, along with the six components positive functioning that are used to measure well-being. These qualities may be important in facilitating the recovery experiences, which are of interest in Mental Health and Social Inclusion.FindingsFour categories of empirical evidence about eudaimonia are reviewed: how it changes with aging, how it matters for health, what are its biological and neurological underpinnings and whether it can be promoted. Major contemporary forces against eudaimonia are also considered, including ever-widening inequality, the enduring pandemic and world-wide strife. In contrast, encounters with the arts and nature are put forth as forces for eudaimonia. The relevance of these ideas for mental health research and practice is considered.Practical implicationsEnormous suffering defines our contemporary world. Such realities call for greater attention to factors that undermine as well as nurture the realization of human potential, the core of eudaimonic well-being.Originality/valueMental health is often defined as the absence of mental illness. The novelty of the eudaimonic approach is to define mental health as the presence of well-being, assessed with different components of positive functioning.

The Functional Significance of a Novel Conceptualization of Intrusion Symptoms of PTSD

IntroductionIntrusion symptoms are a core defining feature of posttraumatic stress disorder (PTSD). It was recently proposed that intrusions may be comprised of two distinct underlying processes: internally-cued intrusions (e.g., memories), and externally-cued intrusions (e.g., reactions to one’s environment). Preliminary empirical evidence demonstrated superior fit of an 8-factor model of PTSD, separating intrusion symptoms into an in internally-cued and externally-cued symptom cluster over other factor models of PTSD. However, whether these two clusters are related differently with functional outcomes was not investigated previously.ObjectivesThis is the first study to examine the functional correlates of the internally-cued and externally-cued intrusion symptom clusters in PTSD to assess whether separating intrusion symptoms into these two clusters is of clinical and scientific relevance.MethodsParticipants included 7460 veterans discharged from 40 VA PTSD residential treatment programs (RRTPs) across the United States in fiscal years 2018 through 2020. Demographic data was collected using a self-report form during the admission process. Symptoms of PTSD, anxiety, depression, and emotional and physical functioning were assessed with the PTSD Checklist for DSM-5, the Patient Health Questionnaire-9, the Generalized Anxiety Disorder Questionnaire-7, and the corresponding subscales of the Short Form 12-item Health Survey, respectively. Latent network modeling was used to test the fit of the 8-factor model of PTSD. Structural equation modelling was used to investigate the associations between the factors of PTSD and the functional outcomes. All associations were adjusted for demographic characteristics, and standardized.ResultsThe 8-factor model, with separate intrusion factors, showed good model fit (CFI 0.965, RMSEA 0.045, χ2 2453.022, and P <.001). Internally-cued intrusions were negatively associated with physical functioning and positively with emotional functioning. No relationship with depression or anxiety was found. In contrast, externally-cued intrusions were negatively associated with emotional functioning and positively associated with anxiety, but not related to physical functioning and depression.ConclusionsThis study provides initial support for the functional utility of distinguishing between internally- and externally-cued intrusions in veterans with PTSD. Consequently, researchers focusing on the biological underpinnings of intrusion symptoms (e.g., in imaging or genetic studies) should account for differences in the origin of the cue triggering intrusions. Our findings are of potential clinical relevance as they might help patients adapt their coping strategies for intrusions depending on whether they originate internally (e.g., thoughts) or externally (e.g., loud noises).Disclosure of InterestNone Declared

Multimorbidity and Functional Disability among Older Adults: The Role of Inflammation and Glycemic Status – An Observational Longitudinal Study

Introduction: Specific multimorbidity combinations, in particular those including arthritis, stroke, and cognitive impairment, have been associated with high burden of activities of daily living (ADL)-instrumental activities of daily living (IADL) disability in older adults. The biologic underpinnings of these associations are still unclear. Methods: Observational longitudinal study using data from the Health and Retirement Study (N = 8,618, mean age = 74 years, 58% female, 25% non-white) and negative binomial regression models stratified by sex to evaluate the role of inflammatory and glycemic biomarkers (high-sensitivity C-reactive protein (hs-CRP) and HbA1c) in the association between specific multimorbidity combinations (grouped around one of eight index diseases: arthritis, cancer, cognitive impairment, diabetes, heart disease, hypertension, lung disease, and stroke; assessed between 2006 and 2014) and prospective ADL-IADL disability (2 years later, 2008–2016). Results were adjusted for sociodemographic characteristics, body mass index, number of coexisting diseases, and baseline ADL-IADL score. Results: Multimorbidity combinations indexed by arthritis (IRR = 1.1, 95% CI = 1.01–1.20), diabetes (IRR = 1.19, 95% CI = 1.09–1.30), and cognitive impairment (IRR = 1.11, 95% CI = 1.01–1.23) among men and diabetes-indexed multimorbidity combinations (IRR = 1.07, 95% CI = 1.01–1.14) among women were associated with higher ADL-IADL scores at increasing levels of HbA1c. Across higher levels of hs-CRP, multimorbidity combinations indexed by arthritis (IRR = 1.06, 95% CI = 1.02–1.11), hypertension (IRR = 1.06, 95% CI = 1.02–1.11), heart disease (IRR = 1.06, 95% CI = 1.01–1.12), and lung disease (IRR = 1.14, 95% CI = 1.07–1.23) were associated with higher ADL-IADL scores among women, while there were no significant associations among men. Conclusion: The findings suggest potential for anti-inflammatory management among older women and optimal glycemic control among older men with these particular multimorbidity combinations as focus for therapeutic/preventive options for maintaining functional health.

Rational Targets of Therapy in Extranodal NK/T-Cell Lymphoma

Extranodal NK/T-cell lymphoma (ENKTL) is an aggressive extranodal non-Hodgkin lymphoma (NHL) with poor outcomes, particularly in advanced-stage and relapsed/refractory disease. Emerging research on molecular drivers of ENKTL lymphomagenesis by next-generation and whole genome sequencing has revealed diverse genomic mutations in multiple signaling pathways, with the identification of multiple putative targets for novel therapeutic agents. In this review, we summarize the biological underpinnings of newly-understood therapeutic targets in ENKTL with a focus on translational implications, including epigenetic and histone regulatory aberrations, activation of cell proliferation signaling pathways, suppression of apoptosis and tumor suppressor genes, changes in the tumor microenvironment, and EBV-mediated oncogenesis. In addition, we highlight prognostic and predictive biomarkers which may enable a personalized medicine approach toward ENKTL therapy.

Cytomegalovirus viremia and advanced HIV disease: is there an argument for anti-CMV treatment?

ABSTRACT Introduction The role of cytomegalovirus (CMV) infection as a co-factor in HIV disease has been a topic of considerable interest since the beginning of the HIV pandemic. CMV is believed to function both as a co-factor in the progression of HIV infection, and as a contributor to enhanced disease for other opportunistic infections. Areas covered In this special article, we review several recent studies that have enhanced our understanding of the role that CMV infection plays in the natural history of other HIV-related opportunistic infections. We review the clinical evidence that demonstrates how CMV viremia has emerged as an independent risk factor for the progression of infections such as those caused by C. neoformans and M. tuberculosis. We outline the biological underpinnings of the various hypotheses by which CMV, as an immunomodulatory virus, may modify the natural history of HIV-related infections. Expert opinion Evidence suggests that active CMV replication, manifest as CMV viremia (DNAemia), may play a key role in driving progression of HIV-associated opportunistic infections. We propose that control of CMV replication, independent of the known benefit of HAART therapy on reducing CMV end-organ disease, could reduce the risk of disease and mortality attributable to opportunistic infections such as cryptococcosis and tuberculosis. This could be achieved by the targeted use of CMV antivirals. The advent of newer (and safer) orally bioavailable CMV antivirals has renewed interest in, and opportunities for, randomized controlled trials to evaluate CMV viremia as a modifiable risk factor in high-risk persons with HIV disease.

In utero metabolomic signatures of refined grain intake and risk of gestational diabetes: A metabolome-wide association study

BackgroundEpidemiologic evidence has linked refined grain intake to a higher risk of gestational diabetes (GDM), but the biological underpinnings remain unclear. ObjectivesWe aimed to identify and validate refined grain-related metabolomic biomarkers for GDM risk. MethodsIn a metabolome-wide association study of 91 cases with GDM and 180 matched controls without GDM (discovery set) nested in the prospective Pregnancy Environment and Lifestyle Study (PETALS), refined grain intake during preconception and early pregnancy and serum untargeted metabolomics were assessed at gestational weeks 10–13. We identified refined grain-related metabolites using multivariable linear regression and examined their prospective associations with GDM risk using conditional logistic regression. We further examined the predictivity of refined grain-related metabolites selected by least absolute shrinkage and selection operator regression in the discovery set and validation set (a random PETALS subsample of 38 individuals with and 336 without GDM). ResultsAmong 821 annotated serum (87.4% fasting) metabolites, 42 were associated with refined grain intake, of which 17 (70.6% in glycerolipids, glycerophospholipids, and sphingolipids clusters) were associated with subsequent GDM risk (all false discovery rate-adjusted P values <0.05). Adding 7 of 17 metabolites to a conventional risk factor-based prediction model increased the C-statistic for GDM risk in the discovery set from 0.71 (95% CI: 0.64, 0.77) to 0.77 (95% CI: 0.71, 0.83) and in the validation set from 0.77 (95% CI: 0.69, 0.86) to 0.81 (95% CI: 0.74, 0.89), both with P-for-difference <0.05. ConclusionsClusters of glycerolipids, glycerophospholipids, and sphingolipids may be implicated in the association between refined grain intake and GDM risk, as demonstrated by the significant associations of these metabolites with both refined grains and GDM risk and the incremental predictive value of these metabolites for GDM risk beyond the conventional risk factors. These findings provide evidence on the potential biological underpinnings linking refined grain intake to the risk of GDM and help identify novel disease-related dietary biomarkers to inform diet-related preventive strategies for GDM.

Robust correlation estimation and UMAP assisted topological analysis of omics data for disease subtyping

Deciphering information hidden in the gene expression assays for identifying disease subtypes has significant importance in precision medicine. However, computational limitations thwart this process due to the intricacy of the biological networks and the curse of dimensionality of gene expression data. Therefore, clustering in such scenarios often becomes the first choice of exploratory data analysis to identify natural structures and intrinsic patterns in the data. However, sparse and high dimensional nature of omics data prevents conventional clustering algorithms to discover subtypes that are clinically relevant and statistically significant. Hence, non-linear dimensionality reduction techniques coupled with clustering in such scenarios often becomes imperative to improve the clustering results. In this study, we present a robust pipeline to discover disease subtypes with clinical relevance. Specifically, we focus on discovering patient sub-groups that have a residual life patterns remarkably different from other sub-groups. This is significant because by refining prognosis, subtyping can reduce uncertainty in approximating patients expected outcome. The methodology present is based on robust correlation estimation, UMAP– a non-linear dimensionality reduction method and mapper– a tool from topology. Notably, we suggest a method for improving the robustness of the correlation matrix of gene expression data for improving the clustering results. The performance of the model is evaluated by applying to five cancer datasets obtained through TCGA and comparisons are performed with some state of the art methods of NEMO, RSC-OTRI and SNF with regard to log−rank test and Restricted Life Expectancy Difference. For example in GBM dataset, the minimum separation for any two discovered subtypes is 221 days which is significantly higher than the other methodologies. We also compared the results without using the robust correlation based estimate and observed that robust correlation improves separability between survival curves significantly. From the results we infer that our methodology performs better compared to other methodologies with regard to separating survival curves of patient sub-groups despite using single omics profiles of patients compared to multiple omics profiles of SNF and NEMO. Pathway over-representation analysis is performed on the final clustering results to investigate the biological underpinnings characterizing each subtype.

Human Cloning: Biology, Ethics, and Social Implications.

This scholarly article delves into the multifaceted domains of human cloning, encompassing its biological underpinnings, ethical dimensions, and broader societal implications. The exposition commences with a succinct historical and contextual overview of human cloning, segueing into an in-depth exploration of its biological intri-cacies. Central to this biological scrutiny is a comprehensive analysis of somatic cell nuclear transfer (SCNT) and its assorted iterations. The accomplishments and discoveries in cloning technology, such as successful animal cloning operations and advances in the efficiency and viability of cloned embryos, are reviewed. Future improvements, such as reprogramming procedures and gene editing technology, are also discussed. The discourse extends to ethical quandaries intrinsic to human cloning, entailing an extensive contemplation of values such as human dignity, autonomy, and safety. Furthermore, the ramifications of human cloning on a societal plane are subjected to scrutiny, with a dedicated emphasis on ramifications encompassing personal identity, kinship connections, and the fundamental notion of maternity. Culminating the analysis is a reiteration of the imperative to develop and govern human cloning technology judiciously and conscientiously. Finally, it discusses several ethical and practical issues, such as safety concerns, the possibility of exploitation, and the erosion of human dignity, and emphasizes the significance of carefully considering these issues.

Abstract WMP105: Gluteofemoral Fat Distribution Is Associated With Decreased Stroke Risk: A Mendelian Randomization Study

Introduction: Previous studies have suggested that increased body fat is associated with stroke risk. Advances in imaging-based fat distribution measurements have uncovered distinct biological underpinnings of local fat depots. Here, we explored associations between biologically relevant local adiposity profiles and stroke risk, aiming to refine the association between body fat distribution and stroke. Methods: Utilizing data from Genome-Wide Association Studies of MRI-derived visceral (VAT), abdominal subcutaneous (ASAT) and gluteofemoral (GFAT) adipose tissue volumes in the UK Biobank (n= 37,750), we selected genome-wide (p&lt;5x10 -8 ), independent (r 2 &lt;0.01), BMI- and height-adjusted variants associated with each trait. We performed Mendelian Randomization (MR) analyses of each trait on ischemic stroke (n=34,217) and subtypes (large artery (LAS)=4,373; cardioembolic (CES)=7,193; small vessel (SVS)=5,386) in MEGASTROKE. We performed multivariable MR, adjusting for relevant cardiometabolic factors (low-density lipoprotein, systolic blood pressure, type 2 diabetes, coronary artery disease). Estimates were expressed as per liter increase in fat volume. Results: GFAT distribution was associated with an overall decreased risk of ischemic stroke (OR 0.89; 95% CI: 0.82-96; p=0.04), mainly driven by SVS risk (OR 0.76; 95% CI: 0.64-0.88; p&lt;0.001) (Figure 1A). Associations were largely consistent in weighted-median and MR-Egger analyses. After adjusting for cardiometabolic factors, only the association between GFAT and SVS remained significant (Figure 1B) . Neither VAT nor ASAT volumes were associated with ischemic stroke risk (both p&gt;0.05). Conclusions: GFAT distribution is associated with a favorable stroke risk profile, suggesting that increases in stroke risk in the setting of an unhealthy body fat distribution may potentially primarily be driven by relative decreases in GFAT rather than increases in VAT or ASAT.

Th17.1 cell driven sarcoidosis-like inflammation after anti-BCMA CAR T cells in multiple myeloma

Pseudo-progression and flare-up phenomena constitute a novel diagnostic challenge in the follow-up of patients treated with immune-oncology drugs. We present a case study on pulmonary flare-up after Idecabtagen Vicleucel (Ide-cel), a BCMA targeting CAR T-cell therapy, and used single-cell RNA-seq (scRNA-seq) to identify a Th17.1 driven autoimmune mechanism as the biological underpinning of this phenomenon. By integrating datasets of various lung pathological conditions, we revealed transcriptomic similarities between post CAR T pulmonary lesions and sarcoidosis. Furthermore, we explored a noninvasive PET based diagnostic approach and showed that tracers binding to CXCR4 complement FDG PET imaging in this setting, allowing discrimination between immune-mediated changes and true relapse after CAR T-cell treatment. In conclusion, our study highlights a Th17.1 driven autoimmune phenomenon after CAR T, which may be misinterpreted as disease relapse, and that imaging with multiple PET tracers and scRNA-seq could help in this diagnostic dilemma.

The genome of sheep ked (Melophagus ovinus) reveals potential mechanisms underlying reproduction and narrower ecological niches

BackgroundMelophagus ovinus is considered to be of great veterinary health significance. However, little is known about the information on genetic mechanisms of the specific biological characteristics and novel methods for controlling M. ovinus.ResultsIn total, the de novo genome assembly of M. ovinus was 188.421 Mb in size (330 scaffolds, N50 Length: 10.666 Mb), with a mean GC content of 27.74%. A total of 13,372 protein-coding genes were functionally annotated. Phylogenetic analysis indicated that the diversification of M. ovinus and Glossina fuscipes took place 72.76 Mya within the Late Cretaceous. Gene family expansion and contraction analysis revealed that M. ovinus has 65 rapidly-evolving families (26 expansion and 39 contractions) mainly involved DNA metabolic activity, transposases activity, odorant receptor 59a/67d-like, IMD domain-containing protein, and cuticle protein, etc. The universal and tightly conserved list of milk protein orthologues has been assembled from the genome of M. ovinus. Contractions and losses of sensory receptors and vision-associated Rhodopsin genes were significant in M. ovinus, which indicate that the M. ovinus has narrower ecological niches.ConclusionsWe sequenced, assembled, and annotated the whole genome sequence of M. ovinus, and launches into the preliminary genetic mechanisms analysis of the adaptive evolution characteristics of M. ovinus. These resources will provide insights to understand the biological underpinnings of this parasite and the disease control strategies.