Search results for: gene variants

Authors: Agboka Komi Mensah, John Odindi, Elfatih M. Abdel-Rahman, Onisimo Mutanga, Henri Ez Tonnang

Abstract:

Ecosystems are networks of organisms and populations that form a community of various species interacting within their habitats. Such habitats are defined by abiotic and biotic conditions that establish the initial limits to a population's growth, development, and reproduction. The habitat’s conditions explain the context in which species interact to access resources such as food, water, space, shelter, and mates, allowing for feeding, dispersal, and reproduction. Dispersal is an essential life-history strategy that affects gene flow, resource competition, population dynamics, and species distributions. Despite the importance of dispersal in population dynamics and survival, understanding the mechanism underpinning the dispersal of organisms remains challenging. For instance, when an organism moves into an ecosystem for survival and resource competition, its progression is highly influenced by extrinsic factors such as its physiological state, climatic variables and ability to evade predation. Therefore, greater spatial detail is necessary to understand organism dispersal dynamics. Understanding organisms dispersal can be addressed using empirical and mechanistic modelling approaches, with the adopted approach depending on the study's purpose Cellular automata (CA) is an example of these approaches that have been successfully used in biological studies to analyze the dispersal of living organisms. Cellular automata can be briefly described as occupied cells by an individual that evolves based on proper decisions based on a set of neighbours' rules. However, in the ambit of modelling individual organisms dispersal at the landscape scale, we lack user friendly tools that do not require expertise in mathematical models and computing ability; such as a visual analytics framework for tracking and forecasting the dispersal behaviour of organisms. The term "visual analytics" (VA) describes a semiautomated approach to electronic data processing that is guided by users who can interact with data via an interface. Essentially, VA converts large amounts of quantitative or qualitative data into graphical formats that can be customized based on the operator's needs. Additionally, this approach can be used to enhance the ability of users from various backgrounds to understand data, communicate results, and disseminate information across a wide range of disciplines. To support effective analysis of the dispersal of organisms at the landscape scale, we therefore designed Pydisp which is a free visual data analytics tool for spatiotemporal dispersal modeling built in Python. Its user interface allows users to perform a quick and interactive spatiotemporal analysis of species dispersal using bioecological and climatic data. Pydisp enables reuse and upgrade through the use of simple principles such as Fuzzy cellular automata algorithms. The potential of dispersal modeling is demonstrated in a case study by predicting the dispersal of Fopius arisanus (Sonan), endoparasitoids to control Bactrocera dorsalis (Hendel) (Diptera: Tephritidae) in Kenya. The results obtained from our example clearly illustrate the parasitoid's dispersal process at the landscape level and confirm that dynamic processes in an agroecosystem are better understood when designed using mechanistic modelling approaches. Furthermore, as demonstrated in the example, the built software is highly effective in portraying the dispersal of organisms despite the unavailability of detailed data on the species dispersal mechanisms.

Keywords: cellular automata, fuzzy logic, landscape, spatiotemporal

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Authors: Paul J. McKay

Abstract:

Large-scale genome-wide association studies (GWAS) investigating genetic contributions to sexual orientation and gender identity are largely lacking and may reduce stigma experienced in the LGBTQ+ community by providing an underlying biological explanation for queerness. While there is a growing consensus within the scientific community that genetic makeup contributes – at least in part – to sexual orientation and gender identity, there is a marked lack of genomics research exploring polygenic contributions to queerness. Based on recent (2019) findings from a large-scale GWAS investigating the genetic architecture of same-sex sexual behavior, and various additional peer-reviewed publications detailing novel insights into the molecular mechanisms of sexual orientation and gender identity, we hypothesize that sexual orientation and gender identity are complex, multifactorial, and polygenic; meaning that many genetic factors contribute to these phenomena, and environmental factors play a possible role through epigenetic modulation. In recent years, large-scale GWAS studies have been paramount to our modern understanding of many other complex human traits, such as in the case of autism spectrum disorder (ASD). Despite possible benefits of such research, including reduced stigma towards queer people, improved outcomes for LGBTQ+ in familial, socio-cultural, and political contexts, and improved access to healthcare (particularly for trans populations); important risks and considerations remain surrounding this type of research. To mitigate possibilities such as invalidation of the queer identities of existing LGBTQ+ individuals, genetic discrimination, or the possibility of euthanasia of embryos with a genetic predisposition to queerness (through reproductive technologies like IVF and/or gene-editing in utero), we propose a community-engaged research (CER) framework which emphasizes the privacy and confidentiality of research participants. Importantly, the historical legacy of scientific research attempting to pathologize queerness (in particular, falsely equating gender variance to mental illness) must be acknowledged to ensure any future research conducted in this realm does not propagate notions of homophobia, transphobia or stigma against queer people. Ultimately, in a world where same-sex sexual activity is criminalized in 69 UN member states, with 67 of these states imposing imprisonment, 8 imposing public flogging, 6 (Brunei, Iran, Mauritania, Nigeria, Saudi Arabia, Yemen) invoking the death penalty, and another 5 (Afghanistan, Pakistan, Qatar, Somalia, United Arab Emirates) possibly invoking the death penalty, the importance of this research cannot be understated, as finding a biological basis for queerness would directly oppose the harmful rhetoric that “being LGBTQ+ is a choice.” Anti-trans legislation is similarly widespread: In the United States in 2022 alone (as of Oct. 13), 155 anti-trans bills have been introduced preventing trans girls and women from playing on female sports teams, barring trans youth from using bathrooms and locker rooms that align with their gender identity, banning access to gender affirming medical care (e.g., hormone-replacement therapy, gender-affirming surgeries), and imposing legal restrictions on name changes. Understanding that a general lack of knowledge about the biological basis of queerness may be a contributing factor to the societal stigma faced by gender and sexual orientation minorities, we propose the initiation of large-scale GWAS studies investigating the genetic basis of gender identity and sexual orientation.

Keywords: genome-wide association studies (GWAS), sexual and gender minorities (SGM), polygenicity, community-engaged research (CER)

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Authors: Leila Noori, Rosario Barone, Francesca Rappa, Antonella Marino Gammazza, Alessandra Maria Vitale, Giuseppe Donato Mangano, Giusy Sentiero, Filippo Macaluso, Kathryn H. Myburgh, Francesco Cappello, Federica Scalia

Abstract:

The neuromuscular system controls, directs, and allows movement of the body through the action of neural circuits, which include motor neurons, sensory neurons, and skeletal muscle fibers. Protein homeostasis of the involved cytotypes appears crucial to maintain the correct and prolonged functions of the neuromuscular system, and both neuronal cells and skeletal muscle fibers express significant quantities of protein chaperones, the molecular machinery responsible to maintain the protein turnover. Genetic mutations or defective post-translational modifications of molecular chaperones (i.e., genetic or acquired chaperonopathies) may lead to neuromuscular disorders called as neurochaperonopathies. The limited knowledge of the effects of the defective chaperones on skeletal muscle fibers and neurons impedes the progression of therapeutic approaches. A distinct genetic variation of CCT5 gene encoding for the subunit 5 of the chaperonin CCT (Chaperonin Containing TCP1; also known as TRiC, TCP1 Ring Complex) was recently described associated with severe distal motor neuropathy by our team. In this study, we investigated the histopathological abnormalities of the skeletal muscle biopsy of the pediatric patient affected by the mutation Leu224Val in the CCT5 subunit. We provide molecular and structural features of the diseased skeletal muscle tissue that we believe may be useful to identify undiagnosed cases of this rare genetic disorder. We investigated the histological abnormalities of the affected tissue via hematoxylin and eosin staining. Then we used immunofluorescence and qPCR techniques to explore the expression and distribution of CCT5 in diseased and healthy skeletal muscle tissue. Immunofluorescence and immunohistochemistry assays were performed to study the sarcomeric and structural proteins of skeletal muscle, including actin, myosin, tubulin, troponin-T, telethonin, and titin. We performed Western blot to examine the protein expression of CCT5 and some heat shock proteins, Hsp90, Hsp60, Hsp27, and α-B crystallin, along with the main client proteins of the CCT5, actin, and tubulin. Our findings revealed muscular atrophy, abnormal morphology, and different sizes of muscle fibers in affected tissue. The swollen nuclei and wide interfiber spaces were seen. Expression of CCT5 had been decreased and showed a different distribution pattern in the affected tissue. Altered expression, distribution, and bandage pattern were detected by confocal microscopy for the interested muscular proteins in tissue from the patient compared to the healthy control. Protein levels of the studied Hsps normally located at the Z-disk were reduced. Western blot results showed increased levels of the actin and tubulin proteins in the diseased skeletal muscle biopsy compared to healthy tissue. Chaperones must be expressed at high levels in skeletal muscle to counteract various stressors such as mechanical, oxidative, and thermal crises; therefore, it seems relevant that defects of molecular chaperones may result in damaged skeletal muscle fibers. So far, several chaperones or cochaperones involved in neuromuscular disorders have been defined. Our study shows that alteration of the CCT5 subunit is associated with the damaged structure of skeletal muscle fibers and alterations of chaperone system components and paves the way to explore possible alternative substrates of chaperonin CCT. However, further studies are underway to investigate the CCT mechanisms of action to design applicable therapeutic strategies.

Keywords: molecular chaperones, neurochaperonopathy, neuromuscular system, protein homeostasis

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Authors: Claire Harrison, Raajit K. Rampal, Vikas Gupta, Srdan Verstovsek, Moshe Talpaz, Jean-Jacques Kiladjian, Ruben Mesa, Andrew Kuykendall, Alessandro Vannucchi, Francesca Palandri, Sebastian Grosicki, Timothy Devos, Eric Jourdan, Marielle J. Wondergem, Haifa Kathrin Al-Ali, Veronika Buxhofer-Ausch, Alberto Alvarez-Larrán, Sanjay Akhani, Rafael Muñoz-Carerras, Yury Sheykin, Gozde Colak, Morgan Harris, John Mascarenhas

Abstract:

Myelofibrosis (MF) is characterized by bone marrow fibrosis, anemia, splenomegaly and constitutional symptoms. Progressive bone marrow fibrosis results from aberrant megakaryopoeisis and expression of proinflammatory cytokines, both of which are heavily influenced by bromodomain and extraterminal domain (BET)-mediated gene regulation and lead to myeloproliferation and cytopenias. Pelabresib (CPI-0610) is an oral small-molecule investigational inhibitor of BET protein bromodomains currently being developed for the treatment of patients with MF. It is designed to downregulate BET target genes and modify nuclear factor kappa B (NF-κB) signaling. MANIFEST-2 was initiated based on data from Arm 3 of the ongoing Phase 2 MANIFEST study (NCT02158858), which is evaluating the combination of pelabresib and ruxolitinib in Janus kinase inhibitor (JAKi) treatment-naïve patients with MF. Primary endpoint analyses showed splenic and symptom responses in 68% and 56% of 84 enrolled patients, respectively. MANIFEST-2 (NCT04603495) is a global, Phase 3, randomized, double-blind, active-control study of pelabresib and ruxolitinib versus placebo and ruxolitinib in JAKi treatment-naïve patients with primary MF, post-polycythemia vera MF or post-essential thrombocythemia MF. The aim of this study is to evaluate the efficacy and safety of pelabresib in combination with ruxolitinib. Here we report updates from a recent protocol amendment. The MANIFEST-2 study schema is shown in Figure 1. Key eligibility criteria include a Dynamic International Prognostic Scoring System (DIPSS) score of Intermediate-1 or higher, platelet count ≥100 × 10^9/L, spleen volume ≥450 cc by computerized tomography or magnetic resonance imaging, ≥2 symptoms with an average score ≥3 or a Total Symptom Score (TSS) of ≥10 using the Myelofibrosis Symptom Assessment Form v4.0, peripheral blast count <5% and Eastern Cooperative Oncology Group performance status ≤2. Patient randomization will be stratified by DIPSS risk category (Intermediate-1 vs Intermediate-2 vs High), platelet count (>200 × 10^9/L vs 100–200 × 10^9/L) and spleen volume (≥1800 cm^3 vs <1800 cm^3). Double-blind treatment (pelabresib or matching placebo) will be administered once daily for 14 consecutive days, followed by a 7 day break, which is considered one cycle of treatment. Ruxolitinib will be administered twice daily for all 21 days of the cycle. The primary endpoint is SVR35 response (≥35% reduction in spleen volume from baseline) at Week 24, and the key secondary endpoint is TSS50 response (≥50% reduction in TSS from baseline) at Week 24. Other secondary endpoints include safety, pharmacokinetics, changes in bone marrow fibrosis, duration of SVR35 response, duration of TSS50 response, progression-free survival, overall survival, conversion from transfusion dependence to independence and rate of red blood cell transfusion for the first 24 weeks. Study recruitment is ongoing; 400 patients (200 per arm) from North America, Europe, Asia and Australia will be enrolled. The study opened for enrollment in November 2020. MANIFEST-2 was initiated based on data from the ongoing Phase 2 MANIFEST study with the aim of assessing the efficacy and safety of pelabresib and ruxolitinib in JAKi treatment-naïve patients with MF. MANIFEST-2 is currently open for enrollment.

Keywords: CPI-0610, JAKi treatment-naïve, MANIFEST-2, myelofibrosis, pelabresib

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