Functional Defects Research Articles

A Review of Limbic System-Associated Membrane Protein in Tumorigenesis

Purpose of Review: This review aims to describe the role of limbic system-associated membrane protein (LSAMP) in normal- and pathophysiology, and its potential implications in oncogenesis. We have summarized research articles reporting the role of LSAMP in the development of a variety of malignancies, such as clear cell renal cell carcinoma, prostatic adenocarcinoma, lung adenocarcinoma, osteosarcoma, neuroblastoma, acute myeloid leukemia, and epithelial ovarian cancer. We also examine the current understanding of how defects in LSAMP gene function may contribute to oncogenesis. Finally, this review discusses the implications of future LSAMP research and clinical applications. Recent Findings: LSAMP has been originally described as a surface adhesion glycoprotein expressed on cortical and subcortical neuronal somas and dendrites during the development of the limbic system. It is categorized as part of the IgLON immunoglobulin superfamily of cell-adhesion molecules and is involved in regulating neurite outgrowth and neural synapse generation. LSAMP is both aberrantly expressed and implicated in the development of neuropsychiatric disorders due to its role in the formation of specific neuronal connections within the brain. Additionally, LSAMP has been shown to support brain plasticity via the formation of neuronal synapses and is involved in modulating the hypothalamus in anxiogenic environments. In murine studies, the loss of LSAMP expression was associated with decreased sensitivity to amphetamine, increased sensitivity to benzodiazepines, increased hyperactivity in new environments, abnormal social behavior, decreased aggressive behavior, and decreased anxiety. Findings have suggested that LSAMP plays a role in attuning serotonergic activity as well as GABA activity. Given its importance to limbic system development, LSAMP has also been studied in the context of suicide. In malignancies, LSAMP may play a significant role as a putative tumor suppressor, the loss of which leads to more aggressive phenotypes and mortality from metastatic disease. Loss of the LSAMP gene facilitates epithelial-mesenchymal transition, or EMT, where epithelial cells lose adhesion and gain the motile properties associated with mesenchymal cells. Additionally, LSAMP and the function of the RTK pathway have been implicated in tumorigenesis through the modulation of RTK expression in cell membranes and the activation of second messenger pathways and β-catenin. Summary: Beyond its many roles in the limbic system, LSAMP functions as a putative tumor suppressor protein. Loss of the LSAMP gene is thought to facilitate epithelial-mesenchymal transition, or EMT, where cells lose adhesion and migrate to distant organs. LSAMP’s role in modulating RTK activity and downstream ERK and Akt pathways adds to a large body of data investigating RTK expression in oncogenesis. The characteristics of LSAMP defects and their association with aggressive and metastatic disease are evident in reports on clear cell renal cell carcinoma, prostatic adenocarcinoma, lung adenocarcinoma, osteosarcoma, neuroblastoma, acute myeloid leukemia, and epithelial ovarian cancer.

Leveraging homologous recombination deficiency for sarcoma

Abstract Background Homologous recombination deficiency (HRD) in tumors correlates with poor prognosis and metastases development. Determining HRD is of major clinical relevance as it can be treated with PARP inhibitors (PARPi). HRD remains poorly investigated in sarcoma, a rare and heterogeneous cancer of mesenchymal origin. Objective We aimed (i) to investigate predictive biomarkers of HRD in several independent sarcoma cohorts using a cross-functional strategy by combining genomic, transcriptomic and phenotypic approaches and (ii) to evaluate the therapeutic potential of PARPi and DNA damage response (DDR)-based therapies ex vivo. Materials and methods We performed a comprehensive genomic and transcriptomic characterization of sarcoma using datasets from The Cancer Genome Atlas (TCGA) and Therapeutically Applicable Research to Generate Effective Treatments (TARGET), and our own bone and soft tissue sarcoma cohorts. We evaluated PARP1/2 and WEE1 inhibition ex vivo in patient-derived sarcoma cell models as monotherapy and in combination with chemotherapeutic agents to identify synergistic effects. Results Firstly, we identified genomic traits of HRD in a subset of sarcomas associated with molecular alterations in homologous recombination repair (HRR) pathway genes and high chromosomal instability. Secondly, we identified and validated distinct SARC-HRD transcriptional signatures that predicted sensitivity to PARPi. Finally, we showed functional defects in HRR in sarcoma cells that were associated with functional dependency towards PARPi and WEE1i and support the clinical use of RAD51 as a predictive biomarker for PARPi sensitivity. Conclusion We provide a personalized oncological approach to potentially improve the treatment of sarcoma patients. We encourage the evaluation of gene expression signatures to enhance the identification of patients who might benefit from DDR-based therapies.

CNSC-06. NAVIGATING BRAIN CANCER: PATIENT STORIES AND MEDICAL BREAKTHROUGH

Abstract The complex interplay of genetic mutation, dys regulated signalling pathways, Epigenetic modifications and Interaction with tumor microenvironment are the major aggravating factors for Brain Tumors. Neurological complications involve Increased Intracranial pressure, Seizures, Motor and Sensory deficits, Aphasia, Hydrocephaly, Behavioral and personality changes, Cerebellar Symptoms. It is diagnosed in a sequential steps. Collecting good history from patient in primary then examining the patient all through and making some investigations to come to a final diagnosis. On asking history to a patient he complains of recurrent convulsions, Personality changes and some motor activity deficit and loss of few senses. On examination we can reveal defect in cranial nerve functions, Motor or sensory deficits, loss of reflexes and coordination. Then Investigations being the next step for diagnosis, We ask the patient to undergo for a test for Blood Biomarkers and CSF analysis in case of suspection of metastatic Brain tumors. Biopsy to obtain for Histopathological Examination. Histopathological examination is done for analysis of genetic mutations and molecular markers. The other imaging techniques like MRI, MRS, CT, PET, EEG are done. This gives a clear picture of what actually caused tumor and shows a way for treatment. Now the treatment involves both Medical and Surgical treatment. Medical treatment includes Chemotherapy along with radiation therapy where the drugs given are Temozolomide and targeted therapy included EGFR BRAF inhibitors for glioblastoma and low grade gliomas respectively. Tumor treating fields- Optune is given. Surgical treatment involves Craniotomy for removal of primary Brain tumors, Neuro Endoscopy if tumor is present in ventricles or base of Brain, Laser interstitial Thermal therapy for deap seated and recurrent brain tumors. This is all about the treatment and now the patient management is very important for further clinical help. Physical, occupational and speech therapy helps patients recover. Symptomatic approach for inoperable tumors Provide comprehensive support for patients nearing end of life, Emphasise confidence and Quality of life.

Oral mucosa reconstruction methods in cancer patients

Resection of malignant neoplasms of the oral cavity causes esthetic, functional, and anatomical defects irrespective of the advancement of tumor process. The methods of oral cavity organ reconstruction include the use of distant flaps and microsurgical autotransplantation. microsurgical techniques have limits and are not always applicable in clinical practice.The article presents the main techniques of oral cavity organ reconstruction alternative to microsurgical techniques. Detailed literature review on this topic is performed, advantages and disadvantages of the various methods of defect reconstruction are presented. In clinical practice, the use of distant flaps is an adequate alternative to microsurgical autotransplantation. This method can be successfully used in weakened patients with locally advanced squamous cell carcinoma of the oral mucosa.

Neurexin facilitates glycosylation of Dystroglycan to sustain muscle architecture and function in Drosophila

Neurexin, a molecule associated with autism spectrum disorders, is thought to function mainly in neurons. Recently, it was reported that Neurexin is also present in muscle, but the role of Neurexin in muscle is still poorly understood. Here, we demonstrate that the overexpression of Neurexin in muscles effectively restored the locomotor function of Drosophila neurexin mutants, while rescuing effects are observed within the nervous. Notably, the defects in muscle structure and function caused by Neurexin deficiency were similar to those caused by mutations in dystroglycan, a gene associated with progressive muscular dystrophy. The absence of Neurexin leads to muscle attachment defects, emphasizing the essential role of Neurexin in muscle integrity. Furthermore, Neurexin deficiency reduces Dystroglycan glycosylation on the cell surface, which is crucial for maintaining proper muscle structure and function. Finally, Neurexin guides Dystroglycan to the glycosyltransferase complex through interactions with Rotated Abdomen, a homolog of mammalian POMT1. Our findings reveal that Neurexin mediates muscle development and function through Dystroglycan glycosylation, suggesting a potential association between autism spectrum disorders and muscular dystrophy.

Subjective and objective effects of anxiety and fatigue on social function in patients with enterostomy and their family caregivers.

Many patients with enterostomy and their family caregivers experience severe anxiety and fatigue, which affects their participation in normal social activities and family life, resulting in impaired social function. The purpose of this study was to understand the status of social function of patients with enterostomy and their family caregivers;at the same time to analyze the subjective and objective effects of anxiety and fatigue on their social functions. The self-made general information questionnaire, WHO Social Disability rating Scale, Miao Yu's Multidimensional Fatigue Scale-20 and Zung et al. 's Self-rating Anxiety Scale were used to investigate the general situation, social function, fatigue and anxiety of enterostomy patients and their family caregivers who came to the hospital for treatment from March 28, 2023 to November 30, 2023. SPSS27.0 was used to complete the statistical analysis of the data, and AMOS26.0 was used to establish the structural equation model to complete the subject and object effect analysis. A total of 260 pairs of enterostomy patients and their family caregivers were included in this study. The social function scores of enterostomy patients and their family caregivers were (8.80±3.44) and (6.44±3.60). The anxiety scores were (37.81±7.60) and (34.73±7.50). The fatigue scores were (63.35±12.80) and (51.21±12.38).The results of the subject-object effect analysis reported the subject effect: the anxiety of patients with enterostomy had a significant positive impact on the degree of social dysfunction (β = 0.154, P = 0.015); The fatigue of patients with enterostomy had a significant positive effect on the degree of social dysfunction (β = 0.132, P = 0.034). The anxiety of family caregivers had a significant positive effect on the degree of social dysfunction (β = 0.161, P = 0.023). The fatigue of family caregivers had a significant positive effect on the degree of social dysfunction (β = 0.201, P = 0.005). In terms of object effects: only the fatigue of family caregivers had a significant positive impact on the degree of social dysfunction of enterostomy patients (β = 0.224, P < 0.001), and other ways had no object effects. Patients with enterostomy and their family caregivers have serious social function defects. Clinical medical staff should take care of them as a whole in order to better return to family and society after surgery.

Glycoside-Mediated Enhancement of Stability in Aluminum Oxyhydroxide Nanoadjuvants during Freeze-Drying.

Aluminum-based adjuvants have been indispensable to vaccine potency. However, their effectiveness is difficult to maintain after freeze-drying, which limits the storage and application of aluminum-adjuvanted vaccines. In this study, the impact of freeze-drying on aluminum oxyhydroxide nanorods (AlOOH NRs) was investigated. Freeze-drying led to aggregation and resulted in the loss of the surface hydroxyl content of aluminum adjuvants. To alleviate freeze-drying-induced damage, the potency of different alkyl glycosides as protectants was further evaluated. It was demonstrated that the structural balance of the head and tail of a glycoside was more conducive to protecting AlOOH NRs from aggregation and loss of surface hydroxyl groups. These results underline the proper selection of protectants to protect adjuvants against functional defects caused by freeze-drying, which is important for the stability and efficacy of vaccines and biopharmaceutical products.

2D Nitrogen-Doped Graphene Materials for Noble Gas Separation.

Noble gases, notably xenon, play a pivotal role in diverse high-tech applications. However, manufacturing xenon is an inherently challenging task, due to its unique properties and trace abundance in the Earth's atmosphere. Consequently, there is a pressing need for the development of efficient methods for the separation of noble gases. Using mild fluorographene chemistry, nitrogen-doped graphene (GNs) materials are synthesized with abundant aromatic regions and extensive nitrogen doping within the vacancies and holes of the aromatic lattice. Due to the organized interlayer "nanochannels", nitrogen functional groups, and defects within the two-dimensional (2D)structures, GNs exhibits effective selectivity for Xe over Kr at low pressure. This enhanced selectivity is attributed to the stronger binding affinity of Xe to GN compared to Kr. The adsorption is governed by London dispersion forces, as revealed by theoretical calculations using symmetry-adapted perturbation theory (SAPT). Investigation of other GNs differing in nitrogen content, surface area, and pore sizes underscores the significance of nitrogen functional groups, defects, and interlayer nanochannels over thesurface area in achieving superior selectivity. This work offers a new perspective on the design and fabrication of functionalized graphene derivatives, exhibiting superior noble gas storage and separation activity exploitable in gas production technologies.

Immune response to topical sodium lauryl sulfate differs from classical irritant and allergic contact dermatitis.

Sodium lauryl sulfate (SLS) is used as a control irritant in patch testing for allergic contact dermatitis (ACD). However, up to 20% of those tested react to SLS, whereby the pathophysiological basis of this reaction is still unclear. To mimic patch test reactions, we repeatedly applied SLS to the skin of wild-type mice. Reactions were compared with those in a classical ACD model induced by oxazolone and an irritant contact dermatitis (ICD) model induced by croton oil. Skin inflammation was assessed with ear thickness measurements, immunohistochemistry, qRT-PCR, and flow cytometry. Topical SLS treatment was further investigated in Flg/Hrnr-/-, Myd88/Tlr3-/-, and Rag1-/- mouse models. All three compounds caused ear swelling with different courses. Oxazolone treatment, compared with the ICD model, resulted in a greater influx of immune cells (CD4+, MHCII+, CD11b+). Similarly, SLS did not induce immune cell infiltration or expression of selected inflammatory and regulatory cytokines. SLS induced the most pronounced keratinocyte proliferation. Compared with wild-type mice, topical SLS application did not increase ear swelling in skin barrier deficient Flg/Hrnr-/- mice, but led to significantly delayed swelling in mice with defects in innate or adaptive immune functions (Myd88/Tlr3-/-, Rag1-/-). SLS-induced contact dermatitis differed from classical ACD and ICD, as it elicited less pronounced immune alterations. Skin barrier impairment does not affect SLS-induced contact dermatitis, whereas both innate and adaptive components are involved in SLS skin reactions.

Elucidating the Chemical Pre-Lithiation Mechanism of Hard Carbon Anodes for Ultra-high Stability Lithium-Ion Batteries.

The hard carbon (HC) anode materials demonstrate high capacity and excellent rate performance in lithium-ion batteries. However, HC anodes suffer from excessive loss of Li+ ions during the formation of the solid electrolyte interphase (SEI) film, leading to poor cycling stability, which hinders their large-scale applications. Herein, a facile pre-lithiation strategy is proposed to achieve multi-functional precompensation of carbon nanofibers (CNFs) anodes. Both experimental and density functional theory (DFT) calculation results revealed that the strategy compensated for the loss of Li+ ions and reacted with four structures of CNFs during pre-lithiation, including tiny graphite domains, CO-containing functional groups, defects, and micropores. Furthermore, the lithium in pre-lithiated carbon nanofibers (pCNFs) existed in various forms, consisting of LiC24 and LiC18, Li─O─C, quasi-metallic lithium, and Li+ ions. Moreover, the uniformly distributed lithium on the surface of pCNFs induced the formation of denser and more robust LiF/Li2CO3-rich SEI film, which promoted Li+ ions transport. As a result, pCNFs showed more stable cycling performance (369.8mAhg-1, almost no decay for 1500 cycles). This work provides deeper insight into chemical pre-lithiation and offers a simple and mild strategy for highly stable batteries.

Quantitative structure–activity relationships of chemical bioactivity toward proteins associated with molecular initiating events of organ-specific toxicity

The adverse outcome pathway (AOP) concept has gained attention as a way to explore the mechanism of chemical toxicity. In this study, quantitative structure–activity relationship (QSAR) models were developed to predict compound activity toward protein targets relevant to molecular initiating events (MIE) upstream of organ-specific toxicities, namely liver steatosis, cholestasis, nephrotoxicity, neural tube closure defects, and cognitive functional defects. Utilizing bioactivity data from the ChEMBL 33 database, various machine learning algorithms, chemical features and methods to assess prediction reliability were compared and applied to develop robust models to predict compound activity. The results demonstrate high predictive performance across multiple targets, with balanced accuracy exceeding 0.80 for the majority of models. Furthermore, stability checks confirmed the consistency of predictive performance across multiple training-test splits. The results obtained by using QSAR predictions to identify known markers of adversities highlighted the utility of the models for risk assessment and for prioritizing compounds for further experimental evaluation.Scientific contributionThe work describes the development of QSAR models as tools for screening chemicals with potential systemic toxicity, thus contributing to resource savings and providing indications for further better-targeted testing. This study provides advances in the field of computational modeling of MIEs and information from AOP which is still relatively young and unexplored. The comprehensive modeling procedure is highly generalizable, and offers a robust framework for predicting a wide range of toxicological endpoints.

IMPACTO DAS ANOMALIAS CONGÊNITAS NA MORTALIDADE NEONATAL: UMA REVISÃO SOBRE FATORES DE RISCO E PREVENÇÃO

This integrative review aimed to analyze the incidence of congenital anomalies in neonates and identify associated risk factors, as well as explore the most effective preventive measures described in the scientific literature. Congenital anomalies are structural or functional defects that develop during intrauterine life and are a major cause of neonatal and infant mortality. An estimated 303,000 newborns die annually within the first month of life due to these conditions (WHO, 2016). This study was conducted through the analysis of scientific articles published in the PubMed, SciELO, and Google Scholar databases, using keywords such as "congenital anomalies," "neonates," and "risk factors." Studies published in the last ten years, in Portuguese and English, addressing the incidence and risk factors of congenital anomalies in neonates were included. The results showed that the most common congenital anomalies include neural tube defects, cardiac malformations, and chromosomal abnormalities, such as Down syndrome (PACHECO et al., 2009). The prevalence of these conditions varies according to geographic region and population (BRASIL, 2021). Several maternal risk factors were identified, including advanced maternal age, smoking, alcohol consumption, and exposure to teratogenic substances during pregnancy (ANDRADE et al., 2017). Additionally, adverse socioeconomic conditions and lack of access to quality prenatal care were highlighted as important determinants for the increased incidence of congenital anomalies (LANSKY et al., 2014). Preventive strategies suggested by the literature include folic acid supplementation before and during pregnancy, proper vaccination of pregnant women, and genetic counseling (BRASIL, 2013; ACGO, 2018). Early diagnosis through neonatal screening tests, such as the heel prick test, pulse oximetry, and hearing screening, is crucial for early identification of anomalies and enabling interventions that can improve health outcomes for neonates (MINISTÉRIO DA SAÚDE, 2021). The review also emphasized the importance of early interventions, such as corrective surgeries and supportive therapies, to improve the prognosis of neonates affected by congenital anomalies (CHRISTIANSON, 2006). These interventions can significantly reduce morbidity and mortality rates associated with these conditions, improving the quality of life of affected individuals. In conclusion, this integrative review identified significant risk factors for congenital anomalies and highlighted the importance of preventive interventions and early diagnosis to improve neonatal health outcomes. The effective prevention and management of congenital anomalies require a multidisciplinary approach, including awareness among healthcare professionals, effective public policies, and family involvement in implementing preventive strategies. Ongoing research is recommended to further understand the causes, risk factors, and effective interventions to reduce the incidence of congenital anomalies and improve neonatal health outcomes.

Nitrogen-doped carbon quantum dot-decorated In2O3 synaptic transistors for neuromorphic computing

Nitrogen-doped carbon quantum dots (N-CQDs) are promising materials for electronic devices due to their variable bandgap and structural stability. Here, we integrate N-CQDs into In2O3 synaptic transistors with electrolyte gating, resulting in a hybrid structure. The surface functional groups and defects of N-CQDs empower the charge trapping mechanism, permitting controlled conduction and charge regulation, which are crucial for emulating linear and symmetric artificial synaptic devices. Devices incorporating N-CQDs demonstrate enhanced stability and memory characteristics, low energy consumption, consistent retention, and a significant hysteresis window across multiple voltage cycles. Finally, the study emulates biological synapses and cognitive functions, achieving an energy consumption of 10 fJ per synaptic event and a pattern recognition accuracy of 91.2% on the MNIST dataset in hardware neural networks. This work demonstrates the potential of well-manipulating charge trapping in N-CQDs to develop high-performance, nonvolatile synaptic devices.

JANUS KINASE INHIBITOR IN COMBINATION THERAPY IN ATOPIC DERMATITIS

BACKGROUND: Atopic dermatitis (AD) is a chronic recurrent immunoinflammatory skin disease that develops against the background of a genotypic defect in the skin barrier function and innate and adaptive autoimmunity. Currently, there is no specific therapy for AD, so there remains a need to constantly search for effective pathogenetic approaches to its treatment. Today, the Janus kinase type 1 inhibitor abrocitinib is recommended for the treatment of moderate to severe AD. AIMS: to conduct a comparative assessment of the effectiveness of the combination of UVB 311 nm with abrocitinib and UVB 311 nm phototherapy against the background of standard therapy according to indications in the treatment of patients with moderate and severe atopic dermatitis. MATERIALS AND METHODS: During the period from 2023 to 2024, the dermatological status and quality of life were assessed in 40 patients with moderate to severe atopic dermatitis who were prone to frequent relapses. The patients were treated at the clinic for skin and venereal diseases. Depending on the therapy, all patients were divided into two groups. The first group consisted of 20 patients receiving systemic, topical therapy in combination with UVB 311 phototherapy and additionally abrocitinib, at an induction dose of 200 mg followed by a dose of 100 mg. The second group included 20 patients who received systemic, local therapy in combination with UVB 311 phototherapy. Upon admission to the hospital and after two months of therapy, a comparative assessment of the DLQI index and an assessment of the prevalence and intensity of skin lesions in accordance with the SCORAD and IGA index were performed, an assessment of the level of IgE in the blood were performed RESULTS: after the course of therapy, the SCORAD index in patients of the first and second groups decreased statistically significantly (p=0.001) by 2.4 times and 1.6 times, respectively. The DLQI index in patients of the first and second groups after the course of therapy significantly (p=0.001) decreased by 3.2 times, 2.1 times, respectively. CONCLUSIONS: Our study revealed a more significant effectiveness of therapy with abrocitinib in combination with UVB 311 compared with UVB 311 monotherapy in patients with moderate and severe atopic dermatitis.

Preclinical ex vivo IL2RG gene therapy using autologous hematopoietic stem cells as an effective and safe treatment for X-linked severe combined immunodeficiency disease

X-linked severe combined immunodeficiency disease (X-SCID) is a rare inherited disease caused by mutations in the interleukin 2 receptor subunit gamma gene (IL2RG), which encodes the common γ chain protein, a subunit of the receptor for lymphocytes. X-SCID is characterized by profound defects in T-cell, B-cell, and natural killer cell function. Here, we report a Chinese cohort of nine X-SCID patients with six novel IL2RG mutations. Among those, the two adolescent patients carrying missense mutation with an atypical immunotype were confirmed by further analyzing IL-2-JAK-STAT5 signaling, T cell proliferation, and T cell receptor excision circles (Trecs). Interestingly, Bacillus Calmette-Guérin (BCG) disease occurred commonly in this cohort. Although allogeneic hematopoietic stem-cell transplantation is curative for the disease, it is not available to all patients due to the lack of suitable matched donors. Autologous gene therapy using a self-inactivating lentiviral vector (SIN-LV) technology, developed in recent decades has provided an alternative therapy for treating such mono-genetic diseases. Here, we performed the pre-clinical studies to assess our SIN-LV carrying IL2RG on human ED7R cells deficient in IL2RG and CD34+ stem cells derived from the bone marrow of a healthy donor and a patient with X-SCID. This work is done complied with the established "Good Manufacturing Practice" (GMP) used in the clinical trials. In addition, a safety study is performed using the transduced CD34+ cells implanted into the axilla of nude mice in vivo. Overall, our studies have demonstrated the efficiency and safety of SIN-IL2RG-LV, which paves the way for conducting X-SCID gene therapy clinical trials in China in the near future.

Biogenesis of Cytochromes c and c1 in the Electron Transport Chain of Malaria Parasites.

Plasmodium malaria parasites retain an essential mitochondrional electron transport chain (ETC) that is critical for growth within humans and mosquitoes and is a key antimalarial drug target. ETC function requires cytochromes c and c1, which are unusual among heme proteins due to their covalent binding to heme via conserved CXXCH sequence motifs. Heme attachment to these proteins in most eukaryotes requires the mitochondrial enzyme holocytochrome c synthase (HCCS) that binds heme and the apo cytochrome to facilitate the biogenesis of the mature cytochrome c or c1. Although humans encode a single bifunctional HCCS that attaches heme to both proteins, Plasmodium parasites are like yeast and encode two separate HCCS homologues thought to be specific for heme attachment to cyt c (HCCS) or cyt c1 (HCC1S). To test the function and specificity of Plasmodium falciparum HCCS and HCC1S, we used CRISPR/Cas9 to tag both genes for conditional expression. HCC1S knockdown selectively impaired cyt c1 biogenesis and caused lethal ETC dysfunction that was not reversed by the overexpression of HCCS. Knockdown of HCCS caused a more modest growth defect but strongly sensitized parasites to mitochondrial depolarization by proguanil, revealing key defects in ETC function. These results and prior heterologous studies in Escherichia coli of cyt c hemylation by P. falciparum HCCS and HCC1S strongly suggest that both homologues are essential for mitochondrial ETC function and have distinct specificities for the biogenesis of cyt c and c1, respectively, in parasites. This study lays a foundation to develop novel strategies to selectively block ETC function in malaria parasites.

Methylmalonic acid induces metabolic abnormalities and exhaustion in CD8+ T cells to suppress anti-tumor immunity.

Systemic levels of methylmalonic acid (MMA), a byproduct of propionate metabolism, increase with age and MMA promotes tumor progression via its direct effects in tumor cells. However, the role of MMA in modulating the tumor ecosystem remains to be investigated. The proliferation and function of CD8+ T cells, key anti-tumor immune cells, declines with age and in conditions of vitamin B12 deficiency, which are the two most well-established conditions that lead to increased systemic levels of MMA. Thus, we hypothesized that increased circulatory levels of MMA would lead to a suppression of CD8+ T cell immunity. Treatment of primary CD8+ T cells with MMA induced a dysfunctional phenotype characterized by robust immunosuppressive transcriptional reprogramming and marked increases in the expression of the exhaustion regulator, TOX. Accordingly, MMA treatment upregulated exhaustion markers in CD8+ T cells and decreased their effector functions, which drove the suppression of anti-tumor immunity in vitro and in vivo. Mechanistically, MMA-induced CD8+ T cell exhaustion was associated with a suppression of NADH-regenerating reactions in the TCA cycle and concomitant defects in mitochondrial function. Thus, MMA has immunomodulatory roles, thereby highlighting MMA as an important link between aging, immune dysfunction, and cancer.

Ball-Milling-Assisted N/O Codoping for Enhanced Sodium Storage Performance of Coconut-Shell-Derived Hard Carbon Anodes in Sodium-Ion Batteries.

Sodium-ion batteries (SIBs) are regarded as cost-effective alternatives or competitors to lithium-ion batteries for large-scale electric energy storage applications. However, their development has been hindered by the high cost of hard carbon (HC) anodes and poor electrochemical performance. To enhance the sodium storage capacity and rate performance of HC, this study accelerated the electrochemical performance of coconut-shell-derived HC anodes for SIBs through N/O codoping using ball milling and pyrolysis. Experimental results demonstrate that the simultaneous introduction of N and O generates a synergistic effect, increasing the surface oxygen-containing functional groups, defects, and interlayer spacing of coconut-shell-derived HC through the codoping of light elements. The excellent strategy has increased the slope capacity and platform capacity of HC, and the synergistic modification of N/O has increased its reversible specific capacity from 272 to 343 mA h g-1 (30 mA g-1), with a retention rate of approximately 92.1% after 100 cycles. In addition, it also exhibits an excellent rate performance, reaching 178 mA h g-1 at 1500 mA g-1. In summary, this study presents an effective strategy for modifying biomass-derived HC.

Identification of a divalent metal transporter required for cellular iron metabolism in malaria parasites

Plasmodium falciparum malaria parasites invade and multiply inside red blood cells (RBCs), the most iron-rich compartment in humans. Like all cells, P. falciparum requires nutritional iron to support essential metabolic pathways, but the critical mechanisms of iron acquisition and trafficking during RBC infection have remained obscure. Parasites internalize and liberate massive amounts of heme during large-scale digestion of RBC hemoglobin within an acidic food vacuole (FV) but lack a heme oxygenase to release porphyrin-bound iron. Although most FV heme is sequestered into inert hemozoin crystals, prior studies indicate that trace heme escapes biomineralization and is susceptible to nonenzymatic degradation within the oxidizing FV environment to release labile iron. Parasites retain a homolog of divalent metal transporter 1 (DMT1), a known mammalian iron transporter, but its role in P. falciparum iron acquisition has not been tested. Our phylogenetic studies indicate that P. falciparum DMT1 (PfDMT1) retains conserved molecular features critical for metal transport. We localized this protein to the FV membrane and defined its orientation in an export-competent topology. Conditional knockdown of PfDMT1 expression is lethal to parasites, which display broad cellular defects in iron-dependent functions, including impaired apicoplast biogenesis and mitochondrial polarization. Parasites are selectively rescued from partial PfDMT1 knockdown by supplementation with exogenous iron, but not other metals. These results support a cellular paradigm whereby PfDMT1 is the molecular gatekeeper to essential iron acquisition by blood-stage malaria parasites and suggest that therapeutic targeting of PfDMT1 may be a potent antimalarial strategy.

Exome sequencing identifies a novel FBN1 variant in a Chinese family with Marfan syndrome that includes aberrant right subclavian artery

Abstract Background Marfan syndrome (MFS) is an inherited autosomal dominant disorder that affects connective tissue with an incidence of about 1 in 5,000 to 10,000 people. Ninety percent of MFS is caused by mutations in the fibrillin-1 (fbn1) gene. We recruited a family with MFS phenotype in South China and identified a novel variant in fbn1 by whole exome sequencing (WES). The zebrafish share high genetic similarity to humans. This study aimed to generate this novel mutation in the fbn1 gene of zebrafish using the CRISPR/Cas9 technology and researched whether this variant is pathogenic. Methods A three-generation consanguineous family was recruited in this study, which was visited and interviewed for the clinical data and family history. Peripheral blood samples were collected from family members for DNA isolation and WES. The 3D structure of the protein was predicted by Alphafold. CRISPR/Cas9 was applied to generate an fbn1 nonsense mutation (fbn1+/−) in zebrafish. Morphological abnormalities were assessed in F2 fbn1+/− zebrafish by comparing with the wild-type (WT) controls at different development stages. Results Our study recruited a family with MFS phenotype in South China and identified a novel variant [NM_000138.5; c.7764C&amp;gt;G: p.(Y2588*)] in fbn1. Through Sanger sequencing, we found that family members Ⅲ-1 (son) and Ⅲ-2 (daughter) had the fbn1 variant segregated with MFS in the family. The p.Y2588* mutation resulted in the absence of 283 amino acids, thereby leading to the deficiency of 17 β-folded structures, 4 α-helix structures, and various loop structures. Compared with WT zebrafish, F2 fbn1+/− zebrafish exhibited aortic arches bleeding, abnormal angiogenesis, decreased cardiac volume, cardiac function defects, curly tail, and cartilage malformations. Conclusion A novel variant [NM_000138.5; c.7764C&amp;gt;G: p.(Y2588*)] was identified in fbn1 gene, which has not been reported in previous literature. The variant caused loss of function through premature protein truncation or nonsense-mediated mRNA decay. In zebrafish, we identified functional evidence of the detected nonsense mutation, which aligns with the clinical significance, suggesting a pathogenic variant of fbn1. Zebrafish as a novel, efficient tool to allow for the quick classification of unknown variants in fbn1 and improve the clinical diagnosis and treatment of MFS. It has brought the implementation of personal and precision medicine in the clinic within reach and made it possible to find patient-specific treatments.Marfanoid symptoms of the patient.Phenotypic Spectrum of fbn1+/− Zebrafish