Consequences of defective mitochondrial protein import: From targeting signals to pathology.

Comamonas testosteroni TA441 is a model aerobic steroid-degrading bacterium whose sterane degradation pathway has been elucidated in the greatest detail to date. Similar pathways have been identified in many genera of bacteria, including both proteobacteria and actinobacteria, such as Mycobacterium tuberculosis. However, the genes encoding the C9-hydrogenase for 9,17-dioxo-1,2,3,4,10,19-hexanorandrostan-5-oic acid (9,17-DOHNA, also known as HIP) and the 7α-dehydratase essential for initiating β-oxidation of the B-, C-, and D-rings had not been identified. In this study, we identified these missing genes, located adjacent to the chsE1E2H1H2ltp2 cluster involved in C17 side-chain degradation, and designated them scdB and scdH, respectively. This finding completes the elucidation of all degradation steps of 9,17-DOHNA prior to D-ring cleavage. AlphaFold models showed that ScdB and at least five hydrogenases/dehydrogenases involved in steroid degradation in TA441 share a similar dimer structures with Rossmann fold motif. In contrast, ScdH was predicted to form a homohexameric structure similar to ScdY and ScdN, involved in B-, C-, and D-ring degradation in TA441. Furthermore, AlphaFold modeling revealed that SteC, the dehydratase responsible for removing the C12β-hydroxyl group from 9,17-DOHNA derivatives, exhibits strong structural similarity to BaiE, the bile acid 7α-dehydratase of Clostridium scindens JCM 10418/VPI 12708, despite sharing only ~28% amino acid sequence identity.IMPORTANCEResearch on bacterial aerobic steroid degradation began more than 70 years ago, initially to produce intermediates for steroid drug synthesis. Recently, this field has gained renewed attention due to its implications for human health-for example, the role of cholesterol import and degradation in the persistence of Mycobacterium tuberculosis H37Rv within chronically infected lungs. Comamonas testosteroni TA441 serves as a key model organism for elucidating aerobic steroid degradation, with pathways for cleavage of the A-, B-, C-, and D-rings already well established. The functions and structures of the enzymes identified in TA441 display striking similarities to those in actinobacteria, such as M. tuberculosis. In this study, we identified two enzymes indispensable for initiating β-oxidation of the B-, C-, and D-rings, thereby filling the last remaining gaps for initiating this pathway. Our AlphaFold-based structural analysis of these enzymes not only provides new insights into the steroid metabolism of M. tuberculosis but also broadens understanding of the ecological and physiological significance of bacterial steroid degradation.

Stress at the gates: Mitochondrial import dysfunctions, response pathways, and therapeutic potential.

The United States is one of the major seafood product importers in the world. Despite the increases in global seafood and aquaculture consumption over the past decades, there is a need for updated information on the trade dynamics of the U.S. imports of key aquaculture species such as catfish and trout. To address this gap, this study uses an augmented gravity model to evaluate the factors that have influenced catfish and trout imports into the United States. The analysis was conducted using the Poisson Pseudo Maximum Likelihood (PPML) estimator to address issues of heteroskedasticity, autocorrelation, and zero trade flows. The results highlight the importance of Gross Domestic Product (GDP) and exchange rates in explaining catfish trade, while distance and free trade agreements (FTAs) play a significant role in trout imports. The inclusion of country-pair and seasonal fixed effects demonstrates how unobserved factors tend to influence trade volumes, diminishing the importance of key variables in the gravity model, such as GDP. Moreover, findings indicate that protective measures such as tariffs and antidumping duties may not affect imports as intended.

Acute myeloid leukemia (AML) is an aggressive malignancy of hematopoietic stem and progenitor cells characterized by profound metabolic dysregulation. Pyrimidine biosynthesis has emerged as a critical metabolic dependency in AML, but clinical translation has been hampered by unacceptable toxicity of current pyrimidine synthesis inhibitors. Since aspartate is an essential nutrient for pyrimidine biosynthesis, we investigated the role of aspartate import via the excitatory amino acid transporter 1 (EAAT1) in AML. We found that EAAT1 is broadly expressed across AML cell lines and patient samples, with enrichment in M4 and M5 subtypes and increasing levels following chemotherapy treatment. Pharmacological inhibition of EAAT1 impaired AML cell viability in vitro, but metabolomic profiling and nutrient rescue experiments showed that these effects were independent of intracellular aspartate levels. Moreover, AML cells cultured in aspartate-free medium maintained proliferation and did not become more sensitive to chemotherapy. EAAT1 inhibition in mice increased bone marrow plasma aspartate levels, confirming inhibition of cellular aspartate uptake, but did not affect growth or chemosensitivity of MLL-AF9-expressing AML cells in vivo. These findings suggest that AML cells possess several complementary mechanisms to support their aspartate requirements and that EAAT1 inhibition does not impair AML growth or response to chemotherapy.

Key Points Disorders of sex development (DSD) are congenital conditions in which development of chromosomal, gonadal, or anatomical (genital) sex is not typical for that expected for a male or female.Most DSDs are caused by genetic mutations in hormone metabolism or action, or in gonadal development.The evaluation for a suspected DSD in the newborn period involves a detailed gestational and family history, as well as a detailed examination of genitalia.Late or atypical pubertal development, or fertility concerns, may indicate an undiagnosed DSD.Care through a specialized multidisciplinary program is optimal, but pediatricians have an important role in providing resources and psychosocial support, and in navigating family discussions.

Mitochondrial protein import is required for maintaining organellar function1. Perturbations in this process are associated with various physiological and disease conditions2. Several stress responses, including the mitochondrial compromised protein import response (mitoCPR), combat damage caused by mitochondrial protein import defects2. However, how this defect is sensed remains largely unknown. Here we reveal that the conserved mitochondrial Hsp70 co-chaperone, Mge1, acts as a stress messenger in budding yeast. During mitochondrial stress, unimported Mge1 entered the nucleus and triggered the transcription of mitoCPR target genes. This was mediated by the interaction of Mge1 with the transcription factor Pdr3 on DNA regulatory elements. The mitochondrial targeting sequence of Mge1 was both sufficient and essential for mitoCPR induction, demonstrating that in addition to their roles in mitochondrial protein import, targeting sequences can also function as signalling molecules. As protein import defects are a common consequence of various types of mitochondrial damage3,4, these findings suggest a novel function for the targeting sequence of Mge1 as an indicator of mitochondrial health.

Background: Public planning plays an increasingly important role as planning acts issued by the administration form the basis for the actions of public authorities, including determining the directions of legislative activity. Therefore, they are the subject of interest in the doctrine of public law. Research objectives: The aim of this paper is to explore selected governmental development policy documents assessed from the point of view of social economy development in order to show both their complexity and the range of their subject matter. The issue of theoretical foundations of planning in administration and their scope was also taken into account.. Research design and methods: The research method used in the study is the legal-dogmatic method and the theoretical-legal method. Results: Findings of the study expose that although in selected government strategic documents reference is made to social economy issues, due to the exclusively internal nature of planning acts and the overly general provisions of the analysed strategies, they can hardly provide a basis for coordinated action. Conclusions: The study identifies a need for greater precision in the provisions so that they can become a basis for specific actions by the administration, including drafting of legislation.

Agriculture is the largest sector in any economy in developing countries. The agricultural sector is expected to be able to give a bigger role to farmers in determining the priority of agricultural business commodities which are the mainstay of business in Indonesia. The agricultural sector is one of the people's food providers, therefore the acceleration of agricultural development plays an important role in the provision of sufficient and affordable food for the community. This study aims to analyze the effect of harvested area, fertilizer and labor on farmers' production. This research was conducted in Mengwi District, Badung Regency. The object of research is harvested area, fertilizer, and labor. The population for this study were all rice farming in the Mengwi District, Badung Regency, totaling 3,571 people and the number of samples calculated using the slovin formula was 97 people. This study uses data collection techniques, namely observation, interviews, documentation and questionnaires. The analysis technique in this research is regression analysis. The results of this study are that harvested area has a positive effect on farmer production, fertilizer has a positive effect on farmer production, and labor has a positive effect on farmer production. keyword: Harvest Area,Fertilizer,Labor,Farmer's Production

Cleavage of mangiferin by Acinetobacter SM902 isolated from Mangifera indica rhizosphere: Production of norathyriol and other phenolic compounds.

Abstract Breast cancer is the most common malignancy in women. Bearing in mind these circumstances, a review of new molecular mechanisms underlying breast cancer progression, resistance and various aspects of existing therapeutic methods would lead to new insights for biologists and clinicians. In this regard, we conducted a study covering recent advances in breast cancer biology with a focus on the p21 protein. The study included 147 patients diagnosed with invasive breast cancer. The presence of non-invasive lesions was noted in each invasive breast cancer and surrounding tissue. p21 expression was determined by reading the percentage of nuclear expression in epithelial cells of invasive breast cancer and non-invasive lesions. Results showed that expression of p21 increases with the progression of cytological changes in the epithelium; it is significantly higher in invasive breast cancer compared to non-invasive lesions (p<0.001). There is a difference in p21 expression between different molecular subtypes of breast cancer (p=0.004). Statistically significantly higher values of p21 expression were observed in those breast cancers that showed overexpression of HER2 compared to HER2-negative tumors (p=0.001). Depending on Ki67 expression, the highest p21 expression is in the group with high Ki67 expression values (p=0.019). The increase in p21 expression in tumor cells was accompanied by a statistically significantly reduced expression of ER (p=0.015, ρ=−0.225) and PR (p=0.027, ρ=−0.205). p21 protein plays an important role in proliferation, malignant transformation, as well as in progression from non-invasive lesions to invasive breast cancer.

Background: Helminth infections caused by parasitic worms due to poor sanitation are a major public health problem. As the infections are often asymptomatic but can lead to malnutrition and growth problems, and also because of resistance to anthelmintics, effective treatments are crucial. Traditional herbal remedies, which are particularly important in resource-poor regions, such as northeast India, play an important role in addressing this challenge. Objective: The study focuses on anthelmintic herbal remedies and aims to explore and analyze the indigenous herbal treatments in Northeast India. The review combines a comprehensive review of literature, field studies, and traditional knowledge and provides insights into plant species, preparation techniques and research studies that have been reported. Methods: The information presented was assessed using a variety of electronic resources, including ScienceDirect, Wiley, Elsevier, Springer, Google Scholar, and PubMed (National Library of Medicines). Results: The focus of this review is on the phytochemicals present in these herbal remedies from Northeastern India, which play a pivotal role in their efficacy against parasitic worms. The analysis explores the mechanisms of action behind these remedies and sheds light on the scientific basis of traditional therapies. It emphasizes the merging of ancient and modern research and emphasizes interdisciplinary collaboration and knowledge sharing. Conclusion: This review highlights the scope for effective anthelmintic therapies and explores the synergy between synthetic compounds and natural phytometabolites that offer the potential for effective interventions. This ethnopharmacological review not only scientifically validates traditional wisdom but also demonstrates the value of indigenous approaches in the treatment of modern health issues.

Omega squared (ω^2) is a measure of effect size for analysis of variance (ANOVA) designs. It is less biased than eta squared, but reported less often. This is in part due to lack of clear guidance on how to calculate it. In this paper, we discuss the logic behind effect size measures, the problem with eta squared, the history of omega squared, and why it has been underused. We then provide a user-friendly guide to omega squared and partial omega squared for ANOVA designs with fixed factors, including one-way, two-way, and three-way designs, using within-subjects factors and/or between-subjects factors. We show how to calculate omega squared using output from SPSS. We provide information on the calculation of confidence intervals. We examine the problems of nonadditivity, and intrinsic versus extrinsic factors. We argue that statistical package developers could play an important role in making the calculation of omega squared easier. Finally, we recommend that researchers report the formulas used in calculating effect sizes, include confidence intervals if possible, and include ANOVA tables in the online supplemental materials of their work. (PsycInfo Database Record (c) 2025 APA, all rights reserved).

Neurodegenerative diseases are a group of disorders characterized by the progressive degeneration of the neurons and function of the nervous system. These diseases typically result in a decline in cognitive, motor, or sensory functions and often lead to disability in many cases. Rotenone is a naturally occurring compound isolated from the roots and stems of several plants that induced neurotoxicity by inhibiting the mitochondrial complex I resulting in the generation of reactive oxygen species (ROS) and induced the ROS generation. Natural plant products can play an important role in the treatment of neurodegenerative diseases. This review focusses on the therapeutic potential of natural products and their bioavailability to exert neuroprotective effects against the neurodegenerative diseases.

Tom70 mediates mitochondrial protein import by coordinating the transfer of cytosolic preproteins from Hsp70/Hsp90 to the translocase of the outer membrane (TOM) complex. In humans, the cytosolic domain of Tom70 (HsTom70c) is entirely α-helical and comprises modular TPR motifs divided into an N-terminal chaperone-binding domain (NTD) and a C-terminal preprotein-binding domain (CTD). However, the mechanisms linking these functional regions remain poorly understood. Here, we present the 2.04 Å crystal structure of unliganded HsTom70c, revealing two distinct conformations – open and closed – within the asymmetric unit. These states are stabilized in part by interdomain crystal contacts and are supported in solution by hydrogen–deuterium exchange mass spectrometry (HDX-MS) and molecular dynamics (MD) simulations. Principal component and dynamical network analyses reveal a continuum of motion linking the NTD and CTD via key structural elements, notably residues in helices α7, α8, and α25. Engagement of the CTD by the viral protein Orf9b interrupts this network, stabilizing a partially-closed intermediate conformation and dampening dynamics at distal NTD sites. Collectively, our findings lay the groundwork for understanding Tom70 allostery and provide a framework for dissecting its mechanistic roles in chaperone engagement, mitochondrial import, and viral subversion.

Abstract Acute myeloid leukemia (AML) is an aggressive malignancy of hematopoietic stem and progenitor cells characterized by profound metabolic dysregulation. Pyrimidine biosynthesis has emerged as a critical metabolic dependency in AML, but clinical translation has been hampered by unacceptable toxicity of current pyrimidine synthesis inhibitors. Since aspartate is an essential nutrient for pyrimidine biosynthesis, we investigated the role of aspartate import via the excitatory amino acid transporter 1 (EAAT1) in AML. We found that EAAT1 is broadly expressed across AML cell lines and patient samples, with enrichment in M4 and M5 subtypes and increasing levels following chemotherapy treatment. Pharmacological inhibition of EAAT1 impaired AML cell viability in vitro, but metabolomic profiling and nutrient rescue experiments showed that these effects were independent of intracellular aspartate levels. Moreover, AML cells cultured in aspartate-free medium maintained proliferation and did not become more sensitive to chemotherapy. EAAT1 inhibition in mice increased bone marrow plasma aspartate levels, confirming inhibition of cellular aspartate uptake, but did not affect growth or chemosensitivity of MLL-AF9-expressing AML cells in vivo. These findings suggest that AML cells possess several complementary mechanisms to support their aspartate requirements and that EAAT1 inhibition does not impair AML growth or response to chemotherapy.

Feedback plays an important role in language learning. Feedback-seeking be-havior (FSB) includes feedback monitoring and inquiry and the diagnostic in-formation obtained through FSB can help seekers improve their performance. Most of the previous studies have explored the factors that influence FSB, such as language mindsets and motivational factors. However, FSB itself has an im-portant role to play in second language writing. Therefore, this study tries to combine FSB with second language writing to investigate the following ques-tions: 1. What is the role of FSB in second language writing? 2. How can FSB ex-ert its influence in second language writing? This research has selected 20 sen-ior students from science class to join in an semi-structural interview and ques-tionnaire. The results reveal that monitoring feedback unconditionally but in-quiring feedback conditionally. Herein, implications for L2 writing pedagogy are provided.

Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world, but molecular complexity and tumor heterogeneity make predictive models for HCC prognosis ineffective. Many recent studies have suggested that autophagy is important in tumor progression. Using autophagy-related genes (ARGs), we attempted to create a novel signature for individual prognosis prediction in patients with HCC. Differentially expressed ARGs (DE-ARGs) in HCC and normal samples were screened using TCGA datasets. Univariate Cox and multivariate Cox regression analyses were performed to determine ARGs related to survival in HCC. An autophagy-based signature was constructed using LASSO, and its correlation with the prognosis and the immune infiltration of HCC patients was explored. In this study, we screened 32 survival-related DE-ARGs by analyzing TCGA datasets. Functional enrichment indicated that the 32 DE-ARGs may play important functional and regulatory roles in cellular autophagy, the regulation of multiple signaling pathways, as well as in the context of cancer and neurological diseases. Based on PPI Network, we identified several hub genes. LASSO Cox regression analysis selected five genes (CASP8, FOXO1, PRKCD, SPHK1, and SQSTM1) for a novel prognostic model. AUCs of 0.752, 0.686, and 0.665 in the TCGA whole set indicated that the model accurately predicted 1-, 3-, and 5-year overall survival, respectively. Cox regression analysis showed that the five-gene signature is an independent and robust predictor in patients with HCC. The high-risk group demonstrated higher levels of immune cell infiltration and exhibited a strong correlation with the immune microenvironment and tumor stem cells. In addition, we further identified PRKCD and SQSTM1 as critical regulators involved in HCC progression. The expression levels of PRKCD and SQSTM1 genes play a crucial role in chemotherapy drug sensitivity and resistance. We introduce here a novel ARG-based predictive feature for HCC patients. Effective use of this signature will aid in determining a patient's prognosis and may lead to novel approaches to clinical decision-making and therapy.

In the age of the Internet, the development of new media has broadened the channels for civilizational exchange. Overseas Chinese play an important role in bridging the gap between Chinese and foreign cultures because of their natural affinity with the Chinese people, who share the same roots and ethnicity. Based on the theory of use and satisfaction, the research analysed the content of notes published by ten overseas Xiaohongshu APP accounts from January 1, 2022 to January 1, 2023, and found that the notes were mainly about life topics, which satisfied users’ social, emotional, practical and cognitive needs to varying degrees. The content of the website has been analysed and found to be social, emotional, practical, and cognitive.

Image enhancement plays an important role in biometric systems, this paper presented automatic latent fingerprint segmentation and matching. While considerable progress has made in both rolled and plain fingerprint image enhancement, latent fingerprint enhancement is a challenging problem due to the poor image quality of latent fingerprint with unclear ridge structures and various overlapping patterns, along with the presence of structured noise. Prior to latent fingerprint segmentation and feature extraction, latent fingerprint image enhancement is important to suppress various types of noise and to clarify the ridge structure. This paper reviews the current techniques used for latent fingerprint enhancement and presents a hybrid model which combines the edge directional total variation model (EDTV) and quality image enhancement with lost minutia reconstruction. The NIST SD27 database is used to test the performance of the proposed techniques with RMSE and PSNR. The proposed technique is effectively clarify input latent fingerprint images and eliminate noise in good, bad and ugly latent fingerprint images. A statistically significant difference, which focused on the mean lengths of PSNR and RMSE for different categories of latent fingerprint, images (good, bad and ugly). The proposed technique performs well for the good latent fingerprint images compare to bad and ugly images. Enhancement respectively presents RMSE averages of 0.018373, 0.022287, and 0.023199 for the good, bad and ugly image SD27 image set, as opposed to 82.99068, 81.39749, and 81.07826 for PSNR. The proposed enhancement technique improved the matching accuracy of latent fingerprint images by about 30%.