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Sphingolipids are membrane and bioactive lipids that are required for many aspects of normal mammalian development and physiology. However, the importance of the regulatory mechanisms that control sphingolipid levels in these processes is not well understood. The mammalian ORMDL proteins (ORMDL1, 2 and 3) mediate feedback inhibition of the de novo synthesis pathway of sphingolipids by inhibiting serine palmitoyl transferase in response to elevated ceramide levels. To understand the function of ORMDL proteins in vivo, we studied mouse knockouts (KOs) of the Ormdl genes. We found that Ormdl1 and Ormdl3 function redundantly to suppress the levels of bioactive sphingolipid metabolites during myelination of the sciatic nerve. Without proper ORMDL-mediated regulation of sphingolipid synthesis, severe dysmyelination results. Our data indicate that the Ormdls function to restrain sphingolipid metabolism in order to limit levels of dangerous metabolic intermediates that can interfere with essential physiological processes such as myelination.

Objective Acute lymphoblastic leukemia (ALL) is the most common form of childhood cancer. Fingolimod (FTY720) is a sphingosine-1-phosphate (S1P) receptor agonist that prevents lymphocytes from egressing from lymphoid tissues and has shown a cytotoxic effect on T-cell ALL (T-ALL) cells. However, the mechanism of action of FTY720 cytotoxicity in hematological malignancies is still unclear, and cell-specific effects have been reported. Here, we investigated the mechanism of cytotoxicity of FTY720 in T-ALL cells using a CRISPR-Cas9 genomic screening. Our goal was to identify novel positive regulators for the cytotoxic effect of FTY720 in T-ALL. Results Cells treated with FTY720 were enriched for single-guide RNAs (sgRNAs) such as ZNF575 , GPX3 , FBXL15 , DNAJB5 , UBE2D1 , ATXN7 , C6orf201 , RIC8A , RAB13 , and C10orf12 when compared to the DMSO (vehicle control) samples. Altogether, our study identified novel genes that, when silenced, were positively correlated with the survival of T-ALL cells treated with FTY720.

Maintenance of sphingolipid homeostasis is critical for cell growth and programmed cell death (PCD). Serine palmitoyltransferase (SPT), composed of LCB1 and LCB2 subunits, catalyzes the primary regulatory point for sphingolipid synthesis. Small subunits of SPT (ssSPT) that strongly stimulate SPT activity have been identified in mammals, but the role of ssSPT in eukaryotic cells is unclear. Candidate Arabidopsis thaliana ssSPTs, ssSPTa and ssSPTb, were identified and characterized. Expression of these 56—amino acid polypeptides in a Saccharomyces cerevisiae SPT null mutant stimulated SPT activity from the Arabidopsis LCB1/LCB2 heterodimer by >100-fold through physical interaction with LCB1/LCB2. ssSPTa transcripts were more enriched in all organs and >400-fold more abundant in pollen than ssSPTb transcripts. Accordingly, homozygous ssSPTa T-DNA mutants were not recoverable, and 50% nonviable pollen was detected in heterozygous ssspta mutants. Pollen viability was recovered by expression of wild-type ssSPTa or ssSPTb under control of the ssSPTa promoter, indicating ssSPTa and ssSPTb functional redundancy. SPT activity and sensitivity to the PCD-inducing mycotoxin fumonisin B 1 (FB 1 ) were increased by ssSPTa overexpression. Conversely, SPT activity and FB 1 sensitivity were reduced in ssSPTa RNA interference lines. These results demonstrate that ssSPTs are essential for male gametophytes, are important for FB 1 sensitivity, and limit sphingolipid synthesis in planta.

Sphingolipids play key roles in cellular systems both as membrane components and as signaling molecules. Their biosynthesis, which occurs in the endoplasmic reticulum (ER), begins with the condensation of an amino acid, typically serine, and a fatty acyl-CoA. Under certain pathological conditions, alanine can be substituted for serine in the condensation reaction, producing 1-deoxysphingolipids, which lack the 1-hydroxyl group on the sphingoid base. Unlike typical sphingolipids, 1-deoxysphingolipids are unable to accept a head group modification, which alters their metabolic processing and prevents their canonical degradation. The accumulation of these \"headless\" 1-deoxysphingolipids causes neurotoxicity in various neurological and metabolic disorders. Here, we conducted a genome-wide CRISPR-Cas9 screen to identify pathways leading to 1-deoxysphinganine-induced toxicity in SH-SY5Y cells, a model used to study neurotoxic responses. Our top genetic hits highlighted the pathway involved in synthesizing ceramides with very-long-chain fatty acids (C22-C26). Using CRISPR-Cas9-modified SH-SY5Y cells with loss-of-function (LOF) mutations in the or genes-both critical for producing very-long-chain ceramides-we validated that this pathway was essential for 1-deoxysphinganine-mediated toxicity. Furthermore, we demonstrated that the ceramide synthesis pathway is required for 1-deoxysphinganine to trigger ER stress, as evidenced by significantly increased expression of the unfolded protein response in WT, but not or LOF mutant, SH-SY5Y cells exposed to 1-deoxysphinganine. Collectively, these findings identify a specific metabolic pathway for 1-deoxysphinganine leading to very-long-chain 1-deoxyceramide production that culminates in ER stress and toxicity. The findings highlight potential therapeutic targets for neuropathological diseases caused by 1-deoxysphingolipid accumulation.

Background A thorough psychosocial assessment is time-consuming, often requiring multiple sessions to uncover the psychological factors contributing to mental illness, such as depression. The duration varies depending on the severity of the patient’s condition and how effectively the psychotherapist can establish rapport. However, prolonged assessment periods pose a significant risk of patient deterioration. Methods The comprehensive psychosocial intervention, led by the Multi-Criteria Decision-Making (MCDM) approach utilizing the Multi-Objective Optimization by Ratio Analysis (MOORA) method, played a pivotal role in identifying the key psychological factors contributing to the depression of the client among the 21 factors specified by BDI-II analysis. Results The integration of the MOORA strategy compared to traditional psychotherapy on 254 samples demonstrates a Jaccard similarity coefficient of 0.8, with a minimum error margin of 7% (vulnerability index = 0.57), indicating a significant agreement between the two approaches, both converging towards a similar solution. For patients with extreme depression, the number of sessions reduced from 18 ± 2 to 11 ± 2, showing a 33–35% reduction ( χ 2  = 6.94, p = 0.008). Severe depression patients experienced a reduction from 14 ± 2 to 8  ±  1 sessions i.e., 34–39% reduction ( χ 2  = 8.32, p = 0.004). Moderate depression patients saw sessions drop from 9 ± 1 to 5 ± 1, i.e., 37–43% reduction ( χ 2  = 0.29, p = 0.001). The accuracy for detecting dominant psychological factors improved to 82.88% for extreme, 86.74% for severe, and 90.34% for moderate depression, respectively. Conclusion The implementation of MOORA facilitated the identification and prioritization of key psychosocial intervention strategies, making the process significantly faster compared to traditional methods. This acceleration greatly enhanced the precision and efficacy of the work. Additionally, critical vulnerable factors were identified through ordered statistics and correlation analysis [Pearson ( r ) = 0.8929 and Spearman’s rank ( ρ ) = 0.7551] on the Beck Depression Inventory-II model. These findings were supported by other MCDM schemes such as EDAS and TOPSIS, demonstrating high stability and robustness in dynamic decision-making environments, maintaining consistency across scenarios adapted by different psychotherapists. Overall, the combined application of MCDM (MOORA) and targeted psychological interventions yielded substantial positive outcomes in enhancing the well-being of individuals with psychological illnesses, such as depression, cognitive, affective, and somatic syndromes.

Background: With the reports of indigenous cases of dengue and chikungunya in the forest-covered rural tribal malaria-endemic villages of Dhalai District, Tripura, India, an exploratory study was undertaken to identify the vector breeding sites. Methods: From June 2021 to August 2022, mosquito larvae were collected from both natural and artificial sources in the villages, house premises, and their nearby forested areas outside of the houses. Other than morphological characterisation, Aedes species were confirmed by polymerase chain reaction targeting both nuclear (ITS2) and mitochondrial genes (COI) followed by bidirectional Sanger sequencing. Results: Aedes albopictus was abundantly found in this area in both natural and artificial containers, whereas Ae. aegypti was absent. Among the breeding sources of molecularly confirmed Ae. albopictus species, rubber collection bowls were found to be a breeding source reported for the first time. Plastic and indigenously made bamboo–polythene containers for storing supply water and harvesting rainwater in the villages with a shortage of water were found to be other major breeding sources, which calls for specific vector control strategies. Natural sources like ponds and rainwater collected on Tectona grandis leaves and Colocasia axil were also found to harbour the breeding, along with other commonly found sources like bamboo stumps and tree holes. No artificial containers as a breeding source were found inside the houses. Mixed breeding was observed in many containers with other Aedes and other mosquito species, necessitating molecular identification. We report six haplotypes in this study, among which two are reported for the first time. However, Aedes aegypti was not found in the area. Additionally, rubber collection bowls, ponds, and water containers also showed the presence of Culex quinquefasciatus and Culex vishnui, known JE vectors from this area, and reported JE cases as well. Different Anopheles vector spp. from this known malaria-endemic area were also found, corroborating this area as a hotbed of several vectors and vector-borne diseases. Conclusions: This study, for the first time, reports the breeding sources of Aedes albopictus in the forested areas of Tripura, with rubber collection bowls and large water storage containers as major sources. Also, for the first time, this study reports the molecular characterisation of the Ae. albopictus species of Tripura, elucidating the limitations of morphological identification and highlighting the importance of molecular studies for designing appropriate vector control strategies. The study also reports the co-breeding of JE and malaria vectors for the first time in the area reporting these vector-borne diseases.

Background: With the reports of indigenous cases of dengue and chikungunya in the forest-covered rural tribal malaria-endemic villages of Dhalai District, Tripura, India, an exploratory study was undertaken to identify the vector breeding sites. Methods: From June 2021 to August 2022, mosquito larvae were collected from both natural and artificial sources in the villages, house premises, and their nearby forested areas outside of the houses. Other than morphological characterisation, Aedes species were confirmed by polymerase chain reaction targeting both nuclear (ITS2) and mitochondrial genes (COI) followed by bidirectional Sanger sequencing. Results: Aedes albopictus was abundantly found in this area in both natural and artificial containers, whereas Ae. aegypti was absent. Among the breeding sources of molecularly confirmed Ae. albopictus species, rubber collection bowls were found to be a breeding source reported for the first time. Plastic and indigenously made bamboo–polythene containers for storing supply water and harvesting rainwater in the villages with a shortage of water were found to be other major breeding sources, which calls for specific vector control strategies. Natural sources like ponds and rainwater collected on Tectona grandis leaves and Colocasia axil were also found to harbour the breeding, along with other commonly found sources like bamboo stumps and tree holes. No artificial containers as a breeding source were found inside the houses. Mixed breeding was observed in many containers with other Aedes and other mosquito species, necessitating molecular identification. We report six haplotypes in this study, among which two are reported for the first time. However, Aedes aegypti was not found in the area. Additionally, rubber collection bowls, ponds, and water containers also showed the presence of Culex quinquefasciatus and Culex vishnui, known JE vectors from this area, and reported JE cases as well. Different Anopheles vector spp. from this known malaria-endemic area were also found, corroborating this area as a hotbed of several vectors and vector-borne diseases. Conclusions: This study, for the first time, reports the breeding sources of Aedes albopictus in the forested areas of Tripura, with rubber collection bowls and large water storage containers as major sources. Also, for the first time, this study reports the molecular characterisation of the Ae. albopictus species of Tripura, elucidating the limitations of morphological identification and highlighting the importance of molecular studies for designing appropriate vector control strategies. The study also reports the co-breeding of JE and malaria vectors for the first time in the area reporting these vector-borne diseases.

Real-time monitoring and responses to emerging public health threats rely on the availability of timely surveillance data. During the early stages of an epidemic, the ready availability of line lists with detailed tabular information about laboratory-confirmed cases can assist epidemiologists in making reliable inferences and forecasts. Such inferences are crucial to understand the epidemiology of a specific disease early enough to stop or control the outbreak. However, construction of such line lists requires considerable human supervision and therefore, difficult to generate in real-time. In this paper, we motivate Guided Deep List, the first tool for building automated line lists (in near real-time) from open source reports of emerging disease outbreaks. Specifically, we focus on deriving epidemiological characteristics of an emerging disease and the affected population from reports of illness. Guided Deep List uses distributed vector representations (ala word2vec) to discover a set of indicators for each line list feature. This discovery of indicators is followed by the use of dependency parsing based techniques for final extraction in tabular form. We evaluate the performance of Guided Deep List against a human annotated line list provided by HealthMap corresponding to MERS outbreaks in Saudi Arabia. We demonstrate that Guided Deep List extracts line list features with increased accuracy compared to a baseline method. We further show how these automatically extracted line list features can be used for making epidemiological inferences, such as inferring demographics and symptoms-to-hospitalization period of affected individuals.