CCR9 overexpression promotes T-ALL progression by enhancing cholesterol biosynthesis

Introduction: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy of the lymphoid progenitor cells, contributing to ∼ 20% of the total ALL cases, with a higher prevalence in adults than children. Despite the important role of human T-ALL cell lines in understanding the pathobiology of the disease, a detailed comparison of the tumorigenic potentials of two commonly used T-ALL cell lines, MOLT4 and JURKAT cells, is still lacking.Methodology: In the present study, NOD-PrkdcscidIL2rgdull (NTG) mice were intravenously injected with MOLT4, JURKAT cells, and PBS as a control. The leukemiac cell homing/infiltration into the bone marrow, blood, liver and spleen was investigated for bioluminescence imaging, flow cytometry, and immunohistochemistry staining. Gene expression profiling of the two cell lines was performed via RNA-seq to identify the differentially expressed genes (DEGs). CCR9 identified as a DEG, was further screened for its role in invasion and metastasis in both cell lines in vitro. Moreover, a JURKAT cell line with overexpressed CCR9 (Jurkat-OeCCR9) was investigated for T-ALL formation in the NTG mice as compared to the GFP control. Jurkat-OeCCR9 cells were then subjected to transcriptome analysis to identify the genes and pathways associated with the upregulation of CCR9 leading to enhanced tumirogenesis. The DEGs of the CCR9-associated upregulation were validated both at mRNA and protein levels. Simvastatin was used to assess the effect of cholesterol biosynthesis inhibition on the aggressiveness of T-ALL cells.Results: Comparison of the leukemogenic potentials of the two T-ALL cell lines showed the relatively higher leukemogenic potential of MOLT4 cells, characterized by their enhanced tissue infiltration in NOD-PrkdcscidIL2rgdull (NTG) mice. Transcriptmoe analysis of the two cell lines revealed numerous DEGs, including CCR9, enriched in vital signaling pathways associated with growth and proliferation. Notably, the upregulation of CCR9 also promoted the tissue infiltration of JURKAT cells in vitro and in NTG mice. Transcriptome analysis revealed that CCR9 overexpression facilitated cholesterol production by upregulating the expression of the transcriptional factor SREBF2, and the downstream genes: MSMO1, MVD, HMGCS1, and HMGCR, which was then corroborated at the protein levels. Notably, simvastatin treatment reduced the migration of the CCR9-overexpressing JURKAT cells, suggesting the importance of cholesterol in T-ALL progression.Conclusions: This study highlights the distinct tumorigenic potentials of two T-ALL cell lines and reveals CCR9-regulated enhanced cholesterol biosynthesis in T-ALL

Focus on What Is Within Your Control? A “Balance” Intervention in Coping with Stress

How do people cope with stressors? One common approach is to focus on the aspects of a stressful situation that may be controlled. However, initial studies from our lab show that people report less stress from COVID-19 when they consider the balance between what they can and cannot control rather than focusing only on what they can control. Given how unusual the COVID-19 context is, the current research examines whether a “balance” intervention can be effective for coping with other stressors. We also investigate potential behavioral effects (i.e., improving performance and motivating behaviors) of this intervention. Across two studies (N = 1,797), we find preliminary, directional evidence suggesting that a “balance” intervention can reduce emotional distress in taxing situations other than COVID-19. Whereas previous research highlights the importance of increasing one’s sense of control and the benefits of focusing exclusively on controllable aspects of otherwise stressful events, we find that simultaneously drawing attention to the uncontrollable aspects can be more effective in alleviating distress. Thus, we provide a low-cost and available self-help intervention for people in need of an effective coping strategy to deal with emotional distress

Detecting influential subjects in intensive longitudinal data using mixed-effects location scale models

Background: Collection of intensive longitudinal health outcomes allows joint modeling of their mean (location) and variability (scale). Focusing on the location of the outcome, measures to detect influential subjects in longitudinal data using standard mixed-effects regression models (MRMs) have been widely discussed. However, no existing approach enables the detection of subjects that heavily influence the scale of the outcome. Methods: We propose applying mixed-effects location scale (MELS) modeling combined with commonly used influence measures such as Cook’s distance and DFBETAS to fill this gap. In this paper, we provide a framework for researchers to follow when trying to detect influential subjects for both the scale and location of the outcome. The framework allows detailed examination of each subject’s influence on model fit as well as point estimates and precision of coefficients in different components of a MELS model. Results: We simulated two common scenarios in longitudinal healthcare studies and found that influence measures in our framework successfully capture influential subjects over 99% of the time. We also re-analyzed data from a health behavior study and found 4 particularly influential subjects, among which two cannot be detected by influence analyses via regular MRMs. Conclusion: The proposed framework can help researchers detect influential subject(s) that will be otherwise overlooked by influential analysis using regular MRMs and analyze all data in one model despite influential subjects.</p

Additional file 1 of Decoding the complete organelle genomic architecture of Stewartia gemmata: an early-diverging species in Theaceae

Additional file 1: Supplementary Figure 1. Construction of the mitochondrial genome assembly graph for Stewartia gemmata. (A) illustrates the preliminary draft of the mitochondrial genome. (B) describes the major circular conformation of the mitochondrial genome, while (C) explores potential alternative conformations of (B). Supplementary Figure 2. Depth of coverage of organelle genomes by sequenced sequences. (A), (B), and (C) show the depth of coverage of the genome by short-reads and long-reads mapped to the mitochondrial genome and short-reads mapped to the chloroplast genome, respectively. Supplementary Figure 3. Comparative analysis of the gene content in mitochondrial genomes of representative species in Ericales. Displayed are protein-coding genes (A), rRNA genes (B), and tRNA genes (C). Yellow means one copy exists; white means no copy exists. The red font indicates the genome released in this study. Supplementary Figure 4. Comparative analysis of the gene content in chloroplast genomes of representative species in Ericales. Displayed are protein-coding genes (A), trRNA genes (B), and rRNA genes (C). Yellow means a copy exists, white means no copy exists. The red font indicates the genome released in this study. Supplementary Figure 5. Distribution of long-reads mapping of the MTPT (Mitochondrial plastid DNAs) region of the mitochondrial genome. The long-reads from chloroplasts and mitochondria are mapped onto the mitochondrial genome, and the corresponding regions mapped are observed. In the figure, mitochondrial reads can map to the MTPT and regions on both sides, while chloroplast reads can only map to the MTPT region and not to the regions on both sides. MTPTs below 80 bp in length are not shown here due to their short length. For each MTPT, the gray area indicates the region covered by the sequence and the dark blue line segments highlight the mitochondrial (top) and chloroplast (bottom) reads, respectively, as representative of the two reads. Supplementary Figure 6. Best maximum likelihood phylogenetic tree based on mitochondrial genomes of 36 species (including seven species of Theaceae). Numbers above each branch are the maximum likelihood bootstrap of each clade >50%. The four different background colors indicate different orders, respectively. Red font indicates the species of this study. The top right corner is a tree with branch length information

Social Vulnerability and Risk of Suicide in US Adults, 2016-2020

Importance: There were over 45 000 suicides in the US in 2020, making suicide the 12th leading cause of death. If social vulnerability is associated with suicide rates, targeted interventions for at-risk segments of the population may reduce US suicide rates. Objective: To determine the association between social vulnerability and suicide in adults. Design, setting, and participants: This cohort study analyzed 2 county-level social vulnerability measures (the Social Vulnerability Index [SVI] and the Social Vulnerability Metric [SVM]) and US Centers for Disease Control and Prevention-reported county-level suicides from 2016 to 2020. Data were analyzed November and December 2022. Exposures: County-level variability in social vulnerability. Main outcomes and measures: The primary outcome measure was number of county-level adult suicides from 2016 to 2020, offset by county adult population during those years. The association between social vulnerability (measured using the SVI and the newly created SVM for 2018) and suicide was modeled using a bayesian-censored Poisson regression model to account for the CDC's suppression of county-level suicide counts of less than 10, adjusted for age, racial and ethnic minority, and urban-rural county characteristics. Results: From 2016 to 2020, there were a total of 222 018 suicides in 3141 counties. Comparing the least socially vulnerable (0% to 10%) to the most socially vulnerable (90% to 100%) counties, there was a 56% increase in suicide rate (17.3 per 100 000 persons to 27.0 per 100 000 persons) as measured by the SVI (incidence rate ratio, 1.56; 95% credible interval, 1.51-1.60) and an 82% increase in suicide rate (13.8 per 100 000 persons to 25.1 per 100 000 persons) as measured by the SVM (incidence rate ratio, 1.82; 95% credible interval, 1.72-1.92). Conclusions and relevance: This cohort study found that social vulnerability had a direct association with risk for adult suicide. Reducing social vulnerability may lead to life-saving reduction in the rate of suicide.</p

Self-Reported Severity and Causes of Traumatic Brain Injury in Patients With Epileptic or Functional Seizures

Background and objectivesAlthough moderate and severe traumatic brain injury (TBI) can cause posttraumatic epilepsy (PTE), many patients with functional seizures (FS) also report a history of mild TBI. To determine whether features of TBI history differ between patients with epileptic seizures (ES) and FS, we compared patient reports of TBI severity, symptoms, and causes of injury.MethodsWe recruited patients undergoing video-EEG evaluation for the diagnosis of ES, FS, mixed ES and FS, or physiologic seizure-like events at an academic, tertiary referral center. Patients and their caregivers were interviewed before final video-EEG diagnosis regarding their TBI histories, including concussive symptoms and causes of injury.ResultsOf 506 patients, a greater percentage of patients with FS reported a history of TBI than patients with ES (70% vs 59%, aOR = 1.75 [95% CI: 1.00-3.05], p = 0.047). TBI with loss of consciousness (LOC) lasting less than 30 minutes was more frequently reported among patients with FS than with ES (27% vs 13%, aOR = 2.38 [1.26-4.47], p &lt; 0.01). The proportion of patients reporting other neurologic symptoms immediately after TBI was not significantly different between FS and ES (40% vs 29%, p = 0.08). Causes of TBI were found to differ, with TBIs caused by falls from a height (17% vs 10%, aOR = 2.24 [1.06-4.70], p = 0.03) or motor vehicle collisions (27% vs 11%, aOR = 2.96 [1.54-5.67], p &lt; 0.01) reported more frequently in FS than ES.DiscussionOur findings further the association of mild TBI with FS and prompt reconsideration of typical assumptions regarding the significance of a reported TBI history in patients with previously undifferentiated seizures. Although common in both groups, TBI with LOC less than 30 minutes and causes of injury that are commonly believed to be more severe were reported more frequently in FS than ES. This suggests that a patient or caregiver reporting of these features does not imply that PTE is a more probable diagnosis than FS. Although a history of TBI with LOC and presumed high-risk causes of injury intuitively raises suspicion for PTE, clinicians should be cautioned that these historical factors also were a frequent finding in patients with FS

Reliability of additional reported seizure manifestations to identify dissociative seizures.

PurposeDescriptions of seizure manifestations (SM), or semiology, can help localize the symptomatogenic zone and subsequently included brain regions involved in epileptic seizures, as well as identify patients with dissociative seizures (DS). Patients and witnesses are not trained observers, so these descriptions may vary from expert review of seizure video recordings of seizures. To better understand how reported factors can help identify patients with DS or epileptic seizures (ES), we evaluated the associations between more than 30 SMs and diagnosis using standardized interviews.MethodsBased on patient- and observer-reported data from 490 patients with diagnoses documented by video-electoencephalography, we compared the rate of each SM in five mutually exclusive groups: epileptic seizures (ES), DS, physiologic seizure-like events (PSLE), mixed DS and ES, and inconclusive testing.ResultsIn addition to SMs that we described in a prior manuscript, the following were associated with DS: light triggers, emotional stress trigger, pre-ictal and post-ictal headache, post-ictal muscle soreness, and ictal sensory symptoms. The following were associated with ES: triggered by missing medication, aura of déjà vu, and leftward eye deviation. There were numerous manifestations separately associated with mixed ES and DS.ConclusionsReported SM can help identify patients with DS, but no manifestation is pathognomonic for either ES or DS. Patients with mixed ES and DS reported factors divergent from both ES-alone and DS-alone