Amygdala inhibitory neurons as loci for translation in emotional memories.

To survive in a dynamic environment, animals need to identify and appropriately respond to stimuli that signal danger1. Survival also depends on suppressing the threat-response during a stimulus that predicts the absence of threat (safety)2-5. An understanding of the biological substrates of emotional memories during a task in which animals learn to flexibly execute defensive responses to a threat-predictive cue and a safety cue is critical for developing treatments for memory disorders such as post-traumatic stress disorder5. The centrolateral amygdala is an important node in the neuronal circuit that mediates defensive responses6-9, and a key brain area for processing and storing threat memories. Here we applied intersectional chemogenetic strategies to inhibitory neurons in the centrolateral amygdala of mice to block cell-type-specific translation programs that are sensitive to depletion of eukaryotic initiation factor 4E (eIF4E) and phosphorylation of eukaryotic initiation factor 2α (p-eIF2α). We show that de novo translation in somatostatin-expressing inhibitory neurons in the centrolateral amygdala is necessary for the long-term storage of conditioned-threat responses, whereas de novo translation in protein kinase Cδ-expressing inhibitory neurons in the centrolateral amygdala is necessary for the inhibition of a conditioned response to a safety cue. Our results provide insight into the role of de novo protein synthesis in distinct inhibitory neuron populations in the centrolateral amygdala during the consolidation of long-term memories.

Transcriptome-wide subtyping of pediatric and adult T cell acute lymphoblastic leukemia in an international study of 707 cases.

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy of T cell progenitors, known to be a heterogeneous disease in pediatric and adult patients. Here we attempted to better understand the disease at the molecular level based on the transcriptomic landscape of 707 T-ALL patients (510 pediatric, 190 adult patients, and 7 with unknown age; 599 from published cohorts and 108 newly investigated). Leveraging the information of gene expression enabled us to identify 10 subtypes (G1­G10), including the previously undescribed one characterized by GATA3 mutations, with GATA3R276Q capable of affecting lymphocyte development in zebrafish. Through associating with T cell differentiation stages, we found that high expression of LYL1/LMO2/SPI1/HOXA (G1­G6) might represent the early T cell progenitor, pro/precortical/cortical stage with a relatively high age of disease onset, and lymphoblasts with TLX3/TLX1 high expression (G7­G8) could be blocked at the cortical/postcortical stage, while those with high expression of NKX2-1/TAL1/LMO1 (G9­G10) might correspond to cortical/postcortical/mature stages of T cell development. Notably, adult patients harbored more cooperative mutations among epigenetic regulators, and genes involved in JAK-STAT and RAS signaling pathways, with 44% of patients aged 40 y or above in G1 bearing DNMT3A/IDH2 mutations usually seen in acute myeloid leukemia, suggesting the nature of mixed phenotype acute leukemia.

Integrative genomic and transcriptomic profiling reveals distinct molecular subsets in adult mixed phenotype acute leukemia.

Mixed phenotype acute leukemia (MPAL) is a subtype of leukemia in which lymphoid and myeloid markers are co-expressed. Knowledge regarding the genetic features of MPAL is lacking due to its rarity and heterogeneity. Here, we applied an integrated genomic and transcriptomic approach to explore the molecular characteristics of 176 adult patients with MPAL, including 86 patients with T-lymphoid/myeloid MPAL (T/My MPAL-NOS), 42 with Ph+ MPAL, 36 with B-lymphoid/myeloid MPAL (B/My MPAL-NOS), 4 with t(v;11q23), and 8 with MPAL, NOS, rare types. Genetically, T/My MPAL-NOS was similar to B/T MPAL-NOS but differed from Ph+ MPAL and B/My MPAL-NOS. T/My MPAL-NOS exhibited higher CEBPA, DNMT3A, and NOTCH1 mutations. Ph+ MPAL demonstrated higher RUNX1 mutations. B/T MPAL-NOS showed higher NOTCH1 mutations. By integrating next-generation sequencing and RNA sequencing data of 89 MPAL patients, we defined eight molecular subgroups (G1-G8) with distinct mutational and gene expression characteristics. G1 was associated with CEBPA mutations, G2 and G3 with NOTCH1 mutations, G4 with BCL11B rearrangement and FLT3 mutations, G5 and G8 with BCR::ABL1 fusion, G6 with KMT2A rearrangement/KMT2A rearrangement-like features, and G7 with ZNF384 rearrangement/ZNF384 rearrangement-like characteristics. Subsequently, we analyzed single-cell RNA sequencing data from five patients. Groups G1, G2, G3, and G4 exhibited overexpression of hematopoietic stem cell disease-like and common myeloid progenitor disease-like signatures, G5 and G6 had high expression of granulocyte-monocyte progenitor disease-like and monocyte disease-like signatures, and G7 and G8 had common lymphoid progenitor disease-like signatures. Collectively, our findings indicate that integrative genomic and transcriptomic profiling may facilitate more precise diagnosis and develop better treatment options for MPAL.

The Impact of Accelerated Digitization on Patient Portal Use by Underprivileged Racial Minority Groups During COVID-19: Longitudinal Study.

BACKGROUND: Prior research on the digital divide has documented substantial racial inequality in using web-based health resources. The recent COVID-19 pandemic led to accelerated mass digitization, raising alarms that underprivileged racial minority groups are left further behind. However, it is unclear to what extent the use of health information and communications technology by underprivileged racial minority groups is affected. OBJECTIVE: We have considered the COVID-19 disruption as a rare exogenous shock and estimated the impact of the accelerated digitization on the quantity and variety of patient portal use. In this study, we aimed to answer the following 2 key research questions. Did patients alter their use of health information and communications technology owing to COVID-19-induced digital acceleration? Does the effect differ across racial lines? METHODS: We used a longitudinal patient portal use data set gathered from a large urban academic medical center to explore the effect of accelerated digitization on the racial digital gap in health care. We limited the sample period of our study to 2 same periods (March 11 to August 30) in 2019 and 2020. Our final sample consisted of 25,612 patients belonging to 1 of the 3 racial groups: Black or African American (n=5157, 20.13%), Hispanic (n=253, 0.99%), and White (n=20,202, 78.88%) patients. We estimated the panel data regression using 3 different models: pooled ordinary least squares (OLS), random effect (RE), and fixed effect (FE). RESULTS: Our study yielded 4 findings. First, we confirmed that the racial digital divide remains a significant issue for telehealth; underprivileged racial minority group patients had lower patient portal use than White patients before the pandemic (Minority: OLS, ß=-.158; P<.001; RE, ß=-.168; P<.001). Second, we found that the digital gap regarding patient portal use frequency between underprivileged racial minority groups and White patients is shrinking rather than widening after the COVID-19 pandemic started (COVID_Period×Minority: OLS, ß=.028; P=.002; RE, ß=.037; P<.001; FE, ß=.043; P<.001). Third, the shrinking gap is foremost driven by access through mobile (vs desktop) devices (COVID_Period×Minority: web, ß=-.020; P=.02; mobile, ß=.037; P<.001). Finally, underprivileged racial minority groups expanded their use of a variety of portal functionalities faster than White patients during the pandemic (COVID_Period×Minority [for functionality]: OLS, ß=-.004; P<.001; RE, ß=-.004; P<.001; FE, ß=-.003; P=.001). CONCLUSIONS: Using the COVID-19 pandemic as a natural experiment, we offer empirical evidence that accelerated digitization has shrunk the racial digital divide in telehealth, and the trend is mostly driven by mobile devices. These findings provide new insights into the digital behaviors among underprivileged racial minority groups during accelerated digitization. They also offer policy makers an opportunity to identify new strategies to help close the racial digital gap in the postpandemic world.

Extracellular vesicles derived from human bone marrow stem cells inhibit acute lymphoblastic leukemia cell growth by inhibiting MAPK pathway via the miR-29b-3p/GDF15 axis.

INTRODUCTION: Acute lymphoblastic leukemia (ALL) is a common hematologic neoplastic disease. This study discussed the effect of extracellular vesicles (EVs) released from bone marrow mesenchymal stem cells (BMSC) on ALL cells and the mechanism. METHODS: BMSCs-EVs were isolated by differential centrifugation and identified. The effect of BMSCs-EVs on ALL cell proliferation and apoptosis was evaluated. The expression of miR-29b-3p in ALL cells and EVs was detected. The uptake of EVs by ALL cells was observed. The effect of miR-29b-3p on ALL cell proliferation and apoptosis was assessed after silencing miR-29b-3p. The targeting relation of miR-29b-3p and GDF15 was analyzed by bioinformatics website and dual-luciferase assay. The role of GDF15 in proliferation and apoptosis of ALL cells was further confirmed and Western blot assay was performed to measure MAPK pathway-related protein levels. RESULTS: BMSCs-derived EVs inhibited proliferation and promoted apoptosis of ALL cells, as shown by the up-regulation of Caspase 3 and Bax expressions and down-regulation of Bcl-2 expression. EVs carried miR-29b-3p into ALL cells, upregulated miR-29b-3p expression in ALL cells, and inhibited GDF15 expression. Silencing of miR-29b-3p or overexpression of GDF15 partially reversed the effect of EVs. EVs inhibited the MAPK pathway through the miR-29b-3p/GDF15 axis. CONCLUSION: BMSCs-EVs carried miR-29b-3p into ALL cells, upregulated miR-29b-3p, and inhibited GDF15 to suppress the MAPK pathway and further inhibit proliferation and promote apoptosis of ALL cells.

The Impact of Predation Risks on the Development and Fecundity of Bactrocera dorsalis Hendel.

Predators are dependent on the capture of prey to meet their energetic and nutritive requirements, which brings the risk of predation to prey. The predation risk is divided into consumptive and non-consumptive effects. Non-consumptive effects may manifest through altered growth and ontogenetic trajectories in prey species, a dynamic modulated by olfactory or other sensory cues from predators. Bactrocera dorsalis Hendel represents a major invasive threat to global horticulture. While earlier research was primarily centered on the consumptive interactions between B. dorsalis and its natural enemies, the potential consequences of non-consumptive interactions on the development of B. dorsalis have been overlooked. In this study, we investigated the impact of predation risk effects, induced by both visual exposure to the predatory mantis Hierodula patellifera Serville and its associated odor, on the life history traits of B. dorsalis. Female B. dorsalis demonstrated a reduced developmental time in the presence of a caged predator (H. patellifera) or predator odors, but showed significantly increased fecundity. Conversely, males displayed no significant change in developmental time. Additionally, neither the female nor male body weight at death was significantly influenced by the predation risk from the caged predator or predator odors. This study investigated the effects of predation risk on the development and reproduction of B. dorsalis, emphasizing the potential importance of odor risk in biological and pest control.

Relationship between the Degree of Illness in Elderly Patients with Rheumatoid Arthritis and Parameters of Musculoskeletal Ultrasound and Oswestry Dysfunction Index and Clinical Value Analysis.

Objective: The aim of the study is to explore the relationship between the degree of illness in elderly patients with rheumatoid arthritis (RA) and parameters of musculoskeletal ultrasound (MSUS) and Oswestry Dysfunction Index (ODI) and its clinical value. Methods: The clinical data of 100 elderly patients with RA admitted to our hospital from May 2016 to May 2022 were retrospectively analyzed. The patients were divided into four groups, including the remission group (DAS28 ≤ 2.6, n = 25), low activity group (2.6 ≤ DAS28 ≤ 3.2, n = 25), middle activity group (3.2 ≤ DAS28 ≤ 5.1, n = 25), and high activity group (DAS > 5.1, n = 25) according to the disease activity score-28 (DAS28). All patients underwent ultrasonic detection to compare the relationship between the degree of illness in elderly patients with RA and parameters of MSUS and ODI. Results: The total semiquantitative score of MSUS and ODI score in the remission group were obviously lower than those in the other three groups (P < 0.001). The degree of illness in elderly patients with RA was positively correlated with parameters of MSUS (r = 0.886, P < 0.001). The degree of illness in elderly patients with RA was positively correlated with ODI (r = 0.907, P < 0.001). Conclusion: The degree of illness in elderly patients with RA is closely related to parameters of MSUS and ODI, and the parameters of MSUS have a higher evaluation value for the degree of illness in elderly patients with RA, which are correlated with ODI.

The potential role of dashboard use and navigation in reducing medical errors of an electronic health record system: a mixed-method simulation handoff study.

The dashboards of electronic health record (EHR) systems could potentially support the chart biopsy that occurs before or after physician handoffs. In this study, we conducted a simulation handoff study and recorded the participants' navigation patterns in an EHR system mock-up. We analyzed the navigation patterns of dashboard use in terms of duration, frequency, and sequence, and we examined the relationship between dashboard use in chart biopsy and the errors identified after handoffs. The results show that the participants frequently used the dashboard as an information hub and as an information resource to help them navigate the EHR system and answer the questions in a nursing call. Moreover, using the dashboard as an information hub can help reduce imprecision and factual errors in handoffs. Our findings suggest the need for a "context-aware" dashboard to accommodate dynamic navigation patterns and to support clinical work as well as to reduce medical errors.

Oxymatrine ameliorates agomelatine-induced hepatocyte injury through promoting proteasome-mediated CHOP degradation.

BACKGROUND: The novel antidepressant drug agomelatine has been observed to cause adverse effect of hepatotoxicity in clinical applications. This study was designed to explore protective agents and investigated the underlying mechanism on L02 cells. METHOD: L02 cells were treated with agomelatine and oxymatrine (OMT) and cell apoptosis were analyzed through flow cytometric analysis, CCK-8 assay and TUNEL assay. In a separate experiment, the expressions of ER stress-related proteins were determined by western blot. In addition, MG132, chloroquine (CQ) and bafilomycinA1(BafA1) were used to investigate the potential pathway participating in CHOP degradation. RESULTS: OMT significantly rescued agomelatine-induced hepatocyte apoptosis. Agomelatine treatment resulted in accumulation of CHOP protein in L02 cells, and this phenomenon could be significantly reduced by OMT, whereas abolished by MG132 treatment. CONCLUSION: We have demonstrated for the first time that OMT ameliorates the hepatocyte toxicity induced by agomelatine through decreasing CHOP on protein level. The underlying mechanism was proved to involve the molecular events that OMT promotes CHOP degradation via proteasome pathway. Overall, these results suggest that using OMT in combination with agomelatine may provide a safety strategy for clinical depression treatment.

Mesoporous Fe2O3 microspheres: rapid and effective enrichment of phosphopeptides for MALDI-TOF MS analysis.

Mesoporous Fe(2)O(3) microspheres have been successfully synthesized by the polymerization (urea and formaldehyde)-induced ferric hydroxide colloid aggregation. The urea-formaldehyde resin was removed by calcination in air. The obtained mesoporous Fe(2)O(3) materials have spherical morphology with uniform particle size of approximately 3.0 microm and porous surface with large inter-particle pores of approximately 48.0 nm. The surface area is as large as approximately 33.3 m(2)/g and the pore volume is 0.31 cm(3)/g. The mesoporous Fe(2)O(3) microspheres were used for the enrichment of phosphopeptides for the first time, in which high sensitivity, selectivity and capacity of specifically enriched phosphopeptides were achieved under a mild condition in a relative short time. After enriched from tryptic digest products of beta-casein by the novel mesoporous Fe(2)O(3) microspheres, phosphopeptides can be selectively detected with high intensity in MALDI-TOF mass spectrometry. Elimination of "shadow effect" was observed by using mesoporous Fe(2)O(3) microspheres, and the detectable limitation is 5x10(-10) M. This material is also effective for enrichment of phosphopeptides from the complex tryptic digests of commercial phosphoprotein casein, with much more phosphorylated sites (26 in 27 of total) and higher signal/noise ratio in the MALDI-TOF mass spectrometry, compared to commercial Fe(2)O(3) nanoparticles. It shows a great potential application in the field of rapid and effective isolation of phosphopeptides.

Physio-biochemical and molecular mechanism underlying the enhanced heavy metal tolerance in highland barley seedlings pre-treated with low-dose gamma irradiation.

Heavy metal pollution, as a consequence of rapid industrialization and urbanization, poses a threat to highland barley grown in Tibet. This study investigates the effect of different doses of gamma irradiation (50-300 Gy) on the physio-biochemical and molecular mechanism of highland barley under heavy metal stress. Growth data showed that 50-Gy gamma irradiation had the maximal beneficial effects on the highland barley seedlings under lead/cadmium stress. The results of oxidative parameters demonstrated that 50-Gy gamma-irradiated seedlings had lower hydrogen peroxide and malondialdehyde contents under lead/cadmium stress compared to non-irradiated seedlings. Moreover, the activities of antioxidant enzyme and proline levels in 50-Gy gamma-irradiated seedlings were drastically higher than those in non-irradiated seedlings under lead/cadmium stress. Additionally, transmission electron microscopy results revealed that the 50-Gy gamma-irradiated seedlings exhibited improved chloroplasts ultrastructure compared with non-irradiated seedlings exposed to lead/cadmium stress. Notably, transcriptional expression analysis showed that 50-Gy gamma irradiation could significantly affect the expression of genes related to heavy metal transport and abscisic acid metabolism under lead/cadmium stress. Collectively, these results provide insights into the physio-biochemical and molecular mechanisms of low-dose-gamma-irradiation-enhanced heavy metal tolerance in highland barley seedlings, thus proposing gamma irradiation as a potential technology to mitigate heavy metal toxicity in crops.

Mesoporous tungsten titanate as matrix for matrix-assisted laser desorption/ionization time-of-flight mass spectrometry analysis of biomolecules.

In this paper, mesoporous tungsten titanate (WTiO) with different nano-pore structures was utilized as matrix for the analysis of short peptides by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS). Effect of characteristic features of mesoporous matrices on laser desorption/ionization process was investigated. Experiments showed that the ordered two-dimensional and three-dimensional mesoporous matrices were superior in performance to the non-ordered WTiO matrix. The dramatic enhancement of signal sensitivity by the ordered mesoporous matrices can be reasonably attributed to the ordered structure, which facilitated the understanding on structure-function relationship in mesoporous cavity for laser desorption process of adsorbed biomolecules. With the ordered mesoporous matrix, the short peptides are successfully detected. The presence of trace alkali metal salt effectively increased the analyte ion yields and the MALDI-TOFMS using the inorganic mesoporous matrices displayed a high salt tolerance. The developed technique also showed a satisfactory performance in peptide-mapping and amino-acid sequencing analysis.