Major depressive disorder (MDD) is associated with alterations of GABAergic interneurons, notably somatostatin (Sst) as well as parvalbumin (Pvalb), in cortical brain areas. In addition, the ...antidepressant effects of rapid-acting drugs are thought to occur via inhibition of GABA interneurons. However, the impact of these interneuron subtypes in affective behaviors as well as in the effects of rapid-acting antidepressants remains to be determined. Here, we used a Cre-dependent DREADD-chemogenetic approach to determine if inhibition of GABA interneurons in the mPFC of male mice is sufficient to produce antidepressant actions, and conversely if activation of these interneurons blocks the rapid and sustained antidepressant effects of scopolamine, a nonselective acetylcholine muscarinic receptor antagonist. Chemogenetic inhibition of all GABA interneurons (Gad1+), as well as Sst+ and Pvalb+ subtypes in the mPFC produced dose and time-dependent antidepressant effects in the forced swim and novelty suppressed feeding tests, and increased synaptic plasticity. In contrast, stimulation of Gad1, Sst, or Pvalb interneurons in mPFC abolished the effects of scopolamine and prevented scopolamine induction of synaptic plasticity. The results demonstrate that transient inhibition of GABA interneurons promotes synaptic plasticity that underlies rapid antidepressant responses.
Conventional cytogenetics can categorize patients with acute myeloid leukemia (AML) into favorable, intermediate, and unfavorable‐risk groups; however, patients with intermediate‐risk cytogenetics ...represent the major population with variable outcomes. Because molecular profiling can assist with AML prognosis and next‐generation sequencing allows simultaneous sequencing of many target genes, we analyzed 260 genes in 112 patients with de novo AML who received standard treatment. Multivariate analysis showed that karyotypes and mutation status of TET2, PHF6, KIT, and NPM1mutation/FLT3‐ internal tandem duplication (ITD)negative were independent prognostic factors for the entire cohort. Among patients with intermediate‐risk cytogenetics, patients with mutations in CEBPAdouble mutation, IDH2, and NPM1 in the absence of FLT3‐ITD were associated with improved Overall survival (OS), similar to those with favorable‐risk cytogenetics; patients with mutations in TET2, RUNX1, ASXL1, and DNMT3A were associated with reduced OS, similar to those with unfavorable‐risk cytogenetics. We concluded that integration of cytogenetic and molecular profiling improves prognostic stratification of patients into three groups with more distinct prognoses (P < 0.001) and significantly reduces the number of patients classified as intermediate risk. In addition, our study demonstrates that next‐generation sequencing (NGS)‐based multi‐gene sequencing is clinically applicable in establishing an accurate risk stratification system for guiding therapeutic decisions.
We comprehensively analyzed 260 genes by next‐generation sequencing (NGS) in 112 patients with de novo acute myeloid leukemia (AML). Our result suggested that parallel sequencing using NGS was a good strategy to handle the testing of multiple genes and could provide a rapid and accurate risk classification system for the clinical management of AML patients.
Colorectal cancer (CRC) is the third most malignant tumour worldwide, with high mortality and recurrence. Chemoresistance is one of the main factors leading to metastasis and poor prognosis in ...advanced CRC patients. By analysing the Gene Expression Omnibus data set, we found higher hexokinase 2 (HK2) expression levels in patients with metastatic CRC than in those with primary CRC. Moreover, we observed higher enrichment in oxaliplatin resistance‐related gene sets in metastatic CRC than in primary CRC. However, the underlying relationship has not yet been elucidated. In our study, HK2 expression was significantly elevated in CRC patients. Gene set enrichment analysis (GSEA) revealed multi‐drug resistance and epithelial‐mesenchymal transition (EMT) pathways related to high HK2 expression. Our results showed that knockdown of HK2 significantly inhibited vimentin and Twist1 expression and promoted TJP1 and E‐cadherin expression in CRC cells. Additionally, transcriptional and enzymatic inhibition of HK2 by 3‐bromopyruvate (3‐bp) impaired oxaliplatin resistance in vitro and in vivo. Mechanistically, HK2 interacts with and stabilized Twist1 by preventing its ubiquitin‐mediated degradation, which is related to oxaliplatin resistance, in CRC cells. Overexpression of Twist1 reduced the apoptosis rate by HK2 knockdown in CRC cells. Collectively, we discovered that HK2 is a crucial regulator that mediates oxaliplatin resistance through Twist1. These findings identify HK2 and Twist1 as promising drug targets for CRC chemoresistance.
This study investigated the epidemiology and risk factors associated with invasive fungal infections (IFIs) during induction chemotherapy in a cohort of Taiwanese patients with newly-diagnosed acute ...myeloid leukemia (AML). IFIs are a significant complication in the management of immunocompromised cancer patients; such infections are associated with a high incidence of morbidity and mortality, particularly in many South-Asian countries, where IFI rates are increasing. We retrospectively analyzed IFI incidence data from 105 patients with newly diagnosed AML at a single center undergoing their first course of induction chemotherapy without primary antifungal prophylaxis between November 2008 and December 2014. Of 21 cases documented as proven/provable IFIs 16 (76%) were invasive aspergillosis, 2 (10%) were mucormycosis infections, and 3 (14%) were proven yeast infections. The lung was the most commonly affected site (n = 16; 76%); 2 patients (10%) developed fungal sinusitis. IFI cases were more often males (P = 0.020). In multivariate analysis, patients with neutropenia lasting>30 days were more than twice as likely to develop IFI (OR, 2.24 95% CI, 2.81-31.11, P<0.001). We also confirmed patients with smoker and receiving parenteral nutrition during chemotherapy were significant associated with IFIs. Our findings suggest that antifungal prophylaxis should be considered for patients with AML during induction chemotherapy, particularly in patients from Southeastern Asia, an area of potentially high IFI rates. We recommend that clinicians determine which patients receiving induction chemotherapy for AML are at high risk of developing IFI, to allow for targeted therapeutic prophylaxis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Increasing grain yields is a major focus of crop breeders around the world. Here we report that overexpression of the rice microRNA (miRNA) OsmiR397, which is naturally highly expressed in young ...panicles and grains, enlarges grain size and promotes panicle branching, leading to an increase in overall grain yield of up to 25% in a field trial. To our knowledge, no previous report has shown a positive regulatory role of miRNA in the control of plant seed size and grain yield. We determined that OsmiR397 increases grain yield by downregulating its target, OsLAC, whose product is a laccase-like protein that we found to be involved in the sensitivity of plants to brassinosteroids. As miR397 is highly conserved across different species, our results suggest that manipulating miR397 may be useful for increasing grain yield not only in rice but also in other cereal crops.
Background
Recent studies have suggested the suboptimal efficacy of liposomal irinotecan plus 5‐fluorouracil/leucovorin (nal‐IRI+5‐FU/LV) in metastatic pancreatic ductal adenocarcinoma (mPDAC) ...patients previously treated with conventional irinotecan. This study investigated the effect of conventional irinotecan treatment in mPDAC patients receiving nal‐IRI+5‐FU/LV by analyzing a population‐based dataset.
Methods
We reviewed 667 consecutive mPDAC patients treated with nal‐IRI+5‐FU/LV between August 2018 and November 2020 at Taiwanese medical centers. Eighty‐six patients previously treated with conventional irinotecan were matched to 86 patients not treated with conventional irinotecan, following propensity matching for age, sex, performance status, metastatic organ site, pre‐treatment carbohydrate antigen 19‐9 level, lines of prior chemotherapy treatment, and time from first‐line treatment to nal‐IRI+5‐FU/LV therapy.
Results
The median overall survival and time‐to‐treatment failure were 4.8 and 2.6 vs 4.1 and 2.1 months, respectively, for patients who were and were not previously treated with conventional irinotecan. The tumor response and disease control rates were 5.8% and 32.6% vs 5.8% and 37.2%, respectively, for patients previously treated and not treated with conventional irinotecan. No significant differences were observed in survival times and tumor response rates between the two groups.
Conclusions
Previous conventional irinotecan treatment does not compromise the efficacy of subsequent nal‐IRI+5‐FU/LV treatment in mPDAC patients.
HighlightChiu and colleagues conducted a retrospective analysis of a population‐based dataset in Taiwan to investigate the survival outcomes and safety profiles of conventional irinotecan treatment in patients with metastatic pancreatic cancer receiving liposomal irinotecan plus 5‐fluorouracil and leucovorin. Propensity score matching was used to adjust potential confounding variables.
A novel human coronavirus, Middle East respiratory syndrome coronavirus (MERS-CoV), has caused outbreaks of a SARS-like illness with high case fatality rate. The reports of its person-to-person ...transmission through close contacts have raised a global concern about its pandemic potential. Here we characterize the six-helix bundle fusion core structure of MERS-CoV spike protein S2 subunit by X-ray crystallography and biophysical analysis. We find that two peptides, HR1P and HR2P, spanning residues 998-1039 in HR1 and 1251-1286 in HR2 domains, respectively, can form a stable six-helix bundle fusion core structure, suggesting that MERS-CoV enters into the host cell mainly through membrane fusion mechanism. HR2P can effectively inhibit MERS-CoV replication and its spike protein-mediated cell-cell fusion. Introduction of hydrophilic residues into HR2P results in significant improvement of its stability, solubility and antiviral activity. Therefore, the HR2P analogues have good potential to be further developed into effective viral fusion inhibitors for treating MERS-CoV infection.
Mangroves are frequently inundated with saline water and have evolved different anatomical and physiological mechanisms to filter and, in some species, excrete excess salt from the water they take ...up. Because salts impose osmotic stress, interspecific differences in salt tolerance and salt management strategy may influence physiological responses to drought throughout the entire plant hydraulic pathway, from roots to leaves. Here, we characterized embolism vulnerability simultaneously in leaves, stems, and roots of seedlings of two mangrove species (Avicennia marina and Bruguiera gymnorrhiza) along with turgor-loss points in roots and leaves and xylem anatomical traits. In both species, the water potentials causing 50% of total embolism were less negative in roots and leaves than they were in stems, but the water potentials causing incipient embolism (5%) were similar in roots, stems, and leaves. Stomatal closure in leaves and turgor loss in both leaves and roots occurred at water potentials only slightly less negative than the water potentials causing 5% of total embolism. Xylem anatomical traits were unrelated to vulnerability to embolism. Vulnerability segmentation may be important in limiting embolism spread into stems from more vulnerable roots and leaves. Interspecific differences in salt tolerance affected hydraulic traits from roots to leaves: the salt-secretor A. marina lost turgor at more negative water potentials and had more embolism-resistant xylem than the salt-excluder B. gymnorrhiza. Characterizing physiological thresholds of roots may help to explain recent mangrove mortality after drought and extended saltwater inundation.
Upon introducing charge carriers into the copper–oxygen sheets of the enigmatic lamellar cuprates, the ground state evolves from an insulator to a superconductor and eventually to a seemingly ...conventional metal (a Fermi liquid). Much has remained elusive about the nature of this evolution and about the peculiar metallic state at intermediate hole-carrier concentrations (p). The planar resistivity of this unconventional metal exhibits a linear temperature dependence (ρ ∝ T) that is disrupted upon cooling toward the superconducting state by the opening of a partial gap (the pseudogap) on the Fermi surface. Here, we first demonstrate for the quintessential compound HgBa ₂CuO ₄₊δ a dramatic switch from linear to purely quadratic (Fermi liquid-like, ρ ∝ T ²) resistive behavior in the pseudogap regime. Despite the considerable variation in crystal structures and disorder among different compounds, our result together with prior work gives insight into the p-T phase diagram and reveals the fundamental resistance per copper–oxygen sheet in both linear (ρ = A ₁T) and quadratic (ρ = A ₂T ²) regimes, with A ₁ ∝ A ₂ ∝ 1/p. Theoretical models can now be benchmarked against this remarkably simple universal behavior. Deviations from this underlying behavior can be expected to lead to new insight into the nonuniversal features exhibited by certain compounds.
Long noncoding RNAs (lncRNAs) play important roles in a wide range of biological processes in mammals and plants. However, the systematic examination of lncRNAs in plants lags behind that in mammals. ...Recently, lncRNAs have been identified in Arabidopsis and wheat; however, no systematic screening of potential lncRNAs has been reported for the rice genome.
In this study, we perform whole transcriptome strand-specific RNA sequencing (ssRNA-seq) of samples from rice anthers, pistils, and seeds 5 days after pollination and from shoots 14 days after germination. Using these data, together with 40 available rice RNA-seq datasets, we systematically analyze rice lncRNAs and definitively identify lncRNAs that are involved in the reproductive process. The results show that rice lncRNAs have some different characteristics compared to those of Arabidopsis and mammals and are expressed in a highly tissue-specific or stage-specific manner. We further verify the functions of a set of lncRNAs that are preferentially expressed in reproductive stages and identify several lncRNAs as competing endogenous RNAs (ceRNAs), which sequester miR160 or miR164 in a type of target mimicry. More importantly, one lncRNA, XLOC_057324, is demonstrated to play a role in panicle development and fertility. We also develop a source of rice lncRNA-associated insertional mutants.
Genome-wide screening and functional analysis enabled the identification of a set of lncRNAs that are involved in the sexual reproduction of rice. The results also provide a source of lncRNAs and associated insertional mutants in rice.
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