Palmitoylation prevents sustained inflammation by limiting NLRP3 inflammasome activation through chaperone-mediated autophagy.

As a key component of the inflammasome, NLRP3 is a critical intracellular danger sensor emerging as an important clinical target in inflammatory diseases. However, little is known about the mechanisms that determine the kinetics of NLRP3 inflammasome stability and activity to ensure effective and controllable inflammatory responses. Here, we show that S-palmitoylation acts as a brake to turn NLRP3 inflammasome off. zDHHC12 is identified as the S-acyltransferase for NLRP3 palmitoylation, which promotes its degradation through the chaperone-mediated autophagy pathway. Zdhhc12 deficiency in mice enhances inflammatory symptoms and lethality following alum-induced peritonitis and LPS-induced endotoxic shock. Notably, several disease-associated mutations in NLRP3 are associated with defective palmitoylation, resulting in overt NLRP3 inflammasome activation. Thus, our findings identify zDHHC12 as a repressor of NLRP3 inflammasome activation and uncover a previously unknown regulatory mechanism by which the inflammasome pathway is tightly controlled by the dynamic palmitoylation of NLRP3.

Autorecoding A-to-I RNA editing sites in the Adar gene underwent compensatory gains and losses in major insect clades.

As one of the most prevalent RNA modifications in animals, adenosine-to-inosine (A-to-I) RNA editing facilitates the environmental adaptation of organisms by diversifying the proteome in a temporal-spatial manner. In flies and bees, the editing enzyme Adar has independently gained two different autorecoding sites that form an autofeedback loop, stabilizing the overall editing efficiency. This ensures cellular homeostasis by keeping the normal function of target genes. However, in a broader range of insects, the evolutionary dynamics and significance of this Adar autoregulatory mechanism are unclear. We retrieved the genomes of 377 arthropod species covering the five major insect orders (Hemiptera, Hymenoptera, Coleoptera, Diptera, and Lepidoptera) and aligned the Adar autorecoding sites across all genomes. We found that the two autorecoding sites underwent compensatory gains and losses during the evolution of two orders with the most sequenced species (Diptera and Hymenoptera), and that the two editing sites were mutually exclusive among them: One editable site is significantly linked to another uneditable site. This autorecoding mechanism of Adar could flexibly diversify the proteome and stabilize global editing activity. Many insects independently selected different autorecoding sites to achieve a feedback loop and regulate the global RNA editome, revealing an interesting phenomenon during evolution. Our study reveals the evolutionary force acting on accurate regulation of RNA editing activity in insects and thus deepens our understanding of the functional importance of RNA editing in environmental adaptation and evolution.

MOV10 recruits DCP2 to decap human LINE-1 RNA by forming large cytoplasmic granules with phase separation properties.

Long interspersed element 1 (LINE-1) is the only active autonomous mobile element in the human genome. Its transposition can exert deleterious effects on the structure and function of the host genome and cause sporadic genetic diseases. Tight control of LINE-1 mobilization by the host is crucial for genetic stability. In this study, we report that MOV10 recruits the main decapping enzyme DCP2 to LINE-1 RNA and forms a complex of MOV10, DCP2, and LINE-1 RNP, exhibiting liquid-liquid phase separation (LLPS) properties. DCP2 cooperates with MOV10 to decap LINE-1 RNA, which causes degradation of LINE-1 RNA and thus reduces LINE-1 retrotransposition. We here identify DCP2 as one of the key effector proteins determining LINE-1 replication, and elucidate an LLPS mechanism that facilitates the anti-LINE-1 action of MOV10 and DCP2.

Circular mRNA-based TCR-T offers a safe and effective therapeutic strategy for treatment of cytomegalovirus infection.

Circular mRNA (cmRNA) is particular useful due to its high resistance to degradation by exonucleases, resulting in greater stability and protein expression compared to linear mRNA. T cell receptor (TCR)-engineered T cells (TCR-T) represent a promising means of treating viral infections and cancer. This study aimed to evaluate the feasibility and efficacy of cmRNA in antigen-specific-TCR discovery and TCR-T therapy. Using human cytomegalovirus (CMV) pp65 antigen as a model, we found that the expansion of pp65-responsive T cells was induced more effectively by monocyte-derived dendritic cells transfected with pp65-encoding cmRNA compared with linear mRNA. Subsequently, we developed cmRNA-transduced pp65-TCR-T (cm-pp65-TCR-T) that specifically targets the CMV-pp65 epitope. Our results showed that pp65-TCR could be expressed on primary T cells for more than 7 days. Moreover, both in vitro killing and in vivo CDX models demonstrated that cm-pp65-TCR-T cells specifically and persistently kill pp65-and HLA-expressing tumor cells, significantly prolonging the survival of mice. Collectively, our results demonstrated that cmRNA can be used as a more effective technical approach for antigen-specific TCR isolation and identification, and cm-pp65-TCR-T may provide a safe, non-viral, non-integrated therapeutic approach for controlling CMV infection, particularly in patients who have undergone allogeneic hematopoietic stem cell transplantation.

Development of an mRNA-based therapeutic vaccine mHTV-03E2 for high-risk HPV-related malignancies.

Human papillomavirus (HPV) 16 and 18 infections are related to many human cancers. Despite several preventive vaccines for high-risk (hr) HPVs, there is still an urgent need to develop therapeutic HPV vaccines for targeting pre-existing hrHPV infections and lesions. In this study, we developed a lipid nanoparticle (LNP)-formulated mRNA-based HPV therapeutic vaccine (mHTV)-03E2, simultaneously targeting the E2/E6/E7 of both HPV16 and HPV18. mHTV-03E2 dramatically induced antigen-specific cellular immune responses, leading to significant CD8+ T cell infiltration and cytotoxicity in TC-1 tumors derived from primary lung epithelial cells of C57BL/6 mice expressing HPV E6/E7 antigens, mediated significant tumor regression, and prolonged animal survival, in a dose-dependent manner. We further demonstrated significant T cell immunity against HPV16/18 E6/E7 antigens for up to 4 months post-vaccination in immunological and distant tumor rechallenging experiments, suggesting robust memory T cell immunity against relapse. Finally, mHTV-03E2 synergized with immune checkpoint blockade to inhibit tumor growth and extend animal survival, indicating the potential in combination therapy. We conclude that mHTV-03E2 is an excellent candidate therapeutic mRNA vaccine for treating malignancies caused by HPV16 or HPV18 infections.

The first A-to-I RNA editome of hemipteran species Coridius chinensis reveals overrepresented recoding and prevalent intron editing in early-diverging insects.

BACKGROUND: Metazoan adenosine-to-inosine (A-to-I) RNA editing resembles A-to-G mutation and increases proteomic diversity in a temporal-spatial manner, allowing organisms adapting to changeable environment. The RNA editomes in many major animal clades remain unexplored, hampering the understanding on the evolution and adaptation of this essential post-transcriptional modification. METHODS: We assembled the chromosome-level genome of Coridius chinensis belonging to Hemiptera, the fifth largest insect order where RNA editing has not been studied yet. We generated ten head RNA-Seq libraries with DNA-Seq from the matched individuals. RESULTS: We identified thousands of high-confidence RNA editing sites in C. chinensis. Overrepresentation of nonsynonymous editing was observed, but conserved recoding across different orders was very rare. Under cold stress, the global editing efficiency was down-regulated and the general transcriptional processes were shut down. Nevertheless, we found an interesting site with "conserved editing but non-conserved recoding" in potassium channel Shab which was significantly up-regulated in cold, serving as a candidate functional site in response to temperature stress. CONCLUSIONS: RNA editing in C. chinensis largely recodes the proteome. The first RNA editome in Hemiptera indicates independent origin of beneficial recoding during insect evolution, which advances our understanding on the evolution, conservation, and adaptation of RNA editing.

TRIM14 inhibits OPTN-mediated autophagic degradation of KDM4D to epigenetically regulate inflammation.

Autophagy is a fundamental cellular process of protein degradation and recycling that regulates immune signaling pathways via multiple mechanisms. However, it remains unclear how autophagy epigenetically regulates the immune response. Here, we identified TRIM14 as an epigenetic regulator that reduces histone H3K9 trimethylation by inhibiting the autophagic degradation of the histone demethylase KDM4D. TRIM14 recruited the deubiquitinases USP14 and BRCC3 to cleave the K63-linked ubiquitin chains of KDM4D, which prevented KDM4D from undergoing optineurin (OPTN)-mediated selective autophagy. Tripartite motif-containing 14 (TRIM14) deficiency in dendritic cells significantly impaired the expression of the KDM4D-directed proinflammatory cytokines interleukin 12 (Il12) and Il23 and protected mice from autoimmune inflammation. Taken together, these findings highlight the cross-talk between epigenetic regulation and autophagy and suggest TRIM14 is a potential target of therapeutic intervention for inflammation-related diseases.

Reinforced pain catastrophizing during menstrual phase among women with primary dysmenorrhea is mediated by cerebral blood flow in the medial prefrontal cortex.

Pain catastrophizing is a prominent psychological factor that is strongly correlated with pain. Although the complex properties of pain catastrophizing vary across different pain phases, the contribution of chronic pain to its progression from a general trait to a higher state remains unclear. This study aimed to examine the neural mechanisms and degree to which pain catastrophizing is reinforced in the context of primary dysmenorrhea (PDM), one of the most prevalent gynaecological complaints experienced by women of reproductive age. Altogether, 29 women with moderate-to-severe PDM were included in this study. Arterial spin labelling was used to quantify the cerebral blood flow (CBF) in each participant in both the pain-free and painful phases. The pain catastrophizing scale (PCS) was completed in two phases, and the Short-Form McGill Pain Questionnaire was completed in the painful phase. Compared with pain catastrophizing in the pain-free phase (PCSpf), pain catastrophizing in the painful phase (PCSp) is higher and positively correlated with the composite factor of menstrual pain. CBF analysis indicated that the PCSp is positively associated with CBF in the frontal cortex, hippocampus and amygdala. The reinforcement of pain catastrophizing correlates with CBF in the prefrontal cortex. Specifically, the medial prefrontal cortex, which correlates with pain state, plays a crucial role in mediating the reinforcing effect of pain in the PCSp. These results promote the mechanical comprehension of pain catastrophizing management in individuals with chronic pain.

Endoplasmic reticulum stress and therapeutic strategies in metabolic, neurodegenerative diseases and cancer.

The accumulation of unfolded or misfolded proteins within the endoplasmic reticulum (ER), due to genetic determinants and extrinsic environmental factors, leads to endoplasmic reticulum stress (ER stress). As ER stress ensues, the unfolded protein response (UPR), comprising three signaling pathways-inositol-requiring enzyme 1, protein kinase R-like endoplasmic reticulum kinase, and activating transcription factor 6 promptly activates to enhance the ER's protein-folding capacity and restore ER homeostasis. However, prolonged ER stress levels propels the UPR towards cellular demise and the subsequent inflammatory cascade, contributing to the development of human diseases, including cancer, neurodegenerative disorders, and diabetes. Notably, increased expression of all three UPR signaling pathways has been observed in these pathologies, and reduction in signaling molecule expression correlates with decreased proliferation of disease-associated target cells. Consequently, therapeutic strategies targeting ER stress-related interventions have attracted significant research interest. In this review, we elucidate the critical role of ER stress in cancer, metabolic, and neurodegenerative diseases, offering novel therapeutic approaches for these conditions.

Learning from the Codon Table: Convergent Recoding Provides Novel Understanding on the Evolution of A-to-I RNA Editing.

Adenosine-to-inosine (A-to-I) RNA editing recodes the genetic information. Apart from diversifying the proteome, another tempting advantage of RNA recoding is to correct deleterious DNA mutation and restore ancestral allele. Solid evidences for beneficial restorative editing are very rare in animals. By searching for "convergent recoding" under a phylogenetic context, we proposed this term for judging the potential restorative functions of particular editing site. For the well-known mammalian Gln>Arg (Q>R) recoding site, its ancestral state in vertebrate genomes was the pre-editing Gln, and all 470 available mammalian genomes strictly avoid other three equivalent ways to achieve Arg in protein. The absence of convergent recoding from His>Arg, or synonymous mutations on Gln codons, could be attributed to the strong maintenance on editing motif and structure, but the absence of direct A-to-G mutation is extremely unexpected. With similar ideas, we found cases of convergent recoding in Drosophila genus, reducing the possibility of their restorative function. In summary, we defined an interesting scenario of convergent recoding, the occurrence of which could be used as preliminary judgements for whether a recoding site has a sole restorative role. Our work provides novel insights to the natural selection and evolution of RNA editing.

Detoxifying bacterial genes for deoxynivalenol epimerization confer durable resistance to Fusarium head blight in wheat.

Fusarium head blight (FHB) and the presence of mycotoxin deoxynivalenol (DON) pose serious threats to wheat production and food safety worldwide. DON, as a virulence factor, is crucial for the spread of FHB pathogens on plants. However, germplasm resources that are naturally resistant to DON and DON-producing FHB pathogens are inadequate in plants. Here, detoxifying bacteria genes responsible for DON epimerization were used to enhance the resistance of wheat to mycotoxin DON and FHB pathogens. We characterized the complete pathway and molecular basis leading to the thorough detoxification of DON via epimerization through two sequential reactions in the detoxifying bacterium Devosia sp. D6-9. Epimerization efficiently eliminates the phytotoxicity of DON and neutralizes the effects of DON as a virulence factor. Notably, co-expressing of the genes encoding quinoprotein dehydrogenase (QDDH) for DON oxidation in the first reaction step, and aldo-keto reductase AKR13B2 for 3-keto-DON reduction in the second reaction step significantly reduced the accumulation of DON as virulence factor in wheat after the infection of pathogenic Fusarium, and accordingly conferred increased disease resistance to FHB by restricting the spread of pathogenic Fusarium in the transgenic plants. Stable and improved resistance was observed in greenhouse and field conditions over multiple generations. This successful approach presents a promising avenue for enhancing FHB resistance in crops and reducing mycotoxin contents in grains through detoxification of the virulence factor DON by exogenous resistance genes from microbes.

KLF4 activates LATS2 to promote cisplatin sensitivity in ovarian cancer through DNA damage.

We aimed to investigate the role of large tumor suppressor kinase 2 (LATS2) in cisplatin (DDP) sensitivity in ovarian cancer. Bioinformatic analysis explored LATS2 expression, pathways, and regulators. Quantitative reverse transcription-PCR measured LATS2 and KLF4 mRNA levels. Dual-luciferase and chromatin immunoprecipitation assays confirmed their binding relationship. Cell viability, half maximal inhibitory concentration (IC50) values, cell cycle, and DNA damage were assessed using CCK-8, flow cytometry, and comet assays. Western blot analyzed protein expression. The effect of LATS2 on the sensitivity of ovarian cancer to DDP was verified in vivo. LATS2 and KLF4 were downregulated in ovarian cancer, with LATS2 enriched in cell cycle, DNA replication, and mismatch repair pathways. KLF4, an upstream regulator of LATS2, bound to its promoter. Overexpressing LATS2 increased G1-phase cells, reduced cell viability and IC50 values, and induced DNA damage. Silencing KLF4 alone showed the opposite effect on LATS2 overexpression. Knocking out LATS2 reversed the effects of KLF4 overexpression on cell viability, cell cycle, IC50 values, and DNA damage in ovarian cancer cells. Inhibiting LATS2 inactivated the Hippo-YAP signaling pathway. In vivo experiments showed that overexpression of LATS2 enhanced the sensitivity of ovarian cancer to DDP. KLF4 activates LATS2 via DNA damage to enhance DDP sensitivity in ovarian cancer, providing a potential target for improving treatment outcomes.

Shh-Gli2-Runx2 inhibits vascular calcification.

BACKGROUND: In patients with chronic kidney disease (CKD), vascular calcification (VC) is common and is associated with a higher risk of all-cause mortality. Shh, one ligand for Hedgehog (Hh) signaling, participates in osteogenesis and several cardiovascular diseases. However, it remains unclear whether Shh is implicated in the development of VC. METHODS: Inorganic phosphorus 2.6 mM was used to induce vascular smooth muscle cells (VSMCs) calcification. Mice were fed with adenine diet supplement with 1.2% phosphorus to induce VC. RESULTS: Shh was decreased in VSMCs exposed to inorganic phosphorus, calcified arteries in mice fed with an adenine diet, as well as radial arteries from patients with CKD presenting VC. Overexpression of Shh inhibited VSMCs ostosteoblastic differentiation and calcification, whereas its silencing accelerated these processes. Likewise, mice treated with smoothened agonist (SAG; Hh signaling agonist) showed alleviated VC, and mice treated with cyclopamine (CPN; Hh signaling antagonist) exhibited severe VC. Additionally, overexpression of Gli2 significantly reversed the pro-calcification effect of Shh silencing on VSMCs, suggesting that Shh inhibited VC via Gli2. Mechanistically, Gli2 interacted with Runx2 and promoted its ubiquitin proteasomal degradation, therefore protecting against VC. Of interest, the pro-degradation effect of Gli2 on Runx2 was independent of Smurf1 and Cullin4B. CONCLUSIONS: Our study provided deeper insight to the pathogenesis of VC, and Shh might be a novel potential target for VC treatment.

An orthology-based methodology as a complementary approach to retrieve evolutionarily conserved A-to-I RNA editing sites.

Adar-mediated adenosine-to-inosine (A-to-I) mRNA editing is a conserved mechanism that exerts diverse regulatory functions during the development, evolution, and adaptation of metazoans. The accurate detection of RNA editing sites helps us understand their biological significance. In this work, with an improved genome assembly of honeybee (Apis mellifera), we used a new orthology-based methodology to complement the traditional pipeline of (de novo) RNA editing detection. Compared to the outcome of traditional pipeline, we retrieved many novel editing sites in CDS that are deeply conserved between honeybee and other distantly related insects. The newly retrieved sites were missed by the traditional de novo identification due to the stringent criteria for controlling false-positive rate. Caste-specific editing sites are identified, including an Ile>Met auto-recoding site in Adar. This recoding was even conserved between honeybee and bumblebee, suggesting its putative regulatory role in shaping the phenotypic plasticity of eusocial Hymenoptera. In summary, we proposed a complementary approach to the traditional pipeline and retrieved several previously unnoticed CDS editing sites. From both technical and biological aspects, our works facilitate future researches on finding the functional editing sites and advance our understanding on the connection between RNA editing and the great phenotypic diversity of organisms.

Fine mapping of the panicle length QTL qPL5 in rice.

Panicle length is a crucial trait tightly associated with spikelets per panicle and grain yield in rice. To dissect the genetic basis of panicle length, a population of 161 recombinant inbred lines (RILs) was developed from the cross between an aus variety Chuan 7 (C7) and a tropical Geng variety Haoboka (HBK). C7 has a panicle length of 30 cm, 7 cm longer than that of HBK, and the panicle length was normally distributed in the RIL population. A total of six quantitative trait loci (QTLs) for panicle length were identified, and single QTLs explained the phenotypic variance from 4.9 to 18.1%. Among them, three QTLs were mapped to the regions harbored sd1, DLT, and Ehd1, respectively. To validate the genetic effect of a minor QTL qPL5, a near-isogenic F2 (NIF2) population segregated at qPL5 was developed. Interestingly, panicle length displayed bimodal distribution, and heading date also exhibited significant variation in the NIF2 population. qPL5 accounted for 66.5% of the panicle length variance. The C7 allele at qPL5 increased panicle length by 2.4 cm and promoted heading date by 5 days. Finally, qPL5 was narrowed down to an 80-kb region flanked by markers M2197 and M2205 using a large NIF2 population of 7600 plants. LOC_Os05g37540, encoding a phytochrome signal protein whose homolog in Arabidopsis enlarges panicle length, is regarded as the candidate gene because a single-nucleotide mutation (C1099T) caused a premature stop codon in HBK. The characterization of qPL5 with enlarging panicle length but promoting heading date makes its great value in breeding early mature varieties without yield penalty in rice. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-024-01443-2.

A multi-functional fluorescent probe for visualization of H2S and viscosity/polarity and its application in cancer imaging.

As an important endogenous gasotransmitter, hydrogen sulfide (H2S) plays a critical role in various physiological functions and has been regarded as a biomarker of cancer due to its overexpression in cancer cells. In addition, the early stages of cancer are often accompanied by abnormalities in the intracellular microenvironments, and distinguishing between cancer cell/tissues and normal cell/tissues is of great significance to the accuracy of cancer diagnosis. However, deep insights into the simultaneous detection of H2S and viscosity/polarity variations in cancer cells/tissues are rarely reported. In this work, we designed and synthesized a mitochondria-targeting fluorescent probe PDQHS, which exhibits high selectivity for H2S with an emission peak around 632 nm and excellent response (17-fold) to viscosity/polarity beyond 706 nm. Meanwhile, PDQHS shows good biocompatibility and can specifically accumulate into mitochondria. Using PDQHS, the visual distinguishing of cancer cells from normal cells was achieved via dual-channel detection of H2S and viscosity/polarity. More importantly, PDQHS has been successfully applied to visualize endogenous and exogenous H2S in living cells and tumor tissue. Obviously, compared to the detection of a single biomarker, monitoring multiple biomarkers simultaneously through dual-channel response is conducive to amplifying the detection signal, providing a more sensitive and reliable imaging tool in the tumor region, which is beneficial for cancer prediction.

Vitamin D3 supplementation shapes the composition of gut microbiota and improves some obesity parameters induced by high-fat diet in mice.

PURPOSE: Individuals with vitamin D (VD) insufficiency have a greater tendency to develop obesity and have increased systemic inflammation. Gut microbiota are involved in the regulation of host inflammation and energy metabolism, which plays a role in the pathogenesis of obesity. Thus, we aimed to evaluate the effects of different doses of VD3 on body weight, serum lipids, inflammatory factors, and intestinal barrier function in obese mice and to explore the regulatory effect of VD3 on gut microbiota in obese mice. METHODS: Male C57BL/6 J mice received a normal chow diet (NCD, 10% fat) or high-fat diet (HFD, 60% fat) to induce obesity within 10 weeks. Then, HFD mice were supplemented with 5650, 8475, or 11,300 IU VD3/kg diet for 8 weeks. Finally, 16 s rRNA analysis was performed to analyze gut microbiota composition in cecal contents. In addition, body weight, serum lipids, inflammatory factors, and intestinal barrier function were analyzed. RESULTS: VD3 supplementation reduced body weight and the levels of TG, TC, HDL-C, TNF-α, IL-1ß and LPS, and increased ZO-1 in HFD-fed mice. Moreover, it increased α-diversity, reduced F/B ratio and altered microbiota composition by increasing relative abundance of Bacteroidetes, Proteobacteria, Desulfovibrio, Dehalobacterium, Odoribacter, and Parabacteroides and reducing relative abundance of Firmicutes and Ruminococcus. There were significant differences between HFD and NCD groups in several metabolic pathways, including endotoxin biosynthesis, tricarboxylic acid cycle, lipid synthesis and metabolism, and glycolysis. CONCLUSIONS: Low, medium, and high doses of VD3 inhibited weight gain, reduced levels of blood lipids and inflammatory factors, and improved endotoxemia and gut barrier function in obese mice. It also increased the α-diversity of gut microbiota in obese mice and reduced the relative abundance of some intestinal pathogenic bacteria, increased the relative abundance of some beneficial bacteria, and corrected the intestinal flora disorder of obese mice, with the low- and high-dose groups showing better effects than the medium-dose group.

Efficacy of racemic ketamine or esketamine monotherapy for reducing suicidal ideation in uni- or bipolar depression: a systematic review and meta-analysis.

The current systematic review and meta-analysis examined the effect of racemic ketamine or esketamine on suicidal ideation in individuals with uni- or bipolar depression. We searched the MEDLINE, Embase, Central, PsycINFO, and Web of Science databases to identify randomized controlled trials that examined the effect of racemic ketamine or esketamine monotherapy on suicidal ideation (SI) in individuals with uni- or bipolar depression. The two monotherapies were compared; the primary outcome was the rate of remission of SI, and the secondary outcome was the SI score. The risk ratio was used as an effect size measure for binary variables, while the standardized mean difference was used as an effect size measure for continuous variables. Our meta-analysis included 13 randomized controlled trials involving 1,1109 individuals with uni- or bipolar depression. Patients receiving racemic ketamine monotherapy had a significantly higher acute SI remission rate than those receiving placebo or midazolam (RR = 2.06, 95% CI 1.47 to 2.91, P < 0.0001). Racemic ketamine also led to significantly lower SI scores than placebo or midazolam (SMD = -0.36, 95% CI -0.71 to -0.01, P = 0.04). The evidence for the treatment of SI with esketamine was inconsistent. The pooled effect sizes for long-term anti-SI effects did not reveal significant differences between therapies. Our study indicated the efficacy of racemic ketamine monotherapy for rapidly and transiently reducing SI in individuals with uni- or bipolar depression, but the efficacy of racemic ketamine monotherapy against long-term suicidal ideation remains unclear. There is not -sufficient evidence to support the anti-suicidal effects of esketamine monotherapy.Protocol registration: Prospero registration number: CRD42023434380.

Prevalence and genetic basis of Mycobacterium tuberculosis resistance to pretomanid in China.

BACKGROUND: Pretomanid is a key component of new regimens for the treatment of drug-resistant tuberculosis (TB) which are being rolled out globally. However, there is limited information on the prevalence of pre-existing resistance to the drug. METHODS: To investigate pretomanid resistance rates in China and its underlying genetic basis, as well as to generate additional minimum inhibitory concentration (MIC) data for epidemiological cutoff (ECOFF)/breakpoint setting, we performed MIC determinations in the Mycobacterial Growth Indicator Tube™ (MGIT) system, followed by WGS analysis, on 475 Mycobacterium tuberculosis (MTB) isolated from Chinese TB patients between 2013 and 2020. RESULTS: We observed a pretomanid MIC distribution with a 99% ECOFF equal to 0.5 mg/L. Of the 15 isolates with MIC values > 0.5 mg/L, one (MIC = 1 mg/L) was identified as MTB lineage 1 (L1), a genotype previously reported to be intrinsically less susceptible to pretomanid, two were borderline resistant (MIC = 2-4 mg/L) and the remaining 12 isolates were highly resistant (MIC ≥ 16 mg/L) to the drug. Five resistant isolates did not harbor mutations in the known pretomanid resistant genes. CONCLUSIONS: Our results further support a breakpoint of 0.5 mg/L for a non-L1 MTB population, which is characteristic of China. Further, our data point to an unexpected high (14/475, 3%) pre-existing pretomanid resistance rate in the country, as well as to the existence of yet-to-be-discovered pretomanid resistance genes.

Midfrontal theta phase underlies evidence accumulation and response thresholding in cognitive control.

Cognitive control involves evidence accumulation and response thresholding, but the neural underpinnings of these 2 processes are poorly understood. Based on recent findings that midfrontal theta phase coordinates the correlation between theta power and reaction time during cognitive control, this study investigated whether and how theta phase would modulate the relationships between theta power and evidence accumulation and response thresholding in human participants when they performed a flanker task. Our results confirmed the modulation of theta phase on the correlations between ongoing midfrontal theta power and reaction time under both conditions. Using hierarchical drift-diffusion regression modeling, we found that in both conditions, theta power was positively associated with boundary separation in phase bins with optimal power-reaction time correlations, whereas the power-boundary correlation decreased to nonsignificance in phase bins with reduced power-reaction time correlations. In contrast, the power-drift rate correlation was not modulated by theta phase, but by cognitive conflict. Drift rate was positively correlated with theta power for the bottom-up processing in the non-conflict condition, whereas it was negatively correlated with theta power for the top-down control to address conflict. These findings suggest that evidence accumulation is likely to be a phase-coordinated continuous process, whereas thresholding may be a phase-specific transient process.