A Prelimbic Cortex-Thalamus Circuit Bidirectionally Regulates Innate and Stress-Induced Anxiety-Like Behavior.

Anxiety-related disorders respond to cognitive behavioral therapies, which involved the medial prefrontal cortex (mPFC). Previous studies have suggested that subregions of the mPFC have different and even opposite roles in regulating innate anxiety. However, the specific causal targets of their descending projections in modulating innate anxiety and stress-induced anxiety have yet to be fully elucidated. Here, we found that among the various downstream pathways of the prelimbic cortex (PL), a subregion of the mPFC, PL-mediodorsal thalamic nucleus (MD) projection, and PL-ventral tegmental area (VTA) projection exhibited antagonistic effects on anxiety-like behavior, while the PL-MD projection but not PL-VTA projection was necessary for the animal to guide anxiety-related behavior. In addition, MD-projecting PL neurons bidirectionally regulated remote but not recent fear memory retrieval. Notably, restraint stress induced high-anxiety state accompanied by strengthening the excitatory inputs onto MD-projecting PL neurons, and inhibiting PL-MD pathway rescued the stress-induced anxiety. Our findings reveal that the activity of PL-MD pathway may be an essential factor to maintain certain level of anxiety, and stress increased the excitability of this pathway, leading to inappropriate emotional expression, and suggests that targeting specific PL circuits may aid the development of therapies for the treatment of stress-related disorders.

Regulators of early maize leaf development inferred from transcriptomes of laser capture microdissection (LCM)-isolated embryonic leaf cells.

The superior photosynthetic efficiency of C4 leaves over C3 leaves is owing to their unique Kranz anatomy, in which the vein is surrounded by one layer of bundle sheath (BS) cells and one layer of mesophyll (M) cells. Kranz anatomy development starts from three contiguous ground meristem (GM) cells, but its regulators and underlying molecular mechanism are largely unknown. To identify the regulators, we obtained the transcriptomes of 11 maize embryonic leaf cell types from five stages of pre-Kranz cells starting from median GM cells and six stages of pre-M cells starting from undifferentiated cells. Principal component and clustering analyses of transcriptomic data revealed rapid pre-Kranz cell differentiation in the first two stages but slow differentiation in the last three stages, suggesting early Kranz cell fate determination. In contrast, pre-M cells exhibit a more prolonged transcriptional differentiation process. Differential gene expression and coexpression analyses identified gene coexpression modules, one of which included 3 auxin transporter and 18 transcription factor (TF) genes, including known regulators of Kranz anatomy and/or vascular development. In situ hybridization of 11 TF genes validated their expression in early Kranz development. We determined the binding motifs of 15 TFs, predicted TF target gene relationships among the 18 TF and 3 auxin transporter genes, and validated 67 predictions by electrophoresis mobility shift assay. From these data, we constructed a gene regulatory network for Kranz development. Our study sheds light on the regulation of early maize leaf development and provides candidate leaf development regulators for future study.

Dopamine D2 receptors in pyramidal neurons in the medial prefrontal cortex regulate social behavior.

Drugs acting on dopamine D2 receptors are widely used for the treatment of several neuropsychiatric disorders, including schizophrenia and depression. Social deficits are a core symptom of these disorders. Pharmacological manipulation of dopamine D2 receptors (Drd2), a Gi-coupled subtype of dopamine receptors, in the medial prefrontal cortex (mPFC) has shown that Drd2 is implicated in social behaviors. However, the type of neurons expressing Drd2 in the mPFC and the underlying circuit mechanism regulating social behaviors remain largely unknown. Here, we show that Drd2 were mainly expressed in pyramidal neurons in the mPFC and that the activation of the Gi-pathway in Drd2+ pyramidal neurons impaired social behavior in male mice. In contrast, the knockdown of D2R in pyramidal neurons in the mPFC enhanced social approach behaviors in male mice and selectively facilitated the activation of mPFC neurons projecting to the nucleus accumbens (NAc) during social interaction. Remarkably, optogenetic activation of mPFC-to-NAc-projecting neurons mimicked the effects of conditional D2R knockdown on social behaviors. Altogether, these results demonstrate a cell type-specific role for Drd2 in the mPFC in regulating social behavior, which may be mediated by the mPFC-to-NAc pathway.

Clinical implications of additional chromosomal abnormalities in adult acute myeloid leukemia with inv (16)/t(16;16)/CBFB::MYH11.

OBJECTIVES: This study assesses the clinical significance of additional cytogenetic abnormalities (ACAs) and/or the deletion of 3'CBFB (3'CBFBdel) resulting in unbalanced CBFB::MYH11 fusion in acute myeloid leukemia (AML) with inv (16)/t(16;16)/CBFB::MYH11. METHODS: We retrospectively evaluated the clinicopathologic features of 47 adult de novo AML with inv (16)/t(16;16)/CBFB::MYH11 fusion. There were 44 balanced and 3 unbalanced CBFB::MYH11 fusions. Given the low frequency of unbalanced cases, the latter group was combined with 19 published cases (N = 22) for statistic and meta-analysis. RESULTS: Both balanced and unbalanced cases were characterized by frequent ACAs (56.5% and 72.7%, respectively), with +8, +22, and del(7q) as the most frequent abnormalities. The unbalanced group tends to be younger individuals (p = .04) and is associated with a lower remission rate (p = .02), although the median overall survival (OS) was not statistically different (p = .2868). In the balanced group, "ACA" subgroup had higher mortality (p = .013) and shorter OS (p = .011), and patients with relapsed disease had a significantly shorter OS (p = .0011). Cox multivariate regression analysis confirmed that ACAs and history of disease relapse are independent risk factors, irrespective of disease relapse status. In the combined cohort, cases with ACAs had shorter OS than those with "Sole" abnormality (p = .0109). CONCLUSIONS: ACAs are independent high-risk factors in adult AML with inv (16)/t(16;16)/CBFB::MYH11 fusion and should be integrated for risk stratification in this disease. Larger studies are needed to assess the clinical significance of the unbalanced CBFB::MYH11 fusion resulting from the 3'CBFBdel.

LN-439A, a novel BAP1 inhibitor, suppresses the growth of basal-like breast cancer by degrading KLF5.

Basal-like breast cancer (BLBC) is the most malignant subtype of breast cancer because of its aggressive clinical behaviour and lack of effective targeted agents. Krüppel-like factor 5 (KLF5) is an oncogenic transcription factor that is highly expressed in BLBC. The deubiquitinase (DUB) BRCA1-associated protein 1 (BAP1) stabilizes KLF5 and promotes BLBC growth and metastasis. Therefore, pharmacological inhibition of the BAP1‒KLF5 axis is an effective therapeutic strategy for BLBC. Here, through screening, we identified a series of tetrahydro-ß-carboline derivatives that effectively reduced the protein expression of KLF5 and exhibited strong antitumour activity. Among the investigated compounds, the lead compound LN-439A presented the strongest antitumour activity and inhibitory effect on KLF5 expression. LN-439A suppressed the proliferation and migration of BLBC cells, induced G2/M arrest, and induced apoptosis. Mechanistically, LN-439A functions as a small molecule catalytic inhibitor of BAP1 by binding to the catalytic pocket of BAP1, leading to the ubiquitination and degradation of KLF5. Consistent with this finding, the overexpression of KLF5 suppressed the antitumour effects of LN-439A. In summary, LN-439A is a promising therapeutic agent for BLBC that functions by targeting the BAP1‒KLF5 axis.

Assessment of sources and health risks of heavy metals in metropolitan household dust among preschool children: The LEAPP-HIT study.

The most common construction material used in Taiwan is concrete, potentially contaminated by geologic heavy metals (HMs). Younger children spend much time indoors, increasing HM exposure risks from household dust owing to their behaviors. We evaluated arsenic (As), cadmium (Cd), and lead (Pb) concentrations in fingernails among 280 preschoolers between 2017 and 2023. We also analyzed HM concentrations, including As, Cd, Pb, chromium (Cr), nickel (Ni), copper (Cu), zinc (Zn), iron (Fe), and manganese (Mn), in 90 household dust and 50 road dust samples from a residential area where children lived between 2019 and 2021 to deepen the understanding of sources and health risks of exposure to HMs from household dust. The average As, Cd, and Pb concentrations in fingernails were 0.12 ± 0.06, 0.05 ± 0.05, and 0.95 ± 0.77 µg/g, respectively. Soil parent materials, indoor construction activities, vehicle emissions, and mixed indoor combustion were the pollution sources of HMs in household dust. Higher Cr and Pb levels in household dust may pose non-carcinogenic risks to preschoolers. Addressing indoor construction and soil parent materials sources is vital for children's health. The finding of the present survey can be used for indoor environmental management to reduce the risks of HM exposure and avoid potential adverse health effects for younger children.

PV network plasticity mediated by neuregulin1-ErbB4 signalling controls fear extinction.

Neuroplasticity in the medial prefrontal cortex (mPFC) is essential for fear extinction, the process of which forms the basis of the general therapeutic process used to treat human fear disorders. However, the underlying molecules and local circuit elements controlling neuronal activity and concomitant induction of plasticity remain unclear. Here we show that sustained plasticity of the parvalbumin (PV) neuronal network in the infralimbic (IL) mPFC is required for fear extinction in adult male mice and identify the involvement of neuregulin 1-ErbB4 signalling in PV network plasticity-mediated fear extinction. Moreover, regulation of fear extinction by basal medial amygdala (BMA)-projecting IL neurons is dependent on PV network configuration. Together, these results uncover the local molecular circuit mechanisms underlying mPFC-mediated top-down control of fear extinction, suggesting alterative therapeutic approaches to treat fear disorders.

Molecular asymmetry in the cephalochordate embryo revealed by single-blastomere transcriptome profiling.

Studies in various animals have shown that asymmetrically localized maternal transcripts play important roles in axial patterning and cell fate specification in early embryos. However, comprehensive analyses of the maternal transcriptomes with spatial information are scarce and limited to a handful of model organisms. In cephalochordates (amphioxus), an early branching chordate group, maternal transcripts of germline determinants form a compact granule that is inherited by a single blastomere during cleavage stages. Further blastomere separation experiments suggest that other transcripts associated with the granule are likely responsible for organizing the posterior structure in amphioxus; however, the identities of these determinants remain unknown. In this study, we used high-throughput RNA sequencing of separated blastomeres to examine asymmetrically localized transcripts in two-cell and eight-cell stage embryos of the amphioxus Branchiostoma floridae. We identified 111 and 391 differentially enriched transcripts at the 2-cell stage and the 8-cell stage, respectively, and used in situ hybridization to validate the spatial distribution patterns for a subset of these transcripts. The identified transcripts could be categorized into two major groups: (1) vegetal tier/germ granule-enriched and (2) animal tier/anterior-enriched transcripts. Using zebrafish as a surrogate model system, we showed that overexpression of one animal tier/anterior-localized amphioxus transcript, zfp665, causes a dorsalization/anteriorization phenotype in zebrafish embryos by downregulating the expression of the ventral gene, eve1, suggesting a potential function of zfp665 in early axial patterning. Our results provide a global transcriptomic blueprint for early-stage amphioxus embryos. This dataset represents a rich platform to guide future characterization of molecular players in early amphioxus development and to elucidate conservation and divergence of developmental programs during chordate evolution.

Chitinase 3-like-1 Expression in the Microenvironment Is Associated with Neutrophil Infiltration in Bladder Cancer.

Bladder cancer is a common cancer with well-established therapeutic strategies. However, recurrence occurs in 50% of patients with non-muscle-invasive bladder cancer, and 20% of patients progress to muscle-invasive bladder cancer. The 5-year survival rate for muscle-invasive bladder cancer patients is disappointingly low, ranging from 36% to 48%. A molecular marker of interest is chitinase 3-like-1 (CHI3L1), which is elevated in various cancers, including bladder cancer. In addition to its role in cancer cells, CHI3L1 also has regulatory abilities in immune cells. Neutrophil infiltration has been shown to positively correlate with overall survival, progression-free survival, and relapse-free survival in bladder cancer patients. However, the relationship between CHI3L1 and neutrophils remain poorly understood. Therefore, this study investigated the relationship between CHI3L1 level and protumor neutrophil infiltration in bladder cancer. We analyzed the GSE128959 dataset and the data of a bladder cancer cohort undergoing chemotherapy. We observed higher expression of CHI3L1 in bladder cancer patients with invasive or chemotherapy-resistance. Our results revealed a positive correlation between CHI3L1 expression and protumor neutrophil infiltration. Elevated CHI3L1 expression was associated with genes which were related to the recruitment and infiltration of neutrophils. Consequently, CHI3L1 may serve as a novel evaluation factor for the degree of neutrophil infiltration in advanced bladder cancer in those scheduled for chemotherapy.

Comparison of myeloid neoplasms with nonclassic 3q26.2/MECOM versus classic inv(3)/t(3;3) rearrangements reveals diverse clinicopathologic features, genetic profiles, and molecular mechanisms of MECOM activation.

MECOM rearrangements are recurrent in myeloid neoplasms and associated with poor prognosis. However, only inv(3)(q21q26.2) and t(3;3)(q21;q26.2), the classic MECOM rearrangements resulting in RPN1-MECOM rearrangement with Mecom overexpression and GATA2 haploinsufficiency, define the distinct subtype of acute myeloid leukemia (AML), and serve as presumptive evidence for myelodysplastic syndrome based on the current World Health Organization classification. Myeloid neoplasms with nonclassic 3q26.2/MECOM rearrangements have been found to be clinically aggressive, but comparative analysis of clinicopathologic and genomic features is limited. We retrospectively studied cohorts of myeloid neoplasms with classic and nonclassic MECOM rearrangements. Cases with classic rearrangements consisted predominantly of AML, often with inv(3) or t(3;3) as the sole chromosome abnormality, whereas the group of nonclassic rearrangements included a variety of myeloid neoplasms, often with complex karyotype without TP53 mutations and similarly dismal overall survival. Immunohistochemistry revealed Mecom protein overexpression in both groups, but overexpression in cases with nonclassic rearrangements was mediated through a mechanism other than GATA2 distal enhancer involvement typical for classic rearrangement. Our results demonstrated that myeloid neoplasms with nonclassic 3q26.2/MECOM rearrangements encompass a diverse group of diseases with poor clinical outcome, overexpression of Mecom protein as a result of the nonclassic mechanism of MECOM activation.

Whole-Genome Duplication Facilitated the Evolution of C4 Photosynthesis in Gynandropsis gynandra.

In higher plants, whole-genome duplication (WGD) is thought to facilitate the evolution of C4 photosynthesis from C3 photosynthesis. To understand this issue, we used new and existing leaf-development transcriptomes to construct two coding sequence databases for C4Gynandropsis gynandra and C3Tarenaya hassleriana, which shared a WGD before their divergence. We compared duplicated genes in the two species and found that the WGD contributed to four aspects of the evolution of C4 photosynthesis in G. gynandra. First, G. gynandra has retained the duplicates of ALAAT (alanine aminotransferase) and GOGAT (glutamine oxoglutarate aminotransferase) for nitrogen recycling to establish a photorespiratory CO2 pump in bundle sheath (BS) cells for increasing photosynthesis efficiency, suggesting that G. gynandra experienced a C3-C4 intermediate stage during the C4 evolution. Second, G. gynandra has retained almost all known vein-development-related paralogous genes derived from the WGD event, likely contributing to the high vein complexity of G. gynandra. Third, the WGD facilitated the evolution of C4 enzyme genes and their recruitment into the C4 pathway. Fourth, several genes encoding photosystem I proteins were derived from the WGD and are upregulated in G. gynandra, likely enabling the NADH dehydrogenase-like complex to produce extra ATPs for the C4 CO2 concentration mechanism. Thus, the WGD apparently played an enabler role in the evolution of C4 photosynthesis in G. gynandra. Importantly, an ALAAT duplicate became highly expressed in BS cells in G. gynandra, facilitating nitrogen recycling and transition to the C4 cycle. This study revealed how WDG may facilitate C4 photosynthesis evolution.

An Environmentally Benign Multicomponent Cascade Reaction of 3-Formylchromones, 2-Naphthols, and Heterocyclic Ketal Aminals: Site-Selective Synthesis of Functionalized Morphan Derivatives.

A novel protocol has been developed for the preparation of highly functionalized 2-azabicyclo[3.3.1]nonane (morphan) derivatives by the interesting three-component cascade reaction of 3-formylchromones, 2-naphthol, and heterocyclic ketal aminals (HKAs) in the ionic liquid [BMIM]PF6 promoted by the organic base Et3N. A complex cascade reaction is required, which includes a 1,2-addition, two Michael reactions, two tautomerizations, and an N-alkylation accompanied by a ring-opening reaction and involving the cleavage of one C-O bond and the formation of four bonds (one C-N bond, one C-O bond, and two C-C bonds). As a result, functionalized morphans (5 and 6) bearing naphthalene-structured skeletons were prepared by simple heating of a mixture of 3-formylchromones, 2-naphthols, and HKAs in the environmentally friendly ionic liquid [BMIM]PF6. This protocol can be used in the synthesis of various morphans and is suitable for combinatorial and parallel syntheses of natural-like morphan derivatives. This approach has several advantages such as the use of an environmentally friendly solvent, simple and practical operation (multicomponent one-pot reaction), and satisfactory yields (65-88%).

Associations of maternal food safety-related risk perceptions and protective behaviors with daily mercury intake and internal doses of Taiwanese women and their preschool children.

Mercury (Hg) is a well-known toxicant that can affect children's neurodevelopment. This study attempted to evaluate the internal dose of Hg in hair and fingernails and external Hg exposure from dietary consumption in 283 pairs of mothers and their children aged under 6 years in Taiwan. Mean Hg levels in hair and fingernail samples were 1.07 ± 0.67 and 0.42 ± 0.34 µg/g for mothers, and 1.11 ± 1.22 and 0.36 ± 0.26 µg/g for children, respectively. Our results showed that 42% of mothers and 41% of children had hair Hg levels exceeding the US Environmental Protection Agency recommended value of 1 µg/g. Hg exposure in children was greater than that of their mothers. Estimated daily intake (EDI) levels of Hg among preschool children were 3.3-times higher than those of their mothers. A sensitivity analysis indicated that fish consumption was the main potential factor of Hg exposure among both mothers and their children. External Hg exposure using estimated daily dietary ingestion by mothers was a surrogate for internal hair Hg concentrations. However, poor correlations were found between EDI Hg levels and hair Hg levels among children aged 4-6 years. Exposure sources from food and other media, such as soil and dust, need to be considered to arrive at more-valid risk assessments for younger children's exposure to Hg. Children of mothers who did not have food safety-related risk perceptions or protective behaviors had significantly higher hair Hg concentrations compared to children whose mothers had risk perceptions and protective behaviors. Hg exposure of women of childbearing age and preschool children in Taiwan is still an area of great concern. Providing food safety information and risk-benefits of fish consumption for mothers may avoid harm to the developing nervous systems of their children.

Frequent occurrence of respiratory symptoms in children is associated with exposure to air pollution, land use types, and parental mental health in the Greater Taipei area.

Although studies have investigated the individual effects of air pollution, land use types, and parental mental health on children's respiratory health, few studies have examined the effects of these risk factors simultaneously in children aged <2 years. We investigated the effects of exposure to air pollution, land use types surrounding residences, and parental mental health on the frequent occurrence of respiratory symptoms in children aged <2 years in the Greater Taipei area. Participants were recruited from an ongoing Taiwanese birth cohort study. We analyzed the data of the participants who had been recruited from January 2011 to April 2014 and had responded to the follow-up questionnaires at 6, 12, and 24 months. Self-administered questionnaires were used to collect participants' sociodemographic background and health, such as respiratory symptoms, and parental mental health. Pre- and postnatal pollution levels were estimated using the spatial interpolation technique (ordinary kriging) at children's residential addresses. Land use types surrounding participants' homes were evaluated by performing buffer analysis. Multiple logistic regression analyses were conducted to examine the effects of risk factors on the frequent occurrence of child respiratory symptoms in children aged 6, 12, and 24 months. We included 228, 360, and 441 children aged 6, 12, and 24 months, respectively. Our results indicated that postnatal exposure to PM2.5 and O3 was positively associated with children's respiratory symptoms. Traffic-related land-use types, sports facilities, and commercial land surrounding homes exerted adverse effects on children's respiratory symptoms, whereas the presence of schools in the neighborhood was beneficial. Parental mental health was also associated with children's respiratory symptoms. Postnatal exposure to air pollution and land use types surrounding residences were associated with respiratory health in children aged <2 years. The residential environment is a critical factor affecting children's respiratory health of children aged <2 years.

Effects of air pollution, land-use type, and maternal mental health on child development in the first two years of life in the Greater Taipei area.

INTRODUCTION: Few studies have investigated the associations of child development with air pollution, land-use type, and maternal mental health simultaneously. Therefore, we evaluated the effect of exposure to air pollutants during several critical periods of life, with adjustment for land-use type and maternal mental status, on child development at 6, 12, and 24 months of age in the Greater Taipei area. METHODS: Participants were selected from an ongoing Taiwanese birth cohort study. We analyzed the data of the participants who had been recruited from January 2011 to April 2014. Self-administered standardized questionnaires were used to collect information on sociodemographic factors, infant development and health, maternal mental status, etc. Air pollution levels in pre- and postnatal periods were estimated using a spatial interpolation technique (ordinary kriging) at children's residential addresses. Land-use types around participants' homes were evaluated using buffer analysis. We used multiple logistic regression analysis to examine the relationships between child development delay and environmental factors. RESULTS: In total, 228, 361, and 441 families completed child development forms at 6, 12, and 24 months of age, respectively. Our results indicated that prenatal exposure to particulate matter with aerodynamic diameter ≤10 µm and O3 and postnatal exposure to NO2 were negatively associated with child development. Traffic-related land-use types, gas stations, and power generation areas around participants' homes were also adversely correlated with child development. Moreover, poor maternal mental health was associated with child development delay. CONCLUSION: Prenatal exposure and postnatal exposure to air pollution were associated with development delay in children under 2 years of age, specifically those under 1 year of age, even after adjustment for land-use type and maternal mental status. Living environment is critical for the development of children under 2 years of age.

Association of chronic diseases and lifestyle factors with suicidal ideation among adults aged 18-69 years in Eswatini: evidence from a population-based survey.

BACKGROUND: How chronic diseases and lifestyle affect suicidal ideation in the sub-Saharan region remains unclear. We investigated the association of chronic diseases and lifestyle with suicidal ideation in the past year and the potential modifying role of sociodemographic status on this association. The findings can guide suicide prevention interventions. METHODS: We analyzed 3026 respondents from the World Health Organization STEPwise approach to noncommunicable disease risk factor surveillance conducted in Eswatini in 2014. The outcome was past-year suicidal ideation, and the main predictors were chronic diseases and lifestyle. Multiple logistic regression was used to estimate predictors, and subgroup analysis was performed to assess effect modification. RESULTS: The prevalence of past-year suicidal ideation was 9.9%. After adjustment for covariates, including sex, marital status, employment status, and education level, individuals aged 18-30 years (adjusted odds ratio [aOR]: 2.27, 95% confidence interval [CI]: 1.22-4.22) were more likely to have had past-year suicidal ideation than those aged 45-69 years. After adjustment for covariates among employed individuals, having high blood pressure (aOR: 3.38, 95% CI: 1.54-7.40), not exercising (aOR: 2.65, 95% CI: 1.09-6.39), drinking alcohol (aOR: 2.40, 95% CI: 1.14-5.05), being aged 18-30 years (aOR: 3.50, 95% CI: 1.01-12.1), and being exposed to threats (aOR: 2.37, 95% CI: 1.01-5.53) were significantly associated with past-year suicidal ideation. CONCLUSIONS: Among currently employed individuals, having high blood pressure, not exercising, and drinking alcohol were associated with past-year suicidal ideation. The findings highlight the importance of developing and strengthening systems for early identification of suicidal ideation risk.

Aggressive morphologic variants of mantle cell lymphoma characterized with high genomic instability showing frequent chromothripsis, CDKN2A/B loss, and TP53 mutations: A multi-institutional study.

Aggressive morphologic variants of mantle cell lymphoma (MCL), including blastoid and pleomorphic (B/P-MCL), are rare and associated with poor clinical outcomes. The genomic landscape of these variants remains incompletely explored. In this multi-institutional study, we describe recurrent mutations and novel genomic copy number alterations (CNAs) in B/P-MCL, using next generation sequencing and SNP-array. Chromothripsis, a recently described phenomenon of massive chromosomal rearrangements, was identified in eight of 13 (62%) B/P MCL cases, and a high degree of genomic complexity with frequent copy number gains and losses was also seen. In contrast, a comparative cohort of nine cases of conventional MCL (C-MCL) showed no chromothripsis and less complexity. Twelve of 13 (92%) B/P-MCL cases showed loss of CDKN2A/B (6 biallelic and 6 monoallelic losses); while only one C-MCL showed monoallelic CDKN2A/B loss. In B/P-MCL, TP53 was the most commonly mutated gene, with mutations present in eight cases (62%), six of which showed concurrent loss of chromosome 17p. Of the eight cases with chromothripsis, six (85%) harbored TP53 mutations. Other recurrent mutations in B/P-MCL included ATM (7, 53%), CCND1 (5, 38%), NOTCH1 (2, 18%), NOTCH2, and BIRC3 (each in 3, 23%). Here, we describe high genomic instability associated with chromothripsis and a high frequency of CDKN2A/B and TP53 alterations in the aggressive variants of MCL. The nonrandom chromothripsis events observed in B/P-MCL may be an indicator of clinically aggressive MCL. In addition, frequent CDKN2A deletion and high genomic instability may provide potential targets for alternative treatment.

Blast Fungal Genomes Show Frequent Chromosomal Changes, Gene Gains and Losses, and Effector Gene Turnover.

Pyricularia is a fungal genus comprising several pathogenic species causing the blast disease in monocots. Pyricularia oryzae, the best-known species, infects rice, wheat, finger millet, and other crops. As past comparative and population genomics studies mainly focused on isolates of P. oryzae, the genomes of the other Pyricularia species have not been well explored. In this study, we obtained a chromosomal-level genome assembly of the finger millet isolate P. oryzae MZ5-1-6 and also highly contiguous assemblies of Pyricularia sp. LS, P. grisea, and P. pennisetigena. The differences in the genomic content of repetitive DNA sequences could largely explain the variation in genome size among these new genomes. Moreover, we found extensive gene gains and losses and structural changes among Pyricularia genomes, including a large interchromosomal translocation. We searched for homologs of known blast effectors across fungal taxa and found that most avirulence effectors are specific to Pyricularia, whereas many other effectors share homologs with distant fungal taxa. In particular, we discovered a novel effector family with metalloprotease activity, distinct from the well-known AVR-Pita family. We predicted 751 gene families containing putative effectors in 7 Pyricularia genomes and found that 60 of them showed differential expression in the P. oryzae MZ5-1-6 transcriptomes obtained under experimental conditions mimicking the pathogen infection process. In summary, this study increased our understanding of the structural, functional, and evolutionary genomics of the blast pathogen and identified new potential effector genes, providing useful data for developing crops with durable resistance.

Tobacco control within and beyond WHO MPOWER: outcomes from Taiwan SimSmoke.

INTRODUCTION: Adult smoking prevalence in Taiwan rapidly declined from 26.5% in 2005 to 20.0% in 2015. Nevertheless, future projections on smoking-attributable deaths and current per capita consumption do not paint an equally bright picture. METHODS: We used SimSmoke, a tobacco control simulation model to assess the impact of tax increases and other policies by predicting past and projecting over future decades smoking rates and smoking-attributable mortality. RESULTS: The model accurately depicts the decline in smoking prevalence observed in Taiwan from 2000 to 2015. Nonetheless, under the 'status quo' scenario, smoking-attributable mortality is projected to continue growing, peaking at 26 602 annual deaths in 2039 and cumulative deaths >1 million by 2044. By comparing projections with current policies with a counterfactual scenario based on the 2000 policy levels, SimSmoke estimates that tobacco control in Taiwan has been able to reduce smoking prevalence by 30% in 2015 with 450 000 fewer smoking-attributable deaths by 2060. Modified scenarios show that doubling the retail price of cigarettes and fully implementing the remaining MPOWER measures would avert approximately 45 000 lives by 2040 and 130 000 by 2060. CONCLUSIONS: Tobacco will be a leading cause of death in Taiwan for the coming decades, showing yet again the long-term consequences of smoking on public health. The MPOWER package, even if adopted at the highest level with a large tax increase, is unlikely to reduce smoking prevalence to the endgame goal of 5% in the next five decades.

Self-medication and knowledge among pregnant women attending primary healthcare services in Malang, Indonesia: a cross-sectional study.

BACKGROUND: Self-medication with over-the-counter (OTC) drugs is an important public health concern, especially in the vulnerable population of pregnant women due to potential risks to both the mother and fetus. Few studies have studied how factors, such as knowledge, affect self-medication. This study investigated self-medication and its associated factors among pregnant women attending healthcare services in Malang, Indonesia. METHODS: A cross-sectional study was conducted from July to September 2018 in five healthcare services. A self-administered questionnaire was used and the data were analyzed using multiple regression models. RESULTS: Of 333 female participants, 39 (11.7%) used OTC medication. Women with a higher level of knowledge of OTC medication were more likely to self-medicate-adjusted odds ratio (aOR) = 2.15, 95% confidence interval (CI) = 1.03-4.46. Compared with those with less knowledge, pregnant women with more correct knowledge of the possible risk of self-medication were less likely to self-medicate-aOR = 0.29; 95% CI = 0.14-0.60. The effect of a higher level of knowledge of OTC medication was significant among women who had middle school and lower education-aOR = 8.18; 95% CI = 1.70-39.35. The effect of correct knowledge on the possible risks of self-medication was significant only among women with high school and higher education-aOR = 0.17; 95% CI = 0.07-0.42. CONCLUSION: Imparting specific knowledge of the potential risks of using non-prescribed medication during pregnancy may help pregnant women navigate and more safely manage their OTC use. We also suggest further collecting data from more healthcare services, such as hospitals, to obtain more findings generalizable to the Indonesian community.