Repeated loss of function at HD mating-type genes and of recombination suppression without mating-type locus linkage in anther-smut fungi.

A wide diversity of mating systems occur in nature, with frequent evolutionary transitions in mating-compatibility mechanisms. Basidiomycete fungi typically have two mating-type loci controlling mating compatibility, HD and PR, usually residing on different chromosomes. In Microbotryum anther-smut fungi, there have been repeated events of linkage between the two mating-type loci through chromosome fusions, leading to large non-recombining regions. By generating high-quality genome assemblies, we found that two sister Microbotryum species parasitizing Dianthus plants, M. superbum and M. shykoffianum, as well as the distantly related M. scorzonarae, have their HD and PR mating-type loci on different chromosomes, but with the PR mating-type chromosome fused with part of the ancestral HD chromosome. Furthermore, progressive extensions of recombination suppression have generated evolutionary strata. In all three species, rearrangements suggest the existence of a transient stage of HD-PR linkage by whole chromosome fusion, and, unexpectedly, the HD genes lost their function. In M. superbum, multiple natural diploid strains were homozygous, and the disrupted HD2 gene was hardly expressed. Mating tests confirmed that a single genetic factor controlled mating compatibility (i.e. PR) and that haploid strains with identical HD alleles could mate and produce infectious hyphae. The HD genes have therefore lost their function in the control of mating compatibility in these Microbotryum species. While the loss of function of PR genes in mating compatibility has been reported in a few basidiomycete fungi, these are the first documented cases for the loss of mating-type determination by HD genes in heterothallic fungi. The control of mating compatibility by a single genetic factor is beneficial under selfing and can thus be achieved repeatedly, through evolutionary convergence in distant lineages, involving different genomic or similar pathways.

MRI-Based Kinetic Heterogeneity Evaluation in the Accurate Access of Axillary Lymph Node Status in Breast Cancer Using a Hybrid CNN-RNN Model.

BACKGROUND: Accurate evaluation of the axillary lymph node (ALN) status is needed for determining the treatment protocol for breast cancer (BC). The value of magnetic resonance imaging (MRI)-based tumor heterogeneity in assessing ALN metastasis in BC is unclear. PURPOSE: To assess the value of deep learning (DL)-derived kinetic heterogeneity parameters based on BC dynamic contrast-enhanced (DCE)-MRI to infer the ALN status. STUDY TYPE: Retrospective. SUBJECTS: 1256/539/153/115 patients in the training cohort, internal validation cohort, and external validation cohorts I and II, respectively. FIELD STRENGTH/SEQUENCE: 1.5 T/3.0 T, non-contrast T1-weighted spin-echo sequence imaging (T1WI), DCE-T1WI, and diffusion-weighted imaging. ASSESSMENT: Clinical pathological and MRI semantic features were obtained by reviewing histopathology and MRI reports. The segmentation of the tumor lesion on the first phase of T1WI DCE-MRI images was applied to other phases after registration. A DL architecture termed convolutional recurrent neural network (ConvRNN) was developed to generate the KHimage (kinetic heterogeneity of DCE-MRI image) score that indicated the ALN status in patients with BC. The model was trained and optimized on training and internal validation cohorts, tested on two external validation cohorts. We compared ConvRNN model with other 10 models and the subgroup analyses of tumor size, magnetic field strength, and molecular subtype were also evaluated. STATISTICAL TESTS: Chi-squared, Fisher's exact, Student's t, Mann-Whitney U tests, and receiver operating characteristics (ROC) analysis were performed. P < 0.05 was considered significant. RESULTS: The ConvRNN model achieved area under the curve (AUC) of 0.802 in the internal validation cohort and 0.785-0.806 in the external validation cohorts. The ConvRNN model could well evaluate the ALN status of the four molecular subtypes (AUC = 0.685-0.868). The patients with larger tumor sizes (>5 cm) were more susceptible to ALN metastasis with KHimage scores of 0.527-0.827. DATA CONCLUSION: A ConvRNN model outperformed traditional models for determining the ALN status in patients with BC. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

Feasibility analysis of magnetic resonance imaging-based radiomics features for preoperative prediction of nuclear grading of ductal carcinoma in situ.

Background: The nuclear grading of ductal carcinoma in situ (DCIS) affects its clinical risk. The aim of this study was to investigate the possibility of predicting the nuclear grading of DCIS, by magnetic resonance imaging (MRI)-based radiomics features. And to develop a nomogram combining radiomics features and MRI semantic features to explore the potential role of MRI radiomic features in the assessment of DCIS nuclear grading. Methods: A total of 156 patients (159 lesions) with DCIS and DCIS with microinvasive (DCIS-MI) were enrolled in this retrospective study, with 112 lesions included in the training cohort and 47 lesions included in the validation cohort. Radiomics features were extracted from Dynamic contrast-enhanced MRI (DCE-MRI) phases 1st and 5th. After feature selection, radiomics signature was constructed and radiomics score (Rad-score) was calculated. Multivariate analysis was used to identify MRI semantic features that were significantly associated with DCIS nuclear grading and combined with Rad-score to construct a Nomogram. Receiver operating characteristic curves were used to evaluate the predictive performance of Rad-score and Nomogram, and decision curve analysis (DCA) was used to evaluate the clinical utility. Results: In multivariate analyses of MRI semantic features, larger tumor size and heterogeneous enhancement pattern were significantly associated with high-nuclear grade DCIS (HNG DCIS). In the training cohort, Nomogram had an area under curve (AUC) of 0.879 and Rad-score had an AUC of 0.828. Similarly, in the independent validation cohort, Nomogram had an AUC value of 0.828 and Rad-score had an AUC of 0.772. In both the training and validation cohorts, Nomogram had a significantly higher AUC value than Rad-score (P<0.05). DCA confirmed that Nomogram had a higher net clinical benefit. Conclusions: MRI-based radiomic features can be used as potential biomarkers for assessing nuclear grading of DCIS. The nomogram constructed by radiomic features combined with semantic features is feasible in discriminating non-HNG and HNG DCIS.

Complexation of Fluorofenidone by Cucurbit[7]uril and ß-Cyclodextrin: Keto-Enol Tautomerization to Enhance the Solubility.

This study is designed to compare drug encapsulation by cucurbit[7]uril and ß-cyclodextrin, using fluorofenidone as a model drug. Single-crystal X-ray diffraction analysis was employed to successfully determine the crystal structures of fluorofenidone·H+@cucurbit[7]uril Form, fluorofenidone@cucurbit[7]uril Form, and fluorofenidone@ß-cyclodextrin Form. Keto-enol tautomerization of fluorofenidone mediated by cucurbit[7]uril in acid solution is confirmed by crystal structures, pH titration, and nuclear magnetic resonance experiments. However, ß-cyclodextrin cannot cause the keto-enol tautomerization of fluorofenidone under similar conditions. The phase solubility study demonstrates that cucurbit[7]uril has a much higher solubilization capacity for fluorofenidone than ß-cyclodextrin in 0.1 M HCl since the Kc values of fluorofenidone with cucurbit[7]uril and ß-cyclodextrin were 1223.97 ± 452.68 and 78.49 ± 10.56 M-1, respectively. Excellent solubility can be attributed to the keto-enol tautomerization of fluorofenidone under the conditions of cucurbit[7]uril in acid solution. The enol form of fluorofenidone is encapsulated by cucurbit[7]uril by hydrogen bonding interaction and hydrophobic interaction to increase binding affinity. Rat pharmacokinetic studies demonstrate that the area under the plasma concentration-time curve from time 0 to 7 h value of fluorofenidone@cucurbit[7]uril complex is 1.70-fold greater than that of free fluorofenidone, and the mean residence time from time 0 to 7 h is slightly prolonged from 1.29 to 1.76 h (P < 0.01) after oral administration. However, no significant difference is found between fluorofenidone and fluorofenidone@ß-cyclodextrin complex. This work indicates that the induction of keto-enol tautomerization of drugs using macrocyclic molecules has the potential to be an effective method to improve their solubility and bioavailability, providing valuable insights for the application of macrocyclic molecules in the biomedical field.

[Post-stroke dysphagia treated with four-step acupuncture therapy for opening orifices and benefiting throat combined with neuromuscular electrical stimulation: a randomized controlled trial].

OBJECTIVE: To observe the clinical efficacy on post-stroke dysphagia treated with four-step acupuncture therapy for opening orifices and benefiting throat combined with neuromuscular electrical stimulation. METHODS: Sixty patients with post-stroke dysphagia were randomly divided into an observation group and a control group, with 30 cases in each group. The neuromuscular electrical stimulation was adopted in the control group. Besides the treatment as the control group, in the observation group, the four-step acupuncture therapy for opening orifices and benefiting throat was supplemented. Step 1: the three areas of scalp acupuncture on the affected side were stimulated. Step 2: pricking method was operated on the posterior pharyngeal wall. Step 3: bleeding technique was operated at Jinjin (EX-HN 12) and Yuye (EX-HN 13). Step 4: deep insertion of needle was operated at three-pharynx points. The needles were retained for 30 min at the three areas of scalp acupuncture and the three-pharynx points. The intervention of each group was delivered once daily, 6 times a week, at the interval of 1 day. One course of treatment was 1 week and 4 successive courses were required. The rating of Kubota water swallow test, the score of standardized swallowing assessment (SSA) and the rating of Rosenbek penetration- aspiration scale (PAS) were observed before and after treatment in patients of the two groups. The incidence of clinical complications and clinical efficacy were compared between the two groups. RESULTS: Compared with those before treatment, the rating of Kubota water swallow test, the scores of SSA and the rating of PAS of patients in the two groups were decreased after treatment (P<0.01), and the values of the observation group were lower than those of the control group after treatment (P<0.05). The incidence of clinical complications in the observation group was 13.3% (4/30), lower than 36.7% (11/30) in the control group (P<0.05). The total effective rate in the observation group was 93.3% (28/30), which was better than 70.0% (21/30) in the control group (P<0.05). CONCLUSION: The four-step acupuncture therapy for opening orifices and benefiting throat combined with neuromuscular electrical stimulation can improve the swallowing function of patients with post-stroke dysphagia and reduce the incidence of clinical complications.

Hoisted with his own petard: How sex-ratio meiotic drive in Drosophila affinis creates resistance alleles that limit its spread.

Meiotic drivers are selfish genetic elements that tinker with gametogenesis to bias their own transmission into the next generation of offspring. Such tinkering can have significant consequences on gametogenesis and end up hampering the spread of the driver. In Drosophila affinis, sex-ratio meiotic drive is caused by an X-linked complex that, when in males with a susceptible Y chromosome, results in broods that are typically more than 95% female. Interestingly, D. affinis males lacking a Y chromosome (XO) are fertile and males with the meiotic drive X and no Y produce only sons-effectively reversing the sex-ratio effect. Here, we show that meiotic drive dramatically increases the rate of nondisjunction of the Y chromosome (at least 750X), meaning that the driver is creating resistant alleles through the process of driving. We then model how the O might influence the spread, dynamics and equilibrium of the sex-ratio X chromosome. We find that the O can prevent the spread or reduce the equilibrium frequency of the sex-ratio X chromosome, and it can even lead to oscillations in frequency. Finally, with reasonable parameters, the O is unlikely to lead to the loss of the Y chromosome, but we discuss how it might lead to sex-chromosome turnover indirectly.

Stage IV colon cancer patients without DENND2D expression benefit more from neoadjuvant chemotherapy.

According to the EPOC study, chemotherapy could improve 5-year disease-free survival of stage IV colon cancer patients by 8.1%. However, more molecular biomarkers are required to identify patients who need neoadjuvant chemotherapy. DENND2D expression was evaluated by immunohistochemistry in 181 stage IV colon cancer patients. The prognosis was better for patients with DENND2D expression than patients without DENND2D expression (5-year overall survival [OS]: 42% vs. 12%, p = 0.038; 5-year disease-free survival: 20% vs. 10%, p = 0.001). Subgroup analysis of the DENND2D-negative group showed that patients treated with neoadjuvant chemotherapy achieved longer OS than patients without neoadjuvant chemotherapy (RR = 0.179; 95% CI = 0.054-0.598; p = 0.003). DENND2D suppressed CRC proliferation in vitro and in vivo. Downregulation of DENND2D also promoted metastasis to distant organs in vivo. Mechanistically, DENND2D suppressed the MAPK pathway in CRC. Colon cancer patients who were DENND2D negative always showed a worse prognosis and were more likely to benefit from neoadjuvant chemotherapy. DENND2D may be a new prognostic factor and a predictor of the need for neoadjuvant chemotherapy in stage IV colon cancer.

HIF-1α inhibition promotes the efficacy of immune checkpoint blockade in the treatment of non-small cell lung cancer.

The response to immune checkpoint inhibitors (ICIs) monotherapy remains unsatisfactory in patients with NSCLC. Thus, combining ICIs with other potential modalities is of great significance to enhance the response of single drug alone. Here, we identified that HIF-1α inhibition was capable of promoting anti-tumor immunity in NSCLC. We applied NSCLC cell lines and mouse models to evaluate the synergy of combined HIF-1α inhibition and PD-1 blockade on tumor growth and the function of tumor infiltrating lymphocytes (TILs). Public datasets were utilized to investigate patients' prognosis based on expressions of HIF-1α and LOXL2 as well as EMT-associated markers and CD8+ TILs. Moreover, we explored the correlation between HIF-1α and LOXL2 levels and CD8+ TILs in tumor samples from patients with NSCLC by immunohistochemistry, as well as their association to patients' survival. In vitro, PX-478, an HIF-1α inhibitor, promoted tumor cell apoptosis induced by T cells when combined with ICIs. Furthermore, mice treated with PX-478 and anti-PD-1 antibodies exhibited a marked delay in tumor growth and prolonged survival, which correlated with increased TILs and granzyme B secretion. Besides, patients with high HIF-1α expression exhibited high levels of EMT-related markers and low TILs, indicating an immunosuppressive phenotype. Mechanistically, we observed that HIF-1α inhibition suppressed the EMT phenotypes induced by hypoxia and further alleviated tumor immunosuppression, which was related to blockage of HIF-1α/LOXL2 signaling pathway. In summary, we identified that HIF-1α inhibition could synergize with anti-PD-1 to impair tumor growth in vitro and in vivo. Our data suggest that HIF-1α inhibitors represent a promising treatment to enhance anti-tumor immunity and provide preclinical rationale to evaluate the combination of ICIs with HIF-1α inhibition clinically in NSCLC.

Relationships between Kazakh elders' disability severity and informal care time in far north-western low-income areas in China: The mediating roles of caregiver health and home-based care quality.

BACKGROUND: Elders' disability severity and caregiver health could predict elders' informal care time, but the mechanism by which the degree of disability in the elderly affects informal care time is unclear. AIM: The aim of this works is to explore the mediating roles of caregiver health and home-based care quality between disability severity of elders and informal care time in far north-western low-income areas in China. METHOD: From September 2017 to February 2018, three hundred fifty-two dyads of Kazakh disabled elders and informal caregivers in Xinjiang were interviewed. Structural equation modelling analyses were applied. RESULTS: Significant positive correlations were observed between elders' disability severity and informal care time, caregiver health and informal care time, elders' disability severity and caregiver health. Significant negative correlations were observed between home-based care quality and informal care time, elders' disability severity and home-based care quality, caregiver health and home-based care quality. Elders' disability severity had 71.94% direct effect on informal care time, 28.06% indirect effect on informal care time mediated by home-based care quality and caregiver health. CONCLUSION: Caregiver health and home-based care quality play mediating roles on the path relationship between the elders' disability severity and informal care time.

Nomogram for Early Prediction of Pathological Complete Response to Neoadjuvant Chemotherapy in Breast Cancer Using Dynamic Contrast-enhanced and Diffusion-weighted MRI.

RATIONALE AND OBJECTIVES: The study investigated the potential of the combined use of dynamic contrast-enhanced MRI and diffusion-weighted imaging in predicting the pathological complete response (pCR) of neoadjuvant chemotherapy (NAC) after two cycles of NAC. MATERIALS AND METHODS: Eighty-seven patients with breast cancer who underwent MR examination before and after two cycles of NAC were enrolled. The patients were randomly assigned to a training cohort and a validation cohort (3:1 ratio). MRI parameters including tumor longest diameter, time-signal intensity curve, early enhanced ratio (E90), maximal enhanced ratio and ADC value were measured, and percentage change in MRI parameters were calculated. Univariate analysis and multivariate logistic regression analysis were used to evaluate independent predictors of pCR in the training cohort. The validation cohort was used to test the prediction model, and the nomogram was created based on the prediction model. RESULTS: This study demonstrated that the ADC value after two cycles of NAC (OR = 1.041, 95% CI (1.002, 1.081); p = 0.037), percentage decrease in E90 (OR = 0.927, 95% CI (0.881, 0.977); p =0.004) and percentage decrease in tumor size (OR = 0.948, 95% CI (0.909, 0.988); p = 0.011) were significantly important for independently predicting pCR. The prediction model yielded AUC of 0.939 and 0.944 in the training cohort and the validation cohort, respectively. CONCLUSION: The combined use of dynamic contrast-enhanced MRI and diffusion-weighted imaging could accurately predict pCR after two cycles of NAC. The prediction model and the nomogram had strong predictive value to NAC.

Predictive value of a reduction in the level of high-density lipoprotein-cholesterol in patients with non-small-cell lung cancer undergoing radical resection and adjuvant chemotherapy: a retrospective observational study.

BACKGROUND: Cancer patients often exhibit chemotherapy-associated changes in serum lipid profiles, however, their prognostic value before and after adjuvant chemotherapy on survival among non-small-cell lung cancer (NSCLC) patients is unknown. METHODS: NSCLC patients undergoing radical resection and subsequent adjuvant chemotherapy from 2013 to 2017 at Sun Yat-sen University Cancer Center were retrospectively reviewed. Fasted serum lipid levels were measured before and after chemotherapy. The optimal lipid cut-off values at baseline and fluctuation were determined using X-tile™. The fluctuations in serum lipid levels and disease-free survival (DFS) were assessed. RESULTS: Serum cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), triglyceride, apolipoprotein (Apo) A-I, and ApoB all significantly increased after adjuvant chemotherapy. X-tile determined 1.52 mmol/L of HDL-C and 0.74 g/L of ApoB as the optimal cut-off values before chemotherapy. Patients with HDL-C ≥ 1.52 mmol/L (median DFS: not reached vs. 26.30 months, P = 0.0005) and a decreased HDL-C level after adjuvant chemotherapy (median DFS: 80.43 vs. 26.12 months, P = 0.0204) had a longer DFS. An HDL-C level that increased by ≥ 0.32 mmol/L after chemotherapy indicated a worse DFS. A high baseline ApoB level were associated with a superior DFS. In the univariate analysis and the multivariate Cox analyses, a high baseline HDL-C level and a HDL-C reduction after adjuvant chemotherapy were independent indicators for superior DFS. High baseline HDL-C was related to N0-1 stage (χ2 = 6.413, P = 0.011), and HDL-C fluctuation was significantly correlated with specific chemotherapy regimens (χ2 = 5.002, P = 0.025). CONCLUSIONS: Adjuvant chemotherapy increased various lipid levels in resected NSCLC patients. A higher HDL-C level before chemotherapy and a reduced HDL-C level after adjuvant chemotherapy were independent predictors of longer DFS in patients with curable NSCLC.

Gemcitabine and APG-1252, a novel small molecule inhibitor of BCL-2/BCL-XL, display a synergistic antitumor effect in nasopharyngeal carcinoma through the JAK-2/STAT3/MCL-1 signaling pathway.

Advanced nasopharyngeal carcinoma (NPC) has a poor prognosis, with an unfavorable response to palliative chemotherapy. Unfortunately, there are few effective therapeutic regimens. Therefore, we require novel treatment strategies with enhanced efficacy. The present study aimed to investigate the antitumor efficacy of APG-1252-M1, a dual inhibitor of BCL-2/BCL-XL, as a single agent and combined with gemcitabine. We applied various apoptotic assays and used subcutaneous transplanted NPC model to assess the in vitro and in vivo antitumor activity. Moreover, phospho-tyrosine kinase array was used to investigate the combined therapy's potential synergistic mechanism. In addition, further validation was performed using immunohistochemistry and western blotting. In vitro, we observed that APG-1252-M1 had moderate antitumor activity toward NPC cells; however, it markedly improved gemcitabine's ability to promote NPC cell apoptosis and suppress invasion, migration, and proliferation. Specifically, APG-1252 plus gemcitabine exhibited even remarkable antitumor activity in vivo. Mechanistically, the drug combination synergistically suppressed NPC by activating caspase-dependent pathways, blocking the phospho (p)-JAK-2/STAT3/MCL-1 signaling pathway, and inhibiting epithelial-mesenchymal transition. In conclusion, the results indicated that the combination of APG-1252 and gemcitabine has synergistic anticancer activities against NPC, providing a promising treatment modality for patients with NPC.

The Diversity and Evolution of Sex Chromosomes in Frogs.

Frogs are ideal organisms for studying sex chromosome evolution because of their diversity in sex chromosome differentiation and sex-determination systems. We review 222 anuran frogs, spanning ~220 Myr of divergence, with characterized sex chromosomes, and discuss their evolution, phylogenetic distribution and transitions between homomorphic and heteromorphic states, as well as between sex-determination systems. Most (~75%) anurans have homomorphic sex chromosomes, with XY systems being three times more common than ZW systems. Most remaining anurans (~25%) have heteromorphic sex chromosomes, with XY and ZW systems almost equally represented. There are Y-autosome fusions in 11 species, and no W-/Z-/X-autosome fusions are known. The phylogeny represents at least 19 transitions between sex-determination systems and at least 16 cases of independent evolution of heteromorphic sex chromosomes from homomorphy, the likely ancestral state. Five lineages mostly have heteromorphic sex chromosomes, which might have evolved due to demographic and sexual selection attributes of those lineages. Males do not recombine over most of their genome, regardless of which is the heterogametic sex. Nevertheless, telomere-restricted recombination between ZW chromosomes has evolved at least once. More comparative genomic studies are needed to understand the evolutionary trajectories of sex chromosomes among frog lineages, especially in the ZW systems.

A single QTL with large effect is associated with female functional virginity in an asexual parasitoid wasp.

During the transition from sexual to asexual reproduction, a suite of reproduction-related sexual traits become superfluous, and may be selected against if costly. Female functional virginity refers to asexual females resisting to mate or not fertilizing eggs after mating. These traits appear to be among the first that evolve during transitions from sexual to asexual reproduction. The genetic basis of female functional virginity remains elusive. Previously, we reported that female functional virginity segregates as expected for a single recessive locus in the asexual parasitoid wasp Asobara japonica. Here, we investigate the genetic basis of this trait by quantitative trait loci (QTL) mapping and candidate gene analyses. Consistent with the segregation of phenotypes, we found a single QTL of large effect, spanning over 4.23 Mb and comprising at least 131 protein-coding genes, of which 15 featured sex-biased expression in the related sexual species Asobara tabida. Two of the 15 sex-biased genes were previously identified to differ between related sexual and asexual population/species: CD151 antigen and nuclear pore complex protein Nup50. A third gene, hormone receptor 4, is involved in steroid hormone mediated mating behaviour. Overall, our results are consistent with a single locus, or a cluster of closely linked loci, underlying rapid evolution of female functional virginity in the transition to asexuality. Once this variant, causing rejection to mate, has swept through a population, the flanking region does not get smaller owing to lack of recombination in asexuals.

Disability Severity and Home-Based Care Quality in Older Adults: The Mediating Effects of Social Support and Caregiver Competence.

BACKGROUND: The lack of adequate medical care, healthcare, and older adult care in remote, low-income, rural Kazakh areas of China is a particular concern that should be prioritized for improvement. PURPOSE: This study was designed to explore the relationship between the variables of disability severity, social support, and caregiver competence and the quality of home-based care in a population of Kazakh older adults with disabilities and to analyze the path between severity of disability and quality of home-based care in this population. METHODS: A cross-sectional survey was conducted on 335 Kazakh older adults with disabilities living in Xinjiang, China, and their primary informal caregivers. Disability severity was assessed using the Activities of Daily Living Scale, caregiver competence was assessed using the Family Caregiver Task Inventory, social support was assessed using the Social Support Rating Scale, and home-based care quality was assessed using the Family Caregiving Consequences Inventory Scale. Path analysis was used to check the effects of other variables on the quality of home-based care. RESULTS: Significant correlations were found among disability severity, caregiver competence, social support, and home-based care quality. Disability severity was shown to have a 29.28% direct effect on home-based care quality and a 70.72% indirect effect through social support and caregiver competence. CONCLUSIONS: The results of this study confirm that better social support and caregiver competence improves the quality of home-based care available to older adults with disabilities. Policymakers should give priority to improving the quality of care provided to community-dwelling older adults with severe disabilities. Furthermore, health management departments should provide informal caregiver training that teaches care and rehabilitation knowledge and skills to improve the competencies of caregivers.

Differential Gene Expression between Fungal Mating Types Is Associated with Sequence Degeneration.

Degenerative mutations in non-recombining regions, such as in sex chromosomes, may lead to differential expression between alleles if mutations occur stochastically in one or the other allele. Reduced allelic expression due to degeneration has indeed been suggested to occur in various sex-chromosome systems. However, whether an association occurs between specific signatures of degeneration and differential expression between alleles has not been extensively tested, and sexual antagonism can also cause differential expression on sex chromosomes. The anther-smut fungus Microbotryum lychnidis-dioicae is ideal for testing associations between specific degenerative signatures and differential expression because 1) there are multiple evolutionary strata on the mating-type chromosomes, reflecting successive recombination suppression linked to mating-type loci; 2) separate haploid cultures of opposite mating types help identify differential expression between alleles; and 3) there is no sexual antagonism as a confounding factor accounting for differential expression. We found that differentially expressed genes were enriched in the four oldest evolutionary strata compared with other genomic compartments, and that, within compartments, several signatures of sequence degeneration were greater for differentially expressed than non-differentially expressed genes. Two particular degenerative signatures were significantly associated with lower expression levels within differentially expressed allele pairs: upstream insertion of transposable elements and mutations truncating the protein length. Other degenerative mutations associated with differential expression included nonsynonymous substitutions and altered intron or GC content. The association between differential expression and allele degeneration is relevant for a broad range of taxa where mating compatibility or sex is determined by genes located in large regions where recombination is suppressed.

Digest: Climate plays marginal role for homomorphic sex chromosome differentiation in common frogs†.

In systems with early stage sex-chromosome evolution, climate gradients can largely explain changes in the sex-determining systems (i.e., genetic or environmental factors). However, in the common frog Rana temporaria, Phillips et al. found that phylogeography, rather than elevation (used as a proxy for climate), was associated with homomorphic sex-chromosome differentiation levels.

No evidence that Y-chromosome differentiation affects male fitness in a Swiss population of common frogs.

The canonical model of sex-chromosome evolution assigns a key role to sexually antagonistic (SA) genes on the arrest of recombination and ensuing degeneration of Y chromosomes. This assumption cannot be tested in organisms with highly differentiated sex chromosomes, such as mammals or birds, owing to the lack of polymorphism. Fixation of SA alleles, furthermore, might be the consequence rather than the cause of recombination arrest. Here we focus on a population of common frogs (Rana temporaria) where XY males with genetically differentiated Y chromosomes (nonrecombinant Y haplotypes) coexist with both XY° males with proto-Y chromosomes (only differentiated from X chromosomes in the immediate vicinity of the candidate sex-determining locus Dmrt1) and XX males with undifferentiated sex chromosomes (genetically identical to XX females). Our study finds no effect of sex-chromosome differentiation on male phenotype, mating success or fathering success. Our conclusions rejoin genomic studies that found no differences in gene expression between XY, XY° and XX males. Sexual dimorphism in common frogs might result more from the differential expression of autosomal genes than from sex-linked SA genes. Among-male variance in sex-chromosome differentiation seems better explained by a polymorphism in the penetrance of alleles at the sex locus, resulting in variable levels of sex reversal (and thus of X-Y recombination in XY females), independent of sex-linked SA genes.

Contemporary blood lead levels of children aged 0-84 months in China: A national cross-sectional study.

Despite the global abundance of studies on children's lead (Pb) exposure, the magnitude of Pb exposure among children across China remains unclear, especially for rural areas. In 2000, Pb was removed from petrol, marking a change in the sources of Pb exposure in China. To better understand children's Pb exposure and inform potential approaches to exposure reduction, we conducted a national blood Pb survey of 31,373 children (0-84 months old) from May 2013 to March 2015, using a multi-stage and multi-strata sampling method. Blood lead levels (BLLs) were tested using graphite furnace atomic absorption spectrometry with a detection limit of 1 µg/L. The results show that Chinese children had a contemporary geometric mean (GM) BLL of 26.7 µg/L, with 8.6% of BLLs exceeding 50 µg/L. Boys had higher BLLs (GM 27.2 µg/L) compared to girls (GM: 25.9 µg/L) (p < 0.001). Children at the age of 0-36 months had a lower PbB (GM 25.7 µg/L) level compared with those aged 36-84 months (GM 27.9 µg/L) (p < 0.001). When taking into account sociodemographic factors, a multivariate logistic regression analysis shows that the odds ratios (OR) of having a BLL of 27 µg/dL (i.e., median BLL of this study) or higher were 1.88 (95% CI: 1.76, 2.02) and 1.35 (95% CI: 1.22, 1.49) for homes using coal and biomass fuels, respectively, compared to those using gas or electricity. Meanwhile, children in homes close to roads were more likely to have BLLs exceeding 27 µg/dL (OR: 1.11, 95% CI: 1.03, 1.20). In China, rural children had higher BLLs compared to urban children. As a result of pediatric exposure to Pb, there were approximately 144 million and 36 million IQ points lost for rural children and urban children, respectively, revealing a disparity of Pb exposure between rural and urban areas in China. Cleaner domestic fuels and improved cooking/heating equipment will reduce contemporary Pb exposure in rural areas. In addition, the association between contemporary BLLs and distance away from roads further suggests that resuspension of legacy soil/dust Pb should not be neglected in future remediation programs and household interventions. As a large scale survey, this study provides evidence for revising the reference value of BLL, improving the guideline for clinical and public health management, and implementing interventions to prevent adverse health outcomes associated with low-level Pb exposure in children.