Dissection of a Down syndrome-associated trisomy to separate the gene dosage-dependent and -independent effects of an extra chromosome.

As an aneuploidy, trisomy is associated with mammalian embryonic and postnatal abnormalities. Understanding the underlying mechanisms involved in mutant phenotypes is broadly important and may lead to new strategies to treat clinical manifestations in individuals with trisomies, such as trisomy 21 [Down syndrome (DS)]. Although increased gene dosage effects because of a trisomy may account for the mutant phenotypes, there is also the possibility that phenotypic consequences of a trisomy can arise because of the presence of a freely segregating extra chromosome with its own centromere, i.e. a 'free trisomy' independent of gene dosage effects. Presently, there are no reports of attempts to functionally separate these two types of effects in mammals. To fill this gap, here we describe a strategy that employed two new mouse models of DS, Ts65Dn;Df(17)2Yey/+ and Dp(16)1Yey/Df(16)8Yey. Both models carry triplications of the same 103 human chromosome 21 gene orthologs; however, only Ts65Dn;Df(17)2Yey/+ mice carry a free trisomy. Comparison of these models revealed the gene dosage-independent impacts of an extra chromosome at the phenotypic and molecular levels for the first time. They are reflected by impairments of Ts65Dn;Df(17)2Yey/+ males in T-maze tests when compared with Dp(16)1Yey/Df(16)8Yey males. Results from the transcriptomic analysis suggest the extra chromosome plays a major role in trisomy-associated expression alterations of disomic genes beyond gene dosage effects. This model system can now be used to deepen our mechanistic understanding of this common human aneuploidy and obtain new insights into the effects of free trisomies in other human diseases such as cancers.

Gross Hematuria Does not Affect the Selection of Nephrectomy Types for Clinical Stage 1 Clear Cell Renal Cell Carcinoma: A Multicenter, Retrospective Cohort Study.

PURPOSE: This study aimed to discuss the correlation between gross hematuria and postoperative upstaging (from T1 to T3a) in patients with cT1 clear cell renal cell carcinoma (ccRCC) and to compare oncologic outcomes of partial nephrectomy (PN) and radical nephrectomy (RN) in patients with gross hematuria. METHODS: A total of 2145 patients who met the criteria were enrolled in the study (including 363 patients with gross hematuria). The least absolute selection and shrinkage operator logistic regression was used to evaluate the risk factor of postoperative pathological upstaging. The propensity score matching (PSM) and stable inverse probability of treatment weighting (IPTW) analysis were used to balance the confounding factors. The Kaplan-Meier analysis and multivariate Cox proportional risk regression model were used to assess the prognosis. RESULTS: Gross hematuria was a risk factor of postoperative pathological upstaging (odds ratio [OR] = 3.96; 95% confidence interval [CI] 2.44-6.42; P < 0.001). After PSM and stable IPTW adjustment, the characteristics were similar in corresponding patients in the PN and RN groups. In the PSM cohort, PN did not have a statistically significant impact on recurrence-free survival (hazard ratio [HR] = 1.48; 95% CI 0.25-8.88; P = 0.67), metastasis-free survival (HR = 1.24; 95% CI 0.33-4.66; P = 0.75), and overall survival (HR = 1.46; 95% CI 0.31-6.73; P = 0.63) compared with RN. The results were confirmed in sensitivity analyses. CONCLUSIONS: Although gross hematuria was associated with postoperative pathological upstaging in patients with cT1 ccRCC, PN should still be the preferred treatment for such patients.

Patients with high nuclear grade pT1-ccRCC are more suitable for radical nephrectomy than partial nephrectomy: a multicenter retrospective study using propensity score.

BACKGROUND: Partial nephrectomy (PN) is usually recommended for T1 stage clear cell renal cell carcinoma (ccRCC) regardless of the nuclear grades. However, the question remains unresolved as to whether PN is non-inferior to RN in patients with T1-ccRCC at higher risk of recurrence. In fact, we found that patients with high nuclear grades treated with PN had poorer prognosis compared with those treated with radical nephrectomy (RN). Therefore, this study was designed to evaluate the associations of PN and RN in the four nuclear grade subsets with oncologic outcomes. METHODS: A retrospective study was conducted in three Chinese urological centers that included 1,714 patients who underwent PN or RN for sporadic, unilateral, pT1, N0, and M0 ccRCC without positive surgical margins and neoadjuvant therapy between 2010 and 2019. Associations of nephrectomy type with local ipsilateral recurrence, distant metastases, and all-cause mortality (ACM) were evaluated using the Kaplan-Meier method and multivariable Cox proportional hazards regression models after overlap weighting (OW). RESULTS: A total of 1675 patients entered the OW cohort. After OW, in comparison to PN, RN associated with a reduced risk of local ipsilateral recurrence in the G2 subset (HR = 0.148, 95% CI 0.046-0.474; p < 0.05), G3 subset (HR = 0.097, 95% CI 0.021-0.455; p < 0.05), and G4 subset (HR = 0.091, 95% CI 0.011-0.736; p < 0.05), and resulting in increased five-year local recurrence-free survival rates of 7.0%, 17.9%, and 36.2%, respectively. An association between RN and a reduced risk of distant metastases in the G4 subset (HR = 0.071, 95% CI 0.016-0.325; p < 0.05), with the five-year distant metastases-free survival rate increasing by 33.1% was also observed. No significant difference in ACM between PN and RN was identified. CONCLUSIONS: Our findings substantiate that opting for RN, as opposed to PN, is more advantageous for local recurrence-free survival and distant metastases-free survival in patients with high nuclear grade (especially G4) pT1-ccRCC. We recommend placing a heightened emphasis on enhancing preoperative nuclear grade assessment, as it can significantly influence the choice of surgical plan. TRIAL REGISTRATION: This study was registered at Chinese Clinical Trial Registry (ID: ChiCTR2200063333).

Retrotransposition creates sloping shores: a graded influence of hypomethylated CpG islands on flanking CpG sites.

Long interspersed elements (LINEs), through both self-mobilization and trans-mobilization of short interspersed elements and processed pseudogenes, have made an indelible impact on the structure and function of the human genome. One consequence is the creation of new CpG islands (CGIs). In fact, more than half of all CGIs in the genome are associated with repetitive DNA, three-quarters of which are derived from retrotransposons. However, little is known about the epigenetic impact of newly inserted CGIs. We utilized a transgenic LINE-1 mouse model and tracked DNA methylation dynamics of individual germline insertions during mouse development. The retrotransposed GFP marker sequence, a strong CGI, is hypomethylated in male germ cells but hypermethylated in somatic tissues, regardless of genomic location. The GFP marker is similarly methylated when delivered into the genome via the Sleeping Beauty DNA transposon, suggesting that the observed methylation pattern may be independent of the mode of insertion. Comparative analyses between insertion- and non-insertion-containing alleles further reveal a graded influence of the retrotransposed CGI on flanking CpG sites, a phenomenon that we described as "sloping shores." Computational analyses of human and mouse methylomic data at single-base resolution confirm that sloping shores are universal for hypomethylated CGIs in sperm and somatic tissues. Additionally, the slope of a hypomethylated CGI can be affected by closely positioned CGI neighbors. Finally, by tracing sloping shore dynamics through embryonic and germ cell reprogramming, we found evidence of bookmarking, a mechanism that likely determines which CGIs will be eventually hyper- or hypomethylated.

Mitochondrial phylogeny, divergence history and high-altitude adaptation of grassland caterpillars (Lepidoptera: Lymantriinae: Gynaephora) inhabiting the Tibetan Plateau.

Grassland caterpillars (Lepidoptera: Lymantriinae: Gynaephora) are the most important pests in alpine meadows of the Tibetan Plateau (TP) and have well adapted to high-altitude environments. To further understand the evolutionary history and their adaptation to the TP, we newly determined seven complete TP Gynaephora mitogenomes. Compared to single genes, whole mitogenomes provided the best phylogenetic signals and obtained robust results, supporting the monophyly of the TP Gynaephora species and a phylogeny of Arctiinae + (Aganainae + Lymantriinae). Incongruent phylogenetic signals were found among single mitochondrial genes, none of which recovered the same phylogeny as the whole mitogenome. We identified six best-performing single genes using Shimodaira-Hasegawa tests and found that the combinations of rrnS and either cox1 or cox3 generated the same phylogeny as the whole mitogenome, indicating the phylogenetic potential of these three genes for future evolutionary studies of Gynaephora. The TP Gynaephora species were estimated to radiate on the TP during the Pliocene and Quaternary, supporting an association of the diversification and speciation of the TP Gynaephora species with the TP uplifts and associated climate changes during this time. Selection analyses revealed accelerated evolutionary rates of the mitochondrial protein-coding genes in the TP Gynaephora species, suggesting that they accumulated more nonsynonymous substitutions that may benefit their adaptation to high altitudes. Furthermore, signals of positive selection were detected in nad5 of two Gynaephora species with the highest altitude-distributions, indicating that this gene may contribute to Gynaephora's adaptation to divergent altitudes. This study adds to the understanding of the TP Gynaephora evolutionary relationships and suggests a link between mitogenome evolution and ecological adaptation to high-altitude environments in grassland caterpillars.

Genetic dissection of the Down syndrome critical region.

Down syndrome (DS), caused by trisomy 21, is the most common chromosomal disorder associated with developmental cognitive deficits. Despite intensive efforts, the genetic mechanisms underlying developmental cognitive deficits remain poorly understood, and no treatment has been proven effective. The previous mouse-based experiments suggest that the so-called Down syndrome critical region of human chromosome 21 is an important region for this phenotype, which is demarcated by Setd4/Cbr1 and Fam3b/Mx2. We first confirmed the importance of the Cbr1-Fam3b region using compound mutant mice, which carry a duplication spanning the entire human chromosome 21 orthologous region on mouse chromosome 16 [Dp(16)1Yey] and Ms1Rhr. By dividing the Setd4-Mx2 region into complementary Setd4-Kcnj6 and Kcnj15-Mx2 intervals, we started an unbiased dissection through generating and analyzing Dp(16)1Yey/Df(16Setd4-Kcnj6)Yey and Dp(16)1Yey/Df(16Kcnj15-Mx2)Yey mice. Surprisingly, the Dp(16)1Yey-associated cognitive phenotypes were not rescued by either deletion in the compound mutants, suggesting the possible presence of at least one causative gene in each of the two regions. The partial rescue by a Dyrk1a mutation in a compound mutant carrying Dp(16)1Yey and the Dyrk1a mutation confirmed the causative role of Dyrk1a, whereas the absence of a similar rescue by Df(16Dyrk1a-Kcnj6)Yey in Dp(16)1Yey/Df(16Dyrk1a-Kcnj6)Yey mice demonstrated the importance of Kcnj6. Our results revealed the high levels of complexities of gene actions and interactions associated with the Setd4/Cbr1-Fam3b/Mx2 region as well as their relationship with developmental cognitive deficits in DS.

Ultrafast Self-Limited Growth of Strictly Monolayer WSe2 Crystals.

The controllable synthesis of uniform tungsten diselenide (WSe2 ) is crucial for its emerging applications due to the high sensitivity of its extraordinary physicochemical properties to its layer numbers. However, undesirable multilayer regions inevitably form during the fabrication of WSe2 via the traditional chemical vapor deposition process resulted from the lack of significantly energetically favorable competition between layer accumulation and size expansion. This work innovatively introduces Cu to occupy the hexagonal site positioned at the center of the six membered ring of the WSe2 surface, thus filtrates the undesired reaction path through precisely thermodynamical control and achieves self-limited growth WSe2 crystals. The as-obtained WSe2 crystals are characterized as strictly single-layer over the entire wafer. Furthermore, the strictly self-limited growth behavior can achieve the "win-win" cooperation with the synthesis efficiency. The fastest growth (≈15 times of the growth rate in the previous work) of strictly monolayer WSe2 crystals thus far is realized due to the high-efficiency simultaneous selenization process. The as-proposed ultrafast Cu-assisted self-limited growth method opens a new avenue to fabricate strictly monolayer transition metal dichalcogenides crystals and further promotes their practical applications in the future industrial applications.

Mouse-based genetic modeling and analysis of Down syndrome.

INTRODUCTION: Down syndrome (DS), caused by human trisomy 21 (Ts21), can be considered as a prototypical model for understanding the effects of chromosomal aneuploidies in other diseases. Human chromosome 21 (Hsa21) is syntenically conserved with three regions in the mouse genome. SOURCES OF DATA: A review of recent advances in genetic modeling and analysis of DS. Using Cre/loxP-mediated chromosome engineering, a substantial number of new mouse models of DS have recently been generated, which facilitates better understanding of disease mechanisms in DS. AREAS OF AGREEMENT: Based on evolutionary conservation, Ts21 can be modeled by engineered triplication of Hsa21 syntenic regions in mice. The validity of the models is supported by the exhibition of DS-related phenotypes. AREAS OF CONTROVERSY: Although substantial progress has been made, it remains a challenge to unravel the relative importance of specific candidate genes and molecular mechanisms underlying the various clinical phenotypes. GROWING POINTS: Further understanding of mechanisms based on data from mouse models, in parallel with human studies, may lead to novel therapies for clinical manifestations of Ts21 and insights to the roles of aneuploidies in other developmental disorders and cancers.

The Synthesis and Evaluation of Arctigenin Amino Acid Ester Derivatives.

The use of arctigenin (ARG), a traditional medicine with many pharmacological activities, has been restricted due to its poor solubility in water. Five amino acid derivatives of ARG have been synthesized using glycine, o-alanine, valine, leucine, and isoleucine, which have t-butyloxy carbonyl (BOC) as a protective group. In this study, we examined the effects of removing these protective groups. The results showed that the amino acid derivatives have better solubility and nitrite-clearing ability than ARG. Among the compounds tested, the amino acid derivatives without protective group were the best. Based on these results, ARG and its two amino acid derivatives without protective group (ARG8, ARG10) were selected to evaluate their anti-tumor activity in vivo at a dosage of 40 mg/kg. The results indicated that ARG8 and ARG10 both exhibit more anti-tumor activity than ARG in H22 tumor-bearing mice. The tumor inhibition rates of ARG8 and ARG10 were 69.27 and 43.58%, which was much higher than ARG. Furthermore, the mice treated with these compounds exhibited less damage to the liver, kidney and immune organs compared with the positive group. Furthermore, ARG8 and ARG10 improved the serum cytokine levels significantly compared to ARG. In brief, this study provides a method to improve the water solubility of drugs, and we also provide a reference basis for new drug development.

[Spectrophotometric Determination of the Amount of Zinc on the Imprint Left on Hands by Zinc Coatings with 5-Br-PADAP as the Chromogenic Reagent].

Spectrophotometric determination of the amount of zinc on the imprint left on hands by zinc coatings with 2-(5-Bromo-2-pyridylazo)-5-(diethylamino)-phenol (5-Br-PADAP) as a chromogenic reagent has been studied in this paper. The effect of reaction conditions including volume and pH of buffer solution as well as the volume of chromogenic reagent on the determination has also been studied. On the optimized condition, the standard curve of zinc has been established and the amount of zinc on the imprint left on hands by zinc coatings with different contact time and time elapse has been determined separately. As the results shown, the optimized reaction condition is 4 mL of boric acid and borax buffer solution(pH 8.0), 0.2 mL of 5-Br-PADAP with the concentration of 1 g·L(-1) and 1 mL of Triton-X-100 with volume fraction of 10%. Under this circumstance, high linearity of zinc is followed between 0 and 14 µg and the regression equation of zinc is y=1.851 34x+0.002 29. The amount of zinc on the imprint left on hands by zinc coatings, ranging from 0.425 to 2.377 µg·cm(-2), increases with contact time from 10 second to 5 min and varies insignificantly from 5 to 10 min. The amount of zinc left on hands declines sharply with time elapse from 0 h to 2 h, and then slowly from 2 to 7 h. The amount of zinc within 7 h is only 0.188 µg·cm(-2), which is 90% lower than that of 0 h. Therefore, it is suggested that the trace metal detection should be conducted as soon as possible. Besides, the amount of zinc on the imprint left on hands by zinc coatings with different time elapse is not entirely comply with the intensity of imprint left by zinc coatings. This demonstrates that the amount of zinc on hands is not the only factor influencing the intensity of imprint on hands with different time elapse. Additionally, it also proves the hypothesis that zinc in the complex of zinc and protein can be captured and bonded by 5-Br-PADAP resorting to a stronger chelating capacity in the experiment for the first time. The application of the combined methods in a macro and micro view is useful for study in mechanism of influencing factors in trace metal detection, which lays foundations l for further researches.

Application of an improved proteomics method for abundant protein cleanup: molecular and genomic mechanisms study in plant defense.

High abundance proteins like ribulose-1,5-bisphosphate carboxylase oxygenase (Rubisco) impose a consistent challenge for the whole proteome characterization using shot-gun proteomics. To address this challenge, we developed and evaluated Polyethyleneimine Assisted Rubisco Cleanup (PARC) as a new method by combining both abundant protein removal and fractionation. The new approach was applied to a plant insect interaction study to validate the platform and investigate mechanisms for plant defense against herbivorous insects. Our results indicated that PARC can effectively remove Rubisco, improve the protein identification, and discover almost three times more differentially regulated proteins. The significantly enhanced shot-gun proteomics performance was translated into in-depth proteomic and molecular mechanisms for plant insect interaction, where carbon re-distribution was used to play an essential role. Moreover, the transcriptomic validation also confirmed the reliability of PARC analysis. Finally, functional studies were carried out for two differentially regulated genes as revealed by PARC analysis. Insect resistance was induced by over-expressing either jacalin-like or cupin-like genes in rice. The results further highlighted that PARC can serve as an effective strategy for proteomics analysis and gene discovery.

The prevalence of antinuclear antibodies in the general population of china: a cross-sectional study.

BACKGROUND: The incidence of autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and primary biliary cirrhosis has increased significantly in China. Information about the susceptibility or potential of autoimmune diseases in the general population is lacking. OBJECTIVE: To explore the prevalence of antinuclear antibody (ANA) and its specificities in the general population in China. METHODS: Twenty thousand nine hundred seventy sera samples were taken from the physical examination center in Baoding, China. Indirect immunofluorescence and line immunoassays were used to detect ANA and its specificities, respectively. RESULTS: Samples from females had a higher prevalence of ANA than samples from males (χ(2) = 278.55; P < 0.01). For both sexes, the prevalence of ANA positively correlated with age and there were significant differences among different age groups at 10-year intervals, except the 80 years group (P < 0.05). One thousand two hundred forty-three ANA-positive samples were further analyzed with line immunoassays. There was a significant difference among age groups and between sex groups in terms of the specific autoantibodies (P < 0.01). The autoantibodies with the top-3 positive frequencies were anti-Ro-52, anti-M2, and anti-SSA. CONCLUSIONS: There was a high prevalence of ANA positivity in the general Chinese population that seemed to be influenced by sex and age and correlated with specific autoantibodies.

Identification of molecular subtypes and diagnostic model in clear cell renal cell carcinoma based on collagen-related genes may predict the response of immunotherapy.

Background: Collagen represents a prominent constituent of the tumor's extracellular matrix (ECM). Nonetheless, its correlation with the molecular subtype attributes of clear cell renal cell carcinoma (ccRCC) remains elusive. Our objective is to delineate collagen-associated molecular subtypes and further construct diagnostic model, offering insights conducive to the precise selection of ccRCC patients for immunotherapeutic interventions. Methods: We performed unsupervised non-negative matrix factorization (NMF) analysis on TCGA-KIRC samples, utilizing a set of 33 collagen-related differentially expressed genes (33CRDs) for clustering. Our analysis encompassed evaluations of subtype-associated differences in pathways, immune profiles, and somatic mutations. Through weighted gene co-expression network analysis (WGCNA) and four machine learning algorithms, two core genes were found and a diagnostic model was constructed. This was subsequently validated in a clinical immunotherapy cohort. Single cell sequencing analysis and experiments demonstrated the role of core genes in ccRCC. Finally, we also analyzed the roles of MMP9 and SCGN in pan-cancer. Results: We described two novel collagen related molecular subtypes in ccRCC, designated subtype 1 and subtype 2. Compared with subtype 1, subtype 2 showed more infiltration of immune components, but had a higher TIDE (tumor immunedysfunctionandexclusion) score and increased levels of immune checkpoint molecules. Furthermore, reduced prognosis for subtype 2 was a consistent finding in both high and low mutation load subgroups. MMP9 and SCGN were identified as key genes for distinguishing subtype 1 and subtype 2. The diagnostic model based on them could better distinguish the subtype of patients, and the differentiated patients had different progression free survival (PFS) in the clinical immunotherapy cohort. MMP9 was predominantly expressed in macrophages and has been extensively documented in the literature. Meanwhile, SCGN, which was overexpressed in tumor cells, underwent experimental validation, emphasizing its role in ccRCC. In various cancers, MMP9 and SCGN were associated with immune-related molecules and immune cells. Conclusion: Our study identifies two collagen-related molecular subtypes of ccRCC and constructs a diagnostic model to help select appropriate patients for immunotherapy.

SARS-CoV-2 Infection Causes Heightened Disease Severity and Mortality in a Mouse Model of Down Syndrome.

Recent epidemiological studies suggest that individuals with Down syndrome are more susceptible to SARS-CoV-2 infection and have higher rates of hospitalization and mortality than the general population. However, the main drivers behind these disparate health outcomes remain unknown. Herein, we performed experimental infections with SARS-CoV-2 in a well-established mouse model of Down syndrome. We observed similar SARS-CoV-2 replication kinetics and dissemination in the primary and secondary organs between mice with and without Down syndrome, suggesting that both groups have similar susceptibilities to SARS-CoV-2 infection. However, Down syndrome mice exhibited more severe disease as defined by clinical features including symptoms, weight loss, pulmonary function, and survival of mice. We found that increased disease severity in Down syndrome mice could not be attributed solely to increased infectivity or a more dramatic pro-inflammatory response to infection. Rather, results from RNA sequencing suggested that differences in the expression of genes from other physiological pathways, such as deficient oxidative phosphorylation, cardiopulmonary dysfunction, and deficient mucociliary clearance in the lungs may also contribute to heightened disease severity and mortality in Down syndrome mice following SARS-CoV-2 infection.

[Tiaoshen Jieyu acupuncture combined with sertraline hydrochloride tablet for post-stoke depression: a randomized controlled trial].

OBJECTIVE: To compare the clinical efficacy between Tiaoshen Jieyu acupuncture (acupuncture for regulating mind and relieving depression) combined with sertraline hydrochloride tablet and simple sertraline hydrochloride tablet for post-stroke depression (PSD). METHODS: A total of 76 patients with PSD were randomized into an observation group (38 cases, 6 cases dropped off) and a control group (38 cases, 4 cases dropped off). Both groups were treated with conventional treatment i.e. controlling blood pressure and anti-inflammation. Sertraline hydrochloride tablet was given orally in the control group, 20 mg a time, once a day. On the basis of the treatment in the control group, Tiaoshen Jieyu acupuncture was applied at Baihui (GV 20), Yintang (GV 24+), Neiguan (PC 6), Taichong (LR 3), etc. in the observation group, Baihui (GV 20) and Yintang (GV 24+) were connected to electroacupuncture, with disperse-dense wave, 2 Hz/100 Hz in frequency, 30 min a time, once a day, 6 times a week. Treatment of 8 weeks was required in both groups. Before and after treatment, the scores of Hamilton depression scale (HAMD), National Institutes of Health stroke scale (NIHSS), Barthel index (BI) and Pittsburgh sleep quality index (PSQI) were observed respectively, the therapeutic efficacy and rate of adverse reactions were evaluated in the two groups. RESULTS: After treatment, the scores of HAMD, NIHSS and PSQI were lower while BI scores were higher than those before treatment in both groups (P<0.05); the scores of HAMD, NIHSS and PSQI in the observation group were lower while BI score was higher than those in the control group (P<0.05). The total effective rate was 93.8% (30/32) in the observation group, which was higher than 70.6% (24/34) in the control group (P<0.05). The rate of adverse reactions was 9.4% (3/32) in the observation group, which was lower than 32.4% (11/34) in the control group (P<0.05). CONCLUSION: Tiaoshen Jieyu acupuncture combined with sertraline hydrochloride tablet can improve the depression degree, neurological function, activity of daily living and sleep quality in patients with post-stroke depression, the clinical efficacy is superior to simple sertraline hydrochloride, and can alleviate the adverse reactions caused by medication.

Differential gene expression patterns between the head and thorax of Gynaephora aureata are associated with high-altitude adaptation.

Grassland caterpillars (Lepidoptera: Erebidae: Gynaephora) are important pests in alpine meadows of the Qinghai-Tibetan Plateau (QTP). These pests have morphological, behavioral, and genetic adaptations for survival in high-altitude environments. However, mechanisms underlying high-altitude adaptation in QTP Gynaephora species remain largely unknown. Here, we performed a comparative analysis of the head and thorax transcriptomes of G. aureata to explore the genetic basis of high-altitude adaptation. We detected 8,736 significantly differentially expressed genes (sDEGs) between the head and thorax, including genes related to carbohydrate metabolism, lipid metabolism, epidermal proteins, and detoxification. These sDEGs were significantly enriched in 312 Gene Ontology terms and 16 KEGG pathways. We identified 73 pigment-associated genes, including 8 rhodopsin-associated genes, 19 ommochrome-associated genes, 1 pteridine-associated gene, 37 melanin-associated genes, and 12 heme-associated genes. These pigment-associated genes were related to the formation of the red head and black thorax of G. aureata. A key gene, yellow-h, in the melanin pathway was significantly upregulated in the thorax, suggesting that it is related to the formation of the black body and contributed to the adaptation of G. aureata to low temperatures and high ultraviolet radiation in the QTP. Another key gene, cardinal, in the ommochrome pathway was significantly upregulated in the head and may be related to red warning color formation. We also identified 107 olfactory-related genes in G. aureata, including genes encoding 29 odorant-binding proteins, 16 chemosensory proteins, 22 odorant receptor proteins, 14 ionotropic receptors, 12 gustatory receptors, 12 odorant degrading enzymes, and 2 sensory neuron membrane proteins. Diversification of olfactory-related genes may be associated with the feeding habits of G. aureata, including larvae dispersal and searching for plant resources available in the QTP. These results provide new insights into high-altitude adaptation of Gynaephora in the QTP and may contribute to the development of new control strategies for these pests.

Characterization of Osmads6-5, a null allele, reveals that OsMADS6 is a critical regulator for early flower development in rice (Oryza sativa L.).

AGL6-clade genes are a subfamily of MADS-box genes and preferentially expressed in floral organs. OsMADS6 and OsMADS17 are two AGL6-like genes in rice. OsMADS17 has been shown to play a minor role in floral development and appears to result from a duplication of OsMADS6. OsMADS6 was initially named as MFO1 for mosaic floral organs based on its moderate mutant phenotypes. So far, four moderate or weak mutant alleles of OsMADS6 have been described, providing valuable insights into its role in flower development. Here, we report a null allele of OsMADS6 (Osmads6-5), which exhibited a strong mutant phenotype in spikelet without affecting vegetative traits, causing all floral organs except lemma homeotically transformed into lemma-like organs (LLOs) as well as an indeterminate floral meristem, thus resulting in a mutant floret consisting of reiterating whorls of lemma and LLOs. In consistently, over-expression of OsMADS6 led to additional lodicule-, stamen- and carpel-like organs. Expression analysis showed that OsMADS6 controls the formation of the incipient primordia of lodicule, stamen and carpel via regulating the expression of class B, C and SEP-like MADS-box genes. Taken together, our results revealed that OsMADS6 acts as a critical regulator for early flower development in rice and provide novel insights into the molecular mechanism of OsMADS6.

Hearing impairment in murine model of Down syndrome.

Hearing impairment is a cardinal feature of Down syndrome (DS), but its clinical manifestations have been attributed to multiple factors. Murine models could provide mechanistic insights on various causes of hearing loss in DS. To investigate mechanisms of hearing loss in DS in the absence of the cadherin 23 mutation, we backcrossed our DS mice, Dp(16)1Yey, onto normal-hearing CBA/J mice and evaluated their auditory function. Body weights of wild type (WT) and DS mice were similar at 3-months of age, but at 9-months, WT weighed 30% more than DS mice. Distortion product otoacoustic emissions (DPOAE), a test of sensory outer hair cell (OHC) function negatively impacted by conductive hearing loss, were reduced in amplitude and sensitivity across all frequencies in DS mice. The middle ear space in DS mice appeared normal with no evidence of infection. MicroCT structural imaging of DS temporal bones revealed a smaller tympanic membrane diameter, oval window, and middle ear space and localized thickening of the bony otic capsule, but no gross abnormalities of the middle ear ossicles. Histological analysis of the cochlear and vestibular sensory epithelium revealed a normal density of cochlear and vestibular hair cells; however, the cochlear basal membrane was approximately 0.6 mm shorter in DS than WT mice so that the total number of hair cells was greater in WT than DS mice. In DS mice, the early and late peaks in the auditory brainstem response (ABR), reflecting neural responses from the cochlear auditory nerve followed by subsequent neural centers in the brainstem, were reduced in amplitude and ABR thresholds were elevated to a similar degree across all frequencies, consistent with a conductive hearing impairment. The latency of the peaks in the ABR waveform were longer in DS than WT mice when compared at the same intensity; however, the latency delays disappeared when the data were compared at the same intensity above thresholds to compensate for the conductive hearing loss. Future studies using wideband tympanometry and absorbance together with detailed histological analysis of the middle ear could illuminate the nature of the conductive hearing impairment in DS mice.