A time-resolved multi-omics atlas of transcriptional regulation in response to high-altitude hypoxia across whole-body tissues.

High-altitude hypoxia acclimatization requires whole-body physiological regulation in highland immigrants, but the underlying genetic mechanism has not been clarified. Here we use sheep as an animal model for low-to-high altitude translocation. We generate multi-omics data including whole-genome sequences, time-resolved bulk RNA-Seq, ATAC-Seq and single-cell RNA-Seq from multiple tissues as well as phenotypic data from 20 bio-indicators. We characterize transcriptional changes of all genes in each tissue, and examine multi-tissue temporal dynamics and transcriptional interactions among genes. Particularly, we identify critical functional genes regulating the short response to hypoxia in each tissue (e.g., PARG in the cerebellum and HMOX1 in the colon). We further identify TAD-constrained cis-regulatory elements, which suppress the transcriptional activity of most genes under hypoxia. Phenotypic and transcriptional evidence indicate that antenatal hypoxia could improve hypoxia tolerance in offspring. Furthermore, we provide time-series expression data of candidate genes associated with human mountain sickness (e.g., BMPR2) and high-altitude adaptation (e.g., HIF1A). Our study provides valuable resources and insights for future hypoxia-related studies in mammals.

Series of Viologen-Based Metal-Organic Polyhedra with Photo/Electrochromic Behavior for Inkless Printing and UV Detection.

The fabrication of molecular crystalline materials with fast, multistimuli-responsive behavior and the construction of the corresponding structure-activity relationship are of extraordinary significance for the development of smart materials. In this context, three multistimuli-responsive functional metal-organic polyhedra (MOP), {[Dy2(bcbp)3(NO3)1.5(H2O)7]·Cl4.2·(NO3)0.3·H2O}n (1), {[Dy2(bcbp)4(H2O)8]Cl6}n (2), and {[Eu2(bcbp)4(H2O)10]Cl6·H2O}n (3; bcbp = 1,1'-bis(4-carboxyphenyl)-4,4'-bipyridinium), were successfully prepared and characterized. All of the compounds exhibit rapid and reversible photochromic and electrochromic dual-responsive behaviors. Furthermore, benefiting from the well-defined crystal structure and different responsive behaviors, the photoinduced electron transfer (PIET) process and structure-activity relationship were explored. In addition, considering the excellent photochromic performance, function filter paper and smart organic glass were successfully prepared and used for ink-free printing and UV light detection.

The characterization and comorbidities of heterozygous Bardet-Biedl syndrome carriers.

Introduction: Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder with clinical features of retinal dystrophy, obesity, postaxial polydactyly, renal anomalies, learning disabilities, hypogonadism, and genitourinary abnormalities. Nevertheless, previous studies on the phenotypic traits of BBS heterozygous carriers have generated inconclusive results. The aim of our study was to investigate the impact of BBS heterozygosity on carriers when compared to non-carriers within the Taiwanese population. Materials and Methods: This study follows a hospital-based case-control design. We employed the Taiwan Biobank version 2 (TWBv2) array to identify three specific loci associated with BBS (rs773862084, rs567573386, and rs199910690). In total, 716 patients were included in the case group, and they were compared to a control group of 2,864 patients who lacked BBS alleles. The control group was selected through gender and age matching at a ratio of 1:4. The association between BBS-related loci and comorbidity was assessed using logistic regression models. Results: We found that BBS heterozygous carriers exhibited a significant association with elevated BMI levels, especially the variant rs199910690 in MKS1 (p=0.0037). The prevalence of comorbidities in the carriers' group was not higher than that in the non-carriers' group. Besides, the average values of the biochemistry data showed no significant differences, except for creatinine level. Furthermore, we conducted a BMI-based analysis to identify specific risk factors for chronic kidney disease (CKD). Our findings revealed that individuals carrying the CA/AA genotype of the BBS2 rs773862084 variant or the CT/TT genotype of the MKS1 rs199910690 variant showed a reduced risk of developing CKD, irrespective of their BMI levels. When stratified by BMI level, obese males with the MKS1 rs199910690 variant and obese females with the BBS2 rs773862084 variant exhibited a negative association with CKD development. Conclusion: We found that aside from the association with overweight and obesity, heterozygous BBS mutations did not appear to increase the predisposition of individuals to comorbidities and metabolic diseases. To gain a more comprehensive understanding of the genetic susceptibility associated with Bardet-Biedl Syndrome (BBS), further research is warranted.

Single-cell transcriptome and metagenome profiling reveals the genetic basis of rumen functions and convergent developmental patterns in ruminants.

The rumen undergoes developmental changes during maturation. To characterize this understudied dynamic process, we profiled single-cell transcriptomes of about 308,000 cells from the rumen tissues of sheep and goats at 17 time points. We built comprehensive transcriptome and metagenome atlases from early embryonic to rumination stages, and recapitulated histomorphometric and transcriptional features of the rumen, revealing key transitional signatures associated with the development of ruminal cells, microbiota, and core transcriptional regulatory networks. In addition, we identified and validated potential cross-talk between host cells and microbiomes and revealed their roles in modulating the spatiotemporal expression of key genes in ruminal cells. Cross-species analyses revealed convergent developmental patterns of cellular heterogeneity, gene expression, and cell-cell and microbiome-cell interactions. Finally, we uncovered how the interactions can act upon the symbiotic rumen system to modify the processes of fermentation, fiber digestion, and immune defense. These results significantly enhance understanding of the genetic basis of the unique roles of rumen.

Treatment outcomes of mucosal melanoma of the head and neck: Analysis of 190 cases from a single institution.

Objectives: To analyze the treatment outcomes and prognostic factors of mucosal melanoma of the head and neck (MMHN) from a single institution. Methods: From December 1989 to November 2018, 190 patients diagnosed with MMHN were included. Survival analysis was performed using the Kaplan-Meier method for univariate analysis with a log-rank test for significance and Cox regression for multivariate analysis. Results: With a median follow-up time of 43.5 months, 126 (68.5%) patients died. The median DSS was 35 months. The 3- and 5-year disease-specific survival (DSS) rates were 48.1% and 33.7%, respectively. The median overall survival (OS) was 34 months. The 3- and 5-year OS rates were 47.0% and 32.9%, respectively. In univariate analysis, the T3 stage, received surgery, R0 resection, and combined therapy (surgery+biotherapy/biochemotherapy) were significantly associated with better survival. Multivariable Cox regression analysis revealed that the T4 stage (HR = 1.692; 95% CI, 1.175-2.438; p = .005) and the N1 stage (HR = 1.600; 95% CI, 1.023-2.504; p = .039) were strong prognostic factors for poor survival, and that combined therapy (surgery+biotherapy/biochemotherapy) was a strong prognostic factor for better survival outcome (HR = 0.563; 95% CI, 0.354-0.896; p = .015). Conclusion: The prognosis of MMHN remains poor. Systemic treatment is warranted to reduce MMHN progression. Surgery combined with biotherapy may improve survival.

Whole-body adipose tissue multi-omic analyses in sheep reveal molecular mechanisms underlying local adaptation to extreme environments.

The fat tail of sheep is an important organ that has evolved to adapt to extreme environments. However, the genetic mechanisms underlying the fat tail phenotype remain poorly understood. Here, we characterize transcriptome and lipidome profiles and morphological changes in 250 adipose tissues from two thin-tailed and three fat-tailed sheep populations in summer and winter. We implement whole-genome selective sweep tests to identify genetic variants related to fat-tails. We identify a set of functional genes that show differential expression in the tail fat of fat-tailed and thin-tailed sheep in summer and winter. These genes are significantly enriched in pathways, such as lipid metabolism, extracellular matrix (ECM) remodeling, molecular transport, and inflammatory response. In contrast to thin-tailed sheep, tail fat from fat-tailed sheep show slighter changes in adipocyte size, ECM remodeling, and lipid metabolism, and had less inflammation in response to seasonal changes, indicating improved homeostasis. Whole-genome selective sweep tests identify genes involved in preadipocyte commitment (e.g., BMP2, PDGFD) and terminal adipogenic differentiation (e.g., VEGFA), which could contribute to enhanced adipocyte hyperplasia. Altogether, we establish a model of regulatory networks regulating adipose homeostasis in sheep tails. These findings improve our understanding of how adipose homeostasis is maintained, in response to extreme environments in animals.

Oridonin employs interleukin 1 receptor type 2 to treat noise-induced hearing loss by blocking inner ear inflammation.

NOD-like receptor protein 3 (NLRP3) inflammasomes trigger the inflammatory cascades and participate in various inflammatory diseases, including noise-induced hearing loss (NIHL) caused by oxidative stress. Recently, the anti-inflammatory traditional medicine oridonin (Ori) has been reported to provide hearing protection in mice after noise exposure by blocking the NLRP3-never in mitosis gene A-related kinase 7 (NEK7)-inflammasome complex assembly. Using RNA sequencing analysis, we further elucidated that interleukin 1 receptor type 2 (IL1R2) may be another crucial factor regulated by Ori to protect NIHL. We observed that IL1R2 expression was localized in spiral ganglion neurons, inner and outer hair cells, in Ori-treated mouse cochleae. Additionally, we confirmed that ectopic overexpression of IL1R2 in the inner ears of healthy mice using an adeno-associated virus delivery system significantly reduced noise-induced ribbon synapse lesions and hearing loss by blocking the "cytokine storm" in the inner ear. This study provides a novel theoretical foundation for guiding the clinical treatment of NIHL.

Nickel(II)-catalyzed highly selective 1,2-diborylation of non-activated monosubstituted alkenes.

A practical method for 1,2-diborylation of non-activated monosubstituted alkenes via nickel catalysis has been developed. The protocol features high functional group tolerance and can be applied for the formal synthesis of drugs and modification of natural product derivatives. Preliminary mechanistic studies imply the involvement of a Ni(II) catalytic cycle.

High-Density Genomic Characterization of Native Croatian Sheep Breeds.

A recent comprehensive genomic analysis based on 50K SNP profiles has shown that the regional Balkan sheep populations have considerable genetic overlap but are distinctly different from surrounding breeds. All eight Croatian sheep breeds were represented by a small number of individuals per breed. Here, we genotyped 220 individuals representing the native Croatian sheep breeds (Istrian Sheep, Krk Island Sheep, Cres Island Sheep, Rab Island Sheep, Lika Pramenka, Pag Island Sheep, Dalmatian Pramenka, Dubrovnik Sheep) and mouflon using the Ovine Infinium® HD SNP BeadChip (606,006 SNPs). In addition, we included publicly available Balkan Pramenka and other Mediterranean sheep breeds. Our analyses revealed the complex population structure of Croatian sheep breeds and their origin and geographic barriers (island versus mainland). Migration patterns confirmed the historical establishment of breeds and the pathways of gene flow. Inbreeding coefficients (FROH>2 Mb) between sheep populations ranged from 0.025 to 0.070, with lower inbreeding coefficients observed in Dalmatian Pramenka and Pag Island Sheep and higher inbreeding in Dubrovnik sheep. The estimated effective population size ranged from 61 to 1039 for Krk Island Sheep and Dalmatian Pramenka, respectively. Higher inbreeding levels and lower effective population size indicate the need for improved conservation management to maintain genetic diversity in some breeds. Our results will contribute to breeding and conservation strategies of native Croatian sheep breeds.

Genomic analyses of wild argali, domestic sheep, and their hybrids provide insights into chromosome evolution, phenotypic variation, and germplasm innovation.

Understanding the genetic mechanisms of phenotypic variation in hybrids between domestic animals and their wild relatives may aid germplasm innovation. Here, we report the high-quality genome assemblies of a male Pamir argali (O ammon polii, 2n = 56), a female Tibetan sheep (O aries, 2n = 54), and a male hybrid of Pamir argali and domestic sheep, and the high-throughput sequencing of 425 ovine animals, including the hybrids of argali and domestic sheep. We detected genomic synteny between Chromosome 2 of sheep and two acrocentric chromosomes of argali. We revealed consistent satellite repeats around the chromosome breakpoints, which could have resulted in chromosome fusion. We observed many more hybrids with karyotype 2n = 54 than with 2n = 55, which could be explained by the selfish centromeres, the possible decreased rate of normal/balanced sperm, and the increased incidence of early pregnancy loss in the aneuploid ewes or rams. We identified genes and variants associated with important morphological and production traits (e.g., body weight, cannon circumference, hip height, and tail length) that show significant variations. We revealed a strong selective signature at the mutation (c.334C > A, p.G112W) in TBXT and confirmed its association with tail length among sheep populations of wide geographic and genetic origins. We produced an intercross population of 110 F2 offspring with varied number of vertebrae and validated the causal mutation by whole-genome association analysis. We verified its function using CRISPR-Cas9 genome editing. Our results provide insights into chromosomal speciation and phenotypic evolution and a foundation of genetic variants for the breeding of sheep and other animals.

Perylene Diimide-Fused Dithiophenepyrroles with Different End Groups as Acceptors for Organic Photovoltaics.

In this study, we synthesized four new A-DA'D-A acceptors (where A and D represent acceptor and donor chemical units) incorporating perylene diimide units (A') as their core structures and presenting various modes of halogenation and substitution of the functional groups at their end groups (A). In these acceptors, by fusing dithiophenepyrrole (DTP) moieties (D) to the helical perylene diimide dimer (hPDI) to form fused-hPDI (FhPDI) cores, we could increase the D/A' oscillator strength in the cores and, thus, the intensity of intramolecular charge transfer (ICT), thereby enhancing the intensity of the absorption bands. With four different end group units─IC2F, IC2Cl, IO2F, and IO2Cl─tested, each of these acceptor molecules exhibited different optical characteristics. Among all of these systems, the organic photovoltaic device incorporating the polymer PCE10 blended with the acceptor FhPDI-IC2F (1:1.1 wt %) had the highest power conversion efficiency (PCE) of 9.0%; the optimal PCEs of PCE10:FhPDI-IO2F, PCE10:FhPDI-IO2Cl, and PCE10:FhPDI-IC2Cl (1:1.1 wt %) devices were 5.2, 4.7, and 7.7%, respectively. The relatively high PCE of the PCE10:FhPDI-IC2F device resulted primarily from the higher absorption coefficients of the FhPDI-IC2F acceptor, lower energy loss, and more efficient charge transfer; the FhPDI-IC2F system experienced a lower degree of geminate recombination─as a result of improved delocalization of π-electrons along the acceptor unit─relative to that of the other three acceptors systems. Thus, altering the end groups of multichromophoric PDI units can increase the PCEs of devices incorporating PDI-derived materials and might also be a new pathway for the creation of other valuable fused-ring derivatives.

A Three-Component Donor-Acceptor Hybrid Framework with Low-Power X-ray-Induced Photochromism.

Donor-acceptor (D-A) hybrid frameworks with visual X-ray photochromism at room temperature are fascinating because of their promising applications as X-ray detectors. Herein, a 3-fold interpenetrated D-A hybrid framework, [Eu(bcbp)1.5(DMF)(H2O)2][Co(CN)6]·4H2O·CH3OH (1), has been obtained by incorporating electron-rich Co(CN)63- into the electron-deficient europium viologen framework, which interestingly exhibits ultraviolet and low-power X-ray dual photochromism with a remarkable color change from brown to green. Experimental and theoretical studies revealed that the X-ray photochromic behavior of hybrid 1 could be attributed to its D-A hybrid structural feature increasing the extent of photoinduced electron transfer and thus photogenerated radical species upon X-ray irradiation. Meanwhile, due to the introduction of emissive lanthanide cations in the D-A system, hybrid 1 exhibits photomodulated luminescence properties.

Donor-Acceptor Hybrid Heterostructures: An Emerging Class of Photoactive Materials with Inorganic and Organic Semiconductive Components.

Just as the heterojunctions in physics, donor-acceptor (D-A) heterostructures are an emerging class of photoactive materials fabricated from two semiconductive components at the molecular level. Among them, D-A hybrid heterostructures from organic and inorganic semiconductive components have attracted extensive attention in the past decades due to their combined advantages of high stability for the inorganic semiconductors and modifiability for the organic semiconductors, which are particularly beneficial to efficiently achieve photoinduced charge separation and transfer upon irradiations. In this review, by analogy with the heterojunctions in physics, a definition of the D-A heterostructures and their general design and synthetic strategies are given. Meanwhile, the D-A hybrid heterostructures are focused on and their recent advances in potential applications of photochromism, photomodulated luminescence, and photocatalysis summarized.

Photochromic Polyoxometalate/Perylenediimide Donor-Acceptor Hybrid Crystals with Interesting Luminescent Properties.

The self-assembly of electron-deficient protonated N, N'-dipyridyltetrachloroperylenediimide (4Cl-DPPDI) and electron-rich polyoxometalate acids HnXM12O40 (POMs; X = P or Si; M = W or Mo) resulted in four isomorphous donor-acceptor hybrid crystals 1-4 with segregated POM anions and one-dimensional racemic hydrogen-bonded 4Cl-DPPDI networks as electron-donor and -acceptor components, respectively. Because of the compact contacts between the POM anions and 4Cl-DPPDI tectons induced by anion-π interactions, besides enhanced photochromism, these four unique isostructural hybrids exhibited unusual room-temperature phosphorescence (RTP) emissions. More interestingly, owing to the facial compact contacts of two racemic 4Cl-DPPDI tectons induced by lone pair-π-assisted π-π interactions, they also showed unprecedented photon upconversion by triplet-triplet annihilation (TTA).

Whole-genome sequence analysis unveils different origins of European and Asiatic mouflon and domestication-related genes in sheep.

The domestication and subsequent development of sheep are crucial events in the history of human civilization and the agricultural revolution. However, the impact of interspecific introgression on the genomic regions under domestication and subsequent selection remains unclear. Here, we analyze the whole genomes of domestic sheep and their wild relative species. We found introgression from wild sheep such as the snow sheep and its American relatives (bighorn and thinhorn sheep) into urial, Asiatic and European mouflons. We observed independent events of adaptive introgression from wild sheep into the Asiatic and European mouflons, as well as shared introgressed regions from both snow sheep and argali into Asiatic mouflon before or during the domestication process. We revealed European mouflons might arise through hybridization events between a now extinct sheep in Europe and feral domesticated sheep around 6000-5000 years BP. We also unveiled later introgressions from wild sheep to their sympatric domestic sheep after domestication. Several of the introgression events contain loci with candidate domestication genes (e.g., PAPPA2, NR6A1, SH3GL3, RFX3 and CAMK4), associated with morphological, immune, reproduction or production traits (wool/meat/milk). We also detected introgression events that introduced genes related to nervous response (NEURL1), neurogenesis (PRUNE2), hearing ability (USH2A), and placental viability (PAG11 and PAG3) into domestic sheep and their ancestral wild species from other wild species.

Ancient hybridization patterns between bighorn and thinhorn sheep.

Whole-genome sequencing has advanced the study of species evolution, including the detection of genealogical discordant events such as ancient hybridization and incomplete lineage sorting (ILS). The evolutionary history of bighorn (Ovis canadensis) and thinhorn (Ovis dalli) sheep present an ideal system to investigate evolutionary discordance due to their recent and rapid radiation and putative secondary contact between bighorn and thinhorn sheep subspecies, specifically the dark pelage Stone sheep (O. dalli stonei) and predominately white Dall sheep (O. dalli dalli), during the last ice age. Here, we used multiple genomes of bighorn and thinhorn sheep, together with snow (O. nivicola) and the domestic sheep (O. aries) as outgroups, to assess their phylogenomic history, potential introgression patterns and their adaptive consequences. Among the Pachyceriforms (snow, bighorn and thinhorn sheep) a consistent monophyletic species tree was retrieved; however, many genealogical discordance patterns were observed. Alternative phylogenies frequently placed Stone and bighorn as sister clades. This relationship occurred more often and was less divergent than that between Dall and bighorn. We also observed many blocks containing introgression signal between Stone and bighorn genomes in which coat colour genes were present. Introgression signals observed between Dall and bighorn were more random and less frequent, and therefore probably due to ILS or intermediary secondary contact. These results strongly suggest that Stone sheep originated from a complex series of events, characterized by multiple, ancient periods of secondary contact with bighorn sheep.

Photochromic and Room Temperature Phosphorescent Donor-Acceptor Hybrid Crystals Regulated by Core-Substituted Naphthalenediimides.

Donor-acceptor (D-A) hybrid crystals are an emerging kind of crystalline hybrid material composed of semiconductive inorganic donors and organic acceptors. Except for the intrinsic photochromism, recently we have reported that the anion-π polyoxometalate (POM)/naphthalenediimide (NDI) hybrid crystals could produce an interesting room temperature phosphorescence (RTP) quantum yield up to 7.2%. Herein, we extended into core-substituted NDIs and anticipated the regulation of their photochromic and RTP properties. Thus, two hybrid crystals, namely (H4BDMPy-Br2NDI)·(NMP)4·(HPW12O40) (1) and (H4BDMPy-I2NDI)·(HPW12O40) (2) (H2BDMPy-Br2NDI: N,N'-bis(3,5-dimethylpyrazolyl)-2,6-dibromo-1,4,5,8-naphthalenediimide and H2BDMPy-I2NDI: N,N'-bis(3,5-dimethylpyrazolyl)-2,6-diiodide-1,4,5,8-naphthalenediimide), have been synthesized from phosphotungstic anions (PW12O403-) and Br or I core-substituted NDIs. Compared to the core-unsubstituted analogues (H4BDMPy-NDI)·(NMP)4·(HPW12O40) (3), 2 with photosensitive iodine substituents is more sensitive to light, which can become discolored under natural light. As a result of the heavy-atom effect, hybrid 1 exhibits remarkable RTP with the quantum yield up to 10.2% and a lifetime of 1.14 ms.

Donor-Acceptor Conjugated Heptazine Polymers with Highly Efficient Photocatalytic Degradations towards Tetracyclines.

Photocatalysis is an efficient and green technology in the environmental protection. Due to the high charge separation and transfer, donor-acceptor (D-A) conjugated polymers attract much attention for their photocatalytic degradations towards organic pollutants. Herein, the authors reported three novel D-A conjugated polymers, named as HPBP, HPTP, and HPF, with heptazine moieties as electron acceptors, while biphenyl, terphenyl, or fluorene moieties as electron donors, respectively, which indeed exhibit a highly efficient photocatalytic degradation towards tetracyclines upon the visible-light irradiation. Among them, the photocatalytic performance of HPF is especially noticeable with the degradation rate up to 87% within 30 min, almost 11 times in comparison to those of pristine g-C3 N4 , which is mainly attributed to its high crystallinity and conjugation. For their photocatalytic mechanism, the •O2 - radical anions are regarded as the active species.