Genomic vulnerability to climate change in Quercus acutissima, a dominant tree species in East Asian deciduous forests.

Understanding the evolutionary processes that shape the landscape of genetic variation and influence the response of species to future climate change is critical for biodiversity conservation. Here, we sampled 27 populations across the distribution range of a dominant forest tree, Quercus acutissima, in East Asia, and applied genome-wide analyses to track the evolutionary history and predict the fate of populations under future climate. We found two genetic groups (East and West) in Q. acutissima that diverged during Pliocene. We also found a heterogeneous landscape of genomic variation in this species, which may have been shaped by population demography and linked selections. Using genotype-environment association analyses, we identified climate-associated SNPs in a diverse set of genes and functional categories, indicating a model of polygenic adaptation in Q. acutissima. We further estimated three genetic offset metrics to quantify genomic vulnerability of this species to climate change due to the complex interplay between local adaptation and migration. We found that marginal populations are under higher risk of local extinction because of future climate change, and may not be able to track suitable habitats to maintain the gene-environment relationships observed under the current climate. We also detected higher reverse genetic offsets in northern China, indicating that genetic variation currently present in the whole range of Q. acutissima may not adapt to future climate conditions in this area. Overall, this study illustrates how evolutionary processes have shaped the landscape of genomic variation, and provides a comprehensive genome-wide view of climate maladaptation in Q. acutissima.

Trophic Transfer of Halogenated Organic Pollutants in a Wetland Food Web: Insights from Compound-Specific Nitrogen Isotope of Amino Acids and Food Source Analysis.

A trophic position (TP) model (TPmix model) that simultaneously considered trophic discrimination factor and ßGlu/Phe variations was developed in this study and was first applied to investigate the trophic transfer of halogenated organic pollutants (HOPs) in wetland food webs. The TPmix model characterized the structure of the wetland food web more accurately and significantly improved the reliability of TMF compared to the TPbulk, TPAAs, and TPsimmr models, which were calculated based on the methods of stable nitrogen isotope analysis of bulk, traditional AAs-N-CSIA, and weighted ßGlu/Phe, respectively. Food source analysis revealed three interlocking food webs (kingfisher, crab, and frogs) in this wetland. The highest HOP biomagnification capacities (TMFmix) were found in the kingfisher food web (0.24-82.0), followed by the frog (0.08-34.0) and crab (0.56-11.7) food webs. The parabolic trends of TMFmix across combinations of log KOW in the frog food web were distinct from those of aquatic food webs (kingfisher and crab), which may be related to differences in food web composition and HOP bioaccumulation behaviors between aquatic and terrestrial organisms. This study provides a new tool to accurately study the trophic transfer of contaminants in wetlands and terrestrial food webs with diverse species and complex feeding relationships.

Linked selection shapes the landscape of genomic variation in three oak species.

Natural selection shapes genome-wide patterns of diversity within species and divergence between species. However, quantifying the efficacy of selection and elucidating the relative importance of different types of selection in shaping genomic variation remain challenging. We sequenced whole genomes of 101 individuals of three closely related oak species to track the divergence history, and to dissect the impacts of selective sweeps and background selection on patterns of genomic variation. We estimated that the three species diverged around the late Neogene and experienced a bottleneck during the Pleistocene. We detected genomic regions with elevated relative differentiation ('FST -islands'). Population genetic inferences from the site frequency spectrum and ancestral recombination graph indicated that FST -islands were formed by selective sweeps. We also found extensive positive selection; the fixation of adaptive mutations and reduction neutral diversity around substitutions generated a signature of selective sweeps. Prevalent negative selection and background selection have reduced genetic diversity in both genic and intergenic regions, and contributed substantially to the baseline variation in genetic diversity. Our results demonstrate the importance of linked selection in shaping genomic variation, and illustrate how the extent and strength of different selection models vary across the genome.

[Advances in gene therapy for ß-thalassemia and hemophilia based on the CRISPR/Cas9 technology].

Thalassemia and hemophilia are common inherited blood disorders caused by genetic abnormalities. These diseases are difficult to cure and can be inherited to the next generation, causing severe family and social burden. The emergence of gene therapy provides a new treatment for genetic diseases. However, since its first clinical trial in 1990, the development of gene therapy has not been as optimistic in the past three decades as one could hope. The development of gene-editing technology, particularly the third generation gene-editing technology CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9), has given hope in such therapeutic approach for having advantages in high editing efficiency, simple operation, and low cost. Gene editing-mediated gene therapy has thus received increasing attention from the biomedical community. It has shown promises for the treatment of inherited blood disorders, such as thalassemia and hemophilia. This paper reviews the fundamental research progress of gene therapy for ß-thalassemia and hemophilia based on CRISPR/Cas9 technology in the past six years. It also summarizes the CRISPR/Cas9-based clinical trials of gene therapy. The problems and possible solutions to this technology for gene therapy are also discussed, thereby providing a reference for the research on gene therapy of inherited blood disorders based on CRISPR/Cas9 technology.

MRS1754 inhibits proliferation and migration of bladder urothelial carcinoma by regulating mitogen-activated protein kinase pathway.

Bladder urothelial carcinoma (BUC) is one of the most common urological malignancies. Our previous study found that adenosine A2b receptor (A2bR) was upregulated in BUC tissues and cells. In the present study, we investigated the effect of MRS1754 (a selective A2bR antagonist) on cell proliferation and migration in two well-studied invasive urothelial cell carcinoma lines EJ and T24. Our results showed that MRS1754 reduced BUC cell proliferation and induced a G0/G1 phase cell-cycle arrest. Next, MRS1754 inhibited cell migration and Bay60-6583 (a selective A2bR agonist) treatment could reverse the inhibitory effect of MRS1754 on BUC cells migration. Furthermore, our results showed MRS1754 treatment downregulated the protein levels of p-P38, p-JNK, and phospho-extracellular signal-regulated kinase (p-ERK). These findings suggest that MRS1754 can inhibit progression of BUC via mitogen-activated protein kinase (MAPK) pathway and indicate the therapeutic potential of A2B antagonists in BUC.

Ultra-wide-field scanning laser ophthalmoscopy assists in the clinical detection and evaluation of asymptomatic early-stage familial exudative vitreoretinopathy.

PURPOSE: This study aims to investigate the ability of the ultra-wide-field scanning laser ophthalmoscope (UWF SLO) in clinically detecting and evaluating asymptomatic early-stage familial exudative vitreoretinopathy (FEVR). METHODS: We retrospectively reviewed 163 eyes of 83 asymptomatic family members of 48 patients with FEVR. UWF SLO imaging (Optos® PLC, Scotland, UK) was performed on asymptomatic family members as a preliminary screening test for fundus anomalies, and the findings were compared with subsequent examinations using indirect fundus ophthalmoscopy in full mydriasis, fluorescein angiography (FA), fundus autoflourescence, and genetic sequencing. RESULTS: A total of 86 eyes of 43 asymptomatic family members were clinically diagnosed with early-stage FEVR, and 17 of the affected 43 family members were also genetically diagnosed. Compared with FA as a standard, the UWF SLO was highly effective in diagnosing FEVR with a sensitivity and specificity of 93.0 % and 97.5 %, respectively. The UWF SLO was able to diagnose early-stage FEVR in 93.0 % of eyes, and guided the selection of therapies in 46.5 % of the eyes studied. CONCLUSION: UWF SLO is a valuable imaging tool for detecting fundus anomalies related to early-stage FEVR, and this tool can assist in the clinical diagnosis and evaluation of early-stage FEVR in asymptomatic family members of patients with FEVR.

Clinicopathological characteristics and prognosis of gastric cancer with malignant ascites.

Management of gastric cancer with malignant ascites is a challenge, and limited data are available. We evaluated factors affecting survival for this condition to determine factors that predict survival outcome and to develop a rational treatment plan. We retrospectively studied 5,542 patients with gastric adenocarcinoma from January 2007 to December 2012. Among them, 347 patients (6.26%) were associated with malignant ascites. The patients' overall survival was compared among the different features. Three hundred forty-seven patients (153 females and 194 males; median age, 53 years) were enrolled, including 78 (22.5%) young patients and 63 (18.1%) elderly patients. One hundred forty-three (41.2%) patients presented with malignant ascites at the initial diagnosis of gastric cancer, and 211 (60.8%) received chemotherapy. After a median follow-up duration of 10.4 months, the median survival after the diagnosis of malignant ascites was 5.2 months (95% CI, 4.8-5.6 months), and the 1-year survival rate was 16.1 %. An ECOG score greater than 2 (P < 0.001), the presence of ascites with the diagnosis of gastric cancer (P < 0.001), no chemotherapy (P < 0.001), an albumin level less than 30 g/L (P = 0.013), an ascites volume greater than 2,000 mL (P = 0.019), Helicobacter pylori infection (P = 0.010), and metastases to other organs (P = 0.037) were associated with poor prognosis, and they were all independent prognostic factors. The survival of gastric cancer patients with malignant ascites is relatively short, and ECOG score and the presence of ascites with the diagnosis of gastric cancer are the most important prognostic factors. Additionally, chemotherapy could improve the overall survival.

Mesenchymal Stromal Cells Increase the Natural Killer Resistance of Circulating Tumor Cells via Intercellular Signaling of cGAS-STING-IFNß-HLA.

Circulating tumor cells (CTCs) shed from primary tumors must overcome the cytotoxicity of immune cells, particularly natural killer (NK) cells, to cause metastasis. The tumor microenvironment (TME) protects tumor cells from the cytotoxicity of immune cells, which is partially executed by cancer-associated mesenchymal stromal cells (MSCs). However, the mechanisms by which MSCs influence the NK resistance of CTCs remain poorly understood. This study demonstrates that MSCs enhance the NK resistance of cancer cells in a gap junction-dependent manner, thereby promoting the survival and metastatic seeding of CTCs in immunocompromised mice. Tumor cells crosstalk with MSCs through an intercellular cGAS-cGAMP-STING signaling loop, leading to increased production of interferon-ß (IFNß) by MSCs. IFNß reversely enhances the type I IFN (IFN-I) signaling in tumor cells and hence the expression of human leukocyte antigen class I (HLA-I) on the cell surface, protecting the tumor cells from NK cytotoxicity. Disruption of this loop reverses NK sensitivity in tumor cells and decreases tumor metastasis. Moreover, there are positive correlations between IFN-I signaling, HLA-I expression, and NK tolerance in human tumor samples. Thus, the NK-resistant signaling loop between tumor cells and MSCs may serve as a novel therapeutic target.

Microscopic Electric Rotary Grinding of Plaques Combined with Graft Repair in the Management of Peyronie's Disease.

Peyronie's Disease (PD) is clinically characterized by the development of localized fibrous plaques, primarily on the tunica albuginea, especially on the dorsal area of the penis. These plaques are the hallmark feature of this condition, resulting in penile curvature, deformity, and painful erections for affected individuals. Although various nonsurgical treatment options exist, their overall effectiveness is limited. As a result, surgical intervention has become the ultimate choice for patients with severe penile curvature deformities and associated erectile dysfunction. Our research team has successfully employed a combined approach involving microscopic electric rotary grinding of the fibrous plaques and the use of tunica vaginalis or bovine pericardium as graft materials for the repairing of the defects of tunica albuginea in the treatment of PD. This approach has consistently yielded highly satisfactory results regarding the restoration of penile shape, with excellent cosmetic results and significantly improved sexual satisfaction. This protocol aims to present a comprehensive surgical management strategy utilizing electric rotary grinding of the plaques and repairing the defects of tunica albuginea by using the tunica vaginalis, which represents an optimal surgical strategy for treating PD.

[Integrated therapy of congenital cataract to prevent blindness and low vision].

Congenital cataract is a major cause of treatable blindness in the pediatric population worldwide. Advances in microsurgical techniques have significantly increased the success rate of surgery. However, visual rehabilitation outcomes are not always satisfactory even after a successful surgery. Due to delayed surgery, irrational aphakic correction, and lack of amblyopic training, a large number of infants in China remain blind or low-visioned after cataract surgery. Appropriate timing of surgical intervention, rational surgical methodology as well as systematic optical correction and amblyopic training are critical for the prevention of blindness and low vision in congenital cataract.

Systematic Review on Environmental Design for Adaptive and Problem Behaviors of People With Intellectual and Developmental Disabilities.

OBJECTIVES: The presented systematic review explores the empirical studies regarding environmental design strategies that support adaptive behaviors while improving problem behaviors of people with intellectual and developmental disabilities (IDD). BACKGROUND: People with IDD perceive and interact with their environment differently from people without disabilities. Design research has not always considered these differences, and environmental design solutions are not commonly found. METHODS: The review process followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocols. The study reports the findings from the systematic review of 32 peer-reviewed studies published in EBSCO, ERIC, ProQuest, PsycINFO, MEDLINE CINAHL, Consumer Health Complete (EBSCOhost), and Psychology and Behavioral Sciences Collection between 1990 and 2020. In addition, quality assessment tools appraised the study's quality. RESULTS: The review identified 26 design strategies. Five themes qualitatively organized these environmental attributes: coherence, affordance, control, stimulation, and restoration. CONCLUSION: The evidence indicates that adequately designed physical environments can support the adaptive behaviors of people with IDD while alleviating behavioral problems. Design features not supported by strong empirical evidence should be further addressed in future studies.

Case report: Pathological and genetic features of pancreatic undifferentiated carcinoma with osteoclast-like giant cells.

Objectives: Pancreatic undifferentiated carcinoma accounts for 2%-7% of pancreatic carcinomas. We aimed to investigate the pathological and genetic characteristics of pancreatic undifferentiated carcinoma with osteoclast-like giant cells and the key points of treatment. Methods: The clinical data and follow-up results of four patients diagnosed with pancreatic undifferentiated carcinoma with osteoclast-like giant cells between May 2015 and May 2020 at the First Affiliated Hospital of Xi'an Jiaotong University were retrospectively analyzed. Results: Chief complaints included "pain and discomfort in the upper abdomen" (2/4), "nausea and vomiting" (1/4) or no symptoms (1/4). Preoperative mildly elevated tumor markers included carcinoembryonic antigen (1/4) and CA19-9 (1/4). The tumors were located in the tail of the pancreas in three patients and the head and neck in one patient. Tumor metastasis was found in pancreatic adipose tissue in two patients and lymph node metastasis in one patient, with microscopic heterogeneous mononuclear cells and scattered osteoclast-like giant cells of various sizes. One patient (1/4) had a mucinous cystic tumor of the pancreas, and two patients (2/4) had adenocarcinoma of the pancreatic duct. Only one patient received postoperative gemcitabine combined with albumin-bound paclitaxel chemotherapy. Conclusion: Currently, treatment guidelines are lacking for PUC-OGC, and prognosis varies markedly. More cases must be reported to clarify its origination. The long-term follow-up of diagnosed patients and genetic mutation testing can also contribute to improving treatment and prognosis of this disease.

Definitive Endodermal Cells Supply an in vitro Source of Mesenchymal Stem/Stromal Cells.

Mesenchymal stem/Stromal cells (MSCs) have great therapeutic potentials, and they have been isolated from various tissues and organs including definitive endoderm (DE) organs, such as the lung, liver and intestine. MSCs have been induced from human pluripotent stem cells (hPSCs) through multiple embryonic lineages, including the mesoderm, neural crest, and extraembryonic cells. However, it remains unclear whether hPSCs could give rise to MSCs in vitro through the endodermal lineage. Here, we report that hPSC-derived, SOX17+ definitive endoderm progenitors can further differentiate to cells expressing classic MSC markers, which we name definitive endoderm-derived MSCs (DE-MSCs). Single cell RNA sequencing demonstrates the stepwise emergence of DE-MSCs, while endoderm-specific gene expression can be elevated by signaling modulation. DE-MSCs display multipotency and immunomodulatory activity in vitro and possess therapeutic effects in a mouse ulcerative colitis model. This study reveals that, in addition to the other germ layers, the definitive endoderm can also contribute to MSCs and DE-MSCs could be a cell source for regenerative medicine.

A chromosome-scale genome assembly of Castanopsis hystrix provides new insights into the evolution and adaptation of Fagaceae species.

Fagaceae species dominate forests and shrublands throughout the Northern Hemisphere, and have been used as models to investigate the processes and mechanisms of adaptation and speciation. Compared with the well-studied genus Quercus, genomic data is limited for the tropical-subtropical genus Castanopsis. Castanopsis hystrix is an ecologically and economically valuable species with a wide distribution in the evergreen broad-leaved forests of tropical-subtropical Asia. Here, we present a high-quality chromosome-scale reference genome of C. hystrix, obtained using a combination of Illumina and PacBio HiFi reads with Hi-C technology. The assembled genome size is 882.6 Mb with a contig N50 of 40.9 Mb and a BUSCO estimate of 99.5%, which are higher than those of recently published Fagaceae species. Genome annotation identified 37,750 protein-coding genes, of which 97.91% were functionally annotated. Repeat sequences constituted 50.95% of the genome and LTRs were the most abundant repetitive elements. Comparative genomic analysis revealed high genome synteny between C. hystrix and other Fagaceae species, despite the long divergence time between them. Considerable gene family expansion and contraction were detected in Castanopsis species. These expanded genes were involved in multiple important biological processes and molecular functions, which may have contributed to the adaptation of the genus to a tropical-subtropical climate. In summary, the genome assembly of C. hystrix provides important genomic resources for Fagaceae genomic research communities, and improves understanding of the adaptation and evolution of forest trees.

Corrigendum: Serum cytokine levels for predicting immune-related adverse events and the clinical response in lung cancer treated with immunotherapy.

[This corrects the article DOI: 10.3389/fonc.2022.923531.].