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Background. Diabetic neuropathic osteoarthropathy (DNOAP) is a rare and easily missed complication for diabetes that leads to increased morbidity and mortality. DNOAP is characterized by progressive destruction of bone and joint, but its pathogenesis remains elusive. We herein aimed to investigate the pathological features and pathogenesis of the cartilages damage in DNOAP patients. Methods. The articular cartilages of eight patients with DNOAP and eight normal controls were included. Masson staining and safranine O/fixed green staining (S-O) were used to observe the histopathological characteristics of cartilage. The ultrastructure and morphology of chondrocytes were detected by electron microscopy and toluidine blue staining. Chondrocytes were isolated from DNOAP group and control group. The expression of receptor activator of nuclear factor kappaB ligand (RANKL), osteoprotegerin (OPG), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and Aggrecan protein was evaluated by western blot. Reactive oxygen species (ROS) levels were measured using a 2′,7′-dichlorofluorescin diacetate (DCFH-DA) probe. The percentage of apoptotic cells was determined by flow cytometry (FCM). The chondrocytes were cultured with different glucose concentrations to observe the expression of RANKL and OPG. Results. Compared with the control group, the DNOAP group showed fewer chondrocytes, subchondral bone hyperplasia, and structural disorder, and a large number of osteoclasts formed in the subchondral bone area. Moreover, mitochondrial and endoplasmic reticulum swellings were observed in the DNOAP chondrocytes. The chromatin was partially broken and concentrated at the edge of nuclear membrane. The ROS fluorescence intensity of chondrocyte in DNOAP group was higher than that in normal control group ( 28.1 ± 2.3 vs. 11.9 ± 0.7 ; P < 0.05 ). The expression of RANKL, TNF-α, IL-1β, and IL-6 protein in DNOAP group was higher than that in normal control group, whereas OPG and Aggrecan protein were lower than that in normal control group (both P < 0.05 ). FCM showed that the apoptotic rate of chondrocyte in DNOAP group was higher than that in normal control group ( P < 0.05 ). The RANKL/OPG ratio showed significant upward trend when the concentration of glucose was over than 15 mM. Conclusions. DNOAP patients tend to have severe destruction of articular cartilage and collapse of organelle structure including mitochondrion and endoplasm reticulum. Indicators of bone metabolism (RANKL and OPG) and inflammatory cytokines (IL-1β, IL-6, and TNF-α) play an important role in promoting the pathogenesis of DNOAP. The glucose concentration higher than 15 mM made the RANKL/OPG ratio change rapidly.

A new species Veronica hongii, from western Hubei Province, Central China is described and illustrated. The species is morphologically similar to V. henryi Yamazaki, but mainly differs in the glabrous plant, except pedicels, broadly ovate leaf blades, glandular-pubescent pedicels, obovate calyx lobes, smaller corolla, broadly ovate capsule and much smaller seeds.

To predict and prevent the collapse and mud inrush caused by the deep karst trough in tunnels, an engineering case is studied. Firstly, a comprehensive identification method for the hazard-causing structure of the deep karst trough in tunnels is proposed and successfully applied. Secondly, the morphological characteristics and developmental mechanism of the deep karst trough are studied. The hazard-causing structure is mainly developed at the entrance section of the karst tunnel, which is funnel-shaped, mostly filled with clay and a small amount of gravel. The development scale is affected by the geological structure, tectonic movement, formation lithology and inclination, sunshine and precipitation, and surface soil. Thirdly, four hazard-causing modes of the collapse and mud inrush are proposed, i.e., rock mass failure of tunnel face, direct exposure of tunnel face, direct exposure of tunnel roof, and rock mass failure of tunnel roof. Finally, a treatment technology for collapse and mud inrush is put forward. The treatment technology is to “remove the mud, fill the karst cave, conduct advance grouting, strengthen the support, waterproof the collapse area, backfill the collapse pit.” The collapse and mud inrush of Qiyueshan Tunnel was successfully treated by using the above technology.

Carbon-rich macrocycles and carbon nanoribbons act as unusual optical materials in the free form or when combined with other guests.

A new species of the genus Asplenium L. from northern Qinghai, A. delinghaense S. Q. Liang et X.C. Zhang, is described and illustrated here. This new species resembles A. iskardense Viane et Reichst., A.daghestanicum Christ, and A. neovarians Ching but differs in frond and perispore morphology. Molecular phylogenetic evidence supported the close relationship of A. delinghaense with members of the A. varians complex and the A. pekinense complex and indicated an allotetraploid origin of it., Описан и проиллюстрирован новый вид рода Asplenium L. из северного Цинхая – A.delinghaense S. Q. Liang et X. C. Zhang. Новый вид напоминает A. iskardense Viane et Reichstein, A.daghestanicum Christ и A. neovariansChing, но отличается формой вай и морфологией периспория. Молекулярно-филогенетические данные подтверждают тесную связь A. delinghaense с видами комплексов A.varians и A. pekinense и указывают на его аллотетраплоидное происхождение.

The evolutionary direction of gonochorism and hermaphroditism is an intriguing mystery to be solved. The special transient hermaphroditic stage makes the little yellow croaker (Larimichthys polyactis) an appealing model for studying hermaphrodite formation. However, the origin and evolutionary relationship between of L. polyactis and Larimichthys crocea, the most famous commercial fish species in East Asia, remain unclear. Here, we report the sequence of the L. polyactis genome, which we found is ~706 Mb long (contig N50 = 1.21 Mb and scaffold N50 = 4.52 Mb) and contains 25,233 protein-coding genes. Phylogenomic analysis suggested that L. polyactis diverged from the common ancestor, L. crocea, approximately 25.4 million years ago. Our high-quality genome assembly enabled comparative genomic analysis, which revealed several within-chromosome rearrangements and translocations, without major chromosome fission or fusion events between the two species. The dmrt1 gene was identified as the male-specific gene in L. polyactis. Transcriptome analysis showed that the expression of dmrt1 and its upstream regulatory gene (rnf183) were both sexually dimorphic. Rnf183, unlike its two paralogues rnf223 and rnf225, is only present in Larimichthys and Lates but not in other teleost species, suggesting that it originated from lineage-specific duplication or was lost in other teleosts. Phylogenetic analysis shows that the hermaphrodite stage in male L. polyactis may be explained by the sequence evolution of dmrt1. Decoding the L. polyactis genome not only provides insight into the genetic underpinnings of hermaphrodite evolution, but also provides valuable information for enhancing fish aquaculture.

Objective: To investigate the effect of short-term nutritional support on improving preoperative nutritional status of infants with non-restrictive ventricular septal defect. Methods: A prospective randomized controlled study was conducted from June 2021 to December 2021 at a provincial children's hospital in China. The difference of nutritional status between the intervention group and the control group after short-term nutritional support was compared. Results: After one month of nutritional support, the weight, STRONGkids score, albumin, prealbumin, and hemoglobin in the intervention group significantly were higher than those in the control group (P < 0.05). The postoperative intensive care time and discharge time of the two groups significantly were lower in the intervention group than those in the control group (P < 0.05). Conclusion: The preoperative nutritional support of 1 month for infants with non-restrictive ventricular septal defect can effectively improve their preoperative nutritional status and promote postoperative recovery.

Purpose. This study aims to explore the risk factors of asthenopia in the myopic population. Methods. In this cross-sectional study, myopia patients were inquired about their eye habits and were requested to complete an asthenopia questionnaire and ocular examinations. Age, gender, occupation, anisometropia, eye care education, weekly outdoor activity time, duration of continuous near work, daily screen time, dry eye, near phoria, and binocular accommodative facility were calculated using the Student’s test-test, Mann Whitney U test, and Pearson’s chi-square test. Spherical equivalents and astigmatism were calculated using a generalized estimating equation. Binary logistic regression was performed on factors with a p -value p = 0.004 ). Daily screen time, continuous near-work time, eye care education, and dry eye were positively correlated with asthenopia (χ2 = 8.64, p = 0.003 ; χ2 = 13.873, p < 0.001 , χ2 = 9.643, p = 0.002 ; χ2 = 7.035, p = 0.008 ). After eliminating collinearity, eye care education and continuous near-work time were identified as independent risk factors of asthenopia, with odds ratios of 0.115 and 4.227, respectively. Conclusion. This study shows that receiving eye care education from schools and hospitals and limiting near-work duration to less than 45 minutes per session could reduce the occurrence of asthenopia in myopic patients. This approach may be a more economical and convenient way for myopic people to relieve asthenopia.

The genus Phaeomycocentrospora (Dothidotthiaceae) is a fungal pathogen causing plant leaf spots. A new species, Phaeomycocentrospora xinjangensis sp. nov. is introduced from Xinjiang Uygur Autonomous Region, Northwest China. Multi-gene phylogenetic analyses based on a concatenated ITS, LSU, and ACT sequence dataset were used to confirm the phylogenetic position of the new species. Phaeomycocentrospora xinjangensis can easily be distinguished from the remaining species based on multi-gene phylogenetic analyses coupled with morphological characters. Morphologically, P. xinjangensis differs from other species in the genus by the presence of dark hyphae, dark brown conidiophores, few branched conidiogenous cells. Phylogenetically, our three strains were clustered together and formed a separate subclade with high support values. Moreover, we provided a description, illustrations, and phylogenetic tree for the new species.

Background: To compare the clinical/functional outcomes of supramalleolar osteotomy (SMOT) and ankle arthrodesis (AA) for the treatment of modified Takakura stage 3B ankle osteoarthritis. Methods: Outcomes of 28 SMOT patients and 30 AA patients were reviewed at an average of 50 and 51 months, respectively. The baseline characteristics of the 2 groups were similar. The preoperative tibial articular surface angle and talar tilt angle in the SMOT group were 82.6 and 10 degrees and in the AA group, 83.9 and 9.1 degrees, respectively. The American Orthopaedic Foot & Ankle Society (AOFAS) ankle-hindfoot score, visual analog scale (VAS) score, 12-item Short-Form Health Survey (SF-12) mental component summary (MCS) and physical component summary (PCS) scores, range of motion (ROM), radiologic parameters, and complications were compared. Results: The AOFAS, VAS, and SF-12 MCS and PCS scores improved significantly postoperatively in both groups ( P < .001). The VAS and SF-12 PCS scores indicate marginally better improvement in the AA group ( P < .05). The patient satisfaction value ( P = .028) and the possibility of repeated surgery value ( P = .012) were also significantly higher in the AA group. The early ( P = .905) and late ( P = .181) complications did not significantly differ between the 2 groups. The reoperation rate was significantly higher in the SMOT group ( P = .038). Conclusion: Both SMOT and AA showed improvements in function, pain, alignment, and quality of life after surgery. Patients in the AA group reported better pain relief, had a lower reoperation rate, and better hindfoot alignment during a short- to mid-term follow-up time. Level of Evidence: Level III, retrospective comparative study.

Background: Reperfusion Injury Acute ischemic stroke is increasing in people recently and Musk, as a commonly used Traditional Chinese Medicine (TCM), has been suggested as a potential agent against acute ischemic stroke, but the efficacies and underlying mechanisms of it remain unknown. Objective: This study was aimed to tested the hypotheses that volatile compounds of musk could attenuate nerve injury and identify the bioactive compounds and potential mechanisms of Musk. Method: Transient middle cerebral artery occlusion (MCAO) model in vivo in Sprague-Dawley rats (SD rats) was used to test this hypothesis. Collecting ingredients of Musk and their related targets were discerned from the Gas chromatography-olfactory mass spectrometry (GC-O-MS) experiment. Then the potential mechanisms and targets of the compounds were searched by network pharmacology techniques. Finally, the pathway was verified by Western Bolt (WB). Results: First, Musk treatment significantly up-regulated the relative levels of AKT1, PI3KA, and VEGFA in the hippocampus, and improved the sport functions in the post-MCAO ischemic rats in vivo. Next, twenty potential flavor active compounds were recognized by GC-O-MS. A total of 89 key targets including HIF-1, PIK3CA, TNF signaling pathway, and VEGF were identified. AKT1, HIF1A, PIK3CA, and VEGFA were viewed as the most important genes, which were validated by molecular docking simulation. Conclusion: The Volatile compounds of musk can attenuate nerve injury and improving post-cerebral ischemic exercise functions by HIF1A pathways, and the combined data provide novel insight for Musk volatile compounds developed as new drug for improving reperfusion injury in acute ischemic stroke.

Purpose Based on the background of the restricted stock has gradually replaced stock option and has become the mainstream equity incentive model in China, this paper aims to investigate the which factors affect the choice of equity incentive model, and the impacts of equity incentive model. Design/methodology/approach The theoretical analysis is based on the game theory between shareholders and top executives. The empirical analysis is based on the detailed data of equity incentives in China’s listed companies from 2006 to 2017; the logit method and least square method are implemented to estimate the regression coefficients and Black–Scholes options pricing model to estimate the value of restricted stock/option granted to the CEO. Findings This paper documents that enterprises with serious agency problems, high investment risks, high stock price synchronicity and great executive power are significantly and positively related to restricted stock. The main empirical findings still hold after several robust tests. In addition, restricted stock can significantly improve corporate performance when the performance evaluation index is strict and the validity period is long, while for the sample group with loose performance index and short validity period, restricted stock significantly reduces corporate performance. Originality/value This paper analyzes the “black box” of equity incentive model selection from the stakeholders’ game perspective by constructing a game theory model to investigate the reasons for the choice of equity incentive model in various situations, which enriches the research in this field. Moreover, this paper finds that restricted stock has both incentive and welfare characteristics, and the rationality of performance appraisal goals is the key factor leading to the difference in incentive effects. Overall, the research indicates that only well-designed equity incentive plans can improve corporate performance, which contributes to regulators and practitioners to form a rational understanding of restricted stock model and provides a reference for their decision-making.

Background Research on the association of physical activity and sedentary time with dementia is accumulating, though elusive, and the interaction effects of the two remain unclear. We analysed the joint associations of accelerometer-measured physical activity and sedentary time with risk of incident dementia (all-cause dementia, Alzheimer’s disease and vascular dementia). Methods A total of 90,320 individuals from the UK Biobank were included. Accelerometer-measured total volume of physical activity (TPA) and sedentary time were measured at baseline and dichotomised by median (low TPA [ Results During a median follow-up of 6.9 years, 501 cases of all-cause dementia were identified. Higher TPA was associated with a lower risk of all-cause dementia, Alzheimer’s disease and vascular dementia; the multivariate adjusted hazard ratios (HRs) (95% CI) per 10 milli-g increase were 0.63 (0.55–0.71), 0.74 (0.60–0.90) and 0.69 (0.51–0.93), respectively. Sedentary time was only found to be linked to all-cause dementia, and the HR for high sedentary time was 1.03 (1.01–1.06) compared with that for low sedentary time. No additive and multiplicative relationship of TPA and sedentary time to incident dementia was found (all P values > 0.05). Conclusion Higher TPA level was related to a lower risk of incident dementia irrespective of sedentary time, which highlighted the implication of promoting physical activity participation to counteract the potential detrimental effect of sedentary time on dementia.

Supraglacial lakes are widespread on the surface of the Antarctic Ice Sheet and Greenland Ice Sheet due to global warming. Estimating the location and depth of supraglacial lakes is critical for evaluating the impact of surface meltwater on ice dynamics. The accuracy of traditional image-based methods is limited, especially when supraglacial lakes are deep. Recently, Ice, Clouds, and land Elevation Satellite-2 data have been used to develop algorithms to measure the depth of supraglacial lakes. The ICESat-2-based methods are currently either semiautomated or sensitive to noise, which makes them less efficient and less accurate in detecting supraglacial lakes. In this study, we develop an automated algorithm for the retrieval of the location and depth of supraglacial lakes using ICESat-2 ATL03 data. We investigated 10 supraglacial lakes as case studies over Antarctica and Greenland (4 lakes on the Amery Ice Shelf, Antarctica and 6 lakes in southwestern Greenland). The results show that our algorithm can detect supraglacial lakes at depths up to 8.25 m. The RMSE for the lake depth retrievals in Antarctica is approximately 0.30 m and that of the lakes in Greenland is approximately 0.32 m. Our algorithm reveals high robustness and accuracy, especially in shallow areas. Additionally, the fully automated algorithm does not require prior knowledge and guarantees efficiency when there is an extensive study area. This result implies that our algorithm has the potential to address large amounts of data and may even be useful to estimate meltwater volumes across the surface of the entire ice sheet.

Avicennia marina (Forsk.) Vierh. is a typical mangrove plant. Its epidermis contains salt glands, which can secrete excess salts onto the leaf surfaces, improving the salt tolerance of the plants. However, knowledge on the epidermis-specific transcriptional responses of A. marina to salinity treatment is lacking. Thus, physiological and transcriptomic techniques were applied to unravel the salt tolerance mechanism of A. marina. Our results showed that 400 mM NaCl significantly reduced the plant height, leaf area, leaf biomass and photosynthesis of A. marina. In addition, 1565 differentially expressed genes were identified, of which 634 and 931 were up- and down-regulated. Based on Kyoto Encyclopedia of Genes and Genomes metabolic pathway enrichment analysis, we demonstrated that decreased gene expression, especially that of OEE1, PQL2, FDX3, ATPC, GAPDH, PRK, FBP and RPE, could explain the inhibited photosynthesis caused by salt treatment. Furthermore, the ability of A. marina to cope with 400 mM NaCl treatment was dependent on appropriate hormone signalling and potential sulfur-containing metabolites, such as hydrogen sulfide and cysteine biosynthesis. Overall, the present study provides a theoretical basis for the adaption of A. marina to saline habitats and a reference for studying the salt tolerance mechanism of other mangrove plants.

Objective To explore the effect of using WeChat to guide preparation before transthoracic echocardiography (TTE) on reducing anxiety and improving the satisfaction of parents of infants with congenital heart disease (CHD). Methods This study was a retrospective study conducted in a children’s hospital. The clinical data of 44 patients and the anxiety and satisfaction data of their parents who received WeChat guidance were collected between December 2021 and January 2022 (the WeChat group). The corresponding data of 47 patients and their parents who received educational brochure guidance were collected between September 2021 and November 2021 (the routine group). Guidance was used to help the parents prepare for TTE performed by medical professionals. The State-Trait Anxiety Inventory scale and the Patient Satisfaction Questionnaire-18 (PSQ-18) were used. The data of the two groups were compared and analyzed. Results The comparison of parental anxiety between the two groups showed that the scores of state anxiety and trait anxiety in the WeChat group were significantly lower than those in the routine group (p Conclusion Using WeChat to guide preparation before TTE for infants with CHD can effectively reduce the anxiety of their parents and improve their parents’ satisfaction with medical treatment.

IntroductionProbiotic Lactiplantibacillus plantarum MC5 produces large amounts of exopolysaccharides (EPS), and its use as a compound fermentor can greatly improve the quality of fermented milk.MethodsTo gain insight into the genomic characteristics of probiotic MC5 and reveal the relationship between its EPS biosynthetic phenotype and genotype, we analyzed the carbohydrate metabolic capacity, nucleotide sugar formation pathways, and EPS biosynthesis-related gene clusters of strain MC5 based on its whole genome sequence. Finally, we performed validation tests on the monosaccharides and disaccharides that strain MC5 may metabolize.ResultsGenomic analysis showed that MC5 has seven nucleotide sugar biosynthesis pathways and 11 sugar-specific phosphate transport systems, suggesting that the strain can metabolize mannose, fructose, sucrose, cellobiose, glucose, lactose, and galactose. Validation results showed that strain MC5 can metabolize these seven sugars and produce significant amounts of EPS (> 250 mg/L). In addition, strain MC5 possesses two typical eps biosynthesis gene clusters, which include the conserved genes epsABCDE, wzx, and wzy, six key genes for polysaccharide biosynthesis, and one MC5-specific epsG gene.DiscussionThese insights into the mechanism of EPS-MC5 biosynthesis can be used to promote the production of EPS through genetic engineering.

Hawthorn is an important medicine food homology (MFH) species. Charred hawthorn (CH) is derived from the thermal processing of raw hawthorn (RH). Traditional Chinese medicine theory suggests that CH has a stronger effect to promote digestion than RH. In this study, based on the functional dyspepsia (FD) model in rats, the effects of RH and CH on gastrointestinal motility were investigated, and the mechanism of action was revealed from the perspectives of gut microbiota and metabolomics. FD model was established by various stimulation and chronic induction methods for 21 days. After 7 days of intervention, CH could improve the gastric emptying rate and intestinal propulsion rate; correct the abnormal levels of 20 different metabolites in the feces; regulate the metabolic pathways of vitamin A and niacin; increase the diversity and richness of intestinal microbiota and adjust the structure and composition of gut microbiota in FD rats. And the effect of CH is better than RH. The results of this study show that CH can better modulate the metabolites and gut microbiota of rats with FD, to provide a theoretical basis for the development of dietary therapy of hawthorn as a treatment plan or adjuvant treatment for FD.

PurposeThe aim of this study was to evaluate the vessel density (VD) of the macular choriocapillaris (CC) and retina in thyroid-associated ophthalmopathy (TAO) patients with chorioretinal folds (CRFs) with and without optic disc edema (ODE) and the correlations of these characteristics with visual function.MethodThis was a cross-sectional study. Twenty TAO patients with CRFs (35 eyes) and 20 normal subjects (normal group, 40 eyes) were recruited at the Ophthalmology Department of the Sun Yat-sen Memorial Hospital from March 2018 to October 2022. Then, CRF patients were divided into two groups, the ODE and non-ODE groups (NODE), based on the presence or absence of ODE. All the patients underwent optical coherence tomography angiography (OCTA) and the VD of the macular CC and retina was computed. The correlation of VD and visual function was analyzed.ResultsCompared with the normal group, the macular whole-image VD in the retinal superficial layer (SLR-mwiVD: 49.82 ± 3.38 in the normal group, 42.44 ± 5.40 in the NODE group, and 42.51 ± 5.37 in the ODE group), deep layer (DLR-mwiVD: 51.05 ± 6.23 in the normal group, 45.71 ± 6.66 in the NODE group, and 46.31 ± 5.48 in the ODE group), and CC (CC-mwiVD: 70.23 ± 2.47 in the normal group, 68.04 ± 3.73 in the NODE group, and 63.09 ± 6.51 in the ODE group) was decreased in the NODE (all p < 0.05) and ODE group (all p < 0.01). There was no difference in these parameters except CC-mwiVD between the ODE and NODE groups. The CC-mwiVD in the ODE group (63.09 ± 6.51) was significantly reduced compared with that in the NODE group (68.04 ± 3.73, p = 0.004). All these VD parameters were negatively correlated with BCVA, VF-PSD, and P100 latency and positively associated with VF-MD, P100 amplitude, and HRR scores (all p < 0.05).ConclusionsThere was a significant decrease in the VD of the macular CC and retina of patients with CRFs with or without ODE, which was correlated with visual dysfunction. The VD of the macular CC in CRF patients with ODE was significantly reduced compared with that in the NODE group, but similar results were not observed in the retina.

Trigeminal neuralgia (TN) is a debilitating condition and often leads to mood disorders such as depression and anxiety. The present study aimed to determine the molecular mechanisms involved in the pathogenesis of TN and its associated anxiety. We found that partial transection of the infraorbital nerve (pT-ION) in mice induced stable and long-lasting primary and secondary orofacial allodynia and anxiety-like behaviors. Gene microarray analysis found that Foxg1 expression was significantly upregulated after pT-ION, and knocking down Foxg1 by microinjection of adeno-associated virus carrying Foxg1 shRNA into the bilateral lateral habenula (LHb) effectively alleviated pain-related and anxiety-like behaviors. RNA sequencing showed that Prkcd may be the downstream gene modulated by Foxg1. Pharmacological inhibition of protein kinase C delta, the Prkcd-encoded protein, in the LHb effectively reversed pT-ION-induced pain-related and anxiety-like behaviors. Dual luciferase reporter analysis indicated the direct promotion of Prkcd gene expression by Foxg1. In conclusion, trigeminal nerve injury induced the upregulation of Foxg1 in the LHb, which promoted the expression of Prkcd, thus resulting in orofacial pain and anxiety-like behaviors. This finding provides potential therapeutic targets and a theoretical basis for the clinical treatment of TN and its associated anxiety.

AntilCOS

Supplementary Figures 1-9

Metadata for the 5 NSCLC patients

Isotype control

Figure and tables legends of supplementary data

The immunosuppressive tumor microenvironment constitutes a significant hurdle to immune checkpoint inhibitor responses. Both soluble factors and specialized immune cells, such as regulatory T cells (Treg), are key components of active intratumoral immunosuppression. Inducible costimulatory receptor (ICOS) can be highly expressed in the tumor microenvironment, especially on immunosuppressive Treg, suggesting that it represents a relevant target for preferential depletion of these cells. Here, we performed immune profiling of samples from tumor-bearing mice and patients with cancer to demonstrate differential expression of ICOS in immune T-cell subsets in different tissues. ICOS expression was higher on intratumoral Treg than on effector CD8 T cells. In addition, by immunizing an Icos knockout transgenic mouse line expressing antibodies with human variable domains, we selected a fully human IgG1 antibody called KY1044 that bound ICOS from different species. We showed that KY1044 induced sustained depletion of ICOShigh T cells but was also associated with increased secretion of proinflammatory cytokines from ICOSlow effector T cells (Teff). In syngeneic mouse tumor models, KY1044 depleted ICOShigh Treg and increased the intratumoral TEff:Treg ratio, resulting in increased secretion of IFNγ and TNFα by TEff cells. KY1044 demonstrated monotherapy antitumor efficacy and improved anti–PD-L1 efficacy. In summary, we demonstrated that using KY1044, one can exploit the differential expression of ICOS on T-cell subtypes to improve the intratumoral immune contexture and restore an antitumor immune response.

Genes used to define Immune cell subtypes

Germplasm resource is the source of herbal medicine production. Cultivation of superior germplasm resources helps to resolve the serious conflict between long-term population persistence and growing market demand by producing materials with high quality consistently.Cibotium barometzis the original plant of cibotii rhizoma (“Gouji”), a traditional Chinese medicine used in the therapy of pain, weakness, and numbness of lower extremity. Long-history use ofCibotiumhas rendered wild populations of this species declined seriously in China. Without sufficient understanding of species and lineage diversity ofCibotium, it is difficult to propose a targeted conservation scheme at present, let alone selecting high-quality germplasm resources. In order to fill such a knowledge gap, this study sampledC. barometzand relative species throughout their distribution in China, performed genome skimming to obtain plastome data, and conducted phylogenomic analyses. We constructed a well-supported plastome phylogeny of ChineseCibotium, which showed that three species with significant genetic difference distributed in China, namelyC. barometz,C. cumingii, andC. sino-burmaense, a cryptic species endemic to NW Yunnan and adjacent region of NE Myanmar. Moreover, our results revealed two differentiated lineages ofC. barometzdistributed in the east and west side of a classic phylogeographic boundary that probably shaped by monsoons and landforms in China. We also evaluated the resolution of nine traditional barcode loci, and designed five new DNA barcodes based on the plastome data which can discriminate all these species and lineages of ChineseCibotiumaccurately. These novel findings integrated genetic basis will guide conservation planners and medicinal plant breeders to build systematic conservation plans and exploit germplasm resources ofCibotiumin China.