MxB inhibits long interspersed element type 1 retrotransposition.

Long interspersed element type 1 (LINE-1, also L1 for short) is the only autonomously transposable element in the human genome. Its insertion into a new genomic site may disrupt the function of genes, potentially causing genetic diseases. Cells have thus evolved a battery of mechanisms to tightly control LINE-1 activity. Here, we report that a cellular antiviral protein, myxovirus resistance protein B (MxB), restricts the mobilization of LINE-1. This function of MxB requires the nuclear localization signal located at its N-terminus, its GTPase activity and its ability to form oligomers. We further found that MxB associates with LINE-1 protein ORF1p and promotes sequestration of ORF1p to G3BP1-containing cytoplasmic granules. Since knockdown of stress granule marker proteins G3BP1 or TIA1 abolishes MxB inhibition of LINE-1, we conclude that MxB engages stress granule components to effectively sequester LINE-1 proteins within the cytoplasmic granules, thus hindering LINE-1 from accessing the nucleus to complete retrotransposition. Thus, MxB protein provides one mechanism for cells to control the mobility of retroelements.

SERINC5 restricts influenza virus infectivity.

SERINC5 is a multi-span transmembrane protein that is incorporated into HIV-1 particles in producing cells and inhibits HIV-1 entry. Multiple retroviruses like HIV-1, equine infectious anemia virus and murine leukemia virus are subject to SERINC5 inhibition, while HIV-1 pseudotyped with envelope glycoproteins of vesicular stomatitis virus and Ebola virus are resistant to SERINC5. The antiviral spectrum and the underlying mechanisms of SERINC5 restriction are not completely understood. Here we show that SERINC5 inhibits influenza A virus infection by targeting virus-cell membrane fusion at an early step of infection. Further results show that different influenza hemagglutinin (HA) subtypes exhibit diverse sensitivities to SERINC5 restriction. Analysis of the amino acid sequences of influenza HA1 strains indicates that HA glycosylation sites correlate with the sensitivity of influenza HA to SERINC5, and the inhibitory effect of SERINC5 was lost when certain HA glycosylation sites were mutated. Our study not only expands the antiviral spectrum of SERINC5, but also reveals the role of viral envelope glycosylation in resisting SERINC5 restriction.

A field diagnostic method for rapid and sensitive detection of mpox virus.

The mpox outbreak has subdued with fewer reported cases at the present in high-income countries. It is known that mpox virus (MPXV) infection has been epidemic for more than 50 years in African countries. The ancestral MPXV strain has changed into multiple clades, indicating the ongoing evolution of MPXV, which reflects the historical neglect of mpox in Africa, especially after smallpox eradication, and bestows the danger of more severe mpox epidemics in the future. It is thus imperative to continue the development of mpox diagnostics and treatments so we can be prepared in the event of a new mpox epidemic. In this study, we have developed an MPXV detection tool that leverages the recombinase-aid amplification assay by integrating lateral flow strips (RAA-LF) and one-step sample DNA preparation, with visible readout, no need of laboratory instrument, and ready for field deployment. The detection limit reaches 10 copies per reaction. The performance of our RAA-FL assay in diagnosing mpox clinical samples is on par with that of the quantitative polymerase chain reaction (PCR) assay. Taken together, we have developed a point-of-care RAA-LF method of high accuracy and sensitivity, readily deployable for field detection of MPXV. This diagnostic tool is expected to improve and accelerate field- and self-diagnosis, allow timely isolation and treatment, reduce the spread of MPXV, thus effectively mitigate MPXV outbreak in the future.

PHLDA1 promotes glioblastoma cell growth via sustaining the activation state of Ras.

Activation of the Ras signaling pathway promotes the growth of malignant human glioblastoma multiforme (GBM). Mutations in Ras are rare in GBM, elevated levels of activated Ras are prevalently observed in GBM. However, the potential mechanism of how Ras is activated in GBM remains unclear. In this study, we screened a new interacted protein of Ras, PHLDA1. Our findings confirmed that PHLDA1 acted as an oncogene and promoted glioma progression and recurrence. We demonstrated that PHLDA1 was upregulated in GBM tissues and cells. PHLDA1 overexpression promoted cell proliferation and tumor growth. In terms of mechanism, PHLDA1 promoted cell proliferation by regulating Ras/Raf/Mek/Erk signaling pathway. Moreover, Src promotes GTPase activity of Ras via tyrosine 32 phosphorylation. PHLDA1 and Src competed for binding with Ras, inhibiting Ras phosphorylation by Src and rescuing Ras activity. This study may provide a new idea of the molecular mechanism underlying glioma progression and a novel potential therapeutic target for comprehensive glioblastoma treatment.

Astaxanthin improves preserved semen quality at 17°C by enhancing sperm antioxidant and motility properties.

Porcine sperm is rich in polyunsaturated fatty acids; therefore, it is highly susceptible to oxidative damage during storage. Inhibition of oxidative stress during preservation is essential for maintaining sperm motility. Astaxanthin is a potent antioxidant used in the cosmetic and pharmaceutical industries. This study aimed to explore the effect of supplementing astaxanthin as an extender of porcine semen preservation dilutions at 17°C. Various concentrations of astaxanthin were added to diluted porcine semen at 17°C. We performed computer-assisted semen analysis, evaluation of plasma membrane integrity and acrosome integrity, and measurement of total antioxidant activity, malondialdehyde (MDA) content, reactive oxygen species levels, superoxide dismutase (SOD) activity, catalase (CAT) activity, glutathione peroxidase (GSH-PX) activity and sperm motility parameters. Compared with the control group, the addition of 0.25 µg/ml astaxanthin group significantly improved sperm motility parameters stored on the fifth day; these were increased levels of sperm SOD, GSH-PX and CAT (p < .05), increased sperm adenosine trisphosphate and lactate dehydrogenase levels and decreased sperm MDA levels (p < .05). These findings suggest that adding 0.25 µg/ml of astaxanthin improves the quality of porcine semen stored at 17°C. Our findings provide theoretical support for developing new protective agents critical for preserving pig semen at 17°C.

Zinc transporters belonging to the Cation Diffusion Facilitator (CDF) family have complementary roles in transporting zinc out of the cytosol.

Zinc is an essential trace element that is required for the function of a large number of proteins. As these zinc-binding proteins are found within the cytosol and organelles, all eukaryotes require mechanisms to ensure that zinc is delivered to organelles, even under conditions of zinc deficiency. Although many zinc transporters belonging to the Cation Diffusion Facilitator (CDF) families have well characterized roles in transporting zinc into the lumens of intracellular compartments, relatively little is known about the mechanisms that maintain organelle zinc homeostasis. The fission yeast Schizosaccharomyces pombe is a useful model system to study organelle zinc homeostasis as it expresses three CDF family members that transport zinc out of the cytosol into intracellular compartments: Zhf1, Cis4, and Zrg17. Zhf1 transports zinc into the endoplasmic reticulum, and Cis4 and Zrg17 form a heterodimeric complex that transports zinc into the cis-Golgi. Here we have used the high and low affinity ZapCY zinc-responsive FRET sensors to examine cytosolic zinc levels in yeast mutants that lack each of these CDF proteins. We find that deletion of cis4 or zrg17 leads to higher levels of zinc accumulating in the cytosol under conditions of zinc deficiency, whereas deletion of zhf1 results in zinc accumulating in the cytosol when zinc is not limiting. We also show that the expression of cis4, zrg17, and zhf1 is independent of cellular zinc status. Taken together our results suggest that the Cis4/Zrg17 complex is necessary for zinc transport out of the cytosol under conditions of zinc-deficiency, while Zhf1 plays the dominant role in removing zinc from the cytosol when labile zinc is present. We propose that the properties and/or activities of individual CDF family members are fine-tuned to enable cells to control the flux of zinc out of the cytosol over a broad range of environmental zinc stress.

Zinc-dependent activation of the Pho8 alkaline phosphatase in Schizosaccharomyces pombe.

Genome-wide analyses have revealed that during metal ion starvation, many cells undergo programmed changes in their transcriptome or proteome that lower the levels of abundant metalloproteins, conserving metal ions for more critical functions. Here we investigated how changes in cellular zinc status affect the expression and activity of the zinc-requiring Pho8 alkaline phosphatase from fission yeast (Schizosaccharomyces pombe). In S. pombe, Pho8 is a membrane-tethered and processed glycoprotein that resides in the vacuole. Using alkaline phosphatase activity assays along with various biochemical analyses, we found that Pho8 is active when zinc is plentiful and inactive when zinc is limited. Although Pho8 activity depended on zinc, we also found that higher levels of pho8 mRNAs and Pho8 protein accumulate in zinc-deficient cells. To gain a better understanding of the inverse relationship between pho8 mRNA levels and Pho8 activity, we examined the effects of zinc on the stability and processing of the Pho8 protein. We show that Pho8 is processed regardless of zinc status and that mature Pho8 accumulates under all conditions. We also noted that alkaline phosphatase activity is rapidly restored when zinc is resupplied to cells, even in the presence of the protein synthesis inhibitor cycloheximide. Our results suggest that S. pombe cells maintain inactive pools of Pho8 proteins under low-zinc conditions and that these pools facilitate rapid restoration of Pho8 activity when zinc ions become available.

microRNA-10b confers cisplatin resistance by activating AKT/mTOR/P70S6K signaling via targeting PPARγ in esophageal cancer.

It is well known that the acquisition of chemoresistance is a major obstacle for the effective treatment of human cancers. It is reported that microRNAs (miRNAs) are implicated in chemotherapy resistance of various malignancies. miR-10b was previously proved as an oncogene in multiple malignancies, including esophageal cancer. However, its biological significance in regulating cisplatin (DDP) resistance in esophageal cancer is still elusive. Here, we observed that miR-10b expression was upregulated and peroxisome proliferator-activated receptor-γ (PPARγ) expression was downregulated in esophageal cancer tumor tissues and cells. PPARγ was proved as a functional target of miR-10b. Moreover, suppression of miR-10b enhanced the chemosensitivity of esophageal cancer cells to DDP in vitro and in vivo. In addition, PPARγ-mediated DDP sensitivity was weakened by miR-10b overexpression. Furthermore, miR-10b-activated AKT/mTOR/p70S6K signaling pathway through targeting PPARγ. Inactivation of AKT/mTOR/p70S6K by AKT inhibitor (GSK690693) attenuated miR-10b-induced DDP resistance in esophageal cancer cells. Taken together these observation, miRNA-10b-mediated PPARγ inhibition enhanced DDP resistance by activating the AKT/mTOR/P70S6K signaling in esophageal cancer, suggesting a potential target to improve therapeutic response of patients with esophageal cancer to DDP.

Remote Ischemic Post-Conditioning may Improve Post-Stroke Cognitive Impairment: A Pilot Single Center Randomized Controlled Trial.

BACKGROUND AND PURPOSE: We aimed to demonstrate the tolerability and feasibility and the effect of remote ischemic post-conditioning on cognitive functioning in patients with post-stroke cognitive impairment. METHODS: This was a single-center, randomized, outcome-blinded, placebo-controlled trial, randomized 1:1 to receive 4 cycles of remote ischemic post-conditioning or a sham procedure for 7 days. The primary outcome measure was tolerability and feasibility of remote ischemic post-conditioning. Secondary outcomes to measure the neurological function with national institute of health stroke scale and the cognitive impairment with Montreal Cognitive Assessment scale and Alzheimer's disease assessment scale-cognitive (at baseline, 90 days, 180 days). RESULTS: 48 patients (24 RIPC and 24 Control) were recruited. remote ischemic post-conditioning was well tolerated with 90 out of 96 cycles completed in full. 4 patients experienced vascular events in the control group: 3 cerebrovascular and 1 cardiovascular event versus only 2 cerebrovascular events in the RIPC group. We showed the similar result in the neurological function with national institute of health stroke scale score with no statistically significant differences between RIPC and control group at baseline (P = 0.796) and 90 days (P = 0.401) and 180 days (P = 0.695). But compare with baseline, it was significantly difference in the control and RIPC group at 90 days (P < 0.05) and 180 days (P < 0.05). The comparison of Montreal Cognitive Assessment scale between two groups both showed that P > 0.05 at baseline which was no statistical difference, but P < 0.05 at 90 days and 180 days which were significant statistical difference. The comparison of Alzheimer's disease assessment scale-cognitive between two groups showed that P > 0.05 at baseline (P = 0.955) and 90 days (P = 0.138) was no statistical difference, but P = 0.005<0.05 at 180 days was significant statistical difference. CONCLUSIONS: The remote ischemic post-conditioning for post-stroke cognitive impairment was well tolerated, safe and feasible. The remote ischemic post-conditioning may improve neurological and cognitive outcomes in patients with post-stroke cognitive impairment. A larger trial is warranted. (Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: ChiCTR1800015231.).

Rev-erbα Inhibits Proliferation and Promotes Apoptosis of Preadipocytes through the Agonist GSK4112.

Proliferation and apoptosis are important physiological processes of preadipocytes. Rev-erbα is a circadian clock gene, and its activity contributes to several physiological processes in various cells. Previous studies demonstrated that Rev-erbα promotes preadipocyte differentiation, but a role of Rev-erbα on preadipocyte proliferation and apoptosis has not been demonstrated. GSK4112 is often used as an agonist of Rev-erbα. In this study, we used GSK4112 to explore the effects of Rev-erbα on preadipocyte proliferation and apoptosis by RT-qPCR, Western blot, Cell Counting Kit-8 (CCK8) measurement, 5-Ethynyl-2'-deoxyuridine (EdU) staining, Annexin V-FITC/PI staining, and flow cytometry. These results revealed that GSK4112 inhibited the viability of 3T3-L1 preadipocytes and decreased cell numbers. There was also decreased expression of the proliferation-related gene Cyclin D and the canonical Wingless-type (Wnt) signaling effect factor ß-catenin. Furthermore, palmitate (PA)-inducing cell apoptosis was promoted. Overall, these results reveal that Rev-erbα plays a role in proliferation and palmitate (PA)-inducing apoptosis of 3T3-L1 preadipocytes, and thus may be a new molecular target in efforts to prevent and treat obesity and related disease.

Upper Limb Ischemic Postconditioning as Adjunct Therapy in Acute Stroke Patients: A Randomized Pilot.

OBJECTIVE: This study aims to observe the clinical effect of upper limb ischemic postconditioning (LIPostC) as an adjunct to treatment with acute stroke patients, possibly due to increased cerebral perfusion. METHODS: We perform a randomized blinded placebo controlled trial in nonthrombolysis patients with acute ischemic stroke, within 72hours of ictus, divided into the LIPostC group and control group. The LIPostC group is induced by 4 cycles of intermittent repeated limb ischemia: alternating 5 minutes inflation (20mm Hg above systolic blood pressure) and 5 minutes deflation performed manually using a standard upper arm blood pressure cuff in the nonparetic arm. The control group receives a sham procedure (cuff inflation to 30mm Hg). Patients underwent the intervention from the time of enrollment to Day 14. Comparison of National Institutes of Health Stroke Scale (NIHSS) score, cerebral infarction volume, relative Perfusion weighted imaging (PWI) parameters (regional relative cerebral blood flow, regional relative mean transit time; preintervention [day 0], day 14, day 90), modified Rankin Scale (mRS; the preintervention score [day 0], the curative ratio at day 90 [we define 0-1 score as close to recovery or full recovery]). RESULTS: Sixty eligible patients with acute stroke (29 LIPostC and 31 control) are recruited age 65years (SD 12.22), blood pressure 156/74mm Hg (SD 14/10), and NIHSS score 5.98 (SD 3.35), mRS score 2.25 (SD .79). Only 1 in the LIPostC group is intolerant the first cycle to give up. All patients tolerate the sham procedure. Two patients experience recurrent stroke versus none in the LIPostC group. Day 90, compared with the control group, there is a significant decrease the NIHSS score, regional relative mean transit time (P < .05) and increase the curative ratio of mRS, regional relative cerebral blood flow(P < .05) in the LIPostC group, which infarct volume decreased by 31.3% (P < .05). CONCLUSIONS: LIPostC after acute stroke is well tolerated and appears safe and feasible. LIPostC may improve neurological outcome, and protective mechanisms may be increased cerebral blood flow to improve cerebral perfusion. A larger trial is warranted.

Zinc finger protein Loz1 is required for zinc-responsive regulation of gene expression in fission yeast.

In Schizosaccharomyces pombe, alcohol dehydrogenase 1 (Adh1) is an abundant zinc-requiring enzyme that catalyses the conversion of acetaldehyde to ethanol during fermentation. In a zinc-replete cell, adh1 is highly expressed. However, in zinc-limited cells, adh1 gene expression is repressed, and cells induce the expression of an alternative alcohol dehydrogenase encoded by the adh4 gene. In our studies examining this zinc-dependent switch in alcohol dehydrogenase gene expression, we isolated an adh1Δ strain containing a partial loss of function mutation that resulted in higher levels of adh4 transcripts in zinc-replete cells. This mutation also led to the aberrant expression of other genes that are typically regulated by zinc. Using linkage analysis, we have mapped the position of this mutation to a single gene called Loss Of Zinc sensing 1 (loz1). Loz1 is a 55-kDa protein that contains a double C2H2-type zinc finger domain. The mapped mutation that disrupts Loz1 function leads to an arginine to glycine substitution in the second zinc finger domain, suggesting that the double zinc finger domain is important for Loz1 function. We show that loz1Δ cells hyperaccumulate zinc and that Loz1 is required for gene repression in zinc-replete cells. We also have found that Loz1 negatively autoregulates its own expression. We propose that Loz1 is a unique metalloregulatory factor that plays a central role in zinc homeostasis in S. pombe.

Preferential cytotoxicity of bortezomib toward highly malignant human liposarcoma cells via suppression of MDR1 expression and function.

Liposarcoma is the most common soft tissue sarcoma with a high risk of relapse. Few therapeutic options are available for the aggressive local or metastatic disease. Here, we report that the clinically used proteasome inhibitor bortezomib exhibits significantly stronger cytotoxicity toward highly malignant human liposarcoma SW872-S cells compared with its parental SW872 cells, which is accompanied by enhanced activation of apoptotic signaling both in vitro and in vivo. Treatment of cells with Jun-N-terminal kinase (JNK) inhibitor SP60015 or the translation inhibitor cycloheximide ameliorated this enhanced apoptosis. Bortezomib inhibited MDR1 expression and function more effectively in SW872-S cells than in SW872 cells, indicating that the increased cytotoxicity relies on the degree of proteasome inhibition. Furthermore, the pharmacological or genetic inhibition of sarco/endoplasmic reticulum calcium-ATPase (SERCA) 2, which is highly expressed in SW872-S cells, resulted in partial reversal of cell growth inhibition and increase of MDR1 expression in bortezomib-treated SW872-S cells. These results show that bortezomib exhibits preferential cytotoxicity toward SW872-S cells possibly via highly expressed SERCA2-associated MDR1 suppression and suggest that bortezomib may serve as a potent agent for treating advanced liposarcoma.

[Research for the antiapoptotic mechanisms of bone marrow mesenchymal stem cells in the treatment of brain ischemia stroke].

OBJECTIVE: To evaluate the anti-apoptosis role of bone marrow mesenchymal stem cells (BMMCs) transplantation to cell cerebral brain ischemia mice. METHODS: BMMCs were separated through Ficoll from bone marrow, after amplified in vitro, flow cytometry was used to identify the surface markers. Then cells were transplanted into Middle cerebral artery occlusion (MACO) mice, in situ cell death detection kit and Western blot were used to examine the cell apoptosis. Immunofluorescence and Western blot were used to detect the expression of eNOS, ICAM-1, CD31 which are related to the repair of vascular endothelial cells. RESULTS: After BMMCs transplantation, the number of apoptosis cells was decreased from (78.2±1.4) to (12.8±3.0), P<0.05. The expression of eNOS (80.0±6.2 vs 31.2±1.6, P<0.01) and CD31 (85±3 vs 45±5, P<0.01), were higher than MACO, while ICAM-1 was lower than MACO (34.1±2.2 vs 85.2±2.8, P<0.01). CONCLUSION: BMMCs reduce the cell apoptosis of ischemia mice through regulate the expression of vascular endothelial cells relate genes.

Unraveling the complexity of STAT3 in cancer: molecular understanding and drug discovery.

Signal transducer and activator of transcription 3 (STAT3) is a transcriptional factor involved in almost all cancer hallmark features including tumor proliferation, metastasis, angiogenesis, immunosuppression, tumor inflammation, metabolism reprogramming, drug resistance, cancer stemness. Therefore, STAT3 has become a promising therapeutic target in a wide range of cancers. This review focuses on the up-to-date knowledge of STAT3 signaling in cancer. We summarize both the positive and negative modulators of STAT3 together with the cancer hallmarks involving activities regulated by STAT3 and highlight its extremely sophisticated regulation on immunosuppression in tumor microenvironment and metabolic reprogramming. Direct and indirect inhibitors of STAT3 in preclinical and clinical studies also have been summarized and discussed. Additionally, we highlight and propose new strategies of targeting STAT3 and STAT3-based combinations with established chemotherapy, targeted therapy, immunotherapy and combination therapy. These efforts may provide new perspectives for STAT3-based target therapy in cancer.

Revolutionizing cattle breeding: Gene editing advancements for enhancing economic traits.

Beef and dairy products are rich in protein and amino acids, making them highly nutritious for human consumption. The increasing use of gene editing technology in agriculture has paved the way for genetic improvement in cattle breeding via the development of the CRISPR/Cas (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein) system. Gene sequences are artificially altered and employed in the pursuit of improving bovine breeding research through targeted knockout, knock-in, substitution, and mutation methods. This review offers a comprehensive analysis of the advancements in gene editing technology and its diverse applications in enhancing both quantitative and qualitative traits across livestock. These applications encompass areas such as meat quality, milk quality, fertility, disease resistance, environmental adaptability, sex control, horn development, and coat colour. Furthermore, the review considers prospective ideas and insights that may be employed to refine breeding traits, enhance editing efficiency, and navigate the ethical considerations associated with these advancements. The review's focus on improving the quality of beef and milk is intended to enhance the economic viability of these products. Furthermore, it constitutes a valuable resource for scholars and researchers engaged in the fields of cattle genetic improvement and breeding.

Analysis of blood biochemistry and non-targeted metabolomics of endometritis in dairy cows.

The incidence of bovine endometritis, which has a negative impact on the reproduction of dairy cows, has been recently increasing. In this study, the differential markers and metabolites of healthy cows and cows with endometritis were analyzed by measuring blood biochemical indicators and immune factors using biochemical and enzyme-linked immunosorbent assay kits combined with nontargeted metabolomics. The LC-QTOF platform was used to evaluate the serum metabolomics of healthy cows and cows with endometritis after 21-27 days of calving. The results showed that glucose, free fatty acid, calcium, sodium, albumin, and alanine aminotransferase levels were significantly lower in the serum of cows with endometritis than in healthy cows (P < 0.05). However, the serum potassium, interleukin-1, interleukin-6, and tumor necrosis factor levels were significantly higher in cows with endometritis (P < 0.05). In addition, the serum metabolome data analysis of the two groups showed that the expression of 468 metabolites was significantly different (P < 0.05), of which 291 were upregulated and 177 were downregulated. These metabolites were involved in 78 metabolic pathways, including amino acid, nucleotide, carbohydrate, lipid, and vitamin metabolism pathways; signal transduction pathways, and other biological pathways. Taken together, negative energy balance and immune activation, which are related to local abnormalities in amino acid, lipid, and carbohydrate metabolism, were the important causes of endometritis in dairy cows. Metabolites such as glucose, carnosine, dehydroascorbic acid, L-malic acid, tetrahydrofolic acid, and UDP-glucose may be used as key indicators in the hematological diagnosis and treatment of endometritis in dairy cows.

Development of a multiplex real-time PCR assay for the simultaneous detection of mpox virus and orthopoxvirus infections.

Since May 2022, the multi-country outbreak of monkeypox (mpox) has raised a great concern worldwide. Early detection of mpox virus infection is recognized as an efficient way to prevent mpox transmission. Mpox specific detection methods reported up to now are based on the SNPs among mpox virus and other orthopoxviruses. We have therefore developed a real-time PCR based mpox detection method targeting mpox virus specific sequences (N3R and B18Rplus). We have also optimized an orthopoxvirus detection system which targets the highly conserved E9L and D6R genes. The mpox and orthopoxvirus real-time PCR assays have a high sensitivity (1 copy/reaction) and specificity. Mpox viral DNA and clinical samples from mpox patients are detected with the mpox detection system. Furthermore, we have established a multiplex real-time PCR detection system allowing simultaneous and efficient detection of mpox and orthopoxvirus infections.

Androgen receptor activity inversely correlates with immune cell infiltration and immunotherapy response across multiple cancer lineages.

There is now increasing recognition of the important role of androgen receptor (AR) in modulating immune function. To gain a comprehensive understanding of the effects of AR activity on cancer immunity, we employed a computational approach to profile AR activity in 33 human tumor types using RNA-Seq datasets from The Cancer Genome Atlas. Our pan-cancer analysis revealed that the genes most negatively correlated with AR activity across cancers are involved in active immune system processes. Importantly, we observed a significant negative correlation between AR activity and IFNγ pathway activity at the pan-cancer level. Indeed, using a matched biopsy dataset from subjects with prostate cancer before and after AR-targeted treatment, we verified that inhibiting AR enriches immune cell abundances and is associated with higher IFNγ pathway activity. Furthermore, by analyzing immunotherapy datasets in multiple cancers, our results demonstrate that low AR activity was significantly associated with a favorable response to immunotherapy. Together, our data provide a comprehensive assessment of the relationship between AR signaling and tumor immunity.

Methodological and physiological study of seed dormancy release in Tilia henryana.

Tilia henryana is a rare tree of the Tilia family, found exclusively in China. Its seeds have severe dormancy features that limit its normal conditions of reproduction and renewal. Its seeds have severe dormant characteristics that limit its normal conditions of reproduction and renewal. The Dormancy in T. henryana seeds is a comprehensive dormancy (PY + PD) caused by mechanical and permeability barriers of seed coat and the presence of germination inhibitor in endosperm. L9 (34) orthogonal test was used to determine the best procedure for releasing the dormancy of T. henryana seeds, that is, first treating the seeds with H2SO4 for 15 min, followed by the application of 1 g L-1 GA3, stratification at 5 °C for 45 days, and finally germination at 20 °C, which can achieve a 98% seed germination rate. Large amounts of fat are consumed throughout the dormancy release process. As quantities of protein and starch marginally increase, soluble sugars are continuously decreased. Acid phosphatase and amylase activities increased rapidly, and the combined enzyme activities of G-6-PDH and 6-PGDH related to the PPP were also significantly increased. The levels of GA and ZR continued to increase, while the levels of ABA and IAA gradually decreased, among which GA and ABA changed most rapidly. The total amino acids content continued to decrease. Asp, Cys, Leu, Phe, His, Lys and Arg decreased with dormancy release, while Ser, Glu, Ala, Ile, Pro and Gaba showed an upward trend. The physical dormancy of T. henryana seeds is broken with H2SO4 in order to make the seed coat more permeable, which is a prerequisite for germination. As a result, the seeds can absorb water and engage in physiological metabolic activities, particularly the hydrolysis and metabolism of fat, which supply a significant amount of energy for dormancy release. In addition, rapid variations in the levels of different endogenous hormones and free amino acids, induced by cold stratification and GA3 application, are another important factor promoting the quick physiological activation of seeds and breaking the endosperm barrier.