Discovery of a novel BTK inhibitor S-016 and identification of a new strategy for the treatment of lymphomas including BTK inhibitor-resistant lymphomas.

Bruton's tyrosine kinase (BTK) has emerged as a therapeutic target for B-cell malignancies, which is substantiated by the efficacy of various irreversible or reversible BTK inhibitors. However, on-target BTK mutations facilitating evasion from BTK inhibition lead to resistance that limits the therapeutic efficacy of BTK inhibitors. In this study we employed structure-based drug design strategies based on established BTK inhibitors and yielded a series of BTK targeting compounds. Among them, compound S-016 bearing a unique tricyclic structure exhibited potent BTK kinase inhibitory activity with an IC50 value of 0.5 nM, comparable to a commercially available BTK inhibitor ibrutinib (IC50 = 0.4 nM). S-016, as a novel irreversible BTK inhibitor, displayed superior kinase selectivity compared to ibrutinib and significant therapeutic effects against B-cell lymphoma both in vitro and in vivo. Furthermore, we generated BTK inhibitor-resistant lymphoma cells harboring BTK C481F or A428D to explore strategies for overcoming resistance. Co-culture of these DLBCL cells with M0 macrophages led to the polarization of M0 macrophages toward the M2 phenotype, a process known to support tumor progression. Intriguingly, we demonstrated that SYHA1813, a compound targeting both VEGFR and CSF1R, effectively reshaped the tumor microenvironment (TME) and significantly overcame the acquired resistance to BTK inhibitors in both BTK-mutated and wild-type BTK DLBCL models by inhibiting angiogenesis and modulating macrophage polarization. Overall, this study not only promotes the development of new BTK inhibitors but also offers innovative treatment strategies for B-cell lymphomas, including those with BTK mutations.

Manipulating 2D Materials through Strain Engineering.

This review explores the growing interest in 2D layered materials, such as graphene, h-BN, transition metal dichalcogenides (TMDs), and black phosphorus (BP), with a specific focus on recent advances in strain engineering. Both experimental and theoretical results are delved into, highlighting the potential of strain to modulate physical properties, thereby enhancing device performance. Various strain engineering methods are summarized, and the impact of strain on the electrical, optical, magnetic, thermal, and valleytronic properties of 2D materials is thoroughly examined. Finally, the review concludes by addressing potential applications and challenges in utilizing strain engineering for functional devices, offering valuable insights for further research and applications in optoelectronics, thermionics, and spintronics.

CD3ε of a pan T cell marker involved in mouse Aspergillus fumigatus keratitis.

AIM: To explore whether CD3ε is involved in the adaptive immunity of Aspergillus fumigatus (A. fumigatus) keratitis in mice and the role of innate and adaptive immunity in it. METHODS: Mice models of A. fumigatus keratitis were established by intra-stromal injection and corneal epithelial scratching. Subconjunctival injections of natamycin, wedelolactone, LOX-1 inhibitor (poly I) or Dectin-1 inhibitor (laminarin) were used to treat mice with A. fumigatus keratitis. Mice were pretreated by intraperitoneal injection of anti-mouse CD3ε. We observed the corneal infection of mice under the slit lamp microscope and made a clinical score. The protein expression of CD3ε and interleukin-10 (IL-10) was determined by Western blotting. RESULTS: With the disease progresses, the degree of corneal opacity and edema augmented. In the intra-stromal injection models, CD3ε protein expression began to increase significantly on the 2nd day. However, in the scraping epithelial method models, CD3ε only began to increase on the 3rd day. After natamycin treatment, the degree of corneal inflammation in mice was significantly attenuated on the 3rd day. After wedelolactone treatment, the severity of keratitis worsened. And the amount of CD3ε protein was also reduced, compared with the control group. By inhibiting LOX-1 and Dectin-1, there was no significant difference in CD3ε production compared with the control group. After inhibiting CD3ε, corneal ulcer area and clinical score increased, and IL-10 expression was downregulated. CONCLUSION: As a pan T cell marker, CD3ε participate in the adaptive immunity of A. fumigatus keratitis in mice. In our mice models, the corneas will enter the adaptive immune stage faster. By regulating IL-10, CD3ε exerts anti-inflammatory and repairs effects in the adaptive immune stage.

PhosMap: An ensemble bioinformatic platform to empower interactive analysis of quantitative phosphoproteomics.

BACKGROUND: Liquid chromatography-mass spectrometry (LC-MS)-based quantitative phosphoproteomics has been widely used to detect thousands of protein phosphorylation modifications simultaneously from the biological specimens. However, the complicated procedures for analyzing phosphoproteomics data has become a bottleneck to widening its application. METHODS: Here, we develop PhosMap, a versatile and scalable tool to accomplish phosphoproteomics data analysis. A standardized phosphorylation data format was created for data analyses, from data preprocessing to downstream bioinformatic analyses such as dimension reduction, differential phosphorylation analysis, kinase activity, survival analysis, and so on. For better usability, we distribute PhosMap as a Docker image for easy local deployment upon any of Windows, Linux, and Mac system. RESULTS: The source code is deposited at https://github.com/BADD-XMU/PhosMap. A free PhosMap webserver (https://huggingface.co/spaces/Bio-Add/PhosMap), with easy-to-follow fashion of dashboards, is curated for interactive data analysis. CONCLUSIONS: PhosMap fills the technical gap of large-scale phosphorylation research by empowering researchers to process their own phosphoproteomics data expediently and efficiently, and facilitates better data interpretation.

Nuclear KRT19 is a transcriptional corepressor promoting histone deacetylation and liver tumorigenesis.

BACKGROUND AND AIMS: Epigenetic reprogramming and escape from terminal differentiation are poorly understood enabling characteristics of liver cancer. Keratin 19 (KRT19), classically known to form the intermediate filament cytoskeleton, is a marker of stemness and worse prognosis in liver cancer. This study aimed to address the functional roles of KRT19 in liver tumorigenesis and to elucidate the underlying mechanisms. APPROACH AND RESULTS: Using multiplexed genome editing of hepatocytes in vivo, we demonstrated that KRT19 promoted liver tumorigenesis in mice. Cell fractionation revealed a previously unrecognized nuclear fraction of KRT19. Tandem affinity purification identified histone deacetylase 1 and REST corepressor 1, components of the corepressor of RE-1 silencing transcription factor (CoREST) complex as KRT19-interacting proteins. KRT19 knockout markedly enhanced histone acetylation levels. Mechanistically, KRT19 promotes CoREST complex formation by enhancing histone deacetylase 1 and REST corepressor 1 interaction, thus increasing the deacetylase activity. ChIP-seq revealed hepatocyte-specific genes, such as hepatocyte nuclear factor 4 alpha ( HNF4A ), as direct targets of KRT19-CoREST. In addition, we identified forkhead box P4 as a direct activator of aberrant KRT19 expression in liver cancer. Furthermore, treatment of primary liver tumors and patient-derived xenografts in mice suggest that KRT19 expression has the potential to predict response to histone deacetylase 1 inhibitors especially in combination with lenvatinib. CONCLUSIONS: Our data show that nuclear KRT19 acts as a transcriptional corepressor through promoting the deacetylase activity of the CoREST complex, resulting in dedifferentiation of liver cancer. These findings reveal a previously unrecognized function of KRT19 in directly shaping the epigenetic landscape in cancer.

A Novel IRAK4 Inhibitor DW18134 Ameliorates Peritonitis and Inflammatory Bowel Disease.

IRAK4 is a critical mediator in NF-κB-regulated inflammatory signaling and has emerged as a promising therapeutic target for the treatment of autoimmune diseases; however, none of its inhibitors have received FDA approval. In this study, we identified a novel small-molecule IRAK4 kinase inhibitor, DW18134, with an IC50 value of 11.2 nM. DW18134 dose-dependently inhibited the phosphorylation of IRAK4 and IKK in primary peritoneal macrophages and RAW264.7 cells, inhibiting the secretion of TNF-α and IL-6 in both cell lines. The in vivo study demonstrated the efficacy of DW18134, significantly attenuating behavioral scores in an LPS-induced peritonitis model. Mechanistically, DW18134 reduced serum TNF-α and IL-6 levels and attenuated inflammatory tissue injury. By directly blocking IRAK4 activation, DW18134 diminished liver macrophage infiltration and the expression of related inflammatory cytokines in peritonitis mice. Additionally, in the DSS-induced colitis model, DW18134 significantly reduced the disease activity index (DAI) and normalized food and water intake and body weight. Furthermore, DW18134 restored intestinal damage and reduced inflammatory cytokine expression in mice by blocking the IRAK4 signaling pathway. Notably, DW18134 protected DSS-threatened intestinal barrier function by upregulating tight junction gene expression. In conclusion, our findings reported a novel IRAK4 inhibitor, DW18134, as a promising candidate for treating inflammatory diseases, including peritonitis and IBD.

Research Status and Progress of Studies on Optic Disc Structures in Non-arteritic Anterior Ischemic Optic Neuropathy.

Objective: Non-arteritic anterior ischemic optic neuropathy (NAION) is a prevalent acute optic neuropathy. This article provides a comprehensive overview of the research advancements in regional optic disc structural changes and local risk factors among NAION patients, aiming to establish a foundation for clinical diagnosis, treatment, and future follow-up investigations. Methods: One English database and two Chinese databases were utilized for the purpose of conducting a comprehensive literature search, followed by meticulous analysis. The investigation encompassed an in-depth exploration of the optic disc's structural composition, as well as a thorough examination of the distinctive characteristics exhibited by NAION optic discs. Furthermore, this study aimed to elucidate the intricate relationship between NAION and ODD (Optic Disc Drusen) alongside PHOMS (Peripapillary Hyperreflective Ovoid Mass-like Structures). Results: A total of 44 English articles were retrieved from Pubmed, including case reports, clinical trials, and reviews. Keywords retrieved included NAION, optic disc, optic disc drusen, PHOMS. Conclusion: The risk factors of NAION include systemic factors such as hypertension, diabetes, and nocturnal hypotension and local factors such as small optic cup, crowded optic discs, ODD and PHOMS. Among them, ODD and PHOMS are the local anatomical changes of the optic disc, and their relationship with the occurrence of NAION has received more and more attention in recent years. NAION is more likely to occur in eyes with ODD and PHOMS, and NAION patients with ODD and PHOMS have a high prevalence. In recent years, optical coherence tomography (OCT) and optical coherence tomography angiography(OCTA) can provide accurate anatomical imaging and microvascular imaging. Help us better observe the local structural changes and local-related risk factors. Although ODD and PHOMS are closely associated with the occurrence and progression of NAION, research on their relationship is still in its nascent stages. Specifically, further investigation is needed to determine whether the presence of ODD and PHOMS affects the prognosis of NAION patients, including potential influences on lateral eye involvement.This article summarizes the changes in optic disc structure and local risk factors in NAION patients in order to clinical decision making in NIAON patients and provide a basis for further Research on the relationship between the occurrence of NIAON and optic disc structure.

Asynchronous propagation of atomic force and excited electronic charge in GaAs under proton irradiation.

The studies for the interaction of energetic particles with matter have greatly contributed to the exploration of material properties under irradiation conditions, such as nuclear safety, medical physics and aerospace applications. In this work, we theoretically simulate the non-adiabatic process for GaAs upon proton irradiation using time-dependent density functional theory, and find that the radial propagation of force on atoms and the excitation of electron in GaAs are non-synchronous process. We calculated the electronic stopping power on proton with the velocity of 0.1-0.6 a.u., agreement with the previous empirical results. After further analyzing the force on atoms and the population of excited electrons, we find that under proton irradiation, the electrons around the host atoms at different distances from the proton trajectories are excited almost simultaneously, especially those regions with relatively high charge density. However, the distant atoms have a significant hysteresis in force, which occurs after the surrounding electrons are excited. In addition, hysteresis in force and electron excitation behavior at different positions are closely related to the velocity of proton. This non-synchronous propagation reveals the microscopic dynamic mechanism of energy deposition into the target material under ion irradiation.

Factors affecting the reproductive outcome in reciprocal translocation carriers undergoing preimplantation genetic testing for structural rearrangements (PGTSR).

OBJECTIVE: To investigate the reproductive outcomes of balanced reciprocal translocation carriers and evaluate the association between the number of metaphase-II oocytes retrieved and cumulative live birth rates (LBRs). METHODS: This retrospective analysis included 344 preimplantation genetic testing (PGT) for structural rearrangement cycles of 281 couples with balanced reciprocal translocations between January 2018 and January 2021. All patients included in the analysis had either delivered a baby or had used all their embryos after one stimulation cycle. All women were followed up for at least 2 years. RESULTS: After ovarian stimulation and oocyte fertilization, 44.2% of PGT for structural rearrangements cycles achieved a live birth. Carrier's sex and female age did not affect the cumulative LBR of reciprocal translocation carriers. Cumulative LBRs steadily increased with the number of oocytes, reaching 64% when >20 oocytes were retrieved. The cutoff values for achieving at least one live birth were 9.5 metaphase-II (MII) oocytes and 3.5 biopsied embryos. CONCLUSION: Couples with reciprocal translocations have lower transferable embryo rates and cumulative LBRs. The MII oocytes retrieved may be a crucial factor for cumulative LBRs. A high ovarian response may further increase cumulative LBRs, but avoidance of ovarian hyperstimulation syndrome or other iatrogenic complications should be considered.

Luteal phase support of intramuscular progesterone associated with lower hypertensive disorders of pregnancy as compared to vaginal progesterone: A cohort study.

OBJECTIVE: To compare the hypertensive disorders of pregnancy (HDP) risk between vaginal and intramuscular (IM) progesterone in programmed frozen-thawed embryo transfer (FET) cycles. METHODS: This was a retrospective cohort study at a tertiary hospital, and only women who achieved ongoing pregnancy after programmed FET between January 2018 and June 2022 were included. Women with chronic hypertension before pregnancy or with history of gestational hypertension or pre-eclampsia in previous pregnancies were excluded. All women were divided into IM progesterone or vaginal progesterone groups according to the route of progesterone supplementation. Follow-up information on obstetric complications and neonatal outcomes were obtained by telephonic interviews. The primary outcome was HDP. Association between routes of progesterone supplementation and HDP was assessed by subgroup analysis and multivariable logistic regression. RESULTS: A total of 5891 programmed FET cycles (3196 IM progesterone cycles and 2695 vaginal progesterone cycles) were included in the analysis. The prevalence of HDP in the IM progesterone group was significantly lower than that of the vaginal progesterone group (6.54% vs 9.17%, P < 0.001). Therein, the prevalence of gestational hypertension (3.57% vs 4.94%, P = 0.009) and pre-eclampsia (2.97% vs 4.23%, P = 0.009) in the IM progesterone group were all significantly lower as compared to the vaginal progesterone group. According to subgroup analysis, IM progesterone was associated with lower HDP risk in all subgroups. The logistic regression analysis showed that the IM progesterone cycles were associated with lower risk of HDP compared to vaginal progesterone cycles (adjusted odds ratio 0.66, 95% CI: 0.54-0.80, P < 0.001). CONCLUSION: Among women undergoing programmed FET cycles, progesterone supplementation with IM progesterone was associated with reduced HDP risk compared to vaginal progesterone.

ATG7/GAPLINC/IRF3 axis plays a critical role in regulating pathogenesis of influenza A virus.

Autophagy-related protein 7 (ATG7) is an essential autophagy effector enzyme. Although it is well known that autophagy plays crucial roles in the infections with various viruses including influenza A virus (IAV), function and underlying mechanism of ATG7 in infection and pathogenesis of IAV remain poorly understood. Here, in vitro studies showed that ATG7 had profound effects on replication of IAV. Depletion of ATG7 markedly attenuated the replication of IAV, whereas overexpression of ATG7 facilitated the viral replication. ATG7 conditional knockout mice were further employed and exhibited significantly resistant to viral infections, as evidenced by a lower degree of tissue injury, slower body weight loss, and better survival, than the wild type animals challenged with either IAV (RNA virus) or pseudorabies virus (DNA virus). Interestingly, we found that ATG7 promoted the replication of IAV in autophagy-dependent and -independent manners, as inhibition of autophagy failed to completely block the upregulation of IAV replication by ATG7. To determine the autophagy-independent mechanism, transcriptome analysis was utilized and demonstrated that ATG7 restrained the production of interferons (IFNs). Loss of ATG7 obviously enhanced the expression of type I and III IFNs in ATG7-depleted cells and mice, whereas overexpression of ATG7 impaired the interferon response to IAV infection. Consistently, our experiments demonstrated that ATG7 significantly suppressed IRF3 activation during the IAV infection. Furthermore, we identified long noncoding RNA (lncRNA) GAPLINC as a critical regulator involved in the promotion of IAV replication by ATG7. Importantly, both inactivation of IRF3 and inhibition of IFN response caused by ATG7 were mediated through control over GAPLINC expression, suggesting that GAPLINC contributes to the suppression of antiviral immunity by ATG7. Together, these results uncover an autophagy-independent mechanism by which ATG7 suppresses host innate immunity and establish a critical role for ATG7/GAPLINC/IRF3 axis in regulating IAV infection and pathogenesis.

2D van der Waals Vertical Heterojunction Transistors for Ternary Neural Networks.

Compared with binary systems, ternary computing systems can utilize fewer devices to realize the same information density. However, most ternary computing systems based on binary CMOS circuits require additional devices to bridge binary processing and ternary computing. Exploring new device architectures for direct ternary processing and computing becomes the key to promoting ternary computing systems. Here, we demonstrated a 2D van der Waals vertical heterojunction transistor (V-HTR) with three flat conductance states, which can be the basic cell in ternary circuits to perform ternary processing and computing, without additional devices. A ternary neural network (TNN) and a ternary inverter were demonstrated based on the V-HTRs. The TNN can eliminate fuzzy data and output only clear data by building a ternary quantization function. By demonstrating both ternary logic and a TNN on the same device architecture, the 2D V-HTR shows potential as a basic hardware unit for future ternary computing systems.

Toxicity spectrum and risk factors for chemo-immunotherapy in locally advanced or metastatic lung cancer.

Chemo-immunotherapy has become the best first-line treatment for advanced lung cancer patients without oncogenic drivers. However, it may also lead to an increased incidence and severity of treatment-related adverse events. In this retrospective study, lung cancer patients administrated with either anti-PD-1 or anti-PD-L1 treatment plus chemotherapy were included. Data on demographic characteristics, disease characteristics, treatment strategies, laboratory results, and clinical outcomes were collected from the Electronic Medical Records System and evaluation scales. Chi-square, univariate, and multivariate logistic regression analyses were used to identify the risk factors for immune-related adverse events (irAEs). A total of 116 patients were included in the study, and the majority experienced treatment-related adverse events. Adverse events of any grade were reported in 114 (98.3%) patients, with 73 (62.9%) experiencing Grade 3 or higher events. The most frequent adverse events were anemia (67.2%), decreased appetite (62.9%), and alopecia (53.4%). Fifty-four (46.6%) patients were diagnosed with irAEs, with hypothyroidism (28.4%) being the most commonly reported. Multivariable analysis demonstrated a significant correlation between the number of treatment cycles, elevated baseline levels of thyroid stimulating hormone (TSH) and interleukin-6 (IL-6) with irAEs (OR = 1.222, P = 0.009, OR = 1.945, P = 0.016, OR = 1.176, P = 0.004), and IL-6 was identified as a strong predictor of severe irAEs (OR = 1.084, P = 0.014). Our study demonstrated the safety of chemo-immunotherapy in lung cancer patients without additional toxicity. The number of treatment cycles, higher baseline levels of TSH and IL-6 were identified as potential clinical biomarkers for irAEs.

A liposomal etoposide with a sustained drug release effectively alleviated the therapy-related leukemia.

Etoposide (VP16) can induce therapy-related leukemia, which is reported to occur less frequently with a prolonged dose schedule. Therefore, we hypothesized that nanocarriers could decrease the VP16-induced leukemogenesis by reducing the rate of VP16 exposure via a sustained drug release. To test our hypothesis, the VP16-loaded liposome with a slow drug release behavior was constructed by encapsulating a rapidly-cleaved VP16-maleimide conjugate into liposomes using a glutathione-gradient loading method, and its toxicities and in vivo antitumor efficacy were compared with free VP16 in the LLC lung cancer xenograft. It was found that the repeated injection of free VP16 induced severe splenomegaly, lymphocytosis, and extensive lymphocyte infiltration in various tissues, indicating a sign of VP16 therapy-related leukemia. By contrast, the liposomal VP16 not only remarkably alleviated the syndrome of leukemogenesis, but also exhibited significantly enhanced antitumor activity as compared with free VP16 at the same dose. These results highlighted that the liposomal VP16 having a sustained drug release could effectively decrease the toxicity of leukemogenesis, which provided a new warranty to develop liposomal VP16 as a safe alternative to the commercial VP16 injection.

SCM is potential resource for non-invasive preimplantation genetic testing based on human embryos single-cell sequencing.

The ongoing development of assisted reproductive technologies has provided hope to individuals struggling with infertility, promising the potential for a healthy pregnancy. One significant innovation in field of pre-implantation genetic screening (PGS) requires the biopsy of embryos or oocytes, which has potential implications for the health and development of the resultant offspring. Therefore, a non-invasive approach to preimplantation genetic screening is highly sought after. The clinical application of non-invasive preimplantation genetic testing (ni-PGT) is currently limited, with its sensitivity and specificity requiring further investigation. In this study, we used 218 human embryos for single-cell whole genome amplification (WGA), along with ni-PGT of blastocoele fluid (BF) and spent culture medium (SCM). Whole blastocyst (WB), trophectoderm biopsy (TB), and inner cell mass (ICM) from embryo biopsies were used as controls to track genomic signal alterations. Our results showed that the overall genome similarity between SCM and ICM was higher than that of BF. Apart from the Y chromosome, both SCM and ICM demonstrated numerous variant sites across other chromosomes.Further categorization of gene variants in these two sample types revealed that missense variants were the most prevalent, single nucleotide polymorphisms were more common than insertions or deletions, and C > T was the dominant single nucleotide variants in both ICM and SCM. Lastly, we found that the mutant genes in SCM and ICM had different biological functions and pathways. This study indicates that SCM provides a more effective source of embryonic DNA for preimplantation genetic screening, offering a novel reference point for genetic screening research.

Glycans in spent embryo culture medium are related to the implantation ability of blastocysts.

Research question: Does glycan profile in spent blastocyst culture medium have the potential to be used as a biomarker to predict implantation outcome. Design: A nested case-control study was conducted in Northwest women's and children's Hospital, Xi'an, China. The patients underwent fresh IVF/ICSI cycles with single blastocyst transfer were included. Total 78 cases were included and separated into groups according to success (n = 39) and failure (n = 39) implantation outcomes. The glycosylation patterns in spent blastocyst culture medium were detected by lectin microarray containing 37 lectins using pooled samples and confirmed by reversed lectin microarray using individual sample. Results: Binding signals of 10 lectins were found to be different between samples from successful and failed implantation. And 8 of them were confirmed that glycans binding to lectin NPA, UEA-I, MAL-I, LCA and GNA were significantly increased while DBA and BPL were decreased in the successful implantation compared to failed implantation. The glycan binding to lectin PHA-E + L had no difference between two groups. No significant differences in the glycan profile were found in spent culture medium of embryos with different morphological grades except the glycan binding to UEA-I between blastocysts of Poor and blastocysts of Medium. Conclusion: Detection of glycan profile in spent culture medium may lead to a novel non-invasive assessment assay of embryo viability. In addition, these results may be helpful to further understanding molecular mechanisms in embryo implantation.

Manipulating exchange bias in 2D magnetic heterojunction for high-performance robust memory applications.

The exchange bias (EB) effect plays an undisputed role in the development of highly sensitive, robust, and high-density spintronic devices in magnetic data storage. However, the weak EB field, low blocking temperature, as well as the lack of modulation methods, seriously limit the application of EB in van der Waals (vdW) spintronic devices. Here, we utilized pressure engineering to tune the vdW spacing of the two-dimensional (2D) FePSe3/Fe3GeTe2 heterostructures. The EB field (HEB, from 29.2 mT to 111.2 mT) and blocking temperature (Tb, from 20 K to 110 K) are significantly enhanced, and a highly sensitive and robust spin valve is demonstrated. Interestingly, this enhancement of the EB effect was extended to exposed Fe3GeTe2, due to the single-domain nature of Fe3GeTe2. Our findings provide opportunities for the producing, exploring, and tuning of magnetic vdW heterostructures with strong interlayer coupling, thereby enabling customized 2D spintronic devices in the future.

Hormone replacement treatment regimen is associated with a higher risk of hypertensive disorders of pregnancy in women undergoing frozen-thawed embryo transfer.

Introduction: In frozen-thawed embryo transfer (FET) cycles, hormone replacement treatment (HRT) was associated with a higher risk of hypertensive disorders of pregnancy (HDP) compared with natural cycles (NC). Multiple pregnancy was a risk factor for HDP and several studies did not conduct subgroup analysis of singleton pregnancy and multiple pregnancy. Objective: To investigate whether HRT regimen could be a risk factor for HDP in women undergoing FET cycles in singleton and twin pregnancies. Methods: A retrospective cohort study at a tertiary hospital, including a total of 9120 women who underwent FET and achieved ongoing pregnancy; 7590 patients underwent HRT-FET and 1530 NC-FET. The main outcome was HDP. HDP were analyzed for singleton and twin pregnancies, respectively. Results: In the singleton pregnancy, the risk of HDP in the HRT-FET group was significantly higher than that in the NC-FET group (6.21% vs. 4.09%; P=0.003). After adjusting for female age oocyte pick up, female age at FET and body mass index (BMI), HRT was found as a risk factor for HDP (adjusted odds ration [aOR]: 1.43; 95% confidence interval [CI]: 1.07 to 1.91; P=0.017). In the multiple pregnancy, the risk of HDP in the HRT-FET and NC-FET groups was similar. Conclusion: HRT was associated with a higher risk of HDP in women who underwent FET and achieved singleton pregnancy.

SARS-CoV-2 Spike Protein Post-Translational Modification Landscape and Its Impact on Protein Structure and Function via Computational Prediction.

To elucidate the role of post-translational modifications (PTMs) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein's structure and virulence, we generated a high-resolution map of 87 PTMs using liquid chromatography with tandem mass spectrometry data on the extracted spike protein from SARS-CoV-2 virions and then reconstituted its structure heterogeneity caused by PTMs. Nonetheless, Alphafold2, a high-accuracy artificial intelligence tool to perform protein structure prediction, relies solely on primary amino acid sequence, whereas the impact of PTM, which often modulates critical protein structure and function, is much ignored. To overcome this challenge, we proposed the mutagenesis approach-an in silico, site-directed amino acid substitution to mimic the influence of PTMs on protein structure due to altered physicochemical properties in the post-translationally modified amino acids-and then reconstituted the spike protein's structure from the substituted sequences by Alphafold2. For the first time, the proposed method revealed predicted protein structures resulting from PTMs, a problem that Alphafold2 has yet to address. As an example, we performed computational analyses of the interaction of the post-translationally modified spike protein with its host factors such as angiotensin-converting enzyme 2 to illuminate binding affinity. Mechanistically, this study suggested the structural analysis of post-translationally modified protein via mutagenesis and deep learning. To summarize, the reconstructed spike protein structures showed that specific PTMs can be used to modulate host factor binding, guide antibody design, and pave the way for new therapeutic targets. The code and Supplementary Materials are freely available at https://github.com/LTZHKUSTGZ/SARS-CoV-2-spike-protein-PTM.

Multilevel proteomic analyses reveal molecular diversity between diffuse-type and intestinal-type gastric cancer.

Diffuse-type gastric cancer (DGC) and intestinal-type gastric cancer (IGC) are the major histological types of gastric cancer (GC). The molecular mechanism underlying DGC and IGC differences are poorly understood. In this research, we carry out multilevel proteomic analyses, including proteome, phospho-proteome, and transcription factor (TF) activity profiles, of 196 cases covering DGC and IGC in Chinese patients. Integrative proteogenomic analysis reveals ARIDIA mutation associated with opposite prognostic effects between DGC and IGC, via diverse influences on their corresponding proteomes. Systematical comparison and consensus clustering analysis identify three subtypes of DGC and IGC, respectively, based on distinct patterns of the cell cycle, extracellular matrix organization, and immune response-related proteins expression. TF activity-based subtypes demonstrate that the disease progressions of DGC and IGC were regulated by SWI/SNF and NFKB complexes. Furthermore, inferred immune cell infiltration and immune clustering show Th1/Th2 ratio is an indicator for immunotherapeutic effectiveness, which is validated in an independent GC anti-PD1 therapeutic patient group. Our multilevel proteomic analyses enable a more comprehensive understanding of GC and can further advance the precision medicine.