Live birth of chimeric monkey with high contribution from embryonic stem cells.

A formal demonstration that mammalian pluripotent stem cells possess preimplantation embryonic cell-like (naive) pluripotency is the generation of chimeric animals through early embryo complementation with homologous cells. Whereas such naive pluripotency has been well demonstrated in rodents, poor chimerism has been achieved in other species including non-human primates due to the inability of the donor cells to match the developmental state of the host embryos. Here, we have systematically tested various culture conditions for establishing monkey naive embryonic stem cells and optimized the procedures for chimeric embryo culture. This approach generated an aborted fetus and a live chimeric monkey with high donor cell contribution. A stringent characterization pipeline demonstrated that donor cells efficiently (up to 90%) incorporated into various tissues (including the gonads and placenta) of the chimeric monkeys. Our results have major implications for the study of primate naive pluripotency and genetic engineering of non-human primates.

Cloning of Macaque Monkeys by Somatic Cell Nuclear Transfer.

Generation of genetically uniform non-human primates may help to establish animal models for primate biology and biomedical research. In this study, we have successfully cloned cynomolgus monkeys (Macaca fascicularis) by somatic cell nuclear transfer (SCNT). We found that injection of H3K9me3 demethylase Kdm4d mRNA and treatment with histone deacetylase inhibitor trichostatin A at one-cell stage following SCNT greatly improved blastocyst development and pregnancy rate of transplanted SCNT embryos in surrogate monkeys. For SCNT using fetal monkey fibroblasts, 6 pregnancies were confirmed in 21 surrogates and yielded 2 healthy babies. For SCNT using adult monkey cumulus cells, 22 pregnancies were confirmed in 42 surrogates and yielded 2 babies that were short-lived. In both cases, genetic analyses confirmed that the nuclear DNA and mitochondria DNA of the monkey offspring originated from the nucleus donor cell and the oocyte donor monkey, respectively. Thus, cloning macaque monkeys by SCNT is feasible using fetal fibroblasts.

EGFR signaling controls directionality of epithelial multilayer formation upon loss of cell polarity.

Apical-basal polarity is maintained by distinct protein complexes that reside in membrane junctions, and polarity loss in monolayered epithelial cells can lead to formation of multilayers, cell extrusion, and/or malignant overgrowth. Yet, how polarity loss cooperates with intrinsic signals to control directional invasion toward neighboring epithelial cells remains elusive. Using the Drosophila ovarian follicular epithelium as a model, we found that posterior follicle cells with loss of lethal giant larvae (lgl) or Discs large (Dlg) accumulate apically toward germline cells, whereas cells with loss of Bazooka (Baz) or atypical protein kinase C (aPKC) expand toward the basal side of wildtype neighbors. Further studies revealed that these distinct multilayering patterns in the follicular epithelium were determined by epidermal growth factor receptor (EGFR) signaling and its downstream target Pointed, a zinc-finger transcription factor. Additionally, we identified Rho kinase as a Pointed target that regulates formation of distinct multilayering patterns. These findings provide insight into how cell polarity genes and receptor tyrosine kinase signaling interact to govern epithelial cell organization and directional growth that contribute to epithelial tumor formation.

Nutrient deprivation induces mouse embryonic diapause mediated by Gator1 and Tsc2.

Embryonic diapause is a special reproductive phenomenon in mammals that helps embryos to survive various harsh stresses. However, the mechanisms of embryonic diapause induced by the maternal environment is still unclear. Here, we uncovered that nutrient deficiency in uterine fluid was essential for the induction of mouse embryonic diapause, shown by a decreased concentration of arginine, leucine, isoleucine, lysine, glucose and lactate in the uterine fluid of mice suffering from maternal starvation or ovariectomy. Moreover, mouse blastocysts cultured in a medium with reduced levels of these six components could mimic diapaused blastocysts. Our mechanistic study indicated that amino acid starvation-dependent Gator1 activation and carbohydrate starvation-dependent Tsc2 activation inhibited mTORC1, leading to induction of embryonic diapause. Our study elucidates the essential environmental factors in diapause induction.

Preferred Orientation Deposition via Multifunctional Gel Electrolyte with Molecular Anchor Enabling Highly Reversible Zn Anode.

The high activity of water molecules results in a series of awful parasitic reaction, which seriously impede the development of aqueous zinc batteries. Herein, a new gel electrolyte with multiple molecular anchors is designed by employing natural biomaterials from chitosan and chlorophyll derivative. The gel electrolyte firmly anchors water molecules by ternary hydrogen bonding to reduce the activity of water molecules and inhibit hydrogen evolution reaction. Meanwhile, the multipolar charged functional groups realize the gradient induction and redistribution of Zn2+ , which drives oriented Zn (002) plane deposition of Zn2+ and then achieves uniform Zn deposition and dendrite-free anode. As a result, it endows the Zn||Zn cell with over 1700 h stripping/plating processes and a high efficiency of 99.4% for the Zn||Cu cell. In addition, the Zn||V2 O5 full cells also exhibit capacity retention of 81.7% after 600 cycles at 0.5 A g-1 and excellent long-term stability over 1600 cycles at 2 A g-1 , and the flexible pouch cells can provide stable power for light-emitting diodes even after repeated bending. The gel electrolyte strategy provides a reference for reversible zinc anode and flexible wearable devices.

Improved Photovoltaic Performance of Inverted Two-Dimensional Perovskite Solar Cells via a Simple Molecular Bridge on Buried Interface.

NiOx-based two-dimensional perovskite solar cells (2D-PSCs) have the advantages of low fabrication temperature, suitable energy level matching, suppressed hysteresis, and superior stability, while the poor interfacial contacts between NiOx and perovskite layers limit the perovskite film growth and charge transfer. Herein, a simple molecule, urea, was used as a molecular modifier to form bifacial passivation on the buried interface of NiOx/perovskite, resulting in better interfacial contact and efficient bifacial passivation. We demonstrated that efficient bifacial passivation mainly comes from strong interactions between urea and NiOx or perovskite, which make urea a molecular bridge for smoother charge transfer. Moreover, urea can regulate the ratio of Ni3+/Ni2+, therefore boosting the conductivity of NiOx, and adjust the morphology of the NiOx film for better 2D-perovskite crystal growth. Besides, urea also passivates the bifacial defect states of both NiOx and perovskite film, yielding reduced defect density of the perovskite film and superior charge transfer on the buried interface. Consequently, inverted 2D-PSCs with urea modification proved significant improvements in short-circuit current density and fill factor, resulting in improved power conversion efficiency from 14.64 to 16.84% with better stability in air.

ORP8 inhibits renal cell carcinoma progression by accelerating Stathmin1 degradation and microtubule polymerization.

ORP8 has been reported to suppress tumor progression in various malignancies. However, the functions and underlying mechanisms of ORP8 are still unknown in renal cell carcinoma (RCC). Here, decreased expression of ORP8 was detected in RCC tissues and cell lines. Functional assays verified that ORP8 suppressed RCC cell growth, migration, invasion, and metastasis. Mechanistically, ORP8 attenuated Stathmin1 expression by accelerating ubiquitin-mediated proteasomal degradation and led to an increase in microtubule polymerization. Lastly, ORP8 knockdown partly rescued microtubule polymerization, as well as aggressive cell phenotypes induced by paclitaxel. Our findings elucidated that ORP8 suppressed the malignant progression of RCC by increasing Stathmin1 degradation and microtubule polymerization, thus suggesting that ORP8 might be a novel target for the treatment of RCC.

The association between hepatitis B virus and semen quality: a systematic review and meta-analysis.

BACKGROUND: Some studies have suggested that hepatitis B virus (HBV) infection had a negative association with semen quality, but the conclusions have been inconsistent. The purpose of our study was to systematically assess the association between HBV infection and semen parameters. METHODS: We searched electronic databases for studies published from January 1980 to August 2023. Eleven studies were included in the analysis. Primary outcomes were semen volume, sperm concentration, sperm morphology, sperm motility and sperm progressive motility. We also conducted a subgroup analysis between China and other countries. RESULT: Compared with the semen quality of HBV-negative men, HBV infection had a negative association with semen volume (MD: -0.20 mL, 95%CI: -0.32 to - 0.09, P = 0.0004), sperm concentration (MD: -4.46 × 106/mL, 95%CI: -7.09 to - 1.84, P = 0.0009), sperm morphology (MD: -2.49%, 95%CI: -4.35 to - 0.64, P = 0.008), sperm motility (MD: -6.85%, 95%CI: -11.53 to - 2.18, P = 0.004), and sperm progressive motility (MD: -6.63%, 95%CI: -10.24 to - 3.02, P = 0.0003). However, HBV infection had no significant association with total sperm count (MD: -31.50 × 106, 95%CI: -74.11 to 11.10, P = 0.15). The association between HBV and semen quality were inconsistent between the subgroups. CONCLUSION: HBV infection had a negative association with sperm concentration, motility, morphology, and semen volume. However, The association between HBV and total sperm count remain unclear. This metaanalysis suggests that we should pay attention to the adverse effect of HBV on sperm quality, and several studies have reported the relevant mechanisms. But due to the significant heterogeneity among studies on some semen parameters, further large and well-designed researches are needed before introducing clinical management recommendations.

Remodeling Zinc Deposition via Multisite Zincophilic Chlorophyll for Powerful Aprotic Zinc Batteries.

The organic electrolyte can resolve the hurdle of hydrogen evolution in aqueous electrolytes but suffers from sluggish electrochemical reaction kinetics due to a compromised mass transfer process. Herein, we introduce a chlorophyll, zinc methyl 3-devinyl-3-hydroxymethyl-pyropheophorbide-a (Chl), as a multifunctional electrolyte additive for aprotic zinc batteries to address the related dynamic problems in organic electrolyte systems. The Chl exhibits multisite zincophilicity, which significantly reduces the nucleation potential, increases the nucleation sites, and induces uniform nucleation of Zn metal with a nucleation overpotential close to zero. Furthermore, the lower LUMO of Chl contributes to a Zn-N-bond-containing SEI layer and inhibits the decomposition of the electrolyte. Therefore, the electrolyte enables repeated zinc stripping/plating up to 2000 h (2 Ah cm-2 cumulative capacity) with an overpotential of only 32 mV and a high Coulomb efficiency of 99.4%. This work is expected to enlighten the practical application of organic electrolyte systems.

Structural and rheological characterization of water-soluble and alkaline-soluble fibers from hulless barley.

BACKGROUND: Highland hulless barley has garnered attention as a promising economic product and a potential healthy food ingredient. The present study aimed to comprehensively investigate the molecular structure of extractable fibers obtained from a specific highland hulless barley. Water-soluble fiber (WSF) and alkaline-soluble fiber (ASF) were extracted using enzymatic digestion and an alkaline method, respectively. The purified fibers underwent a thorough investigation for their structural characterization. RESULTS: The monosaccharide composition revealed that WSF primarily consisted of glucose (91.7%), whereas ASF was composed of arabinose (54.5%) and xylose (45.5%), indicating the presence of an arabinoxylan molecule with an A/X ratio of 1.2. The refined structural information was further confirmed through methylation, 1 H NMR and Fourier-transform infrared spectroscopy analyses. WSF fiber exclusively exhibited α-anomeric patterns, suggesting it was an α-glucan. It has a low molecular weight of 5 kDa, as determined by gel permeation chromatography. Conversely, ASF was identified as a heavily branched arabinoxylan with 41.55% of '→2,3,4)-Xylp-(1→' linkages. ASF and WSF exhibited notable differences in their morphology, water absorption capabilities and rheological properties. CONCLUSION: Based on these findings, molecular models of WSF and ASF were proposed. The deep characterization of these fiber structures provides valuable insights into their physicochemical and functional properties, thereby unlocking their potential applications in the food industry. © 2023 Society of Chemical Industry.

Research progress in female pelvic floor rehabilitation aids. / å¥³æ€§ç›†åº•åº·å¤è¾ åŠ©å™¨å ·çš„ç ”ç©¶è¿›å±•.

Pelvic floor dysfunction (PFD) is a common clinical problem that can lead to bladder and bowel dysfunction such as urinary incontinence, urinary retention, fecal incontinence, pelvic organ prolapse, and sexual dysfunction. Pelvic floor rehabilitation aids are essential tools in the treatment of PFD. However, there is limited understanding of the efficacy and mechanisms of these aids, and there is a lack of standardized guidelines for selecting appropriate aids for different types of PFD. To assist patients in choosing suitable pelvic floor rehabilitation aids to their needs, it is necessary to summarize the existing types, mechanisms, and applications of these aids. Based on their mechanisms and target functions, pelvic floor rehabilitation aids can be mainly categorized into 3 main types. The first type includes aids that improve pelvic floor function, such as vaginal dumbbells, vaginal tampons, and vaginal dilators, which aim to strengthen pelvic floor muscles and enhance the contractility of the urethral, vaginal, and anal sphincters, thereby improving incontinence symptoms. The second type consists of aids that mechanically block the outlet, such as pessaries, urethral plugs, incontinence pads, incontinence pants, anal plugs, and vaginal bowel control systems, which directly or indirectly prevent incontinence leakage. The third type includes aids that assist in outlet drainage, such as catheters and anal excreta collection devices, which help patients effectively expel urine, feces, and other waste materials, preventing incontinence leakage. By summarizing the existing pelvic floor rehabilitation aids, personalized guidance can be provided to patients with PFD, helping them select the appropriate aids for their rehabilitation needs.

Cobalt-Doped Bismuth Nanosheet Catalyst for Enhanced Electrochemical CO2 Reduction to Electrolyte-Free Formic acid.

Electrochemical carbon dioxide (CO2) reduction reaction (CO2RR) to valuable liquid fuels, such as formic acid/formate (HCOOH/HCOO-) is a promising strategy for carbon neutrality. Enhancing CO-2RR activity while retaining high selectivity is critical for commercialization. To address this, we developed metal-doped bismuth (Bi) nanosheets via a facile hydrolysis method. These doped nanosheets efficiently generated high-purity HCOOH using a porous solid electrolyte (PSE) layer. Among the evaluated metal-doped Bi catalysts, Co-doped Bi demonstrated improved CO2RR performance compared to pristine Bi, achieving ~90% HCOO- selectivity and boosted activity with a low overpotential of ~1.0 V at a current density of 200 mA cm-2. In a solid electrolyte reactor, Co-doped Bi maintained HCOOH Faradaic efficiency of ~72% after a 100-hour operation under a current density of 100 mA cm-2, generating 0.1 M HCOOH at 3.2 V. Density functional theory (DFT) results revealed that Co-doped Bi required a lower applied potential for HCOOH generation from CO2, due to stronger binding energy to the key intermediates OCHO* compared to pure Bi. This study shows that metal doping in Bi nanosheets modifies the chemical composition, element distribution, and morphology, improving CO2RR catalytic activity performance by tuning surface adsorption affinity and reactivity.

Electrochemical C-N Bond Formation within Boron Imidazolate Cages Featuring Single Copper Sites.

Electrocatalysis expands the ability to generate industrially relevant chemicals locally and on-demand with intermittent renewable energy, thereby improving grid resiliency and reducing supply logistics. Herein, we report the feasibility of using molecular copper boron-imidazolate cages, BIF-29(Cu), to enable coupling between the electroreduction reaction of CO2 (CO2RR) with NO3- reduction (NO3RR) to produce urea with high selectivity of 68.5% and activity of 424 µA cm-2. Remarkably, BIF-29(Cu) is among the most selective systems for this multistep C-N coupling to-date, despite possessing isolated single-metal sites. The mechanism for C-N bond formation was probed with a combination of electrochemical analysis, in situ spectroscopy, and atomic-scale simulations. We found that NO3RR and CO2RR occur in tandem at separate copper sites with the most favorable C-N coupling pathway following the condensation between *CO and NH2OH to produce urea. This work highlights the utility of supramolecular metal-organic cages with atomically discrete active sites to enable highly efficient coupling reactions.

The application of HER2 and CD47 CAR-macrophage in ovarian cancer.

BACKGROUND: The chimeric antigen receptor (CAR)-T therapy has a limited therapeutic effect on solid tumors owing to the limited CAR-T cell infiltration into solid tumors and the inactivation of CAR-T cells by the immunosuppressive tumor microenvironment. Macrophage is an important component of the innate and adaptive immunity, and its unique phagocytic function has been explored to construct CAR macrophages (CAR-Ms) against solid tumors. This study aimed to investigate the therapeutic application of CAR-Ms in ovarian cancer. METHODS: In this study, we constructed novel CAR structures, which consisted of humanized anti-HER2 or CD47 scFv, CD8 hinge region and transmembrane domains, as well as the 4-1BB and CD3ζ intracellular domains. We examined the phagocytosis of HER2 CAR-M and CD47 CAR-M on ovarian cancer cells and the promotion of adaptive immunity. Two syngeneic tumor models were used to estimate the in vivo antitumor activity of HER2 CAR-M and CD47 CAR-M. RESULTS: We constructed CAR-Ms targeting HER2 and CD47 and verified their phagocytic ability to ovarian cancer cells in vivo and in vitro. The constructed CAR-Ms showed antigen-specific phagocytosis of ovarian cancer cells in vitro and could activate CD8+ cytotoxic T lymphocyte (CTL) to secrete various anti-tumor factors. For the in vivo model, mice with human-like immune systems were used. We found that CAR-Ms enhanced CD8+ T cell activation, affected tumor-associated macrophage (TAM) phenotype, and led to tumor regression. CONCLUSIONS: We demonstrated the inhibition effect of our constructed novel HER2 CAR-M and CD47 CAR-M on target antigen-positive ovarian cancer in vitro and in vivo, and preliminarily verified that this inhibitory effect is due to phagocytosis, promotion of adaptive immunity and effect on tumor microenvironment.

Zeolitic Imidazolate Frameworks Derived Co9 S8 /Nitrogen-Doped Hollow Porous Carbon Spheres as Efficient Bifunctional Electrocatalysts for Rechargeable Zinc-Air Batteries.

The development of nonprecious metal-based electrocatalysts with remarkable catalytic activity and long-cycling lifespan toward oxygen reduction reaction (ORR) and evolution reaction (OER) is especially important for rechargeable zinc-air batteries (ZABs). Herein, monodispersed Co9 S8 nanoparticles embedded in nitrogen-doped hierarchically porous hollow carbon spheres (Co9 S8 NPs/NHCS) are synthesized through a template-assisted strategy followed by a co-assembly, thermal annealing, and sulfurization process. Benefiting from larger specific surface area, hierarchically porous hollow structure, and carbon nanotubes self-growth, the obtained Co9 S8 NPs/NHCS-0.5 electrocatalyst exhibits decent performance for ORR (E1/2 =0.85 V) and OER (E10 =1.55 V). A rechargeable ZAB assembled using the Co9 S8 NPs/NHCS-0.5 as air cathode delivers a maximum power density of 116 mW cm-2 , high open circuit voltage of 1.47 V, and good durability (no obvious voltage decay after 1200 cycles (200 hours)). Such a hierarchically porous hollow structure of Co9 S8 NPs/NHCS-0.5 provides a confined space shell and an interconnected hollow core to achieve outstanding bifunctional catalytic activity and cycling stability, which surpass the benchmark Pt/C-RuO2 .

Deep learning based object tracking for 3D microstructure reconstruction.

In medical and material science, 3D reconstruction is of great importance for quantitative analysis of microstructures. After the image segmentation process of serial slices, in order to reconstruct each local structure in volume data, it needs to use precise object tracking algorithm to recognize the same object region in adjacent slice. Suffering from weak representative hand-crafted features, traditional object tracking methods always draw out under-segmentation results. In this work, we have proposed an adjacent similarity based deep learning tracking method (ASDLTrack) to reconstruct 3D microstructure. By transferring object tracking problem to classification problem, it can utilize powerful representative ability of convolutional neural network in pattern recognition. Experiments in three datasets with three metrics demonstrate that our algorithm achieves the promising performance compared to traditional methods.

TSPAN8 regulates EGFR/AKT pathway to enhance metastasis in gastric cancer.

BACKGROUND: Tetraspanin 8 (TSPAN8), a transmembrane glycoprotein, is implicated in various pathological conditions including human malignancies. However, the roles and underlying mechanisms of TSPAN8 in promoting gastric cancer(GC) progression are yet to be fully understood. METHODS AND RESULTS: Our study found that TSPAN8 expression was significantly elevated in GC tissues. We also observed a positive correlation between high TSPAN8 expression and various clinicopathological characteristics of GC, including tumor differentiation, invasion depth, lymph node metastasis, and clinical stage. Moreover, the elevated TSPAN8 expression was indicative of poor prognosis. Functionally, we observed that knockdown of TSPAN8 significantly attenuated while overexpression of TSPAN8 promoted GC cell migration and invasion. In vivo experiments, knockdown of TSPAN8 suppressed lung metastasis in nude mice. We further explored the underlying mechanisms of TSPAN8 and found that it regulated EGFR expression in GC cells by accelerating phosphorylation of EGFR and AKT. CONCLUSIONS: Our study reveals that TSPAN8 plays a significant role in promoting tumor metastasis by activating the EGFR/AKT pathway, indicating that it may serve as a promising therapeutic target of gastric cancer.

Cost-effectiveness of abemaciclib plus endocrine therapy in high-risk HR+/HER2-early breast cancer in China.

OBJECTIVE: The aim of this article is to evaluate the cost-effectiveness of abemaciclib plus endocrine therapy (ABE + ET) vs. ET as adjuvant treatment for high-risk hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) early breast cancer in China. METHODS: From the perspective of the Chinese health care system, a 5-state Markov model was developed with a lifetime horizon. Data of the monarchE phase III clinical trial were used to model the invasive disease-free survival (iDFS) and standard parameters models were used for data extrapolation. Costs were obtained from national data sources, expert opinions and published literature using 2023 US dollars and discounted by 5%. The results were evaluated in terms of life-years (LYs) and quality-adjusted life-years (QALYs). Sensitivity analyses and scenario analyses were performed to test the robustness of the basic results. RESULTS: In the base-case analysis result, the model projected improved outcomes (by 0.65 LYs and 0.72 QALYs) and increased costs (by $16,057.72) for incremental cost-effectiveness ratios (ICERs) of $24,841/LY and $22,385/QALY for ABE + ET vs. ET patients. The results in scenario analysis estimated the ICERs of ABE + ET treatment to be $16,959/LY and $15,264/QALY in a mixture cure model, and $13,560/LY and $12,191/QALY in a non-mixture cure model. The model was sensitive to outcome discount rate and utility of iDFS. CONCLUSION: ABE + ET might not have an economic advantage over ET at a willingness-to-pay (WTP) threshold of one time the per capita GDP in China, but was expected to be more cost-effective at a WTP threshold of three times the per capita GDP. Further analysis will be conducted once data from longer-term studies become available.

Transmissible ER stress between macrophages and tumor cells configures tumor microenvironment.

Endoplasmic reticulum (ER) stress initiates the unfolded protein response (UPR) and is decisive for tumor cell growth and tumor microenvironment (TME) maintenance. Tumor cells persistently undergo ER stress and could transmit it to the neighboring macrophages and surroundings. Tumor infiltrating macrophages can also adapt to the microenvironment variations to fulfill their highly energy-demanding and biological functions via ER stress. However, whether the different macrophage populations differentially sense ER stress and transmit ER stress to surrounding tumor cells has not yet been elucidated. Here, we aimed to investigate the role of transmissible ER stress, a novel regulator of intercellular communication in the TME. Murine bone marrow-derived macrophage (BMDM) can be polarized toward distinct functional endpoints termed classical (M1) and alternative (M2) activation, and their polarization status has been shown to be tightly correlated with their functional significance. We showed that tumor cells could receive the transmissible ER stress from two differentially polarized macrophage populations with different extent of ER stress activation. The proinflammatory M1-like macrophages respond to ER stress with less extent, however they could transmit more ER stress to tumor cells. Moreover, by analyzing the secreted components of two ER-stressed macrophage populations, we identified certain damage-associated molecular patterns (DAMPs), including S100A8 and S100A9, which are dominantly secreted by M1-like macrophages could lead to significant recipient tumor cells death in synergy with transferred ER stress.