Neuronal ablation of GHSR mitigates diet-induced depression and memory impairment via AMPK-autophagy signaling-mediated inflammation.

Obesity is associated with chronic inflammation in the central nervous system (CNS), and neuroinflammation has been shown to have detrimental effects on mood and cognition. The growth hormone secretagogue receptor (GHSR), the biologically relevant receptor of the orexigenic hormone ghrelin, is primarily expressed in the brain. Our previous study showed that neuronal GHSR deletion prevents high-fat diet-induced obesity (DIO). Here, we investigated the effect of neuronal GHSR deletion on emotional and cognitive functions in DIO. The neuron-specific GHSR-deficient mice exhibited reduced depression and improved spatial memory compared to littermate controls under DIO. We further examined the cortex and hippocampus, the major regions regulating cognitive and emotional behaviors, and found that the neuronal deletion of GHSR reduced DIO-induced neuroinflammation by suppressing proinflammatory chemokines/cytokines and decreasing microglial activation. Furthermore, our data showed that neuronal GHSR deletion suppresses neuroinflammation by downregulating AMPK-autophagy signaling in neurons. In conclusion, our data reveal that neuronal GHSR inhibition protects against DIO-induced depressive-like behavior and spatial cognitive dysfunction, at least in part, through AMPK-autophagy signaling-mediated neuroinflammation.

The intestinal epithelial-macrophage-crypt stem cell axis plays a crucial role in regulating and maintaining intestinal homeostasis.

The intestinal tract plays a vital role in both digestion and immunity, making its equilibrium crucial for overall health. This equilibrium relies on the dynamic interplay among intestinal epithelial cells, macrophages, and crypt stem cells. Intestinal epithelial cells play a pivotal role in protecting and regulating the gut. They form vital barriers, modulate immune responses, and engage in pathogen defense and cytokine secretion. Moreover, they supervise the regulation of intestinal stem cells. Macrophages, serving as immune cells, actively influence the immune response through the phagocytosis of pathogens and the release of cytokines. They also contribute to regulating intestinal stem cells. Stem cells, known for their self-renewal and differentiation abilities, play a vital role in repairing damaged intestinal epithelium and maintaining homeostasis. Although research has primarily concentrated on the connections between epithelial and stem cells, interactions with macrophages have been less explored. This review aims to fill this gap by exploring the roles of the intestinal epithelial-macrophage-crypt stem cell axis in maintaining intestinal balance. It seeks to unravel the intricate dynamics and regulatory mechanisms among these essential players. A comprehensive understanding of these cell types' functions and interactions promises insights into intestinal homeostasis regulation. Moreover, it holds potential for innovative approaches to manage conditions like radiation-induced intestinal injury, inflammatory bowel disease, and related diseases.

Further accelerating biologics development from DNA to IND: the journey from COVID-19 to non-COVID-19 programs.

The Coronavirus Disease (COVID-19) pandemic has spurred adoption of revolutionary initiatives by regulatory agencies and pharmaceutical industry worldwide to deliver therapeutic COVID-19 antibodies to patients at unprecedented speed. Among these, timeline of chemistry, manufacturing and control (CMC), which involves process development and manufacturing activities critical for the assurance of product quality and consistency before first-in-human clinical trials, was greatly reduced from typically 12-15 months (using clonal materials) to approximately 3 months (using non-clonal materials) in multiple cases. In this perspective, we briefly review the acceleration approaches published for therapeutic COVID-19 antibodies and subsequently discuss the applicability of these approaches to achieve investigational new drug (IND) timelines of ≤10 months in over 60 COVID-19 and non-COVID-19 programs performed at WuXi Biologics. We are of the view that, with demonstrated product quality and consistency, innovative approaches used for COVID-19 can be widely applied in all disease areas for greater speed to clinic.

Quantized anomalous Hall resistivity achieved in molecular beam epitaxy-grown MnBi2Te4 thin films.

The intrinsic magnetic topological insulator MnBi2Te4 provides a feasible pathway to the high-temperature quantum anomalous Hall (QAH) effect as well as various novel topological quantum phases. Although quantized transport properties have been observed in exfoliated MnBi2Te4 thin flakes, it remains a big challenge to achieve molecular beam epitaxy (MBE)-grown MnBi2Te4 thin films even close to the quantized regime. In this work, we report the realization of quantized anomalous Hall resistivity in MBE-grown MnBi2Te4 thin films with the chemical potential tuned by both controlled in situ oxygen exposure and top gating. We find that elongated post-annealing obviously elevates the temperature to achieve quantization of the Hall resistivity, but also increases the residual longitudinal resistivity, indicating a picture of high-quality QAH puddles weakly coupled by tunnel barriers. These results help to clarify the puzzles in previous experimental studies on MnBi2Te4 and to find a way out of the big difficulty in obtaining MnBi2Te4 samples showing quantized transport properties.

Generation of a modulated versatile spiral beam with varying intensity distribution along the propagation.

A new type of versatile spiral beam (VSB) is generated based on the competition mechanism between the self-focusing property of ring Airy beam and metalens phase distribution, which exhibits twisted properties and optical bottle structure along the propagation direction. The number of spiral lobes, rotation direction, shape and magnification times on the cross section of the proposed beam can be customized by flexibly tuning diffraction distance, topological charge and constant parameter. Therefore, the VSB can be viewed as tunable three-dimensional (3D) spiral beam, and our scheme has the superiority with more diverse and tunable intensity distribution. The properties of intensity distribution variation depended on the propagation distance and topological charge are demonstrated convincingly by employing the Poynting vector intuitive presentation the energy flow. The VSBs with the aid of above-mentioned properties are beneficial for guiding microparticles along the designed spiral path and capturing multiple microparticles into the closed dark regions. Finally, the modulated spiral beams are implemented as tool for particle manipulation in the three dimensional space to demonstrate the advantages of the modulated spiral beam and we can observe the stable trapping of the particles.

Signalling in pancreatic cancer: from pathways to therapy.

Pancreatic cancer (PC) is a common malignant tumour in the digestive system. Due to the lack of sensitive diagnostic markers, strong metastasis ability, and resistance to anti-cancer drugs, the prognosis of PC is inferior. In the past decades, increasing evidence has indicated that the development of PC is closely related to various signalling pathways. With the exploration of RAS-driven, epidermal growth factor receptor, Hedgehog, NF-κB, TGF-ß, and NOTCH signalling pathways, breakthroughs have been made to explore the mechanism of pancreatic carcinogenesis, as well as the novel therapies. In this review, we discussed the signalling pathways involved in PC and summarised current targeted agents in the treatment of PC. Furthermore, opportunities and challenges in the exploration of potential therapies targeting signalling pathways were also highlighted.

Identification and targeting of cancer-associated fibroblast signature genes for prognosis and therapy in Cutaneous melanoma.

BACKGROUND: Cancer-associated fibroblasts (CAFs) play pivotal roles in tumor invasion and metastasis. However, studies on CAF biomarkers in Cutaneous Melanoma (CM) are still scarce. This study aimed to explore the potential CAF biomarkers in CM, propose the potential therapeutic targets, and provide new insights for targeted therapy of CAFs in CM. METHODS: We utilized weighted gene co-expression network analysis to identify CAF signature genes in CM, and conducted comprehensive bioinformatics analysis on the CAF risk score established by these genes. Moreover, single-cell sequencing analysis, spatial transcriptome analysis, and cell experiments were utilized for verifying the expression and distribution pattern of signature genes. Furthermore, molecular docking was employed to screen potential target drugs. RESULTS: FBLN1 and COL5A1, two crucial CAF signature genes, were screened to establish the CAF risk score. Subsequently, a comprehensive bioinformatic analysis of the CAF risk score revealed that high-risk score group was significantly enriched in pathways associated with tumor progression. Besides, CAF risk score was significantly negatively correlated with clinical prognosis, immunotherapy response, and tumor mutational burden in CM patients. In addition, FBLN1 and COL5A1 were further identified as CAF-specific biomarkers in CM by multi-omics analysis and experimental validation. Eventually, based on these two targets, Mifepristone and Dexamethasone were screened as potential anti-CAFs drugs. CONCLUSION: The findings indicated that FBLN1 and COL5A1 were the CAF signature genes in CM, which were associated with the progression, treatment, and prognosis of CM. The comprehensive exploration of CAF signature genes is expected to provide new insight for clinical CM therapy.

Synergistic activation of persulfate by a manganese cobalt oxide/reduced graphene oxide nanocomposite with enhanced degradation of trichloroethylene.

Advanced oxidation technology based on persulfate is one of the most reliable and effective technologies for the degradation of wastewater, however the key lies in developing highly efficient catalysts to activate persulfate. Herein, manganese cobalt oxide/reduced graphene oxide (MnCo2O4/rGO) nanocomposites were successfully synthesized via a facile solvothermal method and employed as a highly efficient catalyst to active persulfate for the degradation of trichloroethylene (TCE). The rGO nanosheets have large surface areas, which can increase the contact area with reactants and make the degradation more efficient. Additionally, the MnCo2O4 nanoparticles are in situ grown on the surface of ultrathin rGO nanosheets, endowing the material with high structural porosity and fast transport channels, and are beneficial for the improvement of catalytic sites and the transport of catalysis-relevant species. More importantly, the close contact between MnCo2O4 nanoparticles and rGO nanosheets synergistically favors the electron transfer, thereby accelerating the electron transfer, improving the activation efficiency, and promoting the generation of sulfate radicals (·SO4-). rGO can also reduce the spillover of metal ions. The kinetics model and degradation mechanism of the nanocomposites are also proposed.

Protein crotonylation: An emerging regulator in DNA damage response.

DNA damage caused by internal or external factors lead to increased genomic instability and various diseases. The DNA damage response (DDR) is a crucial mechanism that maintaining genomic stability through detecting and repairing DNA damage timely. Post-translational modifications (PTMs) play significant roles in regulation of DDR. Among the present PTMs, crotonylation has emerged as a novel identified modification that is involved in a wide range of biological processes including gene expression, spermatogenesis, cell cycle, and the development of diverse diseases. In the past decade, numerous crotonylation sites have been identified in histone and non-histone proteins, leading to a more comprehensive and deep understanding of the function and mechanisms in protein crotonylation. This review provides a comprehensive overview of the regulatory mechanisms of protein crotonylation and the effect of crotonylation in DDR. Furthermore, the effect of protein crotonylation in tumor development and progression is presented, to inspire and explore the novel strategies for tumor therapy.

Interaction of germanium analogue of organic isonitrile with Cu(I) imide in side-on mode.

[NHC → GeN(Ar)Cu2NAr]2, the formal adduct of germanium analogue of organic isonitrile [GeNAr] with Cu(I) imide [(Cu2NAr)2] (Ar = 2,6-iPr2C6H3) was prepared from the N-heterocyclic carbene (NHC) stabilized acyclic germylene Ge[N(H)Ar]2 by reacting with two equivalents of nBuLi and CuCl(PPh3)3. As elucidated by X-ray crystal structural characterization, the two separated [GeNAr] moieties interacted with [(Cu2NAr)2] core in the side-on mode.

The effect of enhanced heat transfer across metal-nonmetal interfaces subject to femtosecond laser irradiation.

The heat transfer across metal-nonmetal interfaces inevitably affects the femtosecond laser processing of thin metal films coated on nonmetal substrates. In the present work, a two-temperature model with a metal-nonmetal interface is employed to numerically investigate the heat transfer across a metal-nonmetal interface. A parallel-series thermal circuit is considered under the drastic electron-phonon nonequilibrium induced by femtosecond laser irradiation. The interfacial thermal resistance affects temporal evolutions of surface electron temperature and phonon temperature, as well as the optical response simulated by the Drude-Lorentz model. By inserting an interlayer and reducing the interfacial thermal resistance, the enhanced heat transfer across Au-Al2O3 and Au-Si interfaces is confirmed. More heat transfers from a metal to a nonmetal due to lower total interfacial thermal resistance, which reshapes the temperature distributions of metal-electrons, metal-phonons, and nonmetal-phonons. Consequently, the higher damage threshold of thin Au films and the lower sensitivity of damage threshold versus film thickness are determined. It implies that the heat transfer across metal-nonmetal interfaces is found to affect the transient thermal reflectivity detection and the repeatable femtosecond laser processing of thin metal films.

Reduced APPL1 impairs osteogenic differentiation of mesenchymal stem cells by facilitating MGP expression to disrupt the BMP2 pathway in osteoporosis.

An imbalance of human mesenchymal stem cells (MSCs) adipogenic and osteogenic differentiation plays an important role in the pathogenesis of osteoporosis. Our previous study verified that Adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1 (APPL1)/myoferlin deficiency promotes adipogenic differentiation of MSCs by blocking autophagic flux in osteoporosis. However, the function of APPL1 in the osteogenic differentiation of MSCs remains unclear. This study aimed to investigate the role of APPL1 in the osteogenic differentiation of MSCs in osteoporosis and the underlying regulatory mechanism. In this study, we demonstrated the downregulation of APPL1 expression in patients with osteoporosis and osteoporosis mice. The severity of clinical osteoporosis was negatively correlated with the expression of APPL1 in bone marrow MSCs. We found that APPL1 positively regulates the osteogenic differentiation of MSCs in vitro and in vivo. Moreover, RNA sequencing showed that the expression of MGP, an osteocalcin/matrix Gla family member, was significantly upregulated after APPL1 knockdown. Mechanistically, our study showed that reduced APPL1 impaired the osteogenic differentiation of mesenchymal stem cells by facilitating Matrix Gla protein expression to disrupt the BMP2 pathway in osteoporosis. We also evaluated the significance of APPL1 in promoting osteogenesis in a mouse model of osteoporosis. These results suggest that APPL1 may be an important target for the diagnosis and treatment of osteoporosis.

Effective oxygen metabolism-based prognostic signature for colorectal cancer.

Backgroud: Oxygen metabolism is an important factor affecting the development of tumors, but its roles and clinical value in Colorectal cancer are not clear. We developed an oxygen metabolism (OM) based prognostic risk model for colorectal cancer and explored the role of OM genes in cancer. Methods: Gene expression and clinical data obtained from The Cancer Genome Atlas, Clinical Proteomic Tumor Analysis Consortium databases were consider as discovery and validation cohort, respectively. The prognostic model based on differently expressed OM genes between tumor and GTEx normal colorectal tissues were constructed in discovery cohort and validated in validation cohort. The Cox proportional hazards analysis was used to test clinical independent. Upstream and downstream regulatory relationships and interaction molecules are used to clarify the roles of prognostic OM genes in colorectal cancer. Results: A total of 72 common differently expressed OM genes were detected in the discovery and validation set. A five-OM gene prognostic model including LRT2, ATP6V0E2, ODC1, SEL1L3 and VDR was established and validated. Risk score determined by the model was an independent prognostic according to routine clinical factors. Besides, the role of prognostic OM genes involves transcriptional regulation of MYC and STAT3, and downstream cell stress and inflammatory response pathways. Conclusions: We developed a five-OM gene prognostic model and study the unique roles of oxygen metabolism in of colorectal cancer.

Recent advances in biological pumps as a building block for bioartificial hearts.

The field of biological pumps is a subset of cardiac tissue engineering and focused on the development of tubular grafts that are designed generate intraluminal pressure. In the simplest embodiment, biological pumps are tubular grafts with contractile cardiomyocytes on the external surface. The rationale for biological pumps is a transition from planar 3D cardiac patches to functional biological pumps, on the way to complete bioartificial hearts. Biological pumps also have applications as a standalone device, for example, to support the Fontan circulation in pediatric patients. In recent years, there has been a lot of progress in the field of biological pumps, with innovative fabrication technologies. Examples include the use of cell sheet engineering, self-organized heart muscle, bioprinting and in vivo bio chambers for vascularization. Several materials have been tested for biological pumps and included resected aortic segments from rodents, type I collagen, and fibrin hydrogel, to name a few. Multiple bioreactors have been tested to condition biological pumps and replicate the complex in vivo environment during controlled in vitro culture. The purpose of this article is to provide an overview of the field of the biological pumps, outlining progress in the field over the past several years. In particular, different fabrication methods, biomaterial platforms for tubular grafts and examples of bioreactors will be presented. In addition, we present an overview of some of the challenges that need to be overcome for the field of biological pumps to move forward.

Increased GABAergic projections in the paraventricular nucleus regulate colonic hypersensitivity via oxytocin in a rat model of irritable bowel syndrome.

Irritable bowel syndrome (IBS) is characterized by gastrointestinal dysmotility and visceral hyperalgesia, and the impaired brain-gut axis is accepted as a crucial cause for the onset of IBS. The objective of this study is to investigate the effects of the adaptive changes in the central neural system induced by stress on IBS-like syndromes in rats. Long-term water avoidance stress (WAS) was used to prepare IBS animals. The changes in neuronal excitation and GABA expression were shown by immunohistochemistry. The mRNA and protein expressions of neurotransmitters were detected with Quantitative reverse-transcription PCR (qRT-PCR) and Enzyme-linked immunosorbent assay (ELISA). The intestinal transit time, fecal moisture content, and abdominal withdrawal reflex scores of rats were recorded to monitor intestinal motility and visceral hyperalgesia. In the WAS-treated rats with enhanced intestinal motility and visceral hypersensitivity, more GABAergic projections were found in the paraventricular nucleus (PVN) of the hypothalamus, which inhibited the firing rate of neurons and decreased the expression of oxytocin. Exogenous oxytocin improved gut motility and decreased AWR scores. The inhibition of oxytocin by the adaptive GABAergic projection in the PVN might be an important mediator of IBS, which indicates a potential novel therapeutic target.

Targeting cancer drug resistance utilizing organoid technology.

Cancer organoids generated from 3D in vitro cell cultures have contributed to the study of drug resistance. Maintenance of genomic and transcriptomic similarity between organoids and parental cancer allows organoids to have the ability of accurate prediction in drug resistance testing. Protocols of establishing therapy-sensitive and therapy-resistant organoids are concluded in two aspects, which are generated directly from respective patients' cancer and by induction of anti-cancer drug. Genomic and transcriptomic analyses and gene editing have been applied to organoid studies to identify key targets in drug resistance and FGFR3, KHDRBS3, lnc-RP11-536 K7.3 and FBN1 were found to be key targets. Furthermore, mechanisms contributing to resistance have been identified, including metabolic adaptation, activation of DNA damage response, defects in apoptosis, reduced cellular senescence, cellular plasticity, subpopulation interactions and gene fusions. Additionally, cancer stem cells (CSCs) have been verified to be involved in drug resistance utilizing organoid technology. Reversal of drug resistance can be achieved by targeting key genes and CSCs in cancer organoids. In this review, we summarize applications of organoids to cancer drug resistance research, indicating prospects and limitations.

Regulation of the central amygdala on intestinal motility and behavior via the lateral hypothalamus in irritable bowel syndrome model mice.

BACKGROUND: Impaired bidirectional communication between the gastrointestinal tract and the central nervous system (CNS) is closely related to the development of irritable bowel syndrome (IBS). Studies in patients with IBS have also shown significant activation of the hypothalamus and amygdala. However, how neural circuits of the CNS participate in and process the emotional and intestinal disorders of IBS remains unclear. METHODS: The GABAergic neural pathway projecting from the central amygdala (CeA) to the lateral hypothalamus (LHA) in mice was investigated by retrograde tracking combined with fluorescence immunohistochemistry. Anxiety, depression-like behavior, and intestinal motility were observed in the water-immersion restraint stress group and the control group. Furthermore, the effects of the chemogenetic activation of the GABAergic neural pathway of CeA-LHA on behavior and intestinal motility, as well as the co-expression of orexin-A and c-Fos in the LHA, were explored. KEY RESULTS: In our study, Fluoro-Gold retrograde tracking combined with fluorescence immunohistochemistry showed that GABAergic neurons in the CeA were projected to the LHA. The microinjection of the gamma-aminobutyric acid (GABA) receptor antagonist into the LHA relieved anxiety, depression-like behavior, and intestinal motility disorder in the IBS mice. The chemogenetic activation of GABAergic neurons in the CeA-LHA pathway led to anxiety, depression-like behavior, and intestinal motility disorder. In addition, GABAergic neurons in the CeA-LHA pathway inhibited the expression of orexin-A in the LHA, and orexin-A was co-expressed with GABAA receptors. CONCLUSIONS & INFERENCES: The CeA-LHA GABAergic pathway might participate in the occurrence and development of IBS by regulating orexin-A neurons.

Rapidly accelerated development of neutralizing COVID-19 antibodies by reducing cell line and CMC development timelines.

Since the Coronavirus Disease 2019 (COVID-19) outbreak, unconventional cell line development (CLD) strategies have been taken to enable development of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-neutralizing antibodies at expedited speed. We previously reported a novel chemistry, manufacturing, and control (CMC) workflow and demonstrated a much-shortened timeline of 3-6 months from DNA to investigational new drug (IND) application. Hereafter, we have incorporated this CMC strategy for many SARS-CoV-2-neutralizing antibody programs at WuXi Biologics. In this paper, we summarize the accelerated development of a total of seven antibody programs, some of which have received emergency use authorization  approval in less than 2 years. Stable pools generated under good manufacturing practice (GMP) conditions consistently exhibited similar productivity and product quality at different scales and batches, enabling rapid initiation of phase I clinical trials. Clones with comparable product quality as parental pools were subsequently screened and selected for late-stage development and manufacturing. Moreover, a preliminary stability study plan was devised to greatly reduce the time required for final clone determination and next-generation sequencing-based viral testing was implemented to support rapid conditional release of the master cell bank for GMP production. The successful execution of these COVID-19 programs relies on our robust, fit for purpose, and continuously improving CLD platform. The speed achieved for pandemic-related biologics development may innovate typical biologics development timelines and become a new standard in the industry.

Crosstalk suppression for high-density traveling-wave MZM array based on static and dynamic combined analysis and circuit-level designs.

Electrical crosstalk severely degrades the performance of Mach-Zehnder modulator (MZM) array. However, conventional crosstalk suppression techniques incur losses of large amounts of chip area for signal isolation, which becomes a bottleneck of high-density electronic-photonic integrated circuit. In this paper, the electrical crosstalk of Traveling-Wave MZM array is originally analyzed with static and dynamic combined crosstalk coefficients. Circuit-level suppression techniques of differential dual-drive electrode schemes with tightly coupled electrode pairs and a virtual ground structure with full-matching termination circuit are investigated for noise-removing effects. Simulation results show that the dynamic electrical crosstalk coefficient between two adjacent modulators is reduced to below 1.5%, which is five times lower than the baseline. The electro-optical link measurements show that the BER is significantly reduced from 1E-3 to 1E-12 for multi-channel operation, which confirms the effectiveness of the crosstalk suppression techniques.