The lactylation index predicts the immune microenvironment and prognosis of pan-cancer patients

Background:Protein lactylation is a new way for the“metabolic waste”lactic acid to perform novel functions.Nevertheless,our understanding of the contribution of protein lactylation to both tumor progression and therapeutic interventions remains imited.The construction of a scoring system for lactylation to predict the prognosis of pancancer patients and to evaluate the tumor immune microenvironment(TIME)would improve our understanding of the clinical significance of lactylation.Methods:Consensus clustering analysis of lactylation-related genes was used to cluster 177 pancreatic adenocarcinoma(PAAD)patients.Subsequently,a scoring system was developed using the least absolute shrinkage and selection operator(LASSO)regression.Internal validation and external validation were both conducted to assess and confirm the predictive accuracy of the scoring system.Finally,leucine rich repeat containing 1(LRRC1),a newly discovered lactylation-related gene,was analyzed in PAAD in vitro.Results:Utilizing the profiles of 332 lactylation-related genes,a total of 177 patients with PAAD were segregated into two distinct groups.LacCluster^(high) patients had a poorer prognosis than LacCluster^(low) patients.Through the differential analysis between the LacCluster^(high) and LacCluster^(low) groups,we identified additional genes associated with lactylation.These genes were then integrated to construct the LacCluster-enhanced system,which enabled more accurate prognosis prediction for patients with PAAD.Then,a lactylation index containing three genes(LacI-3)was constructed using LASSO regression.This was done to enhance the usability of the LacCluster-enhanced system in the clinic.Compared to those in the LacI-3^(high) subgroup,patients in the LacI-3^(low) subgroup exhibited increased expression of immune checkpoint-related genes,more immune cell infiltration,lower tumor mutation burdens,and better prognoses,indicating a“hot tumor”phenotype.Moreover,knocking down the expression of LRRC1,the hub gene in the LacI-3 scoring system,inhibited PAAD cell invasion,migration,and proliferation in vitro.Ultimately,the significance of LacI-3 across cancers was confirmed.Conclusion:Our findings strongly imply that protein lactylation may represent a new approach to diagnosing and treating malignant tumors.

经冠状动脉自体骨髓间充质干细胞移植治疗小型猪急性心肌梗死

目的评价经冠状动脉移植体外分离培养自体骨髓间充质干细胞(MSCs)治疗急性心肌梗死(AMI)的可行性及疗效。方法通过结扎冠状动脉左前降支90min后恢复血流的方法建立AMI模型。采用密度梯度离心法分离骨髓单个核细胞、传代培养后,在AMI造模10～14d后将培养扩增的自体MSCs经冠状动脉植入梗死区,应用超声心动图观察移植前后心功能变化情况,冰冻切片荧光显微镜示踪4'G6-二脒-2-苯基吲哚(DAPI)标记的MSCs,Ⅷ因子免疫荧光染色测定新生血管数目。结果MSCs生长呈纺锤样,生长旺盛呈旋涡样;DAPI标记率为100%。AMI造模10～14d后MSCs移植数量平均为(4～6)×107个,移植术后3个月,MSCs治疗组与对照组比较,左心室射血分数(LVEF)显著升高[(54.65±3.39)%vs(43.98±4.21)%(P<0.01)],可见DAPI标记胞核为蓝色荧光的移植细胞,MSCs治疗组与对照组比较,新生血管数目显著升高[(13.28±4.39)vs(4.27±2.28)个G(P<0.01)]。结论通过体外培养扩增在短期内可以获得相当数量的生物性状稳定的MSCs,在AMI造模10～14d后进行经冠状动脉MSCs自体移植,促进左室功能的恢复。MSCs移植与目前广泛运用的介入治疗相结合,方法简便、经济、有效,可望改善AMI患者的预后,具有良好的临床应用前景。

Potential therapeutic roles of retinoids for prevention of neuroinflammation and neurodegeneration in Alzheimer’s disease

All retinoids, which can be natural and synthetic, are chemically related to vitamin A. Both natural and synthetic retinoids use specific nuclear receptors such as retinoic acid receptors and retinoid X receptors to activate specific signaling pathways in the cells. Retinoic acid signaling is extremely important in the central nervous system. Impairment of retinoic acid signaling pathways causes severe pathological processes in the central nervous system, especially in the adult brain. Retinoids have major roles in neural patterning, differentiation, axon outgrowth in normal development, and function of the brain. Impaired retinoic acid signaling results in neuroinflammation, oxidative stress, mitochondrial malfunction, and neurodegeneration leading to progressive Alzheimer’s disease, which is pathologically characterized by extra-neuronal accumulation of amyloid plaques(aggregated amyloid-beta) and intra-neurofibrillary tangles(hyperphosphorylated tau protein) in the temporal lobe of the brain. Alzheimer’s disease is the most common cause of dementia and loss of memory in old adults. Inactive cholinergic neurotransmission is responsible for cognitive deficits in Alzheimer’s disease patients. Deficiency or deprivation of retinoic acid in mice is associated with loss of spatial learning and memory. Retinoids inhibit expression of chemokines and neuroinflammatory cytokines in microglia and astrocytes, which are activated in Alzheimer’s disease. Stimulation of retinoic acid receptors and retinoid X receptors slows down accumulation of amyloids, reduces neurodegeneration, and thereby prevents pathogenesis of Alzheimer’s disease in mice. In this review, we described chemistry and biochemistry of some natural and synthetic retinoids and potentials of retinoids for prevention of neuroinflammation and neurodegeneration in Alzheimer’s disease.

Harnessing the HDAC–histone deacetylase enzymes,inhibitors and how these can be utilised in tissue engineering

There are large knowledge gaps regarding how to control stem cells growth and differentiation.The limitations of currently available technologies,such as growth factors and/or gene therapies has led to the search of alternatives.We explore here how a cell’s epigenome influences determination of cell type,and potential applications in tissue engineering.A prevalent epigenetic modification is the acetylation of DNA core histone proteins.Acetylation levels heavily influence gene transcription.Histone deacetylase (HDAC) enzymes can remove these acetyl groups,leading to the formation of a condensed and more transcriptionally silenced chromatin.Histone deacetylase inhibitors (HDACis) can inhibit these enzymes,resulting in the increased acetylation of histones,thereby affecting gene expression.There is strong evidence to suggest that HDACis can be utilised in stem cell therapies and tissue engineering,potentially providing novel tools to control stem cell fate.This review introduces the structure/function of HDAC enzymes and their links to different tissue types (specifically bone,cardiac,neural tissues),including the history,current status and future perspectives of using HDACis for stem cell research and tissue engineering,with particular attention paid to how different HDAC isoforms may be integral to this field.

Non-invasive detection of vulnerable coronary plaque

Critical coronary stenosis have been shown to contribute to only a minority of acute coronary syndromes and sudden cardiac death.Autopsy studies have identified a subgroup of high-risk patients with disrupted vulnerable plaque and modest stenosis.Consequently,a clinical need exists to develop methods to identify these plaques prospectively before disruption and clinical expression of disease.Recent advances in invasive and non-invasive imaging techniques have shown the potential to identify these high-risk plaques.Non-invasive imaging with magnetic resonance imaging,computed tomography and positron emission tomography holds the potential to differentiate between low-and highrisk plaques.There have been significant technological advances in non-invasive imaging modalities,and the aim is to achieve a diagnostic sensitivity for these technologies similar to that of the invasive modalities.Molecular imaging with the use of novel targeted nanoparticles may help in detecting high-risk plaques that will ultimately cause acute myocardial infarction.Moreover,nanoparticle-based imaging may even provide non-invasive treatments for these plaques.However,at present none of these imaging modalities are able to detect vulnerable plaque nor have they been shown to definitively predict outcome.Further trials are needed to provide more information regarding the natural history of high-risk but non-flow-limiting plaque to establish patient specific targeted therapy and to refine plaque stabilizing strategies in the future.

Endothelium-derived essential signals involved in pancreas organogenesis

Endothelial cells(ECs) are essential for pancreas differentiation, endocrine specification, and endocrine function. They are also involved in the physiopathology of type 1 and type 2 diabetes. During embryogenesis, aortic ECs provide specific factors that maintain the expression of key genes for pancreas development such as pancreatic and duodenal homeobox-1. Other unknown factors are also important for pancreatic endocrine specification and formation of insulin-producing beta cells. Endocrine precursors proliferate interspersed with ductal cells and exocrine precursors and, at some point of development, these endocrine precursors migrate to pancreatic mesenchyme and start forming the islets of Langerhans. By the end of the gestation and close to birth, these islets contain immature beta cells with the capacity to express vascular endothelial growth factor and therefore to recruit ECs from the surrounding microenvironment. ECs in turn produce factors that are essential to maintain insulin secretion in pancreatic beta cells. Once assembled, a cross talk between endocrine cells and ECs maintain the integrity of islets toward an adequate function during the whole life of the adult individual. This review will focus in the EC role in the differentiation and maturation of pancreatic beta cells during embryogenesis as well as the current knowledge about the involvement of endothelium to derive pancreatic beta cells in vitro from mouse or human pluripotent stem cells.

Optogenetic neuroregeneration

Optogenetics is a powerful technology that employs light and genetics to manipulate physiology and behavior with unprecedented precision.The high acuity of light stimulation permits fine control both in space(e.g.,to target just one tissue in an animal)and in time(e.g.,to interfere with a specific disease stage),whilst genetic targeting restricts manipulation to a functionally-relevant cell population(Figure 1A).

Magnesium metal and its corrosion products:Promising materials for tumor interventional therapy

Magnesium is generally known to degrade in aqueous environments by an electrochemical reaction.The corrosion products of magnesium include hydrogen gas,Mg^(2+),and Mg(OH)_(2).Here,we summarize the published literature describing the corrosion characteristics of magnesium,and the antitumor properties of magnesium-associated corrosion products,aiming to induce the therapeutic properties of magnesium and magnesium alloys in solid tumors.The therapeutic potential of corrosion products of magnesium is enormous.Hydrogen gas exhibits antioxidant and anti-inflammatory properties,which amount to potential anti-tumor characteristics.Mg(OH)_(2),which creates a localized alkaline microenvironment,represents a second approach for anti-tumor therapy with magnesium metal.Upregulated concentrations of Mg^(2+)ions in the local tumor microenvironment remodelling are considered a third approach for anti-tumor therapy.Therefore,we speculate about the different physical forms of magnesium that could create an anti-tumor microenvironment upon tumor interventional therapy,a technique that precisely places anti-tumor implants like particles and stents.Finally,we present our viewpoints on the potential use of magnesium in diverse solid tumor therapies to inhibit tumor progression.

Humanized bone facilitates prostate cancer metastasis and recapitulates therapeutic effects of zoledronic acid in vivo

Advanced prostate cancer(PCa)is known for its high prevalence to metastasize to bone,at which point it is considered incurable.Despite significant effort,there is no animal model capable of recapitulating the complexity of PCa bone metastasis.The humanized mouse model for PCa bone metastasis used in this study aims to provide a platform for the assessment of new drugs by recapitulating the human–human cell interactions relevant for disease development and progression.The humanized tissueengineered bone construct(hTEBC)was created within NOD-scid IL2rgnull(NSG)mice and was used for the study of experimental PC3-Luc bone metastases.It was confirmed that PC3-Luc cells preferentially grew in the hTEBC compared with murine bone.The translational potential of the humanized mouse model for PCa bone metastasis was evaluated with two clinically approved osteoprotective therapies,the non-species-specific bisphosphonate zoledronic acid(ZA)or the human-specific antibody Denosumab,both targeting Receptor Activator of Nuclear Factor Kappa-ΒLigand.ZA,but not Denosumab,significantly decreased metastases in hTEBCs,but not murine femora.These results highlight the importance of humanized models for the preclinical research on PCa bone metastasis and indicate the potential of the bioengineered mouse model to closely mimic the metastatic cascade of PCa cells to human bone.Eventually,it will enable the development of new effective antimetastatic treatments.

Targeted inhibition of osteoclastogenesis reveals the pathogenesis and therapeutics of bone loss under sympathetic neurostress

Sympathetic cues via the adrenergic signaling critically regulate bone homeostasis and contribute to neurostress-induced bone loss,but the mechanisms and therapeutics remain incompletely elucidated.Here,we reveal an osteoclastogenesis-centered functionally important osteopenic pathogenesis under sympatho-adrenergic activation with characterized micro RNA response and efficient therapeutics.We discovered that osteoclastic mi R-21 was tightly regulated by sympatho-adrenergic cues downstream theβ2-adrenergic receptor(β2AR)signaling,critically modulated osteoclastogenesis in vivo by inhibiting programmed cell death 4(Pdcd4),and mediated detrimental effects of both isoproterenol(ISO)and chronic variable stress(CVS)on bone.Intriguingly,without affecting osteoblastic bone formation,bone protection against ISO and CVS was sufficiently achieved by a(D-Asp8)-lipid nanoparticle-mediated targeted inhibition of osteoclastic mi R-21 or by clinically relevant drugs to suppress osteoclastogenesis.Collectively,these results unravel a previously underdetermined molecular and functional paradigm that osteoclastogenesis crucially contributes to sympatho-adrenergic regulation of bone and establish multiple targeted therapeutic strategies to counteract osteopenias under stresses.

The role of YAP in the control of the metastatic potential of oral cancer

The Yes-associated protein(YAP)is a downstream effector of the Hippo pathway and acts as a key transcription co-factor to regulate cell migration,proliferation,and survival.The Hippo pathway is evolutionarily conserved and controls tissue growth and organ size.Dysregulation and heterogeneity of this pathway are found in cancers,including oral squamous cell carcinoma(OSCC),leading to overexpression of YAP and its regulated proliferation machinery.The activity of YAP is associated with its nuclear expression and is negatively regulated by the Hippo kinase-mediated phosphorylation resulting in an induction of its cytoplasmic translocation.This review focuses on the role of YAP in OSCC in the context of cancer metastatic potential and highlights the latestfindings about the heterogeneity of YAP expression and its nuclear transcription activity in oral cancer cell lines.The review also discusses the potential target of YAP in oral cancer therapy and the recentfinding of the unprecedented role of the desmosomal cadherin desmoglein-3(DSG3)in regulating Hippo-YAP signaling.

Spatially resolved transcriptomics in immersive environments

Spatially resolved transcriptomics is an emerging class of high-throughput technologies that enable biologists to systematically investigate the expression of genes along with spatial information.Upon data acquisition,one major hurdle is the subsequent interpretation and visualization of the datasets acquired.To address this challenge,VR-Cardiomics is presented,which is a novel data visualization system with interactive functionalities designed to help biologists interpret spatially resolved transcriptomic datasets.By implementing the system in two separate immersive environments,fish tank virtual reality(FTVR)and head-mounted display virtual reality(HMD-VR),biologists can interact with the data in novel ways not previously possible,such as visually exploring the gene expression patterns of an organ,and comparing genes based on their 3D expression profiles.Further,a biologist-driven use-case is presented,in which immersive environments facilitate biologists to explore and compare the heart expression profiles of different genes.

Current opinion on a role of the astrocytes in neuroprotection

Central nervous system（CNS）injuries remain a leading cause of functional disabilities worldwide,often resulting in permanent neurological impairments,due to the inability to repair and regenerate damaged connections.A major contributing factor to this loss of regenerative capacity is the formation of glial scar tissue（Cregg et al.,2014）,traditionally regarded as a potent mechanical and molecular barrier to repair.

The Effect of Spironolactone Loading on the Properties of 3D-Printed Polycaprolactone/Gold Nanoparticles Composite Scaffolds for Myocardial Tissue Engineering

Engineered cardiac constructs(ECC)aid in the progression of regenerative medicine,disease modeling and targeted drug delivery to adjust and aim the release of remedial combination as well as decrease the side effects of drugs.In this research,polycaprolactone/gold nanoparticles(PCL/GNPs)three-dimensional(3D)composite scaffolds were manufactured by 3D printing using the fused deposition modeling(FDM)method and then coated with gelatin/spironolactone(GEL/SPL).Scanning electron microscopy(SEM)and Fourier transform-infrared spectroscopy(FTIR–ATR)were applied to characterize the samples.Furthermore,drug release,biodegradation,behavior of the myoblasts(H9C2)cell line,and cytotoxicity of the 3D scaffolds were evaluated.The microstructural observation of the scaffolds reported interconnected pores with 150–300µm in diameter.The 3D scaffolds were degraded significantly after 28 days of immersion in stimulated body fluid(SBF),with the maximum rate of GEL-coated 3D scaffolds.SPL release from cross-linked GEL coating demonstrated the excess of drug release over time,and according to the control release systems,the drug delivery systems(DDS)went into balance after the 14th day.In addition,cell culture study showed that with the addition of GNPs,the proliferation of(H9C2)was enhanced,and with GEL/SPL coating the cell attachment and viability were improved significantly.These findings suggested that PCL/GNPs 3D scaffolds coated with GEL/SPL can be an appropriate choice for myocardial tissue engineering.

CD147 facilitates cisplatin resistance in ovarian cancer through FOXM1 degradation inhibition

Currently,the major therapy for patients with ovarian cancer includes post-cytoreductive surgery followed by chemotherapy of carboplatin or cisplatin plus paclitaxel.The rise of drug resistance is a substantial factor in cancer recurrence and mortality among ovarian cancer patients receiving cisplatin treatment.CD147 is widely expressed in a variety of cancer tissues1 and recognized as a drug target for its antibody drug Licartin which has been approved by China’s National Medicines and Pharmaceutical Administration.2 Even though many studies reported that CD147 is involved in the cisplatin resistance of varieties of cancers,3 its mechanism remains unclear.In this investigation,we uncovered a distinctive mechanism by which CD147 regulates cisplatin resistance through the proteasomal degradation of the transcription factor FOXM1,which is associated with DNA damage repair,in ovarian cancer cells.Our results suggest that targeting CD147 may have therapeutic implications for increasing cisplatin efficiency in the management of ovarian cancer.

Charting epimutation dynamics in human hematopoietic differentiation Xiaohuan Qina

DNA methylation plays a critical role in hematopoietic differentiation.Epimutation is a stochastic variation in DNA methylation that induces epigenetic heterogeneity.However,the effects of epimutations on normal hematopoiesis and hematopoietic diseases remain unclear.In this study,we developed a Julia package called EpiMut that enabled rapid and accurate quantification of epimutations.EpiMut was used to evaluate and provide an epimutation landscape in steady-state hematopoietic differentiation involving 13 types of blood cells ranging from hematopoietic stem/progenitor cells to mature cells.We showed that substantial genomic regions exhibited epigenetic variations rather than significant differences in DNA methylation levels between the myeloid and lymphoid lineages.Stepwise dynamics of epimutations were observed during the differentiation of each lineage.Importantly,we found that epimutation significantly enriched signals associated with lineage differentiation.Furthermore,epimutations in hematopoietic stem cells(HSCs)derived from various sources and acute myeloid leukemia were related to the function of HSCs and malignant cell disorders.Taken together,our study comprehensively documented an epimutation map and uncovered its important roles in human hematopoiesis,thereby offering insights into hematopoietic regulation.

Adrenal pheochromocytoma impacts three main pathways: cysteine-methionine, pyrimidine, and tyrosine metabolism

Pheochromocytomas and paragangliomas(PPGLs)cause symptoms by altering the circulation levels of catecholamines and peptide hormones.Currently,the diagnosis of PPGLs relies on diagnostic imaging and the detection of catecholamines.In this study,we used ultra-performance liquid chromatography(UPLC)/quadrupole time-of-flight mass spectrometry(Q-TOF MS)analysis to identify and measure the perioperative differential metabolites in the plasma of adrenal pheochromocytoma patients.We identified differentially expressed genes by comparing the transcriptomic data of pheochromocytoma with the normal adrenal medulla.Through conducting two steps of metabolomics analysis,we identified 111 differential metabolites between the healthy group and the patient group,among which 53 metabolites were validated.By integrating the information of differential metabolites and differentially expressed genes,we inferred that the cysteine-methionine,pyrimidine,and tyrosine metabolism pathways were the three main metabolic pathways altered by the neoplasm.The analysis of transcription levels revealed that the tyrosine and cysteine-methionine metabolism pathways were downregulated in pheochromocytoma,whereas the pyrimidine pathway showed no significant difference.Finally,we developed an optimized diagnostic model of two metabolites,L-dihydroorotic acid and vanylglycol.Our results for these metabolites suggest that they may serve as potential clinical biomarkers and can be used to supplement and improve the diagnosis of pheochromocytoma.

Autophagy mediated tubulobulbar complex components degradation is required for spermiation

Spermiation is the process that releases mature spermatids from Sertoli cells into the lumen of the seminiferous tubule.Tubulobulbar complexes(TBCs)are elaborate cytoskeleton-related structures that are indispensable for spermiation.Despite well-defined ultrastructural events,the molecular regulation of TBCs during spermiation re-mains largely unknown.Here,we show that autophagy is active in TBC regions,and impaired autophagy in Sertoli cells affects spermiation.Further studies demonstrated that many TBC components bound to LC3 and could be selectively degraded through the autophagy-lysosome pathway.Perturbed autophagy impaired the degradation of some TBC components in Sertoli cells,such as VCL and CTTN,and led to the accumulation of TBC compo-nents surrounding the spermatid head,which may be associated with the sperm-releasing defect.Together,our results reveal that autophagy is essential for the TBC components degradation in mouse Sertoli cells and define a functional role of autophagy during spermiation.

CCDC178-mediated cytoskeleton assembly is required for spermiogenesis in mice

Infertility affects around 8%-12%of couples globally,and in about 50%of these cases,male factors are either the primary cause or contribute significantly to infertility.Any defects during spermiogenesis may result in male subfertility or complete infertility in mammals.1 Previously,we found that CFAP53 is localized in the manchette and sperm tail,and it plays an essential role in sperm flagellum biogenesis.

Lactate metabolism in human health and disease

The current understanding of lactate extends from its origins as a byproduct of glycolysis to its role in tumor metabolism,as identified by studies on the Warburg effect.The lactate shuttle hypothesis suggests that lactate plays an important role as a bridging signaling molecule that coordinates signaling among different cells,organs and tissues.Lactylation is a posttranslational modification initially reported by Professor Yingming Zhao’s research group in 2019.Subsequent studies confirmed that lactylation is a vital component of lactate function and is involved in tumor proliferation,neural excitation,inflammation and other biological processes.An indispensable substance for various physiological cellular functions,lactate plays a regulatory role in different aspects of energy metabolism and signal transduction.Therefore,a comprehensive review and summary of lactate is presented to clarify the role of lactate in disease and to provide a reference and direction for future research.This review offers a systematic overview of lactate homeostasis and its roles in physiological and pathological processes,as well as a comprehensive overview of the effects of lactylation in various diseases,particularly inflammation and cancer.