Research Advances in Stem Cell Therapy for Erectile Dysfunction.

Erectile dysfunction (ED) is a common clinical condition that mainly affects men aged over 40 years. Various causes contribute to the progression of ED, including pelvic nerve injury, diabetes, metabolic syndrome, age, Peyronie's disease, smoking, and psychological disorders. Current treatments for ED are limited to symptom relief and do not address the root cause. Stem cells, with their powerful ability to proliferate and differentiate, are a promising approach for the treatment of male ED and are gradually gaining widespread attention. Current uses for treating ED have been studied primarily in experimental animals, with most studies observing improvements in erectile quality as well as improvements in erectile tissue. However, research on stem cell therapy for human ED is still limited. This article summarizes the recent literature on basic stem cell research on ED, including cavernous nerve injury, aging, diabetes, and sclerosing penile disease, and describes mechanisms of action and therapeutic effects of various stem cell therapies in experimental animals. Stem cells are also believed to interact with host tissue in a paracrine manner, and improved function can be supported through both implantation and paracrine factors. To date, stem cells have shown some preliminary promising results in animal and human models of ED.

Cd(II)/Mn(II)/Co(II)/Ni(II)/Zn(II) Coordination Polymers Built from Dicarboxylic Acid/Tetracarboxylic Acid Ligands: Their Structural Diversity and Fluorescence Properties.

Six Cd(II)/Mn(II)/Co(II)/Ni(II)/Zn(II) coordination complexes are formulated as [Cd2(X2-)2(µ3-O)2/3]n (1), [Mn2(X2-)2(µ3-O)2/3]n (2), {[Co1.5(Y4-)0.5(4,4'-bpy)1.5(OH-)]·2H2O}n (3), {[Ni(X2-)(4,4'-bpy)(H2O)2]·4H2O}n (4), [Zn(m-bdc2-)(bebiyh)]n (5), and [Cd(5-tbia2-)(bebiyh)]n (6) (H2X = 3,3'-(2,3,5,6-tetramethyl-1,4-phenylene) dipropionic acid. H4Y = 2,2'-(2,3,5,6-tetramethyl-1,4-phenylene)bis(methylene) dimalonic acid, bebiyh = 1,6-bis(2-ethyl-1H-benzo[d]imidazol-1-yl)hexane, m-H2bdc = 1,3-benzenedicarboxylic acid, and 5-H2tbia = 5-(tert-butyl)isophthalic acid) were obtained by hydrothermal reactions and structurally characterized. Complexes 1 and 2 have a 6-connected 3D architecture and with several point symbols of (36·46·53). Complex 3 features a 5-connected 3D net structure with a point symbol of (5·69). Complex 4 possesses a 4-connected 2D net with a vertex symbol of (44·62). Complex 5 is a 3-connected 2D network with a point symbol of (63). Complex 6 is a (3,3)-connected 2D network with a point symbol of (63)2. In addition, complexes 1 and 4 present good photoluminescence behaviors. The electronic structures of 1 and 4 were investigated with the density functional theory (DFT) method to understand the photoluminescence behaviors.

Study on Fluorescence Recognition of Fe3+, Cr2O72- and p-Nitrophenol by a Cadmium Complex and Related Mechanism.

The effective detection of environmental pollutants is very important to the sustainable development of human health and the environment. A luminescent Cd(II) coordination complex, {[Cd(dbtdb)(1,2,4-H3btc)]·0.5H2O}n (1) (dbtdb = 1-(2,3,5,6-tetramethyl-4-((2-(thiazol-4-yl)-2H-benzo[d]imidazol-3(3aH)-yl)methyl)benzyl)-2,7a-dihydro-2-(thiazol-4-yl)-1H-benzo[d]imidazole, 1,2,4-H3btc = 1,2,4-benzenetricarboxylic acid), was obtained by hydrothermal reactions. Complex 1 has a chain structure decorated with uncoordinated Lewis basic O and S donors and provides good sensing of Fe3+, Cr2O72-, and p-nitrophenol with fluorescence quenching through an energy transfer process. The calculated binding constants were 3.3 × 103 mol-1 for Fe3+, 2.36 × 104 mol-1 for Cr2O72-, and 9.3 × 103 mol-1 for p-nitrophenol, respectively. These results show that 1 is a rare multiresponsive sensory material for efficient detection of Fe3+, Cr2O72-, and p-nitrophenol.

The deubiquitylating enzyme USP15 regulates homologous recombination repair and cancer cell response to PARP inhibitors.

Poly-(ADP-ribose) polymerase inhibitors (PARPi) selectively kill breast and ovarian cancers with defects in homologous recombination (HR) caused by BRCA1/2 mutations. There is also clinical evidence for the utility of PARPi in breast and ovarian cancers without BRCA mutations, but the underlying mechanism is not clear. Here, we report that the deubiquitylating enzyme USP15 affects cancer cell response to PARPi by regulating HR. Mechanistically, USP15 is recruited to DNA double-strand breaks (DSBs) by MDC1, which requires the FHA domain of MDC1 and phosphorylated Ser678 of USP15. Subsequently, USP15 deubiquitinates BARD1 BRCT domain, and promotes BARD1-HP1γ interaction, resulting in BRCA1/BARD1 retention at DSBs. USP15 knockout mice exhibit genomic instability in vivo. Furthermore, cancer-associated USP15 mutations, with decreased USP15-BARD1 interaction, increases PARP inhibitor sensitivity in cancer cells. Thus, our results identify a novel regulator of HR, which is a potential biomarker for therapeutic treatment using PARP inhibitors in cancers.

A region-resolved mucosa proteome of the human stomach.

The human gastric mucosa is the most active layer of the stomach wall, involved in food digestion, metabolic processes and gastric carcinogenesis. Anatomically, the human stomach is divided into seven regions, but the protein basis for cellular specialization is not well understood. Here we present a global analysis of protein profiles of 82 apparently normal mucosa samples obtained from living individuals by endoscopic stomach biopsy. We identify 6,258 high-confidence proteins and estimate the ranges of protein expression in the seven stomach regions, presenting a region-resolved proteome reference map of the near normal, human stomach. Furthermore, we measure mucosa protein profiles of tumor and tumor nearby tissues (TNT) from 58 gastric cancer patients, enabling comparisons between tumor, TNT, and normal tissue. These datasets provide a rich resource for the gastrointestinal tract research community to investigate the molecular basis for region-specific functions in mucosa physiology and pathology including gastric cancer.

Molecular subtyping of cancer and nomination of kinase candidates for inhibition with phosphoproteomics: Reanalysis of CPTAC ovarian cancer.

BACKGROUND: Molecular subtyping of cancer aimed to predict patient overall survival (OS) and nominate drug targets for patient treatments is central to precision oncology. Owing to the rapid development of phosphoproteomics, we can now measure thousands of phosphoproteins in human cancer tissues. However, limited studies report how to analyse the complex phosphoproteomic data for cancer subtyping and to nominate druggable kinase candidates. FINDINGS: In this work, we reanalysed the phosphoproteomic data of high-grade serous ovarian cancer (HGSOC) from the Clinical Proteomic Tumour Analysis Consortium (CPTAC). Our analysis classified HGSOC into 5 major subtypes that were associated with different OS and appeared to be more accurate than that achieved with protein profiling. We provided a workflow to identify 29 kinases whose increased activities in tumours are associated with poor survival. The altered kinase signalling landscape of HGSOC included the PI3K/AKT/mTOR, cell cycle and MAP kinase signalling pathways. We also developed a "patient-specific" hierarchy of clinically actionable kinases and selected kinase inhibitors by considering kinase activation and kinase inhibitor selectivity. INTERPRETATION: Our study offered a global phosphoproteomics data analysis workflow to aid in cancer molecular subtyping, determining phosphorylation-based cancer hallmarks and facilitating nomination of kinase inhibition in cancer.

A time-resolved multi-omic atlas of the developing mouse stomach.

The mammalian stomach is structurally highly diverse and its organ functionality critically depends on a normal embryonic development. Although there have been several studies on the morphological changes during stomach development, a system-wide analysis of the underlying molecular changes is lacking. Here, we present a comprehensive, temporal proteome and transcriptome atlas of the mouse stomach at multiple developmental stages. Quantitative analysis of 12,108 gene products allows identifying three distinct phases based on changes in proteins and RNAs and the gain of stomach functions on a longitudinal time scale. The transcriptome indicates functionally important isoforms relevant to development and identifies several functionally unannotated novel splicing junction transcripts that we validate at the peptide level. Importantly, many proteins differentially expressed in stomach development are also significantly overexpressed in diffuse-type gastric cancer. Overall, our study provides a resource to understand stomach development and its connection to gastric cancer tumorigenesis.

Author Correction: A proteomic landscape of diffuse-type gastric cancer.

The original version of this Article contained an error in the email address of the corresponding author Jun Qin. The correct email is jqin1965@126.com. The error has been corrected in the HTML and PDF versions of the Article.

A proteomics landscape of circadian clock in mouse liver.

As a circadian organ, liver executes diverse functions in different phase of the circadian clock. This process is believed to be driven by a transcription program. Here, we present a transcription factor (TF) DNA-binding activity-centered multi-dimensional proteomics landscape of the mouse liver, which includes DNA-binding profiles of different TFs, phosphorylation, and ubiquitylation patterns, the nuclear sub-proteome, the whole proteome as well as the transcriptome, to portray the hierarchical circadian clock network of this tissue. The TF DNA-binding activity indicates diurnal oscillation in four major pathways, namely the immune response, glucose metabolism, fatty acid metabolism, and the cell cycle. We also isolate the mouse liver Kupffer cells and measure their proteomes during the circadian cycle to reveal a cell-type resolved circadian clock. These comprehensive data sets provide a rich data resource for the understanding of mouse hepatic physiology around the circadian clock.

A reference peptide database for proteome quantification based on experimental mass spectrum response curves.

Motivation: Mass spectrometry (MS) based quantification of proteins/peptides has become a powerful tool in biological research with high sensitivity and throughput. The accuracy of quantification, however, has been problematic as not all peptides are suitable for quantification. Several methods and tools have been developed to identify peptides that response well in mass spectrometry and they are mainly based on predictive models, and rarely consider the linearity of the response curve, limiting the accuracy and applicability of the methods. An alternative solution is to select empirically superior peptides that offer satisfactory MS response intensity and linearity in a wide dynamic range of peptide concentration. Results: We constructed a reference database for proteome quantification based on experimental mass spectrum response curves. The intensity and dynamic range of over 2 647 773 transitions from 121 318 peptides were obtained from a set of dilution experiments, covering 11 040 gene products. These transitions and peptides were evaluated and presented in a database named SCRIPT-MAP. We showed that the best-responder (BR) peptide approach for quantification based on SCRIPT-MAP database is robust, repeatable and accurate in proteome-scale protein quantification. This study provides a reference database as well as a peptides/transitions selection method for quantitative proteomics. Availability and implementation: SCRIPT-MAP database is available at http://www.firmiana.org/responders/. Supplementary information: Supplementary data are available at Bioinformatics online.

A proteomic landscape of diffuse-type gastric cancer.

The diffuse-type gastric cancer (DGC) is a subtype of gastric cancer with the worst prognosis and few treatment options. Here we present a dataset from 84 DGC patients, composed of a proteome of 11,340 gene products and mutation information of 274 cancer driver genes covering paired tumor and nearby tissue. DGC can be classified into three subtypes (PX1-3) based on the altered proteome alone. PX1 and PX2 exhibit dysregulation in the cell cycle and PX2 features an additional EMT process; PX3 is enriched in immune response proteins, has the worst survival, and is insensitive to chemotherapy. Data analysis revealed four major vulnerabilities in DGC that may be targeted for treatment, and allowed the nomination of potential immunotherapy targets for DGC patients, particularly for those in PX3. This dataset provides a rich resource for information and knowledge mining toward altered signaling pathways in DGC and demonstrates the benefit of proteomic analysis in cancer molecular subtyping.

Urine Proteome Profiling Predicts Lung Cancer from Control Cases and Other Tumors.

Development of noninvasive, reliable biomarkers for lung cancer diagnosis has many clinical benefits knowing that most of lung cancer patients are diagnosed at the late stage. For this purpose, we conducted proteomic analyses of 231 human urine samples in healthy individuals (n=33), benign pulmonary diseases (n=40), lung cancer (n=33), bladder cancer (n=17), cervical cancer (n=25), colorectal cancer (n=22), esophageal cancer (n=14), and gastric cancer (n=47) patients collected from multiple medical centers. By random forest modeling, we nominated a list of urine proteins that could separate lung cancers from other cases. With a feature selection algorithm, we selected a panel of five urinary biomarkers (FTL: Ferritin light chain; MAPK1IP1L: Mitogen-Activated Protein Kinase 1 Interacting Protein 1 Like; FGB: Fibrinogen Beta Chain; RAB33B: RAB33B, Member RAS Oncogene Family; RAB15: RAB15, Member RAS Oncogene Family) and established a combinatorial model that can correctly classify the majority of lung cancer cases both in the training set (n=46) and the test sets (n=14-47 per set) with an AUC ranging from 0.8747 to 0.9853. A combination of five urinary biomarkers not only discriminates lung cancer patients from control groups but also differentiates lung cancer from other common tumors. The biomarker panel and the predictive model, when validated by more samples in a multi-center setting, may be used as an auxiliary diagnostic tool along with imaging technology for lung cancer detection.

Regulation of the Hippo-YAP Pathway by Glucose Sensor O-GlcNAcylation.

The Hippo pathway is crucial in organ size control and tissue homeostasis, with deregulation leading to cancer. An extracellular nutrition signal, such as glucose, regulates the Hippo pathway activation. However, the mechanisms are still not clear. Here, we found that the Hippo pathway is directly regulated by the hexosamine biosynthesis pathway (HBP) in response to metabolic nutrients. Mechanistically, the core component of Hippo pathway (YAP) is O-GlcNAcylated by O-GlcNAc transferase (OGT) at serine 109. YAP O-GlcNAcylation disrupts its interaction with upstream kinase LATS1, prevents its phosphorylation, and activates its transcriptional activity. And this activation is not dependent on AMPK. We also identified OGT as a YAP-regulated gene that forms a feedback loop. Finally, we confirmed that glucose-induced YAP O-GlcNAcylation and activation promoted tumorigenesis. Together, our data establish a molecular mechanism and functional significance of the HBP in directly linking extracellular glucose signal to the Hippo-YAP pathway and tumorigenesis.

The anaphase promoting complex impacts repair choice by protecting ubiquitin signalling at DNA damage sites.

Double-strand breaks (DSBs) are repaired through two major pathways, homology-directed recombination (HDR) and non-homologous end joining (NHEJ). While HDR can only occur in S/G2, NHEJ can happen in all cell cycle phases (except mitosis). How then is the repair choice made in S/G2 cells? Here we provide evidence demonstrating that APCCdh1 plays a critical role in choosing the repair pathways in S/G2 cells. Our results suggest that the default for all DSBs is to recruit 53BP1 and RIF1. BRCA1 is blocked from being recruited to broken ends because its recruitment signal, K63-linked poly-ubiquitin chains on histones, is actively destroyed by the deubiquitinating enzyme USP1. We show that the removal of USP1 depends on APCCdh1 and requires Chk1 activation known to be catalysed by ssDNA-RPA-ATR signalling at the ends designated for HDR, linking the status of end processing to RIF1 or BRCA1 recruitment.

Quantitation of circulating GDF-11 and ß2-MG in aged patients with age-related impairment in cognitive function.

Growth differentiation factor 11 (GDF-11) has been implicated in reverse effects of ageing on the central nervous system of humans. ß2-microglobulin (ß2-MG) has been reported to negatively regulate cognition. However, there is a lot of controversy about the role of GDF-11 and ß2-MG in ageing and cognitive regulation. To examine the involvement of GDF-11 and ß2-MG in the ageing process and cognitive dysfunction, a total of 51 healthy subjects and 41 elderly patients with different degrees of age-related cognitive impairment participated in the study. We measured plasma GDF-11 and ß2-MG levels using ELISA and immunoturbidimetry, respectively. The results were statistically analyzed to evaluate the associations between levels of GDF-11 and ß2-MG, and ageing and cognitive impairments. Circulating GDF-11 levels did not decline with age or correlate with ageing in healthy Chinese males. We did not detect differences in circulating GDF-11 levels amongst the healthy advanced age and four cognitive impairment groups. ß2-MG levels increased with age, but there was no significant difference between healthy elderly males and advanced age males. Increased levels of ß2-MG were observed in the dementia group compared with the healthy advanced age group. Our results suggest that circulating GDF-11 may not exert a protective effect during the ageing process or on cognitive function, and ß2-MG may play a role in ageing and cognitive impairment. However, it is possible that the relatively small sample size in the present study affected the quality of the statistical analysis, and future studies are needed to further validate our findings.

A mouse tissue transcription factor atlas.

Transcription factors (TFs) drive various biological processes ranging from embryonic development to carcinogenesis. Here, we employ a recently developed concatenated tandem array of consensus TF response elements (catTFRE) approach to profile the activated TFs in 24 adult and 8 fetal mouse tissues on proteome scale. A total of 941 TFs are quantitatively identified, representing over 60% of the TFs in the mouse genome. Using an integrated omics approach, we present a TF network in the major organs of the mouse, allowing data mining and generating knowledge to elucidate the roles of TFs in various biological processes, including tissue type maintenance and determining the general features of a physiological system. This study provides a landscape of TFs in mouse tissues that can be used to elucidate transcriptional regulatory specificity and programming and as a baseline that may facilitate understanding diseases that are regulated by TFs.

Proof-of-Concept Workflow for Establishing Reference Intervals of Human Urine Proteome for Monitoring Physiological and Pathological Changes.

Urine as a true non-invasive sampling source holds great potential for biomarker discovery. While approximately 2000 proteins can be detected by mass spectrometry in urine from healthy people, the amount of these proteins vary considerably. A systematic evaluation of a large number of samples is needed to determine the range of the variations. Current biomarker studies often measure limited number of urine samples in the discovery phase, which makes it difficult to determine whether proteins differentially expressed between control and disease groups represent actual difference, or are just physiological variations among the individuals, leads to failures in the validation phase with the increased sample numbers. Here, we report a streamlined workflow with capacity of measuring 8 urine proteomes per day at the coverage of >1500 proteins. With this workflow, we evaluated variations in 497 urine proteomes from 167 healthy donors, establishing reference intervals (RIs) that covered urine protein variations. We demonstrated that RIs could be used to monitor physiological changes by detecting transient outlier proteins. Furthermore, we provided a RIs-based algorithm for biomarker discovery and validation to screen for diseases such as cancer. This study provided a proof-of-principle workflow for the use of urine proteome for health monitoring and disease screening.

Differential proteomics profiling identifies LDPs and biological functions in high-fat diet-induced fatty livers.

Eukaryotic cells store neutral lipids in cytoplasmic lipid droplets (LDs) enclosed in a monolayer of phospholipids and associated proteins [LD proteins (LDPs)]. Growing evidence has demonstrated that LDPs play important roles in the pathogenesis of liver diseases. However, the composition of liver LDPs and the role of their alterations in hepatosteatosis are not well-understood. In this study, we performed liver proteome and LD sub-proteome profiling to identify enriched proteins in LDs as LDPs, and quantified their changes in a high-fat diet (HFD)-induced fatty liver model. Among 5,000 quantified liver proteins, 101 were enriched by greater than 10-fold in the LD sub-proteome and were classified as LDPs. Differential profiling of LDPs in HFD-induced fatty liver provided a list of candidate LDPs for functional investigation. We tested the function of an upregulated LDP, S100a10, in vivo with adenovirus-mediated gene silencing and found, unexpectedly, that knockdown of S100a10 accelerated progression of HFD-induced liver steatosis. The S100A10 interactome revealed a connection between S100A10 and lipid transporting proteins, suggesting that S100A10 regulates the development and formation of LDs by transporting and trafficking. This study identified LD-enriched sub-proteome in homeostatic as well as HFD-induced fatty livers, providing a rich resource for the LDP research field.

Erratum: The anaphase promoting complex impacts repair choice by protecting ubiquitin signalling at DNA damage sites.

[This corrects the article DOI: 10.1038/ncomms15751.].

A Cell-type-resolved Liver Proteome.

Parenchymatous organs consist of multiple cell types, primarily defined as parenchymal cells (PCs) and nonparenchymal cells (NPCs). The cellular characteristics of these organs are not well understood. Proteomic studies facilitate the resolution of the molecular details of different cell types in organs. These studies have significantly extended our knowledge about organogenesis and organ cellular composition. Here, we present an atlas of the cell-type-resolved liver proteome. In-depth proteomics identified 6000 to 8000 gene products (GPs) for each cell type and a total of 10,075 GPs for four cell types. This data set revealed features of the cellular composition of the liver: (1) hepatocytes (PCs) express the least GPs, have a unique but highly homogenous proteome pattern, and execute fundamental liver functions; (2) the division of labor among PCs and NPCs follows a model in which PCs make the main components of pathways, but NPCs trigger the pathways; and (3) crosstalk among NPCs and PCs maintains the PC phenotype. This study presents the liver proteome at cell resolution, serving as a research model for dissecting the cell type constitution and organ features at the molecular level.