SLAM medical imaging enabled by pre-chirp and gain jointly managed Yb-fiber laser.

We demonstrate a pre-chirp and gain jointly managed Yb-fiber laser that drives simultaneous label-free autofluorescence-multiharmonic (SLAM) medical imaging. We show that a gain managed Yb-fiber amplifier produces high-quality compressed pulses when the seeding pulses exhibit proper negative pre-chirp. The resulting laser source can generate 43-MHz, 34-fs pulses centered at 1110 nm with more than 90-nJ energy. We apply this ultrafast source to SLAM imaging of cellular and extracellular components in various human tissues of intestinal adenocarcinoma, lung adenocarcinoma, and liver.

Luteal phase support in assisted reproductive technology.

Infertility affects one in six couples, with in vitro fertilization (IVF) offering many the chance of conception. Compared to the solitary oocyte produced during the natural menstrual cycle, the supraphysiological ovarian stimulation needed to produce multiple oocytes during IVF results in a dysfunctional luteal phase that can be insufficient to support implantation and maintain pregnancy. Consequently, hormonal supplementation with luteal phase support, principally exogenous progesterone, is used to optimize pregnancy rates; however, luteal phase support remains largely 'black-box' with insufficient clarity regarding the optimal timing, dosing, route and duration of treatment. Herein, we review the evidence on luteal phase support and highlight remaining uncertainties and future research directions. Specifically, we outline the physiological luteal phase, which is regulated by progesterone from the corpus luteum, and evaluate how it is altered by the supraphysiological ovarian stimulation used during IVF. Additionally, we describe the effects of the hormonal triggers used to mature oocytes on the degree of luteal phase support required. We explain the histological transformation of the endometrium during the luteal phase and evaluate markers of endometrial receptivity that attempt to identify the 'window of implantation'. We also cover progesterone receptor signalling, circulating progesterone levels associated with implantation, and the pharmacokinetics of available progesterone formulations to inform the design of luteal phase support regimens.

Bacterial quorum sensing orchestrates longitudinal interactions to shape microbiota assembly.

BACKGROUND: The mechanism of microbiota assembly is one of the main problems in microbiome research, which is also the primary theoretical basis for precise manipulation of microbial communities. Bacterial quorum sensing (QS), as the most common means for bacteria to exchange information and interactions, is characterized by universality, specificity, and regulatory power, which therefore may influence the assembly processes of human microbiota. However, the regulating role of QS in microbiota assembly is rarely reported. In this study, we developed an optimized in vitro oral biofilm microbiota assembling (OBMA) model to simulate the time-series assembly of oral biofilm microbiota (OBM), by which to excavate the QS network and its regulating power in the process. RESULTS: By using the optimized OBMA model, we were able to restore the assembly process of OBM and generate time-series OBM metagenomes of each day. We discovered a total of 2291 QS protein homologues related to 21 QS pathways. Most of these pathways were newly reported and sequentially enriched during OBM assembling. These QS pathways formed a comprehensive longitudinal QS network that included successively enriched QS hubs, such as Streptococcus, Veillonella-Megasphaera group, and Prevotella-Fusobacteria group, for information delivery. Bidirectional cross-talk among the QS hubs was found to play critical role in the directional turnover of microbiota structure, which in turn, influenced the assembly process. Subsequent QS-interfering experiments accurately predicted and experimentally verified the directional shaping power of the longitudinal QS network in the assembly process. As a result, the QS-interfered OBM exhibited delayed and fragile maturity with prolonged membership of Streptococcus and impeded membership of Prevotella and Fusobacterium. CONCLUSION: Our results revealed an unprecedented longitudinal QS network during OBM assembly and experimentally verified its power in predicting and manipulating the assembling process. Our work provides a new perspective to uncover underlying mechanism in natural complex microbiota assembling and a theoretical basis for ultimately precisely manipulating human microbiota through intervention in the QS network. Video Abstract.

Sophisticated Magneto-Mechanical Actuation Promotes In Situ Stem Cell Assembly and Chondrogenesis for Treating Osteoarthritis.

Abnormal mechanical loading often leads to the progressive degradation of cartilage and causes osteoarthritis (OA). Although multiple mechanoresponsive strategies based on biomaterials have been designed to restore healthy cartilage microenvironments, methods to remotely control the on-demand mechanical forces for cartilage repair pose significant challenges. Here, a magneto-mechanically controlled mesenchymal stem cell (MSC) platform, based on the integration of intercellular mechanical communication and intracellular mechanosignaling processes, is developed for OA treatment. MSCs loaded with antioxidative melanin@Fe3O4 magnetic nanoparticles (Magcells) rapidly assemble into highly ordered cell clusters with enhanced cell-cell communication under a time-varying magnetic field, which enables long-term retention and differentiation of Magcells in the articular cavity. Subsequently, via mimicking the gait cycle, chondrogenesis can be further enhanced by the dynamic activation of mechanical signaling processes in Magcells. This sophisticated magneto-mechanical actuation strategy provides a paradigm for developing mechano-therapeutics to repair cartilage in OA treatment.

Penile implants in low flow priapism.

Priapism is a persistent or prolonged erection, in the absence of sexual stimulation, that fails to subside. Prolonged ischaemic or low flow priapism is defined as a full or partial erection persisting for more than 4 h and unrelated to sexual interest or stimulation, characterised by little or no cavernous blood flow. Low flow priapism leads to progressive corporal fibrosis, which could, in turn, lead to long-lasting erectile dysfunction if left untreated. Penile prosthesis implantation is recognised as a management option in refractory and delayed low flow priapism for restoring erectile function with high patient satisfaction rates. However, the ensuing corporal fibrotic scarring poses a surgical challenge to clinicians, given the higher complication rates in this patient subset. Postoperative patient satisfaction has been closely linked to preoperative expectations and perceived loss of penile length. Therefore, thorough patient counselling concerning the risk and benefits of penile implants should be a priority for all clinicians. Moreover, there is a lack of consensus on the ideal prosthesis choice and procedural timing in refractory low flow priapism. In this review, we will examine the existing literature on penile implants in patients with priapism and discuss the options for managing complications associated with penile prosthesis surgery.

DNA methylation and miR-92a-3p-mediated repression of HIP1R promotes pancreatic cancer progression by activating the PI3K/AKT pathway.

Pancreatic cancer (PAAD) is a highly malignant tumour characterized of high mortality and poor prognosis. Huntingtin-interacting protein 1-related (HIP1R) has been recognized as a tumour suppressor in gastric cancer, while its biological function in PAAD remains to be elucidated. In this study, we reported the downregulation of HIP1R in PAAD tissues and cell lines, and the overexpression of HIP1R suppressed the proliferation, migration and invasion of PAAD cells, while silencing HIP1R showed the opposite effects. DNA methylation analysis revealed that the promoter region of HIP1R was heavily methylated in PAAD cell lines when compared to the normal pancreatic duct epithelial cells. A DNA methylation inhibitor 5-AZA increased the expression of HIP1R in PAAD cells. 5-AZA treatment also inhibited the proliferation, migration and invasion, and induced apoptosis in PAAD cell lines, which could be attenuated by HIP1R silencing. We further demonstrated that HIP1R was negatively regulated by miR-92a-3p, which modulates the malignant phenotype of PAAD cells in vitro and the tumorigenesis in vivo. The miR-92a-3p/HIP1R axis could regulate PI3K/AKT pathway in PAAD cells. Taken together, our data suggest that targeting DNA methylation and miR-92a-3p-mediated repression of HIP1R could serve as novel therapeutic strategies for PAAD treatment.

A Novel Somatic Mutation Implicates ATP6V0D1 in Proinsulin Processing.

Context: Prohormone convertase 1/3 (PC1/3), encoded by protein convertase subtilisin kexin type 1 (PCSK1), converts inactive prohormones into biologically active peptides. Somatic mutations of insulinomas are associated with genetic defects interfering with control of insulin secretion from pancreatic beta cells. However, somatic mutations in proinsulinomas have not been described. Objective: We report a case of a proinsulinoma, with suppressed insulin and C-peptide levels. Methods: A 70-year-old woman presented with a 20-year history of "blackouts." During a 72-hour fast, blood glucose level dropped to 1.9 mmol/L with suppressed plasma insulin and C-peptide levels, but proinsulin levels were raised at 37 pmol/L (<10 pmol/L). Results: Imaging revealed 3 distinct DOTATATE-avid pancreatic lesions. Laparoscopic spleen-preserving distal pancreatomy was performed. In view of discordant insulin, C-peptide, and proinsulin levels, whole exome sequencing analysis was performed on the tumor. In the somatic exome of the tumor, we found mutations in PCSK expression regulators, as well as a novel truncating somatic mutation in ATP6V0D1, a subunit of the ion pump that acidifies the ß-cell compartments where the PCSKs act. Conclusion: Appropriately suppressed insulin levels in the context of hypoglycemia do not always indicate the absence of a neuroendocrine islet cell tumor and proinsulin levels may be indicated to solidify the diagnosis. In the context of elevated proinsulin levels, low insulin and C-peptide levels might be explained by somatic mutations that likely implicate proinsulin processing within the tumor. Furthermore, we propose several mechanistic candidates, including ATP6V0D1. Experimental validation using cellular approaches may in future confirm pathomechanisms involved in this rare condition.

The use of hormone stimulation in male infertility.

Infertility affects 15% of couples worldwide and in approximately 50% of cases the cause is secondary to an abnormality of the sperm. However, treatment options for male infertility are limited and empirical use of hormone stimulation has been utilised. We review the contemporary data regarding the application of hormone stimulation to treat male infertility. There is strong evidence supporting the use of hormone stimulation in hypogonadotropic hypogonadism but there is inadequate evidence for all other indications.

The management of erectile dysfunction in men with diabetes mellitus unresponsive to phosphodiesterase type 5 inhibitors.

INTRODUCTION: Erectile dysfunction is associated with diabetes mellitus with an estimated prevalence of 52.5% in the diabetic population. The first-line therapy for erectile dysfunction is phosphodiesterase type 5 inhibitors, but data suggest that diabetic men may be less responsive than non-diabetic men. Thus, other treatments, including intracavernosal injections, intraurethral prostaglandin, vacuum erection devices and penile prosthetic surgery, should be considered in management of diabetic men with erectile dysfunction refractory to phosphodiesterase type 5 inhibitors. Furthermore, combination therapy of phosphodiesterase type 5 inhibitors and other oral treatments such as arginine or l-carnitine may have synergistic effects resulting in better outcomes. In addition, there are novel therapies such as low-intensity shockwave therapy and stem-cell therapy, which may also be effective in targeted treatment modalities. Furthermore, studies suggest that erectile dysfunction can be improved by targeting concurrent comorbidities or metabolic diseases such as depression, hypertension, hypogonadism, and dyslipidaemia. We present an evidence-based narrative review focusing on the management of erectile dysfunction in diabetic men who have not responded to phosphodiesterase type 5 inhibitors. CONCLUSIONS: Both clinicians and patients should be aware of the different management options in diabetic patients who have not responded to phosphodiesterase type 5 inhibitors.

Understanding and treating ejaculatory dysfunction in men with diabetes mellitus.

Diabetes mellitus is a rapidly rising metabolic disorder with important systemic complications. Global figures have demonstrated the prevalence of diabetes mellitus has almost quadrupled from 108 million in 1980 to 422 million in 2014, with a current prevalence of over 525 million. Of the male sexual dysfunction resulting from diabetes mellitus, significant focus is afforded to erectile dysfunction. Nevertheless, ejaculatory dysfunction constitutes important sexual sequelae in diabetic men, with up to 35%-50% of men with diabetes mellitus suffering from ejaculatory dysfunction. Despite this, aspects of its pathophysiology and treatment are less well understood than erectile dysfunction. The main disorders of ejaculation include premature ejaculation, delayed ejaculation, anejaculation and retrograde ejaculation. Although ejaculatory dysfunction in diabetes mellitus can have complex multifactorial aetiology, understanding its pathophysiological mechanisms has facilitated the development of therapies in the management of ejaculatory dysfunction. Most of our understanding of its pathophysiology is derived from diabetic animal models; however, observational studies in humans have also provided useful information in elucidating important associative factors potentially contributing to ejaculatory dysfunction in diabetic men. These have provided the potential for more tailored treatment regimens in patients depending on the ejaculatory disorder, other co-existing sequelae of diabetes mellitus, specific metabolic factors as well as the need for fertility treatment. However, evidence for treatment of ejaculatory dysfunction, especially delayed ejaculation and retrograde ejaculation, is based on low-level evidence comprising small sample-size series and retrospective or cross-sectional studies. Whilst promising findings from large randomised controlled trials have provided strong evidence for the licensed treatment of premature ejaculation, similar robust studies are needed to accurately elucidate factors predicting ejaculatory dysfunction in diabetes mellitus, as well as for the development of pharmacotherapies for delayed ejaculation and retrograde ejaculation. Similarly, more contemporary robust data are required for fertility outcomes in these patients, including methods of sperm retrieval and assisted reproductive techniques in retrograde ejaculation.

NIR-II Photoacoustic-Active DNA Origami Nanoantenna for Early Diagnosis and Smart Therapy of Acute Kidney Injury.

Herein, we designed and synthesized a novel microRNA (miR)-responsive nanoantenna capable of early diagnosis and smart treatment of acute kidney injury (AKI). The nanoantenna was made of two miniature gold nanorods (AuNRs) (e.g., length: ∼48 nm; width: ∼9 nm) linked together by a rectangular DNA origami nanostructure (rDONs) scaffold (e.g., length: ∼90 nm; width: ∼60 nm) (rDONs@AuNR dimer). The surface plasmon resonance peak of the constructed nanoantenna is located within the NIR-II window (e.g., ∼1060 nm), thus guaranteeing photoacoustic (PA) imaging of the nanoantenna in deep tissues. Intriguingly, the nanoantenna displayed exclusive kidney retention in both healthy mice and ischemia reperfusion-induced AKI mice by leveraging the kidney-targeting ability of rDONs. Distinguished from the stable signals in the healthy mice, the PA signals of the nanoantenna would turn down in the AKI mice due to the AuNR detached from rDONs upon interaction with miR-21, which were up-expressed in AKI mice. The limit of detection toward miR-21 was down to 2.8 nM, enabling diagnosis of AKI as early as 10 min post-treatment with ischemia reperfusion, around 2 orders of magnitude earlier than most established probes. Moreover, the naked rDON scaffold generated by AKI could capture more reactive oxygen species (e.g., 1.5-fold more than rDONs@AuNR dimer), alleviating ischemic AKI. This strategy provided a new avenue for early diagnosis and smart treatment of AKI.

Bibliometric analysis of research trends in stem cell therapy for knee osteoarthritis over the period 2001-2021.

Stem cell therapy is a promising treatment for knee osteoarthritis, but few bibliometric studies have been performed on the subject. Bibliometric analysis is helpful for identifying the most influential studies in a specific field and can evaluate the global research trends in stem cell therapy for knee osteoarthritis. The Web of Science Core Collection was searched for publications from 2001 to 2021. Publication performance was analyzed using several bibliometric parameters, including VOSviewer, to identify the research landscape of trends in topics, and CiteSpace was investigated to identify the keywords that have the strongest citation bursts. From 2001 to 2021, in total, 1,345 publications explored the research on stem cells in knee osteoarthritis. The United States contributed the largest number of publications and at the top list of international collaborations. Tokyo Medical and Dental University ranked first among institutions in the overall number of articles and citations. The journal of Osteoarthritis and Cartilage had the largest number of publications. Sekiya Ichiro was the most cited author, with 32 articles. The keywords with the most frequent occurrence were "osteoarthritis," "mesenchymal stem cells," and "cartilage," in descending order of frequency. "fibroblast growth factor" and "extracellular vesicle" were the first and last searched theme terms, respectively. The number of publications on stem cells for knee osteoarthritis stays growing. Cartilage repair and paracrine function are current research hotspots for the stem cell therapy mechanism. Stem cell therapy has gradually advanced from basic research to the clinical application stage.

On the frequency spanning of SPM-enabled spectral broadening: analytical solutions.

We present an analytical treatment of ultra-short pulses propagating in an optical fiber in the strong nonlinearity regime, in which the interaction between self-phase modulation (SPM) and group-velocity dispersion (GVD) substantially broadens the input spectrum. Supported by excellent agreement with the simulation results, these analytical solutions provide a convenient and reasonable accurate estimation of the peak position of the outermost spectral lobes as well as the full width at half maximum of the broadened spectrum. We show that our unified solutions are valid for either Gaussian pulse or hyperbolic secant pulse propagating inside an optical fiber with positive or negative GVD. Our findings shed light on the optimization of SPM-enabled spectral broadening in various applications.

Novel androgen therapies including selective androgen receptor modulators.

Male hypogonadism is associated with reduced quality of life and the development of co-morbidities including obesity, diabetes mellitus, and dyslipidaemia. The mainstay of treatment for male hypogonadism is testosterone replacement therapy (TRT). However, TRT has recognised side effects including impaired spermatogenesis and there are concerns regarding its use in men with concurrent cardiovascular disease. Thus, there has been an impetus to develop novel androgen therapies for treating male hypogonadism to mitigate the side effects of TRT. This review will discuss the benefits and adverse effects of TRT, and novel therapies including nasal testosterone, aromatase inhibitors, selective oestrogen receptor modulators, and selective androgen receptor modulators.

Apatinib plus 5-fluorouracil as a third or subsequent-line treatment option for metastatic colorectal cancer: a phase-II, single-arm, prospective study.

Background: For metastatic colorectal cancer (mCRC) patients for whom at least 2 lines of previous standard therapies have failed, the prognosis is often unfavorable due to very limited subsequent treatment options. We sought to explore the efficacy of apatinib, an oral small-molecule vascular endothelial growth factor receptor-2 inhibitor, plus 5-fluorouracil (5-FU) as a third- or subsequent-line treatment for mCRC. Methods: In this phase-II, single-arm, prospective study, the eligible patients had been histologically confirmed to have adenocarcinoma of the colon or rectum for which at least 2 previous regimens of standard therapies had failed. All the patients were treated with a daily dose of 250 mg of apatinib, in combination with capecitabine, Tegafur Gimeracil Oteracil Potassium Capsule (S-1), or 5-FU, until disease progression, unacceptable toxicity, or consent withdrawal. Results: From June 2017 to April 2018, 16 patients were enrolled in this study. Among them, 4 achieved partial response, 7 had stable disease, and 5 had progression disease, resulting in an objective response rate of 25.00% [95% confidence interval (CI): 7.27-52.38%], and a disease control rate of 68.75% (95% CI: 41.34-88.98%). The median progression-free survival (PFS) was 4.83 months (95% CI: 2.17-8.90 months), and the median overall survival (OS) was 9.10 months (95% CI: 5.59-15.18 months). The common treatment-related adverse events (AEs) were hand-foot syndrome (56.25%), hypertension (37.50%), proteinuria (37.50%), gingival bleeding (18.75%) and abdominal pain (18.75%). Grade 3 AEs, including hand-foot syndrome (18.75%), hypertension (12.50%), and proteinuria (12.50%), were observed in 7 patients. Conclusions: The combination regimen of apatinib plus 5-FU had encouraging anti-tumor efficacy, and is a feasible third- or subsequent-line treatment option for mCRC. Trial Registration: ClinicalTrials.gov Identifier: NCT03210064.

Metagenome-Assembled Genomes Reveal Mechanisms of Carbohydrate and Nitrogen Metabolism of Schistosomiasis-Transmitting Vector Biomphalaria Glabrata.

Biomphalaria glabrata transmits schistosomiasis mansoni which poses considerable risks to hundreds of thousands of people worldwide, and is widely used as a model organism for studies on the snail-schistosome relationship. Gut microbiota plays important roles in multiple aspects of host including development, metabolism, immunity, and even behavior; however, detailed information on the complete diversity and functional profiles of B. glabrata gut microbiota is still limited. This study is the first to reveal the gut microbiome of B. glabrata based on metagenome-assembled genome (MAG). A total of 28 gut samples spanning diet and age were sequenced and 84 individual microbial genomes with ≥ 70% completeness and ≤ 5% contamination were constructed. Bacteroidota and Proteobacteria were the dominant bacteria in the freshwater snail, unlike terrestrial organisms harboring many species of Firmicutes and Bacteroidota. The microbial consortia in B. glabrata helped in the digestion of complex polysaccharide such as starch, hemicellulose, and chitin for energy supply, and protected the snail from food poisoning and nitrate toxicity. Both microbial community and metabolism of B. glabrata were significantly altered by diet. The polysaccharide-degrading bacterium Chryseobacterium was enriched in the gut of snails fed with high-digestibility protein and high polysaccharide diet (HPHP). Notably, B. glabrata as a mobile repository can escalate biosafety issues regarding transmission of various pathogens such as Acinetobacter nosocomialis and Vibrio parahaemolyticus as well as multiple antibiotic resistance genes in the environment and to other organisms. IMPORTANCE The spread of aquatic gastropod Biomphalaria glabrata, an intermediate host of Schistosoma mansoni, exacerbates the burden of schistosomiasis disease worldwide. This study provides insights into the importance of microbiome for basic biological activities of freshwater snails, and offers a valuable microbial genome resource to fill the gap in the analysis of the snail-microbiota-parasite relationship. The results of this study clarified the reasons for the high adaptability of B. glabrata to diverse environments, and further illustrated the role of B. glabrata in accumulation of antibiotic resistance in the environment and spread of various pathogens. These findings have important implications for further exploration of the control of snail dissemination and schistosomiasis from a microbial perspective.

Safety of androgen therapy in men with prostate cancer.

Prostate cancer is one of the most frequently diagnosed malignancies in men worldwide and the life expectancy for men with prostate cancer is improving due to advancements in diagnostics and treatment. Male hypogonadism is associated with obesity, diabetes, and other comorbidities and also has been linked with increasing age; the primary therapy modality for this condition is testosterone replacement therapy (TRT). There are concerns that testosterone therapy may cause prostate cancer disease progression. However, contemporary evidence suggests that testosterone replacement therapy may be safe in specific groups of patients with prostate cancer. This chapter will summarise the contemporary literature regarding TRT use in hypogonadal men with prostate cancer, including limitations and future research goals.

Particle swarm optimization of SPM-enabled spectral selection to achieve an octave-spanning wavelength-shift.

SPM-enabled spectral selection (SESS) constitutes a powerful fiber-optic technique to generate wavelength broadly tunable femtosecond pulses. In the current demonstration, the maximum tuning range is 400 nm and the energy conversion efficiency from the pump source to the outmost spectral lobes is ∼25%. In this submission, we apply the particle swarm optimization method to the generalized nonlinear Schrödinger equation to identify the optimal parameters that maximize both the tuning range and the conversion efficiency. We show that SESS in an optical fiber with the optimized dispersion can deliver SESS pulses tunable in one octave wavelength range and the conversion efficiency can be as high as 80%. We further show the feasibility of experimental implementation based on specially designed fibers or on-chip waveguides.