Induced pluripotent stem cell-related approaches to generate dopaminergic neurons for Parkinson's disease

The progressive loss of dopaminergic neurons in affected patient brains is one of the pathological features of Parkinson's disease,the second most common human neurodegenerative disease.Although the detailed pathogenesis accounting for dopaminergic neuron degeneration in Parkinson's disease is still unclear,the advancement of stem cell approaches has shown promise for Parkinson's disease research and therapy.The induced pluripotent stem cells have been commonly used to generate dopaminergic neurons,which has provided valuable insights to improve our understanding of Parkinson's disease pathogenesis and contributed to anti-Parkinson's disease therapies.The current review discusses the practical approaches and potential applications of induced pluripotent stem cell techniques for generating and differentiating dopaminergic neurons from induced pluripotent stem cells.The benefits of induced pluripotent stem cell-based research are highlighted.Various dopaminergic neuron differentiation protocols from induced pluripotent stem cells are compared.The emerging three-dimension-based brain organoid models compared with conventional two-dimensional cell culture are evaluated.Finally,limitations,challenges,and future directions of induced pluripotent stem cell–based approaches are analyzed and proposed,which will be significant to the future application of induced pluripotent stem cell-related techniques for Parkinson's disease.

Induced neural stem cells regulate microglial activation through Akt-mediated upregulation of CXCR4 and Crry in a mouse model of closed head injury

Microglial activation that occurs rapidly after closed head injury may play important and complex roles in neuroinflammation-associated neuronal damage and repair.We previously reported that induced neural stem cells can modulate the behavior of activated microglia via CXCL12/CXCR4 signaling,influencing their activation such that they can promote neurological recovery.However,the mechanism of CXCR4 upregulation in induced neural stem cells remains unclear.In this study,we found that nuclear factor-κB activation induced by closed head injury mouse serum in microglia promoted CXCL12 and tumor necrosis factor-αexpression but suppressed insulin-like growth factor-1 expression.However,recombinant complement receptor 2-conjugated Crry(CR2-Crry)reduced the effects of closed head injury mouse serum-induced nuclear factor-κB activation in microglia and the levels of activated microglia,CXCL12,and tumor necrosis factor-α.Additionally,we observed that,in response to stimulation(including stimulation by CXCL12 secreted by activated microglia),CXCR4 and Crry levels can be upregulated in induced neural stem cells via the interplay among CXCL12/CXCR4,Crry,and Akt signaling to modulate microglial activation.In agreement with these in vitro experimental results,we found that Akt activation enhanced the immunoregulatory effects of induced neural stem cell grafts on microglial activation,leading to the promotion of neurological recovery via insulin-like growth factor-1 secretion and the neuroprotective effects of induced neural stem cell grafts through CXCR4 and Crry upregulation in the injured cortices of closed head injury mice.Notably,these beneficial effects of Akt activation in induced neural stem cells were positively correlated with the therapeutic effects of induced neural stem cells on neuronal injury,cerebral edema,and neurological disorders post–closed head injury.In conclusion,our findings reveal that Akt activation may enhance the immunoregulatory effects of induced neural stem cells on microglial activation via upregulation of CXCR4 and Crry,thereby promoting induced neural stem cell–mediated improvement of neuronal injury,cerebral edema,and neurological disorders following closed head injury.

Human induced pluripotent stem cell-derived therapies for regeneration after central nervous system injury

In recent years,the progression of stem cell therapies has shown great promise in advancing the nascent field of regenerative medicine.Considering the non-regenerative nature of the mature central nervous system,the concept that“blank”cells could be reprogrammed and functionally integrated into host neural networks remained intriguing.Previous work has also demonstrated the ability of such cells to stimulate intrinsic growth programs in post-mitotic cells,such as neurons.While embryonic stem cells demonstrated great potential in treating central nervous system pathologies,ethical and technical concerns remained.These barriers,along with the clear necessity for this type of treatment,ultimately prompted the advent of induced pluripotent stem cells.The advantage of pluripotent cells in central nervous system regeneration is multifaceted,permitting differentiation into neural stem cells,neural progenitor cells,glia,and various neuronal subpopulations.The precise spatiotemporal application of extrinsic growth factors in vitro,in addition to microenvironmental signaling in vivo,influences the efficiency of this directed differentiation.While the pluri-or multipotency of these cells is appealing,it also poses the risk of unregulated differentiation and teratoma formation.Cells of the neuroectodermal lineage,such as neuronal subpopulations and glia,have been explored with varying degrees of success.Although the risk of cancer or teratoma formation is greatly reduced,each subpopulation varies in effectiveness and is influenced by a myriad of factors,such as the timing of the transplant,pathology type,and the ratio of accompanying progenitor cells.Furthermore,successful transplantation requires innovative approaches to develop delivery vectors that can mitigate cell death and support integration.Lastly,host immune responses to allogeneic grafts must be thoroughly characterized and further developed to reduce the need for immunosuppression.Translation to a clinical setting will involve careful consideration when assessing both physiologic and functional outcomes.This review will highlight both successes and challenges faced when using human induced pluripotent stem cell-derived cell transplantation therapies to promote endogenous regeneration.

Laboratory Experiment on Wave Induced Turbulence

A laboratory experiment was conducted inside a wind wave tank to investigate the wave induced turbulence. In this experiment, the wave surface elevation and velocity beneath the water surface were measured simultaneously to investigate the relation between the wave status and wave induced turbulence. The profile of the turbulent dissipation rate and Reynolds stress were calculated using experimental data. The effect of the wave status on turbulence is investigated with regard to the wind wave, swell, and mixed wave conditions. It was depicted that the turbulence decreased with increasing depth from the water surface and that the turbulence that was induced by a wave with larger wavelength and wave height is much stronger for the same wave status. Finally, we observed that the wind wave is more effective in activating the wave induced turbulence.

Spontaneous versus Induced Labor Delivery, a Retrospective Analysis

Background: Induction of labor is the stimulation of the uterus to initiate the labor process whether by administering oxytocin, prostaglandin or reputing the membrane [1]. It was realized that the number of induction of labor patients was thought to be increasing in comparison with the spontaneous labor patients. Therefore, the complications of induced labor were higher. A detailed analysis was needed to confirm that. Objective: The aim of the study is to analyze the outcomes between spontaneous versus induced labor. Materials and Methods: A retrospective analysis was conducted at our tertiary care university hospital, in the period from December 2015 to December 2016 when 311 women were divided into two groups: group 1, women who had spontaneous labor (n = 106) compared with group 2, women who were labor induced (n = 205). Complications of pregnancy, delivery type, tear, episiotomy, blood transfusion and instruments used were analyzed retrospectively. Results: The mean ± SD of baseline characteristics, like age, height, weight, BMI and hemoglobin level for all study samples was 28.59 ± 5.95 years, 1.58 ± 0.06 m, 71.77 ± 13.42 kg, 28.59 ± 5.89 kg/m2 and 11.08 ± 1.45 g/dl respectively. A statistically significant difference was noticed in the duration of labor between spontaneous and induced labor (95% CI: 9.194 - 152.130;p-value 0.004 and OR: 0.239). There was no significant difference in complications, delivery type (Spontaneous Vaginal Delivery (SVD) or other), blood transfusion, and instrument used between women who had spontaneous labor versus induced labor. However, significant differences in tear (95% CI: 4.354 - 0.996;p-value 0.035) and episiotomy (95% CI: 0.928 - 0.224;p-value 0.028) were found between the two groups. In conclusion, the induced labor was found to be associated with high incidence of duration of labor, tear and episiotomy. Patients should always be counseled when there it is an option between the two delivery types.

Safety and effectiveness of butorphanol in epidural labor analgesia:A protocol for a systematic review and meta-analysis

BACKGROUND Epidural analgesia is the most effective analgesic method during labor.Butorphanol administered epidurally has been shown to be a successful analgesic method during labor.However,no comprehensive study has examined the safety and efficacy of using butorphanol as an epidural analgesic during labor.AIM To assess butorphanol's safety and efficacy for epidural labor analgesia.METHODS The PubMed,Cochrane Library,EMBASE,Web of Science,China National Knowledge Infrastructure,and Google Scholar databases will be searched from inception.Other types of literature,such as conference abstracts and references to pertinent reviews,will also be reviewed.We will include randomized controlled trials comparing butorphanol with other opioids combined with local anesthetics for epidural analgesia during labor.There will be no language restrictions.The primary outcomes will include the visual analog scale score for the first stage of labor,fetal effects,and Apgar score.Two independent reviewers will evaluate the full texts,extract data,and assess the risk of bias.Publication bias will be evaluated using Egger's or Begg's tests as well as visual analysis of a funnel plot,and heterogeneity will be evaluated using the Cochran Q test,P values,and I2 values.Meta-analysis,subgroup analysis,and sensitivity analysis will be performed using RevMan software version 5.4.This protocol was developed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses(PRISMA)Protocols statement,and the PRISMA statement will be used for the systematic review.RESULTS This study provides reliable information regarding the safety and efficacy of using butorphanol as an epidural analgesic during labor.CONCLUSION To support clinical practice and development,this study provides evidence-based findings regarding the safety and efficacy of using butorphanol as an epidural analgesic during labor.

Uterine Rupture in an Unscarred Uterus Following Induced Labor with Titrated Oral Misoprostol

Misoprostol (Cytotec, Pfizer) is a prostaglandin E1 analogue widely used in labor induction. Understanding of potential risks of misoprostol in labor induction is lacking as the drug is used off-label in most countries. A 35-year-old G3P2 woman with post-date pregnancy at 40 + 3 weeks was induced using titrated oral misoprostol. Following delivery, post-partum hemorrhage was noted and, upon discovery of a uterine wall rupture due to congenital weakness of the myometrium, emergency abdominal total hysterectomy was conducted. Following surgery, the patient made a full recovery and was discharged. The main contraindications for misoprostol in labor induction are a scarred uterus or multipara greater than 4. Uterine wall weakness should be considered as a potential contraindication. Extreme vigilance is required in use of misoprostol for labor induction.

Transplantation of fibrin-thrombin encapsulated human induced neural stem cells promotes functional recovery of spinal cord injury rats through modulation of the microenvironment

Recent studies have mostly focused on engraftment of cells at the lesioned spinal cord,with the expectation that differentiated neurons facilitate recovery.Only a few studies have attempted to use transplanted cells and/or biomaterials as major modulators of the spinal cord injury microenvironment.Here,we aimed to investigate the role of microenvironment modulation by cell graft on functional recovery after spinal cord injury.Induced neural stem cells reprogrammed from human peripheral blood mononuclear cells,and/or thrombin plus fibrinogen,were transplanted into the lesion site of an immunosuppressed rat spinal cord injury model.Basso,Beattie and Bresnahan score,electrophysiological function,and immunofluorescence/histological analyses showed that transplantation facilitates motor and electrophysiological function,reduces lesion volume,and promotes axonal neurofilament expression at the lesion core.Examination of the graft and niche components revealed that although the graft only survived for a relatively short period(up to 15 days),it still had a crucial impact on the microenvironment.Altogether,induced neural stem cells and human fibrin reduced the number of infiltrated immune cells,biased microglia towards a regenerative M2 phenotype,and changed the cytokine expression profile at the lesion site.Graft-induced changes of the microenvironment during the acute and subacute stages might have disrupted the inflammatory cascade chain reactions,which may have exerted a long-term impact on the functional recovery of spinal cord injury rats.

Long non-coding RNA H19 regulates neurogenesis of induced neural stem cells in a mouse model of closed head injury

Stem cell-based therapies have been proposed as a potential treatment for neural regeneration following closed head injury.We previously reported that induced neural stem cells exert beneficial effects on neural regeneration via cell replacement.However,the neural regeneration efficiency of induced neural stem cells remains limited.In this study,we explored differentially expressed genes and long non-coding RNAs to clarify the mechanism underlying the neurogenesis of induced neural stem cells.We found that H19 was the most downregulated neurogenesis-associated lnc RNA in induced neural stem cells compared with induced pluripotent stem cells.Additionally,we demonstrated that H19 levels in induced neural stem cells were markedly lower than those in induced pluripotent stem cells and were substantially higher than those in induced neural stem cell-derived neurons.We predicted the target genes of H19 and discovered that H19 directly interacts with mi R-325-3p,which directly interacts with Ctbp2 in induced pluripotent stem cells and induced neural stem cells.Silencing H19 or Ctbp2 impaired induced neural stem cell proliferation,and mi R-325-3p suppression restored the effect of H19 inhibition but not the effect of Ctbp2 inhibition.Furthermore,H19 silencing substantially promoted the neural differentiation of induced neural stem cells and did not induce apoptosis of induced neural stem cells.Notably,silencing H19 in induced neural stem cell grafts markedly accelerated the neurological recovery of closed head injury mice.Our results reveal that H19 regulates the neurogenesis of induced neural stem cells.H19 inhibition may promote the neural differentiation of induced neural stem cells,which is closely associated with neurological recovery following closed head injury.

Recent advances in the diagnosis of drug-induced liver injury

Drug-induced liver injury(DILI)is a major problem in the United States,commonly leading to hospital admission.Diagnosing DILI is difficult as it is a diagnosis of exclusion requiring a temporal relationship between drug exposure and liver injury and a thorough work up for other causes.In addition,DILI has a very variable clinical and histologic presentation that can mimic many different etiologies of liver disease.Objective scoring systems can assess the probability that a drug caused the liver injury but liver biopsy findings are not part of the criteria used in these systems.This review will address some of the recent updates to the scoring systems and the role of liver biopsy in the diagnosis of DILI.

Coupled multiphysical model for investigation of influence factors in the application of microbially induced calcite precipitation

The study presents a comprehensive coupled thermo-bio-chemo-hydraulic(T-BCH)modeling framework for stabilizing soils using microbially induced calcite precipitation(MICP).The numerical model considers relevant multiphysics involved in MICP,such as bacterial ureolytic activities,biochemical reactions,multiphase and multicomponent transport,and alteration of the porosity and permeability.The model incorporates multiphysical coupling effects through well-established constitutive relations that connect parameters and variables from different physical fields.It was implemented in the open-source finite element code OpenGeoSys(OGS),and a semi-staggered solution strategy was designed to solve the couplings,allowing for flexible model settings.Therefore,the developed model can be easily adapted to simulate MICP applications in different scenarios.The numerical model was employed to analyze the effect of various factors,including temperature,injection strategies,and application scales.Besides,a TBCH modeling study was conducted on the laboratory-scale domain to analyze the effects of temperature on urease activity and precipitated calcium carbonate.To understand the scale dependency of MICP treatment,a large-scale heterogeneous domain was subjected to variable biochemical injection strategies.The simulations conducted at the field-scale guided the selection of an injection strategy to achieve the desired type and amount of precipitation.Additionally,the study emphasized the potential of numerical models as reliable tools for optimizing future developments in field-scale MICP treatment.The present study demonstrates the potential of this numerical framework for designing and optimizing the MICP applications in laboratory-,prototype-,and field-scale scenarios.

Butorphanol in epidural:Could this be the breakthrough solution for safe and effective labor analgesia that we've been waiting for?

The authors have conducted a comprehensive investigation into the safety and effectiveness of butorphanol for epidural analgesia during labor.Their critical analysis of the paper and discussion of the technique's advantages and disadvantages provide a thorough understanding of the topic.

Rural labor migration and farmers’arrangements of rice production systems in Central China:Insight from the intergenerational division of labor

Rice production is crucial for food security in China,and its relationship with rural labor migration has been studied extensively.Labor migration in rural China has taken new forms in recent years.There has been a discernible trend wherein adult children have started migrating to cities while their elderly parents return to villages to re-engage in on-farm work.The phenomenon has notably shaped the intergenerational division of labor(IDL)within households.However,it remains to be seen how farmers adjust their rice production systems in response to the IDL.The age of 60 years for employment injury insurance is the eligibility threshold for off-farm employment and is used to obtain a source of exogenous variation in the IDL.Based on a representative household survey of 1,752 rice farmers in the Hubei Province of Central China,our fuzzy regression discontinuity analysis reveals that farmers in IDL households are more likely to adopt ratoon rice(RR)than single cropping rice(SR)or double cropping rice(DR).The effect of the IDL varies under different levels of operational scales and specialized agricultural service availability.Further analysis suggests that farmers’arrangements are associated with two potential mechanisms of downward intergenerational transfer.Monetary transfer for urban housing purchases increases RR in IDL households,and time transfer for intergenerational childcare significantly promotes SR in IDL households.This study enhances the understanding of the relationship between rural labor migration and rice production in China,providing a reference for adjusting rice production systems to ensure food security.

Laboratory Measurements of Vortex- and Wake-Induced Vibrations of A Tandem Arrangement of Two Flexible Risers

The dynamic response of two flexible model risers in tandem arrangement immersed in a stepped current was analyzed. The risers, with an external diameter of 20 mm and a total length of 6200 mm, had an aspect ratio of 310. They were hinged to the support structure at the center-to-center distances away 3-12 times the external diameter. The top 1200 mm was exposed to a uniform current at a speed which was up to 0.9 m/s（the Reynolds number was 18000） and the rest in still water. The dynamic responses, which were obtained through the Fiber Bragg Grating strain gauges mounted on the surface, were analyzed by studying the cross-flow amplitudes and modal weights. The cross-flow vibration were observed up to the third mode, and the modal transformation from the second mode to the third mode was clearly observed. The experiment confirmed that the typical vortex-induced vibration（VIV） had occurred on the up-stream riser. But for the down-stream riser, the main excitation mechanism was wake-induced vibration（WIV）. The modal transformation of WIV was more complex than that of VIV, which might be helpful for other researchers to study the interference effect.

Fibromyalgia Being Strongly Associated with Manual Labor Among Male Patients Attending Rheumatology Clinic

Introduction: Fibromyalgia is a common chronic pain syndrome, associated with different risk factors, including trauma. Many patients with the current or past history of manual labor attend our rheumatology clinic/s. Should manual labor be considered a risk factor for the development of fibromyalgia? Patients and Methods: A prospective study, where all male patients seen at the rheumatology clinic/s with the diagnosis of fibromyalgia were asked about their present and past type of job/s. Manual job was defined as a job where the participant had a strenuous physical activity of more than 2 hours during the working day. A similar number of Ethnic- and age-matched female patients from the same clinic/s were recruited as a control group. Results: 69 and 40 Arab and Jewish male participants were recruited, respectively. 54% of the Arab male patients and 20% of the Jewish male patients were considered manual laborers. Construction and renovation accounted for 46% of the type of jobs practiced by Arab patients. Only 4% of Arab female patients were considered manual laborers. Conclusion: Manual labor seems to be a risk factor for the development of fibromyalgia among male laborers.

The Function and Realization of Labor Rights in the Labor Code System

Abstract:The fundamental right-based and human right-based nature of labor rights forms the subjective and objective theory of labor rights.The derived objective protection function and subjective realization function constitute the theoretical basis of the labor code system.The objective function of labor rights requires the labor code to provide corresponding institutional guarantees,while the subjective function demands that the code ensure the full realization of labor rights.The dual functions of labor rights are reflected in the structural framework and content logic of the labor code separately:on the one hand,labor rights can serve as the structural thread for narrating and systematically organizing the labor code,with the specific types of labor rights protection and functional systems jointly forming the framework of the code;on the other hand,the content arrangement of the labor code is guided by the value of realizing labor rights,explor-ing the pathways for the code’s realization of labor rights in different situations.

Advances in epidural labor analgesia:Effectiveness and treatment strategies of butorphanol

In this editorial,we provide a critical review of the article by Tang et al published in the World J Clin Cases,focusing on the utilization of butorphanol for epidural analgesia during labor.Our discussion encompasses recent research developments in epidural labor analgesia,specifically highlighting the current status of clinical applications of butorphanol and associated treatment approaches.Epidural analgesia is widely acknowledged as the primary method for pain management during labor,offering effective and prolonged pain relief while allowing mothers to remain alert and actively participate in the delivery process.Among the various drugs utilized for epidural labor analgesia,butorphanol has received increasing attention due to its potential efficacy and distinctive pharmacological properties.As a synthetic opioid analgesic,butorphanol exhibits both agonistic and antagonistic activity on opioid receptors,striking a balance between analgesia and minimizing side effects.Nevertheless,the safety and efficacy of butorphanol in epidural labor analgesia remains controversial.While certain studies have reported positive outcomes with butorphanol,including effective pain relief and a reduced incidence of side effects,others have raised concerns about its safety and efficacy compared to traditional opioids or alternative analgesics.In addition,the optimal dosing strategy and regimen of butorphanol as an adjuvant in epidural labor analgesia still need to be verified.Through comprehensive synthesis and analysis of existing literature,we aim to evaluate the current evidence regarding the use of butorphanol for epidural labor analgesia,delineate areas of consensus and controversy,and propose future avenues for research and clinical practice in this domain.

Prevalence of Induced Abortion among Female Students in Selected Tertiary Learning Institutions in Gaborone City, Botswana

Induced abortion signifies that pregnancy has been tempered with. Abortion is the removal of an embryo or fetus weighing less than 500 grams from its mother. It can either be spontaneous (unprompted) or induced. Abortion remains one of the leading causes of maternal deaths in developing countries with induced abortion being the key cause. In 2014 from January to August, 9 abortion related deaths occurred in Botswana. There are several reasons female students in tertiary institutions resort to seeking induced abortion which include the socio-demographics like age and socio-economic factors like financial instability. Parental fears, unintended pregnancy and pressure from the partner also force females to terminate pregnancy. Induced abortion has claimed many women’s lives especially in developing countries with very restrictive abortion laws like Botswana as women do not access safe abortion care services. The study intends to establish the determinants of induced abortion among female students in selected tertiary learning institutions in Gaborone City, Botswana. It concentrated primarily on determining the prevalence of induced abortion. This was a descriptive cross-sectional study using both quantitative and qualitative data collection techniques. Systematic random sampling technique was used to come up with 278 participants. Prior to commencement of data collection, all ethical and logistical prerequisites were satisfied. Informed consent was solicited from all the study participants and the purpose of the study was fully explained. A self-administered questionnaire was used to collect data. Microsoft Excel spread sheet was used to code, clean, and enter the data, which was then exported for analysis to the statistical package for social sciences version 24. Frequency distribution tables, percentages graphs, and pie charts were used to illustrate the descriptive information. The study revealed that prevalence of induced abortion among female students in Gaborone City is 7.9%. They even suggested that induced abortion be liberalized. Age was the only socio-demographic factor associated with induced abortion with p = 0.047 using Chi Square test χ2 = 7.609, df = 3. The study findings concluded that female students resort to induced abortion as a result of pressure from both parents and male partners especially when the pregnancy is unintended. The study recommends that the abortion law in Botswana be made liberal to ease access to safe abortion care services. It also recommends that contraceptive commodities should consistently be available in public health facilities.

Numerical simulations of earthquake rupture induced by pressure perturbation

The subsurface fluid injection can cause pressure increase within faults,leading to earthquake occurrences.However,the factors controlling earthquake rupture due to pressure perturbation remain poorly understood.To resolve this problem,we simulate the physical processes of earthquake nucleation and rupture on strike-slip faults perturbated by pressure migration based on the slip-weakening law.Multiple kinds of factors,including background stress,fluid injection rates,the area of the pressurized region,fault geometry,and fault friction coefficients,are considered in our simulations.Our simulation results reveal that the ratio of shear stress to normal stress rather than their absolute values controls the rupture behavior.With the large stress ratios,high injection rates,and large pressurized areas,earthquakes are prone to propagate as runaway ruptures.Additionally,faults with large aspect ratios of length to width are also favorable for causing runaway ruptures.In contrast,the factors of fault strike,dip angles and friction coefficients have minor influence on rupture behavior.

Advanced Machine Learning Methods for Prediction of Blast-Induced Flyrock Using Hybrid SVR Methods

Blasting in surface mines aims to fragment rock masses to a proper size.However,flyrock is an undesirable effect of blasting that can result in human injuries.In this study,support vector regression(SVR)is combined with four algorithms:gravitational search algorithm(GSA),biogeography-based optimization(BBO),ant colony optimization(ACO),and whale optimization algorithm(WOA)for predicting flyrock in two surface mines in Iran.Additionally,three other methods,including artificial neural network(ANN),kernel extreme learning machine(KELM),and general regression neural network(GRNN),are employed,and their performances are compared to those of four hybrid SVR models.After modeling,the measured and predicted flyrock values are validated with some performance indices,such as root mean squared error(RMSE).The results revealed that the SVR-WOA model has the most optimal accuracy,with an RMSE of 7.218,while the RMSEs of the KELM,GRNN,SVR-GSA,ANN,SVR-BBO,and SVR-ACO models are 10.668,10.867,15.305,15.661,16.239,and 18.228,respectively.Therefore,combining WOA and SVR can be a valuable tool for accurately predicting flyrock distance in surface mines.