Movement analysis in the diagnosis and management of Parkinson’s disease

Challenges in the diagnosis and treatment of Parkinson’s disease:Parkinson’s disease(PD)is an increasingly prevalent neurodegenerative disease,at first sight primarily characterized by motor symptoms,although non-motor symptoms also constitute a major part of the overall phenotype.Clinically,this disease cannot be diagnosed reliably until a large part of the vulnerable dopaminergic neurons has been irretrievably lost,and the disease progresses inexorably.New biological criteria for PD have been proposed recently and might eventually improve early diagnosis,but they require further validation,and their use will initially be restricted to a research environment(Darweesh et al.,2024).

Age-related changes in seminal polymorphonuclear elastase in men with asymptomatic inflammation of the genital tract

Aim： To investigate age-related inflammatory events in the male genital tract. Methods： In a total of 4 265 randomly collected patients attending the andrological outpatient clinic of the Center for Dermatology and Andrology, University of Giessen, Germany, ejaculate volume, pH-value, sperm concentration, total and progressive sperm motility, concentration of polymorphonuclear （PMN） elastase, number of peroxidase-positive cells and fructose were measured and correlated with patient＇s age. Results： While ejaculate volume, motility and fructose all correlated negatively with age, sperm concentration, PMN elastase and the pH-value showed a positive correlation. The prevalence of male genital tract inflammation （as defined by PMN elastase 〉 250 ng/mL） and its severity increased significantly. PMN elastase did not correlate with sperm motility. Fructose as a marker of seminal vesicle function showed a significant negative relationship with the PMN elastase levels, the number of peroxidase-positive cells and sperm motility. Conclusion： The significant increases of PMN elastase levels as marker of male genital tract inflammation in older men appear to be indicative of age-related changes in local immunoregulatory mechanisms. Because there is no association of PMN elastase with sperm motility, a direct inhibitory effect of this enzyme can be excluded.

Sperm preparation： state-of-the-art--physiological aspects and application of advanced sperm preparation methods

For assisted reproduction technologies （ART）, numerous techniques were developed to isolate spermatozoa capable of fertilizing oocytes. While early methodologies only focused on isolating viable, motile spermatozoa, with progress of ART, particularly intracytoplasmic sperm injection （ICSI）, it became clear that these parameters are insufficient for the identification of the most suitable spermatozoon for fertilization. Conventional sperm preparation techniques, namely, swim-up, density gradient centrifugation and glass wool filtration, are not efficient enough to produce sperm populations free of DNA damage, because these techniques are not physiological and not modeled on the stringent sperm selection processes taking place in the female genital tract. These processes only allow one male germ cell out of tens of millions to fuse with the oocyte. Sites of sperm selection in the female genital tract are the cervix, uterus, uterotubal junction, oviduct, cumulus oophorus and the zona pellucida. Newer strategies of sperm preparation are founded oni （i） morphological assessment by means of＇motile sperm organelle morphological examination （MSOM E）＇; （ii） electrical charge; and （ili） molecular binding characteristics of the sperm cell. Whereas separation methods based on electrical charge take advantage of the sperm＇s adherence to a test tube surface or separate in an electrophoresis, molecular binding techniques use Annexin V or hyaluronic acid （HA） as substrates. Techniques in this category are magnet-activated cell sorting, Annexin V-activated glass wool filtration, flow cytometry and picked spermatozoa for ICSI （PICSI） from HA-coated dishes and HA-containing media. Future developments may include Raman microspectrometry, confocal light absorption and scattering spectroscopic microscopy and polarization microscopy.

Role of the tissue microenvironment as a therapeutic target in hepatocellular carcinoma

Hepatocellular carcinoma is difficult to treat,primarilybecause the underlying molecular mechanisms drivingclinical outcome are still poorly understood.Growingevidence suggests that the tissue microenvironmenthas a role in the biological behavior of the tumor.Themain clinical issue is to identify the best target fortherapeutic approaches.Here,we discuss the hypothesis that the entire tissue microenvironment might beconsidered as a biological target.However,the tissuemicroenvironment consists of several cellular and biochemical components,each of which displays a distinctbiological activity.We discuss the major components ofthis environment and consider how they may interactto promote tumor/host crosstalk.

Influence of Glyphaea brevis twig extract on nucleus, tight junctions and expression of inhibin-β, stem cell factor, and androgen binding protein in TM4 Sertoli cells

Objective: To examine the influence of Glyphaea (G.) brevis twig extract on the mitochondrial dehydrogenase activity, integrity of the tight junctions between adjacent cells, mitochondria, apoptosis, nucleus and expression of inhibin-β, stem cell factor, and androgen binding protein in TM4 Sertoli cells. Methods: TM4 cell line was used in this study as it exhibited properties similar to the Sertoli cells. TM4 Sertoli cells were exposed to G. brevis twig extract (0.1, 1.0, 10.0, 100.0, or 1000.0μg/mL) for 24, 48 and 72 h. Parameters studied included cell viability [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay], mitochondrial membrane potential (tetra methyl rhodamine ethyl ester dye), transepithelial electrical resistance, apoptosis (Annexin V Alexa Fluor?488/propidium iodide assay) and mRNA expression (quantitative reverse transcription polymerase chain reaction). Results: G. brevis twig extract had no cytotoxic impact on cell viability, thus, considerably increasing the activity of mitochondrial dehydrogenase enzyme after 24 and 72 h exposure. Transepithelial electrical resistance values revealed substantial (P<0.05) rise in treated groups, especially after 72 h of treatment. Moreover, there was a significant decrease in mitochondrial depolarization of TM4 Sertoli cells exposed to G. brevis twig extract when compared to controls. In addition, G. brevis twig extract significantly reduced necrosis and apoptosis of TM4 Sertoli cells when compared to control. Nevertheless, fluorescence microscopy revealed that the nuclei were egg-shaped and marked uniformly with consistent cell shape at the middle of the TM4 Sertoli cells. Significant stimulatory effects were observed on mRNA levels of inhibin-β, androgen binding protein and stem cell factor. Conclusions: G. brevis twig extract may increase the secretory roles of TM4 Sertoli cells, cells proliferation, as well as cell-cell tight junction integrity. Thus, G. brevis twig may enhance spermatogenesis.

The impact of male overweight on semen quality and outcome of assisted reproduction

The impact of obesity on male reproductive health remains a contested topic as evidence is inconclusive and inconsistent.1,2 Even more debatable is the effect of male obesity in assisted reproduction. In the manuscript, ＂the impact of male overweight on semen quality and outcome of assisted reproduction＂ published in Asian Journal ofAndrology, Thomsen et al.3 investigated the effect of male obesity on fertilization outcomes in intrauterine insemination, in vitro fertilization （IVF） and intracytoplasmic sperm injection （ICSI） programs further contributes to the increasing body of evidence in this field.

Building Expertise on FAIR Through Evolving Bring Your Own Data(BYOD) Workshops: Describing the Data, Software, and Management-focused Approaches and Their Evolution

Since 2014,"Bring Your Own Data"workshops(BYODs)have been organised to inform people about the process and benefits of making resources Findable,Accessible,Interoperable,and Reusable(FAIR,and the FAIRification process).The BYOD workshops'content and format differ depending on their goal,context,and the background and needs of participants.Data-focused BYODs educate domain experts on how to make their data FAIR to find new answers to research questions.Management-focused BYODs promote the benefits of making data FAIR and instruct project managers and policy-makers on the characteristics of FAIRification projects.Software-focused BYODs gather software developers and experts on FAIR to implement or improve software resources that are used to support FAIRification.Overall,these BYODs intend to foster collaboration between different types of stakeholders involved in data management,curation,and reuse(e.g.domain experts,trainers,developers,data owners,data analysts,FAIR experts).The BYODs also serve as an opportunity to learn what kind of support for FAIRification is needed from different communities and to develop teaching materials based on practical examples and experience.In this paper,we detail the three different structures of the BYODs and describe examples of early BYODs related to plant breeding data,and rare disease registries and biobanks,which have shaped the structure of the workshops.We discuss the latest insights into making BYODs more productive by leveraging our almost ten years of training experience in these workshops,including successes and encountered challenges.Finally,we examine how the participants'feedback has motivated the research on FAIR,including the development of workflows and software.

Leukocytes and oxidative stress： dilemma for sperm Function and male fertility

Spermatozoa are constantly exposed to the interphase between oxidation through high amounts of reactive oxygen species （ROS） and leukocytes, and reduction by means of scavengers and antioxidants. Considering the very special functions as being the only cells with such high polarization and exerting their functions outside the body, even in a different individual, the female genital tract, the membranes of these cells are chemically composed of an extraordinary high amount of polyunsaturated fatty acids. This in turn, renders them very susceptible to oxidative stress, which is defined as an imbalance between oxidation and reduction towards the oxidative status. As a result, ROS deriving from both leukocytes and the male germ cells themselves cause a process called ＇lipid peroxidation＇ and other damages to the sperm cell. On the other hand, a certain limited amount of ROS iS essential in order to trigger vital physiological reactions in cells, including capacitation or the acrosome reaction in sperm. The treatment of patients with antioxidants to compensate the oxidative status caused by oxidative stress is highly debated as uncontrolled antioxidative treatment might derail the system towards the reduced status, which is also unphysiological and can even induce cancer. This paradox is called the ＇antioxidant paradox＇. Therefore, a proper andrological diagnostic work-up, including the evaluation of ROS levels and the antioxidant capacity of the semen, has to he carried out beforehand, aimed at keeping the fine balance between oxidation and scavenging of vital amounts of ROS.

Antioxidant-induced reductive stress has untoward consequences on the brain microvasculature

All cells in the body metabolize oxygen in a series of reactions in the mitochondria to generate energy.A by-product of these reactions is the production of highly reactive oxygen radicals which have the potential to cause irreparable damage to cellular components,and have been linked to mutagenic and neurotoxicity of the nervous system.Under normal conditions,innate molecular systems,glutathione,superoxide dismutases,

Are claudin-5 tight-junction proteins in the blood-brain barrier porous?

The capillaries of the brain are particularly special,as they are not simply conduits for blood,but are primarily responsible to ensure that the neurons function in a strictly regulated homeostatic interstitium.Brain endothelial cells(BECs)express a plethora of ion channels on its luminal and abluminal surfaces,namely:potassium(K^+)channels(i.e.,Kir2 and Kv1),chloride(Cl^)/bicarbonate(HCO3^–)channels,as well as a number of ion-solute exchangers(Redzic et al.,2011).

Critical evaluation of two models of flow cytometers for the assessment of sperm DNA fragmentation:an appeal for performance verification

Lack of standardized,reproducible protocols and referencO values is among the challenges faced when using new or upgraded versions of instruments in reproductive laboratories and flow cytometry.Terminal deoxynucleotidyl transferase dUTP nick end labeling(TUNEL)assay combined with flow cytometry routinely used for diagnostic measurement of sperm DNA fragmentation(SDF)is a unique example.Any change in the setting of the standard instrument,including upgrades of hardware or software,can lead to different results and may affect clinicians'decision for treatment.Therefore,we compared TUNEL results of SDF obtained from a standard(C6)flow cytometer with a newer version of the same instrument(C6 Plus)and examined the cutoff,sensitivity,and specificity without calibration(adjustment)and after adjustment.Identical sperm preparation and matched acquisition settings were used to examine the performance of two flow cytometers.The strength of agreement of the results between the two observers was also assessed.After adjustment of the settings,overall concordance became high and the two cytometers showed 100%positive and negative predictive value with 100%area under the curve.The overall correlation coefficient observed between C6 and C6 Plus was highly significant(P<0.0001;r=0.992;95%confidence interval[Cl]:0.982-0.997).After adjustment,the two cytometers showed very high precisi on of 98%and accuracy of>99%.The in terobserver agreeme nt on C6 flow cytometer for the two observers was 0.801±0.062 and 0.746±0.044 for C6 Plus.We demonstrated a strong agreement between the samples tested on the two flow cytometers after calibration and established the robustness of both instruments.

The future of computer-aided sperm analysis

Computer-aided sperm analysis （CASA） technology was developed in the late 1980s for analyzing sperm movement characteristics or kinematics and has been highly successful in enabling this field of research. CASA has also been used with great success for measuring semen characteristics such as sperm concentration and proportions of progressive motility in many animal species, including wide application in domesticated animal production laboratories and reproductive toxicology. However, attempts to use CASA for human clinical semen analysis have largely met with poor success due to the inherent difficulties presented by many human semen samples caused by sperm clumping and heavy background debris that, until now, have precluded accurate digital image analysis. The authors review the improved capabilities of two modern CASA platforms （Hamilton Thorne CASA-II and Microptic SCA6） and consider their current and future applications with particular reference to directing our focus towards using this technology to assess functional rather than simple descriptive characteristics of spermatozoa. Specific requirements for validating CASA technology as a semi-automated system for human semen analysis are also provided, with particular reference to the accuracy and uncertainty of measurement expected of a robust medical laboratory test for implementation in clinical laboratories operating according to modern accreditation standards.

A single synonymous mutation determines the phosphorylation and stability of the nascent protein

p53 is an intrinsically disordered protein with a large number of post-translational modifications and interacting partners.The hierarchical order and subcellular location of these events are still poorly understood.The activation of p53 during the DNA damage response(DDR)requires a switch in the activity of the E3 ubiquitin ligase MDM2 from a negative to a positive regulator of p53.This is mediated by the ATM kinase that regulates the binding of MDM2 to the p53 mRNA facilitating an increase in p53 synthesis.Here we show that the binding of MDM2 to the p53 mRNA brings ATM to the p53 polysome where it phosphorylates the nascent p53 at serine 15 and prevents MDM2-mediated degradation of p53.A single synonymous mutation in p53 codon 22(L22L)prevents the phosphorylation of the nascent p53 protein and the stabilization of p53 following genotoxic stress.The ATM trafficking from the nucleus to the p53 polysome is mediated by MDM2,which requires its interaction with the ribosomal proteins RPL5 and RPL11.These results show how the ATM kinase phosphorylates the p53 protein while it is bang synthesized and offer a novel mechanism whereby a single synonymous mutation controls the stability and activity of the encoded protein.

The new 6^(th) edition of the WHO Laboratory Manualfor the Examination and Processing of HumanSemen: is it a step toward better standard operatingprocedure?

Semen analysis(SA)remains the cornerstone of male infertility evaluation and should ideally be performed by an accredited andrology laboratory or in vitro fertilization(IVF)clinics based on the standards defined by the World Health Organization(WHO)for the Examination and Processing of Human Semen and in accordance with the International Organization for Standardization’s Basic Semen Examination on Specification and Test Methods.

Comprehensive functional annotation of susceptibility variants identifies genetic heterogeneity between lung adenocarcinoma and squamous cell carcinoma

Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer(NSCLC)risk,biological mechanisms of these variants remain largely unknown.By integrating a large-scale genotype data of 15581 lung adenocarcinoma(AD)cases,8350 squamous cell carcinoma(SqCC)cases,and 27355 controls,as well as multiple transcriptome and epigenomic databases,we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants.We identified 3064 credible risk variants for NSCLC,which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites.Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific.Functional annotation and genebased analysis implicated 894 target genes,including 274 specifics for AD and 123 for SqCC,which were overrepresented in somatic driver genes(ER=1.95,P=0.005).Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways,while SqCC genes were homologous recombination deficiency related.Our results illustrate the molecular basis of both wellstudied and new susceptibility loci of NSCLC,providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.

Bibliometrics： tracking research impact by selecting Lhe appropriate metrics

Traditionally, the success of a researcher is assessed by the number of publications he or she publishes in peer-reviewed, indexed, high impact journals. This essential yardstick, often referred to as the impact of a specific researcher, is assessed through the use of various metrics. While researchers may be acquainted with such matrices, many do not know how to use them to enhance their careers. In addition to these metrics, a number of other factors should be taken into consideration to objectively evaluate a scientist＇s profile as a researcher and academician. Moreover, each metric has its own limitations that need to be considered when selecting an appropriate metric for evaluation. This paper provides a broad overview of the wide array of metrics currently in use in academia and research. Popular metrics are discussed and defined, including traditional metrics and article-level metrics, some of which are applied to researchers for a greater understanding of a particular concept, including varicocete that is the thematic area of this Special Issue of Asian Journal of Andrology. We recommend the combined use of quantitative and qualitative evaluation using judiciously selected metrics for a more objective assessment of scholarly output and research impact.