julilili42/papers huggingface dataset:
Cell Therapy by Mesenchymal Stromal Cells Versus Myoblasts in a Pig Model of Urinary Incontinence
2023-11-07

The leading cause of stress urinary incontinence (SUI) in women is the urethral sphincter muscle deficiency caused by mechanical stress during pregnancy and vaginal delivery. In men, prostate cancer surgery and injury of local nerves and muscles are associated with incontinence. Current treatment often fails to satisfy the patient's needs. Cell therapy may improve the situation. We therefore investigated the regeneration potential of cells in ameliorating sphincter muscle deficiency and UI in a large animal model. Urethral sphincter deficiency was induced surgically in gilts by electrocautery and balloon dilatation. Adipose tissue-derived stromal cells (ADSCs) and myoblasts from <i>Musculus semitendinosus</i> were isolated from male littermates, expanded, characterized in depth for expression of marker genes and <i>in vitro</i> differentiation, and labeled. The cells were injected into the deficient sphincter complex of the incontinent female littermates. Incontinent gilts receiving no cell therapy served as controls. Sphincter deficiency and functional regeneration were recorded by monitoring the urethral wall pressure during follow-up by two independent methods. Cells injected were detected <i>in vivo</i> during follow-up by transurethral fluorimetry, <i>ex vivo</i> by fluorescence imaging, and in cryosections of tissues targeted by immunofluorescence and by polymerase chain reaction of the sex-determining region Y (SRY) gene. Partial spontaneous regeneration of sphincter muscle function was recorded in control gilts, but the sphincter function remained significantly below levels measured before induction of incontinence (67.03% ± 14.00%, <i>n</i> = 6, <i>p</i> < 0.05). Injection of myoblasts yielded an improved sphincter regeneration within 5 weeks of follow-up but did not reach significance compared to control gilts (81.54% ± 25.40%, <i>n</i> = 5). A significant and full recovery of the urethral sphincter function was observed upon injection of ADSCs within 5 weeks of follow-up (100.4% ± 23.13%, <i>n</i> = 6, <i>p</i> < 0.05). Injection of stromal cells provoked slightly stronger infiltration of CD45<sup>pos</sup> leukocytes compared to myoblasts injections and controls. The data of this exploratory study indicate that ADSCs inherit a significant potential to regenerate the function of the urethral sphincter muscle.
Titin copy number variations associated with dominant inherited phenotypes
2023-11-07

Background Titinopathies are caused by mutations in the titin gene ( TTN ). Titin is the largest known human protein; its gene has the longest coding phase with 364 exons. Titinopathies are very complex neuromuscular pathologies due to the variable age of onset of symptoms, the great diversity of pathological and muscular impairment patterns (cardiac, skeletal muscle or mixed) and both autosomal dominant and recessive modes of transmission. Until now, only few CNVs in TTN have been reported without clear genotype–phenotype associations. Methods Our study includes eight families with dominant titinopathies. We performed next-generation sequencing or comparative genomic hybridisation array analyses and found CNVs in the TTN gene. We characterised these CNVs by RNA sequencing (RNAseq) analyses in six patients’ muscles and performed genotype–phenotype inheritance association study by combining the clinical and biological data of these eight families. Results Seven deletion-type CNVs in the TTN gene were identified among these families. Genotype and RNAseq results showed that five deletions do not alter the reading frame and one is out-of-reading frame. The main phenotype identified was distal myopathy associated with contractures. The analysis of morphological, clinical and genetic data and imaging let us draw new genotype–phenotype associations of titinopathies. Conclusion Identifying TTN CNVs will further increase diagnostic sensitivity in these complex neuromuscular pathologies. Our cohort of patients enabled us to identify new deletion-type CNVs in the TTN gene, with unexpected autosomal dominant transmission. This is valuable in establishing new genotype–phenotype associations of titinopathies, mainly distal myopathy in most of the patients.
SERS spectroscopy as a tool for the study of thiopurine drug pharmacokinetics in a model of human B leukemia cells
2023-11-07

Thiopurine drugs are immunomodulatory antimetabolites relevant for pediatric patients characterized by dose-dependent adverse effects such as myelosuppression and hepatotoxicity, often related to inter-individual differences, involving the activity of important enzymes at the basis of their biotransformation, such as thiopurine S-methyltransferase (TPMT). Surface Enhanced Raman Scattering (SERS) spectroscopy is emerging as a bioanalytical tool and represents a valid alternative in terms of affordable costs, shorter analysis time and easier sample preparation in comparison to the most employed methods for pharmacokinetic analysis of drugs. The aim of this study is to investigate mercaptopurine and thioguanine pharmacokinetics by SERS in cell lysates of a B-lymphoblastoid cell line (NALM-6), that did (TPMT*1) or did not (MOCK) overexpress the wild-type form of TPMT as an in vitro cellular lymphocyte model to discriminate between cells with different levels of TPMT activity on the base of the amount of thioguanosine nucleotides (TGN) metabolites formed. SERS analysis of the cell lysates was carried out using SERS substrates constituted by Ag nanoparticles deposited on paper and parallel samples were used for quantification of thiopurine nucleotides with liquid chromatography-tandem mass spectrometry (LC-MS/MS). A direct SERS detection method has been set up that could be a tool to study thiopurine drug pharmacokinetics in in vitro cellular models to qualitatively discriminate between cells that do and do not overexpress the TPMT enzyme, as an alternative to other more laborious techniques. Results underlined decreased levels of TGN and increased levels of methylated metabolites when TPMT was overexpressed, both after mercaptopurine and thioguanine treatments. A strong positive correlation (Spearman's rank correlation coefficient rho = 0.96) exists between absolute quantification of TGMP (pmol/1 x 10<sup>6</sup> cells), obtained by LC-MS/MS, and SERS signal (intensity of TGN at 915 cm<sup>-1</sup>). In future studies, we aim to apply this method to investigate TPMT activity in pediatric patients' leukocytes.
Primary cutaneous anaplastic large cell lymphoma with DUSP22-rearrangement presenting as a mimicker of mycosis fungoides: a case report and review of the literature
2023-11-07

Click to increase image sizeClick to decrease image size Disclosure statementNo potential conflict of interest was reported by the author(s).Additional informationFundingThe author(s) reported there is no funding associated with the work featured in this article.
Cathepsin-Targeting SARS-CoV-2 Inhibitors: Design, Synthesis, and Biological Activity
2023-11-07

Cathepsins (Cats) are proteases that mediate the successful entry of SARS-CoV-2 into host cells. We designed and synthesized a tailored series of 21 peptidomimetics and evaluated their inhibitory activity against human cathepsins L, B, and S. Structural diversity was realized by combinations of different C-terminal warhead functions and N-terminal capping groups, while a central Leu-Phe fragment was maintained. Several compounds were identified as promising cathepsin L and S inhibitors with Ki values in the low nanomolar to subnanomolar range, for example, the peptide aldehydes 9a and 9b (9a, 2.67 nM, CatL; 0.0455 nM, CatS; 9b, 1.76 nM, CatL; 0.0512 nM, CatS). The compounds’ inhibitory activity against the main protease of SARS-CoV-2 (Mpro) was additionally investigated. Based on the results at CatL, CatS, and Mpro, selected inhibitors were subjected to investigations of their antiviral activity in cell-based assays. In particular, the peptide nitrile 11e exhibited promising antiviral activity with an EC50 value of 35.1 nM in Calu-3 cells without showing cytotoxicity. High metabolic stability and favorable pharmacokinetic properties make 11e suitable for further preclinical development.
Teaching transposon classification as a means to crowd source the curation of repeat annotation – a tardigrade perspective
2023-11-07

Abstract The advancement of sequencing technologies results in the rapid release of hundreds of new genome assemblies a year providing unprecedented resources for the study of genome evolution. Within this context, the significance of in-depth analyses of repetitive elements, transposable elements (TEs) in particular, is increasingly recognized in understanding genome evolution. Despite the plethora of available bioinformatic tools for identifying and annotating TEs, the phylogenetic distance of the target species from a curated and classified database of repetitive element sequences constrains any automated annotation effort. Manual curation of raw repeat libraries is deemed essential due to the frequent incompleteness of automatically generated consensus sequences. However, manual curation and classification are time-consuming processes that offer limited short-term academic rewards and are typically confined to a few research groups where methods are taught through hands-on experience. Crowd sourcing efforts could offer a significant opportunity to bridge the gap between learning the methods of curation effectively and empowering the scientific community with high-quality, reusable repeat libraries. Here, we present an example of such crowd sourcing effort developed through both in-person and online courses built around a collaborative peer-reviewed teaching process that can be used as teaching reference guide for similar projects. The collaborative manual curation of TEs from two tardigrade species, for which there were no TE libraries available, resulted in the successful characterization of hundreds of new and diverse TEs: A hidden treasure awaits discovery within non-model organisms.
Structure and function of theS. pombeIII–IV–cytcsupercomplex
2023-11-08

The respiratory chain in aerobic organisms is composed of a number of membrane-bound protein complexes that link electron transfer to proton translocation across the membrane. In mitochondria, the final electron acceptor, complex IV (CIV), receives electrons from dimeric complex III (CIII 2 ), via a mobile electron carrier, cytochrome c . In the present study, we isolated the CIII 2 CIV supercomplex from the fission yeast Schizosaccharomyces pombe and determined its structure with bound cyt. c using single-particle electron cryomicroscopy. A respiratory supercomplex factor 2 was found to be bound at CIV distally positioned in the supercomplex. In addition to the redox-active metal sites, we found a metal ion, presumably Zn 2+ , coordinated in the CIII subunit Cor1, which is encoded by the same gene ( qcr 1 ) as the mitochondrial-processing peptidase subunit β. Our data show that the isolated CIII 2 CIV supercomplex displays proteolytic activity suggesting a dual role of CIII 2 in S. pombe . As in the supercomplex from S. cerevisiae , subunit Cox5 of CIV faces towards one CIII monomer, but in S. pombe, the two complexes are rotated relative to each other by ~45°. This orientation yields equal distances between the cyt. c binding sites at CIV and at each of the two CIII monomers. The structure shows cyt. c bound at four positions, but only along one of the two symmetrical branches. Overall, this combined structural and functional study reveals the integration of peptidase activity with the CIII 2 respiratory system and indicates a two-dimensional cyt. c diffusion mechanism within the CIII 2 –CIV supercomplex.
Testing spasticity mechanisms in chronic stroke before and after intervention with contralesional motor cortex 1 Hz rTMS and physiotherapy
2023-11-08

Abstract Background Previous studies showed that repetitive transcranial magnetic stimulation (rTMS) reduces spasticity after stroke. However, clinical assessments like the modified Ashworth scale, cannot discriminate stretch reflex-mediated stiffness (spasticity) from passive stiffness components of resistance to muscle stretch. The mechanisms through which rTMS might influence spasticity are also not understood. Methods We measured the effects of contralesional motor cortex 1 Hz rTMS (1200 pulses + 50 min physiotherapy: 3×/week, for 4–6 weeks) on spasticity of the wrist flexor muscles in 54 chronic stroke patients using a hand-held dynamometer for objective quantification of the stretch reflex response. In addition, we measured the excitability of three spinal mechanisms thought to be related to post-stroke spasticity: post-activation depression, presynaptic inhibition and reciprocal inhibition before and after the intervention. Effects on motor impairment and function were also assessed using standardized stroke-specific clinical scales. Results The stretch reflex-mediated torque in the wrist flexors was significantly reduced after the intervention, while no change was detected in the passive stiffness. Additionally, there was a significant improvement in the clinical tests of motor impairment and function. There were no significant changes in the excitability of any of the measured spinal mechanisms. Conclusions We demonstrated that contralesional motor cortex 1 Hz rTMS and physiotherapy can reduce the stretch reflex-mediated component of resistance to muscle stretch without affecting passive stiffness in chronic stroke. The specific physiological mechanisms driving this spasticity reduction remain unresolved, as no changes were observed in the excitability of the investigated spinal mechanisms.
Current sampling and sequencing biases of Lassa mammarenavirus limit inference from phylogeography and molecular epidemiology in Lassa fever endemic regions
2023-11-08

Lassa fever (LF) is a potentially lethal viral haemorrhagic infection of humans caused by Lassa mammarenavirus (LASV). It is an important endemic zoonotic disease in West Africa with growing evidence for increasing frequency and sizes of outbreaks. Phylogeographic and molecular epidemiology methods have projected expansion of the Lassa fever endemic zone in the context of future global change. The Natal multimammate mouse ( Mastomys natalensis ) is the predominant LASV reservoir, with few studies investigating the role of other animal species. To explore host sequencing biases, all LASV nucleotide sequences and associated metadata available on GenBank (n = 2,298) were retrieved. Most data originated from Nigeria (54%), Guinea (20%) and Sierra Leone (14%). Data from non-human hosts (n = 703) were limited and only 69 sequences encompassed complete genes. We found a strong positive correlation between the number of confirmed human cases and sequences at the country level ( r = 0.93 (95% Confidence Interval = 0.71–0.98), p &lt; 0.001) but no correlation exists between confirmed cases and the number of available rodent sequences ( r = -0.019 (95% C.I. -0.71–0.69), p = 0.96). Spatial modelling of sequencing effort highlighted current biases in locations of available sequences, with increased sequencing effort observed in Southern Guinea and Southern Nigeria. Phylogenetic analyses showed geographic clustering of LASV lineages, suggestive of isolated events of human-to-rodent transmission and the emergence of currently circulating strains of LASV from the year 1498 in Nigeria. Overall, the current study highlights significant geographic limitations in LASV surveillance, particularly, in non-human hosts. Further investigation of the non-human reservoir of LASV, alongside expanded surveillance, are required for precise characterisation of the emergence and dispersal of LASV. Accurate surveillance of LASV circulation in non-human hosts is vital to guide early detection and initiation of public health interventions for future Lassa fever outbreaks.
Variation in reproductive success in a fragmented Meadow Pipit population: a role for vegetation succession?
2023-11-08

Abstract Most farmland birds experience strong declines across Europe. These declines are typically associated with agricultural intensification but research on alternative local causes remains scarce. We investigated variation in reproductive success as a potential driver for the observed population declines in a fragmented population of the Meadow Pipit Anthus pratensis , a representative inhabitant of extensively managed mountain grasslands across Europe. Intense nest surveys in the entire Meadow Pipit metapopulation of the Northern Black Forest (SW Germany) between 2020 and 2022 provided information on reproductive success for 53 females distributed across nine habitat patches along an 18 km ridge of the Northern Black Forest. Hatching dates delayed by approx. 5.0 days per 100 m altitude and were almost 10 days later in a year with cold and rainy spring weather. Mean reproductive success per female and year (3.45 fledglings) was low compared to literature values (approx. 4.5) and may thus drive ongoing population declines. Mayfield nest survival estimates (approx. 51% across the nesting period) were comparably high, with most nest failures linked with predation or adverse weather. Low reproductive success further associated with comparably small clutch sizes and low fractions of second broods in habitat patches characterized by homogeneously dense swards. We suggest that restoration through extensive permanent cattle grazing coupled with succession control may be a key factor to increase population productivity.
The effects of overseas exhibition games on consumer interest: the case of the English Premier League
2023-11-08

Research question This paper attempts to disentangle the impact of overseas exhibition games, a strategic marketing tool frequently implemented by professional sports clubs in their endeavors to expand into foreign markets, on demand. As such, it contributes to the recently growing literature examining the internationalization processes of leagues and clubs.
Development and Validation of a New Score to Assess the Risk of Posttransplantation Diabetes Mellitus in Kidney Transplant Recipients
2023-11-08

Background. Posttransplantation diabetes mellitus (PTDM) is a serious complication of solid organ transplantation. It is associated with major adverse cardiovascular events, which are a leading cause of morbidity and mortality in transplant patients. This study aimed to develop and validate a score to predict the risk of PTDM in kidney transplant recipients. Methods. A single-center retrospective cohort study was conducted in a tertiary care hospital in Medellín, Colombia, between 2005 and 2019. Data from 727 kidney transplant recipients were used to develop a risk prediction model. Significant predictors with competing risks were identified using time-dependent Cox proportional hazard regression models. To build the prediction model, the score for each variable was weighted using calculated regression coefficients. External validation was performed using independent data, including 198 kidney transplant recipients from Tübingen, Germany. Results. Among the 727 kidney transplant recipients, 122 developed PTDM. The predictive model was based on 5 predictors (age, gender, body mass index, tacrolimus therapy, and transient posttransplantation hyperglycemia) and exhibited good predictive performance (C-index: 0.7 [95% confidence interval, 0.65-0.76]). The risk score, which included 33 patients with PTDM, was used as a validation data set. The results showed good discrimination (C-index: 0.72 [95% confidence interval, 0.62-0.84]). The Brier score and calibration plot demonstrated an acceptable fit capability in external validation. Conclusions. We proposed and validated a prognostic model to predict the risk of PTDM, which performed well in discrimination and calibration, and is a simple score for use and implementation by means of a nomogram for routine clinical application.
Quantum reaction-limited reaction-diffusion dynamics of noninteracting Bose gases
2023-11-08

We investigate quantum reaction-diffusion systems in one-dimension with bosonic particles that coherently hop in a lattice, and when brought in range react dissipatively. Such reactions involve binary annihilation ( ) and coagulation ( ) of particles at distance . We consider the reaction-limited regime, where dissipative reactions take place at a rate that is small compared to that of coherent hopping. In classical reaction-diffusion systems, this regime is correctly captured by the mean-field approximation. In quantum reaction-diffusion systems, for non-interacting fermionic systems, the reaction-limited regime recently attracted considerable attention because it has been shown to give universal power law decay beyond mean-field for the density of particles as a function of time. Here, we address the question whether such universal behavior is present also in the case of the non-interacting Bose gas. We show that beyond mean-field density decay for bosons is possible only for reactions that allow for destructive interference of different decay channels. Furthermore, we study an absorbing-state phase transition induced by the competition between branching , decay and coagulation . We find a stationary phase-diagram, where a first and a second-order transition line meet at a bicritical point which is described by tricritical directed percolation. These results show that quantum statistics significantly impact on both the stationary and the dynamical universal behavior of quantum reaction-diffusion systems.
Editorial: Environmental change in drylands: Past, present, future–volume II
2023-11-08

Dryland environments -defined as landscapes spanning hyper-arid to sub-humid climates -cover 12 40% of the terrestrial surface, host 40% of the world's human population, and are characterized by 13 considerable seasonal and inter-annual variations in precipitation. Climatic and environmental 14 variability in drylands has been a key characteristic over a range of timescales from the Quaternary 15 into the Anthropocene. The climatic oscillations of the Quaternary have influenced dryland 16 landscapes, ecology and hominin populations. Drivers include glacial to interglacial-paced impacts 17 on temperature and hydroclimate, precessional-insolation forcing of global monsoon systems, and 18 teleconnection with millennial-scale extreme climate events at the higher latitudes. approaches, and geographical areas (Figure 1). Both hemispheres and four continents (Africa, 30Europe, Asia and Australasia) are covered. 31
Swift, NuSTAR, and INTEGRAL observations of the symbiotic X-ray binary IGR J16194-2810
2023-11-09

ABSTRACT We report on a simultaneous observational campaign with both Swift/XRT and NuSTAR targeting the symbiotic X-ray binary (SyXB) IGR J16194-2810. The main goal of the campaign was to investigate the possible presence of cyclotron scattering absorption features in the broad-band spectrum of the source, and help advance our understanding of the process of neutron star formation via the accretion-induced collapse of a white dwarf. The 1–30 keV spectrum of the source, as measured during our campaign, did not reveal the presence of any statistically significant absorption feature. The spectrum could be well described using a model comprising a thermal black-body hot component, most likely emerging from the surface of the accreting neutron star, and a power law with no measurable cut-off energy (and affected by a modest absorption column density). Compared to previous analyses in the literature, we could rule out the presence of a colder thermal component emerging from an accretion disc, compatible with the idea that IGR J16194-2810 is a wind-fed binary (as most of the SyXBs). Our results were strengthened by exploiting the archival XRT and INTEGRAL data, extending the validity of the spectral model used up to 0.3–40 keV and demonstrating that IGR J16194-2810 is unlikely to undergo significant spectral variability over time in the X-ray domain.