Advanced therapy with mesenchymal stromal cells for knee osteoarthritis: Systematic review and meta-analysis of randomized controlled trials.

Background: Advanced cell therapies emerged as promising candidates for treatment of knee articular diseases, but robust evidence regarding their clinical applicability is still lacking. Objective: To assess the efficacy and safety of advanced mesenchymal stromal cells (MSC) therapy for knee osteoarthritis (OA) and chondral lesions. Methods: Systematic review of randomized controlled trials conducted in accordance with Cochrane Handbook and reported following PRISMA checklist. GRADE approach was used for assessing the evidence certainty. Results: 25 randomized controlled trials that enrolled 1048 participants were included. Meta-analyses data showed that, compared to viscosupplementation (VS), advanced MSC therapy resulted in a 1.91 lower pain VAS score (95 % CI -3.23 to -0.59; p < 0.00001) for the treatment of knee OA after 12 months. Compared to placebo, the difference was 0.99 lower pain VAS points (95 % CI -1.94 to -0.03; p = 0.76). According to the GRADE approach, the evidence was very uncertain for both comparisons. By excluding studies with high risk of bias, there was a similar size of effect (VAS MD -1.54, 95 % CI -2.09 to -0.98; p = 0.70) with improved (moderate) certainty of evidence, suggesting that MSC therapy probably reduces pain slightly better than VS. Regarding serious adverse events, there was no difference from advanced MSC therapy to placebo or to VS, with very uncertain evidence. Conclusion: Advanced MSC therapy resulted in lower pain compared to placebo or VS for the treatment of knee OA after 12 months, with no difference in adverse events. However, the evidence was considered uncertain. The Translational Potential of this Article: Currently, there is a lack of studies with good methodological structure aiming to evaluate the real clinical impact of advanced cell therapy for knee OA. The present study was well structured and conducted, with Risk of Bias, GRADE certainty assessment and sensitivity analysis. It explores the translational aspect of the benefits and safety of MSC compared with placebo and gold-standard therapy to give practitioners and researchers support to expand this therapy in their practice. PROSPERO registration number: CRD42020158173. Access at https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=158173.

Effect of Hyperbaric Oxygen Therapy and Adipocyte Stem Cell on the Viability of Degloving Injury: A Murine Model.

INTRODUCTION: Degloving soft tissue injuries (DSTIs) involve skin and tissue detachment from muscle or fascia. Surgical treatments exist, but they cannot prevent necrosis. OBJECTIVE: Our aim was to investigate the effects of hyperbaric oxygen therapy (HOT) and adipocyte stem cell (ASC) treatment on tissue viability in degloving injuries in a murine model. METHODS: 32 animals were submitted to a degloving flap surgery in the dorsal region and were allocated in four groups (n=8/group): Control: suture only; HOT: 2-hour daily therapy in 100% oxygen at 2.0 ATA for 7 days; ASC: injected with 1x106 stem cells; ASC+HOT: stem cells injection plus HOT therapy. We performed macroscopic measurements, blood flow, histology, and expression of inflammation genes. RESULTS: After 7 days, HOT, ASC, and ASC+HOT groups had significantly more viable tissue compared to Control (97%, 90%, 81% vs. 6%). Viable area ratios were higher in HOT and ASC than Control. Blood flow in the injury's distal region was higher in HOT, ASC, and ASC+HOT compared to Control. Vascular density was higher in HOT and ASC+HOT than Control. Inflammatory cells decreased by 40% in HOT, 50% in ASC+HOT, and 75% in ASC. Gene Cd68 expression was lower in HOT than Control. Il10 expression was lower in HOT but higher in ASC and ASC+HOT than Control. CONCLUSION: This study suggests that the HOT can benefit the degloving injury flap model in the early phase of wound healing, and the association of ASC with HOT could benefit the wound healing in a later phase. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which evidence-based medicine rankings are applicable. This excludes review articles, book reviews, and manuscripts that concern basic science, animal studies, cadaver studies, and experimental studies. For a full description of these evidence-based medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Enrichment of Fat Graft with Association of ASC and Nanofat in an Animal Model.

INTRODUCTION: Fat graft (FG) absorption rate varies from 20 to 80% in two years. Recently, several bioengineering techniques were applied to improve FG retention rate. Numerous studies investigated the use of adipocyte-derived stem cells (ASC) as FG enrichment. However, ASC production is costly, complex, and time-consuming. In contrast, Nanofat, a combination of lipids, stem cells and growth factors, offers a faster, simpler, and more cost-effective alternative for FG enrichment. OBJECTIVE: This study aims to compare the effects of ASC with those of Nanofat, as a viable option in FG enrichment. MATERIAL AND METHODS: Animals were allocated in three groups: Control group (1 mL fat), ASC group (1 mL fat +1x106 ASC), and NnF group (1 mL of fat + 0.3mL NnF). These groups were subdivided in three subgroups (4, 8, and 12 weeks, n = 6/group). We performed ultrasound and macroscopic measurements for FG volume, histology and expression of healing and inflammation genes. RESULTS: At week 12, ASC and NnF groups showed a higher retention of FG when compared to the Control group (51%, 46%, 12% respectively, p < 0.01). Fibrosis was similar in ASC and Nanofat groups. The Nanofat group showed a higher vascular density then the Control group (p < 0.05). Il-10 gene expression was higher, and Mmp9 was lower in the Nanofat group when compared to the ASC and Control groups. CONCLUSION: This study indicates that enriching FG with both ASC and Nanofat led to an increased retention rate of the FG, suggesting that Nanofat might be a promising alternative for FG enrichment. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Improvement of motor function in mice after implantation of mononuclear stem cells from human umbilical cord and placenta blood after 3 and 6 weeks of experimental spinal cord injury.

STUDY DESIGN: Experimental study utilizing with a standardized model (MASCIS Impactor) of Spinal Cord Injury (SCI) in Balb C mouse model with implantation of mononuclear stem cells derived from the human umbilical cord and placenta blood in the early chronic phase of SCI. OBJECTIVES: The aim of this study was to evaluate the nerve regeneration and motor functional recovery in Balb C mice with surgically induced paraplegia in response to the use of mononuclear stem cells, in early chronic phase (> 2 weeks and < 6 months), because there is yet potential of neuronal and functional recovery as the neuronal scar is not still completely established. METHODS: Forty-eight mice were randomly assigned to 6 groups of 8 animals. Group 1 received the stem cells 3 weeks after the trauma, and Group 2 received them six weeks later. In Group 3, saline solution was injected at the site of the lesion 3 weeks after the trauma, and in Group 4, 6 weeks later. Group 5 underwent only spinal cord injury and Group 6 underwent laminectomy only. The scales used for motor assessment were BMS and MFS for 12 weeks. RESULTS: The intervention groups showed statistically significant motor improvement. In the histopathological analysis, the intervention groups had a lower degree of injury (p < 0.05). Regarding axonal budding, the intervention groups showed increasing in axonal budding in the caudal portion (p < 0.05). CONCLUSIONS: The use of stem cells in mice in the chronic phase after 3 and 6 weeks of SCI brings functional and histopathological benefits to them.

Effect of Gas Exchange Rate, Vessel Type, Planting Density, and Genotype on Growth, Photosynthetic Activity, and Ion Uptake of In Vitro Potato Plants.

The growth of high-quality in vitro potato plants (Solanum stenotomum subsp. stenotomum, Solanum stenotomum subsp. goniocalyx, and Solanum tuberosum subsp. andigena) is affected by multiple biological, operational, and environmental factors. Research on in vitro culture is frequently focused on the species, explant, composition of the culture medium, and incubation conditions, but only limited information is available on the effect of the gas exchange rate and volume of in vitro culture vessels under variable planting densities. In the present study, these factors were evaluated with a set of seven diverse potato landraces. The results were compared to the plants' responses in routinely used in vitro culture vessels, i.e., 13 × 100 mm and 25 × 150 mm test tubes, and GA7® magenta vessels. In vitro potato plants grown in plastic vessels equipped with a HEPA filter delivering a high gas exchange rate developed thicker stems (0.95 mm), a higher total average leaf area (2.51 cm2), increased chlorophyll content in leaves (32.2 ppm), and lower moisture content in their tissues (90.1%) compared to filter systems with lower gas exchange rates. A high planting density of 10 × 10 plants per vessel (360 and 870 mL) negatively affected the average stem width and root length but increased the plant height (3.4 cm). High fluctuations of ion-uptake of NO3-, Ca++, K+, and Na+ were observed between genotypes, with some accessions having a 4.6-times higher Ca++-ion concentration in their tissues (190-234 ppm). The in vitro plants developed more robust stems, longer roots, and larger leaves within in vitro culture vessels equipped with a HEPA filter (high gas exchange rate) compared to the control vessels, in contrast to the chlorophyll content in leaves, which was higher in plants grown in narrow test tubes. Depending on the purpose of the subculture of in vitro plants, their growth and development can be molded using different gas exchange rates, planting densities, and vessel volumes.

Unveiling ancestral threads: Exploring CCR5 ∆32 mutation frequencies in Colombian populations for HIV/AIDS therapeutics.

AIDS remains a significant global health challenge since its emergence in 1981, with millions of deaths and new cases every year. The CCR5 ∆32 genetic deletion confers immunity to HIV infection by altering a cell membrane protein crucial for viral entry. Stem cell transplants from homozygous carriers of this mutation to HIV-infected individuals have resulted in viral load reduction and disease remission, suggesting a potential therapeutic avenue. This study aims to investigate the relationship between genetic ancestry and the frequency of the CCR5 ∆32 mutation in Colombian populations, exploring the feasibility of targeted donor searches based on ancestry composition. Utilizing genomic data from the CÓDIGO-Colombia consortium, comprising 532 individuals, the study assessed the presence of the CCR5 ∆32 mutation and examined if the population was on Hardy-Weinberg equilibrium. Individuals were stratified into clusters based on African, American, and European ancestry percentages, with logistic regression analysis performed to evaluate the association between ancestry and mutation frequency. Additionally, global genomic databases were utilized to visualize the worldwide distribution of the mutation. The findings revealed a significant positive association between European ancestry and the CCR5 ∆32 mutation frequency, underscoring its relevance in donor selection. African and American ancestry showed negative but non-significant associations with CCR5 ∆32 frequency, which may be attributed to the study's limitations. These results emphasize the potential importance of considering ancestry in donor selection strategies, reveal the scarcity of potential donors in Colombia, and underscore the need to consider donors from other populations with mainly European ancestry if the CCR5 ∆32 stem cell transplant becomes a routine treatment for HIV/AIDS in Colombia.

Saxitoxin potentiates human neuronal cell death induced by Zika virus while sparing neural progenitors and astrocytes.

The Zika virus (ZIKV) epidemic declared in Brazil between 2015 and 2016 was associated with an increased prevalence of severe congenital malformations, including microcephaly. The distribution of microcephaly cases was not uniform across the country, with a disproportionately higher incidence in the Northeast region (NE). Our previous work demonstrated that saxitoxin (STX), a toxin present in the drinking water reservoirs of the NE, exacerbated the damaging effects of ZIKV on the developing brain. We hypothesized that the impact of STX might vary among different neural cell types. While ZIKV infection caused severe damages on astrocytes and neural stem cells (NSCs), the addition of STX did not exacerbate these effects. We observed that neurons subjected to STX exposure were more prone to apoptosis and displayed higher ZIKV infection rate. These findings suggest that STX exacerbates the harmful effects of ZIKV on neurons, thereby providing a plausible explanation for the heightened severity of ZIKV-induced congenital malformations observed in Brazil's NE. This study highlights the importance of understanding the interactive effects of environmental toxins and infectious pathogens on neural development, with potential implications for public health policies.

Umbilical Cord Mesenchymal Stem Cell-Derived Extracellular Vesicles as Natural Nanocarriers in the Treatment of Nephrotoxic Injury In Vitro.

Umbilical cord mesenchymal stem cell-derived extracellular vesicles (UC-EVs) are valuable in nanomedicine as natural nanocarriers, carrying information molecules from their parent cells and fusing with targeted cells. miRNA-126, specific to endothelial cells and derived from these vesicles, supports vascular integrity and angiogenesis and has protective effects in kidney diseases. OBJECTIVE: This study investigates the delivery of miRNA-126 and anti-miRNA-126 via UC-EVs as natural nanocarriers for treating nephrotoxic injury in vitro. METHOD: The umbilical cord-derived mesenchymal stem cell and UC-EVs were characterized according to specific guidelines. Rat kidney proximal tubular epithelial cells (tubular cells) were exposed to nephrotoxic injury through of gentamicin and simultaneously treated with UC-EVs carrying miRNA-126 or anti-miRNA-126. Specific molecules that manage cell cycle progression, proliferation cell assays, and newly synthesized DNA and DNA damage markers were evaluated. RESULTS: We observed significant increases in the expression of cell cycle markers, including PCNA, p53, and p21, indicating a positive cell cycle regulation with newly synthesized DNA via BrDU. The treatments reduced the expression of DNA damage marker, such as H2Ax, suggesting a lower rate of cellular damage. CONCLUSIONS: The UC-EVs, acting as natural nanocarriers of miRNA-126 and anti-miRNA-126, offer nephroprotective effects in vitro. Additionally, other components in UC-EVs, such as proteins, lipids, and various RNAs, might also contribute to these effects.

Mesenchymal Stem/Stromal Cells Derived from Dental Tissues Mediate the Immunoregulation of T Cells through the Purinergic Pathway.

Human dental tissue mesenchymal stem cells (DT-MSCs) constitute an attractive alternative to bone marrow-derived mesenchymal stem cells (BM-MSCs) for potential clinical applications because of their accessibility and anti-inflammatory capacity. We previously demonstrated that DT-MSCs from dental pulp (DP-MSCs), periodontal ligaments (PDL-MSCs), and gingival tissue (G-MSCs) show immunosuppressive effects similar to those of BM, but to date, the DT-MSC-mediated immunoregulation of T lymphocytes through the purinergic pathway remains unknown. In the present study, we compared DP-MSCs, PDL-MSCs, and G-MSCs in terms of CD26, CD39, and CD73 expression; their ability to generate adenosine (ADO) from ATP and AMP; and whether the concentrations of ADO that they generate induce an immunomodulatory effect on T lymphocytes. BM-MSCs were included as the gold standard. Our results show that DT-MSCs present similar characteristics among the different sources analyzed in terms of the properties evaluated; however, interestingly, they express more CD39 than BM-MSCs; therefore, they generate more ADO from ATP. In contrast to those produced by BM-MSCs, the concentrations of ADO produced by DT-MSCs from ATP inhibited the proliferation of CD3+ T cells and promoted the generation of CD4+CD25+FoxP3+CD39+CD73+ Tregs and Th17+CD39+ lymphocytes. Our data suggest that DT-MSCs utilize the adenosinergic pathway as an immunomodulatory mechanism and that this mechanism is more efficient than that of BM-MSCs.

Perspectives on Stem Cell Therapy in Diabetic Neuropathic Pain.

Diabetes mellitus-related morbidity and mortality are primarily caused by long-term complications such as retinopathy, nephropathy, cardiomyopathy, and neuropathy. Diabetic neuropathy (DN) involves the progressive degeneration of axons and nerve fibers due to chronic exposure to hyperglycemia. This metabolic disturbance leads to excessive activation of the glycolytic pathway, inducing oxidative stress and mitochondrial dysfunction, ultimately resulting in nerve damage. There is no specific treatment for painful DN, and new approaches should aim not only to relieve pain but also to prevent oxidative stress and reduce inflammation. Given that existing therapies for painful DN are not effective for diabetic patients, mesenchymal stromal cells (MSCs)-based therapy shows promise for providing immunomodulatory and paracrine regulatory functions. MSCs from various sources can improve neuronal dysfunction associated with DN. Transplantation of MSCs has led to a reduction in hyperalgesia and allodynia, along with the recovery of nerve function in diabetic rats. While the pathogenesis of diabetic neuropathic pain is complex, clinical trials have demonstrated the importance of MSCs in modulating the immune response in diabetic patients. MSCs reduce the levels of inflammatory factors and increase anti-inflammatory cytokines, thereby interfering with the progression of DM. Further investigation is necessary to ensure the safety and efficacy of MSCs in preventing or treating neuropathic pain in diabetic patients.

Proteomic analysis of cerebrospinal fluid of amyotrophic lateral sclerosis patients in the presence of autologous bone marrow derived mesenchymal stem cells.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressive motoneuron degenerative disorder. There are still no drugs capable of slowing disease evolution or improving life quality of ALS patients. Thus, autologous stem cell therapy has emerged as an alternative treatment regime to be investigated in clinical ALS. METHOD: Using Proteomics and Protein-Protein Interaction Network analyses combined with bioinformatics, the possible cellular mechanisms and molecular targets related to mesenchymal stem cells (MSCs, 1 × 106 cells/kg, intrathecally in the lumbar region of the spine) were investigated in cerebrospinal fluid (CSF) of ALS patients who received intrathecal infusions of autologous bone marrow-derived MSCs thirty days after cell therapy. Data are available via ProteomeXchange with identifier PXD053129. RESULTS: Proteomics revealed 220 deregulated proteins in CSF of ALS subjects treated with MSCs compared to CSF collected from the same patients prior to MSCs infusion. Bioinformatics enriched analyses highlighted events of Extracellular matrix and Cell adhesion molecules as well as related key targets APOA1, APOE, APP, C4A, C5, FGA, FGB, FGG and PLG in the CSF of cell treated ALS subjects. CONCLUSIONS: Extracellular matrix and cell adhesion molecules as well as their related highlighted components have emerged as key targets of autologous MSCs in CSF of ALS patients. TRIAL REGISTRATION: Clinicaltrial.gov identifier NCT0291768. Registered 28 September 2016.

An approach to autologous stem cell mobilization: trying to define good mobilizers.

BACKGROUND AND OBJECTIVES: Stem cell mobilization is a well-known procedure to harvest hematopoietic stem cells for autologous stem cell transplantation in certain hematologic diseases. Numerous studies have been conducted to identify risk factors for poor mobilization but there are no studies that identify good mobilizers. In our hospital, we decided to explore good mobilizers, defining them as those with ≥40 CD34+ cells/µL on Day +4 in order to start early apheresis. MATERIAL AND METHODS: A descriptive retrospective study was performed at Hospital Universitari Son Espases. A total of 198 patients mobilized with doses of around 10 µg/kg of granulocyte colony-stimulating factor (G-CSF) every 12 h were analyzed for autologous collection between January 2015 and September 2022. Fifty patients who had ≥40 CD34+ cells/µL on Day +4 started early apheresis; the rest continued mobilization as planned. Success was defined as obtaining over 2.5 × 106 CD34+ cells/kg in a single apheresis. RESULTS: The necessary number of CD34+ cells/kg to perform an autologous stem cell transplantation was reached in a single apheresis session in 62 % of patients with ≥40 CD34+ cells/µL in peripheral blood. A cutoff of 102 CD34+ cells/µL on Day +4 was shown to have the best success rate (94 %). In an analysis of success, age, previously failed mobilization and having one or more adverse factors for bad mobilization were statistically significant. CONCLUSION: Patients considered as good mobilizers were matched with our factors of poor mobilization, revealing that most patients (79 %) had none or only one risk factor for poor mobilization. Apheresis on Day +4 in good mobilizers was shown to be an effective alternative to reduce mobilization duration and decrease the amount of granulocyte-colony stimulating factor administered.

Transplantation of autologous mesenchymal stromal cells in complete cervical spinal cord injury: a pilot study.

Objective: Spinal cord injury (SCI) is a serious condition that can lead to partial or complete paraplegia or tetraplegia. Currently, there are few therapeutic options for these conditions, which are mainly directed toward the acute phase, such as surgical intervention and high-dose steroid administration. Mesenchymal stromal cells (MSC) have been shown to improve neurological function following spinal cord injury. The aim of the study was to evaluate the safety, feasibility, and potential efficacy of MSC transplantation in patients with cervical traumatic SCI. Methods: We included seven subjects with chronic traumatic SCI (> 1 year) at the cervical level, classified as American Spinal Cord Injury Association impairment scale (AIS) grade A. Subjects received two doses of autologous bone marrow derived MSC, the first by direct injection into the lesion site after hemilaminectomy and the second three months later by intrathecal injection. Neurologic evaluation, spinal magnetic resonance imaging (MRI), urodynamics, and life quality questionnaires were assessed before and after treatment. Results: Cell transplantation was safe without severe or moderate adverse effects, and the procedures were well tolerated. Neurological evaluation revealed discrete improvements in sensitivity below the lesion level, following treatment. Five subjects showed some degree of bilateral sensory improvement for both superficial and deep mechanical stimuli compared to the pretreatment profile. No significant alterations in bladder function were observed during this study. Conclusion: Transplantation of autologous MSC in patients with chronic cervical SCI is a safe and feasible procedure. Further studies are required to confirm the efficacy of this therapeutic approach. Clinical trial registration: https://clinicaltrials.gov/study/NCT02574572, identifier NCT02574572.

How to enhance MSCs therapeutic properties? An insight on potentiation methods.

Mesenchymal stem/stromal cells (MSCs) have emerged as a promising tool in the field of regenerative medicine due to their unique therapeutic properties as they can differentiate into multiple cell types and exert paracrine effects. However, despite encouraging results obtained in preclinical studies, clinical trials have not achieved the same levels of efficacy. To improve the therapeutic properties of MSCs, several strategies have been explored. Therefore, in this review, the therapeutic properties of MSCs will be analyzed, and an update and overview of the most prominent approaches used to enhance their therapeutic capabilities will be provided. These approaches include using drugs, molecules, strategies based on biomaterials, and modification parameters in culture. The strategy described shows several common factors among those affected by these strategies that lead to an enhancement of the MSCs therapeutic properties such as the activation of the PI3K/AKT pathway and the increased expression of Heat Shock Proteins and Hypoxia-Inducible Factor. The combined effect of these elements shift MSCs towards a glycolytic state, suggesting this shift is essential for their enhancement.

A comprehensive meta-analysis of stem cell therapy for liver failure: Assessing treatment efficacy and modality.

INTRODUCTION AND OBJECTIVES: This meta-analysis aims to evaluate the efficacy of stem cell therapy (SCT) for liver failure. MATERIALS AND METHODS: The study adhered to the recommended guidelines of the PRISMA statement. Eligible studies published prior to May 13, 2023, were comprehensively searched in databases including PubMed, Web of Science, and Embase. Quality assessment was conducted using the Cochrane risk-of-bias tool, and the standard mean differences were calculated for the clinical parameters. The hazard ratios were determined by extracting individual patient data from the Kaplan-Meier curve. RESULTS: A total of 2,937 articles were retrieved, and eight studies were included in the final analysis. Most of the studies focused on HBV-related liver failure and were randomized controlled trials. All studies utilized mesenchymal stem cells (MSCs), with the majority (62.5%) being allogeneic. The analysis revealed that combining stem cell therapy with standard medical treatment or plasma exchange significantly enhanced patient survival and reduced MELD scores. Specifically, allogeneic stem cells showed superior efficacy in improving survival outcomes compared to autologous stem cells. Furthermore, deep vessel injection plus a single injection demonstrated better effectiveness than peripheral vessel injection plus multiple injections in reducing MELD scores. CONCLUSIONS: This comprehensive analysis underscores the potential of MSC therapy in significantly improving survival and clinical outcomes in patients with liver failure, highlighting the superior benefits of allogeneic MSCs and deep vessel plus single injection administration.

Atomic Structure and 3D Shape of a Multibranched Plasmonic Nanostar from a Single Spatially Resolved Electron Diffraction Map.

Despite the interest in improving the sensitivity of optical sensors using plasmonic nanoparticles (NPs) (rods, wires, and stars), the full structural characterization of complex shape nanostructures is challenging. Here, we derive from a single scanning transmission electron microscope diffraction map (4D-STEM) a detailed determination of both the 3D shape and atomic arrangement of an individual 6-branched AuAg nanostar (NS) with high-aspect-ratio legs. The NS core displays an icosahedral structure, and legs are decahedral rods attached along the 5-fold axes at the core apexes. The NS legs show an anomalous anisotropic spatial distribution (all close to a plane) due to an interplay between the icosahedral symmetry and the unzipping of the surfactant layer on the core. The results significantly improve our understanding of the star growth mechanism. This low dose diffraction mapping is promising for the atomic structure study of individual multidomain, multibranched, or multiphase NPs, even when constituted of beam-sensitive materials.

The gender productivity gap in Biochemical and Biophysical sciences. Some evidence to solve the productivity puzzle.

This paper studies the gender productivity gap in biochemical and biophysical sciences in Argentina for the period 2011-2018. Women publish less papers than men due to academic and non-academic differences. We define the former as the individual characteristics related to research activity, that are developed in the public sphere, and non-academic as the ones related to the private sphere (such as housework and breeding). The later tend to negatively impact on the academic characteristics of female researchers, even when they are not supposed to be related. We test whether the gender productivity gap persists even when academic characteristics between men and women are alike, and to what extent these characteristics contribute to reduce the gap. The methodological approached is based on an extension of the Oaxaca-Blinder decomposition, named multivariate decomposition for nonlinear response models. Results show that both observable (academic) and unobservable factors (both academic and non-academic) explain the gender productivity gap and that the former contribute to the reduction but not the elimination.

PTN from Leydig cells activates SDC2 and modulates human spermatogonial stem cell proliferation and survival via GFRA1.

BACKGROUND: Spermatogonial stem cells (SSCs) are essential for the maintenance and initiation of male spermatogenesis. Despite the advances in understanding SSC biology in mouse models, the mechanisms underlying human SSC development remain elusive. RESULTS: Here, we analyzed the signaling pathways involved in SSC regulation by testicular somatic cells using single-cell sequencing data (GEO datasets: GSE149512 and GSE112013) and identified that Leydig cells communicate with SSCs through pleiotrophin (PTN) and its receptor syndecan-2 (SDC2). Immunofluorescence, STRING prediction, and protein immunoprecipitation assays confirmed the interaction between PTN and SDC2 in spermatogonia, but their co-localization was observed only in approximately 50% of the cells. The knockdown of SDC2 in human SSC lines impaired cell proliferation, DNA synthesis, and the expression of PLZF, a key marker for SSC self-renewal. Transcriptome analysis revealed that SDC2 knockdown downregulated the expression of GFRA1, a crucial factor for SSC proliferation and self-renewal, and inhibited the HIF-1 signaling pathway. Exogenous PTN rescued the proliferation and GFRA1 expression in SDC2 knockdown SSC lines. In addition, we found downregulation of PTN and SDC2 as well as altered localization in non-obstructive azoospermia (NOA) patients, suggesting that downregulation of PTN and SDC2 may be associated with impaired spermatogenesis. CONCLUSIONS: Our results uncover a novel mechanism of human SSC regulation by the testicular microenvironment and suggest a potential therapeutic target for male infertility.

Further biological characterization of small molecules UM171 and SR1: In vitro effects on three hematopoietic cell populations from human cord blood.

Small molecules UM171 and SR1 have already been taken into clinically-oriented protocols for the ex vivo expansion of hematopoietic stem (HSCs) and progenitor (HPCs) cells. In order to gain further insight into their biology, in the present study we have assessed their effects, both individually and in combination, on the in vitro long-term proliferation and expansion of HSCs and HPCs contained within three different cord blood-derived cell populations: MNCs (CD34+ cells = 0.8 %), LIN- cells (CD34+ cells = 41 %), and CD34+ cells (CD34+ cells >98 %). Our results show that when added to cultures in the absence of recombinant stimulatory cytokines, neither molecule had any effect. In contrast, when added in the presence of hematopoietic cytokines, UM171 and SR1 had significant stimulatory effects on cell proliferation and expansion in cultures of LIN- and CD34+ cells. No significant effects were observed in cultures of MNCs. The effects of both molecules were more pronounced in cultures with the highest proportion of CD34+ cells, and the greatest effects were observed when both molecules were added in combination. In the absence of small molecules, cell numbers reached a peak by days 25-30, and then declined; whereas in the presence of UM171 or/and SR1 cell numbers were sustained up to day 45 of culture. Our results indicate that besides CD34+ cells, LIN- cells could also be used as input cells in clinically-oriented expansion protocols, and that using both molecules simultaneously would be a better approach than using only one of them.

A systematic review of clinical efficacy and safety of cell-based therapies in Alzheimer's disease.

There is presently no disease-modifying therapy for Alzheimer's Disease (AD), which is the most prevalent cause of dementia. Objective: This study aspires to estimate the efficacy and safety of cell-based treatments in AD. Methods: Observing the Joanna Briggs Institute (JBI) methods and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, a systematic search was accomplished in PubMed, Medical Literature Analysis and Retrieval System Online (Medline, via Ovid), Embase; Cochrane, and Cumulative Index of Nursing and Allied Health Literature - CINAHL (via EBSCO) databases up to June 2023. The relevant clinical studies in which cell-based therapies were utilized to manage AD were included. The risk of bias was evaluated using the JBI checklists, based on the study designs. Results: Out of 1,014 screened records, a total of five studies with 70 individuals (including 59 patients receiving stem cells and 11 placebo controls) were included. In all these studies, despite the discrepancy in the origin of stem cells, cell density, and transplant site, safety goals were obtained. The intracerebroventricular injection of adipose-derived stromal vascular fraction (ADSVF) and umbilical cord-derived mesenchymal stem cells (UC-MSCs), the intravenous injection of Lomecel-B, and the bilateral hippocampi and right precuneus injection of UC-MSCs are not linked to any significant safety concerns, according to the five included studies. Studies also revealed improvements in biomarkers and clinical outcomes as a secondary outcome. Three studies had no control groups and there are concerns regarding the similarity of the groups in others. Also, there is considerable risk of bias regarding the outcome assessment scales. Conclusion: Cell-based therapies are well tolerated by AD patients, which emphasizes the need for further, carefully planned randomized studies to reach evidence-based clinical recommendations in this respect.

Atualmente, não há terapia modificadora da doença para a doença de Alzheimer (DA), que é a causa mais prevalente de demência. Objetivo: Este estudo teve como objetivo estimar a eficácia e segurança dos tratamentos baseados em células na DA. Métodos: Observando os métodos do JBI e a declaração PRISMA, uma busca sistemática foi realizada nas bases de dados PubMed, Medical Literature Analysis and Retrieval System Online ­ Medline (via Ovid), Embase, Cochrane e CINAHL (via EBSCO) até junho de 2023. Foram incluídos os estudos clínicos relevantes nos quais terapias baseadas em células foram utilizadas para gerenciar a DA. O risco de viés foi avaliado utilizando os checklists do JBI, com base nos desenhos dos estudos. Resultados: Dos 1.014 registros examinados, foi incluído um total de cinco estudos com 70 indivíduos (incluindo 59 pacientes que receberam células-tronco e 11 controles de placebo). Em todos esses estudos, apesar da discrepância na origem das células-tronco, densidade celular e local de transplante, os objetivos de segurança foram alcançados. A injeção intracerebroventricular de ADSVF e UC-MSCs, a injeção intravenosa de Lomecel-B e a injeção bilateral dos hipocampos e precuneus direito de UC-MSCs não estão relacionadas a quaisquer preocupações significativas de segurança, de acordo com os cinco estudos incluídos. Os estudos também revelaram melhorias nos biomarcadores e resultados clínicos como um desfecho secundário. Três estudos não tinham grupos de controle e há preocupações quanto à semelhança dos grupos em outros. Além disso, há um risco considerável de viés em relação às escalas de avaliação de desfechos. Conclusão: As terapias baseadas em células são bem toleradas por pacientes com DA, o que enfatiza a necessidade de mais estudos randomizados cuidadosamente planejados para alcançar recomendações clínicas baseadas em evidências.