dataesr/scientific-paragraphs-categorization huggingface dataset:
Data acquisition. Microscopy experiments on neutrophils were performed using our in-house-built fluorescence microscope with dual illumination (see above), equipped with a UI-3080CP-M-GL (IDS GmbH) or an Orca-Flash4. 0 V3 (Hamamatsu Photonics KK) camera. The NIR beam, modulated with an SC10 mechanical shutter (Thorlabs), was expanded before being injected into the microscope objective to produce a homogeneous 80-µm-diameter spot at the sample that typically covered 2-3 neutrophils per field of view. The neutrophil dishes were thermostated at 37 °C ± 0. 2 °C using the same heating stage as for temperature measurements. To avoid pH drift, cells observed for 30-60 min were returned to the CO 2 incubator for 1-2 h before any re-observation. Cells were imaged for 5 min under weak (0. 8 W/cm 2 , 200 ms of exposure every 1 s) or strong (20 W/cm 2 , 200-400 ms of exposure every 1 s) 470-nm excitation in the presence or absence of 900-nm light (2 kW/cm 2 , 200-400 ms of exposure every 1 s).
Neutrophils segmentation and tracking. Image analysis was performed using BACMMAN software  29  (https://github. com/jeanollion/ bacmman) that allows automatic cell segmentation and tracking as well as manual curation of both processes. We developed a method for segmentation using a deep neural network (DNN) trained on a very small training set of nine partially annotated images. Our method involves predicting three classes: background, contours and foreground. We found that predicting contours improved the precision of segmentation. See Supplementary Note 2 for details on DNN architecture, training parameters, training set and data augmentation. The cells were then segmented by applying a watershed transform to the predicted probability of the foreground class. Tracking was performed with BACMMAN by integrating the TrackMate 30 implementation of the algorithm by Jaqaman et al.
Once the liquid was absorbed, the cavity was sealed with a coverslip, and the slide was incubated at 37 °C for several hours before imaging (~2 h for cells growing in LB and ~3 h for cells growing in MMcasa), allowing cells to grow into small microcolonies. Optical setup, data acquisition and analysis. The bacterial growth experiments were performed with a Nikon Eclipse Ti microscope controlled by NIS software, whose epifluorescence illuminator was modified to deliver dual visible and NIR illumination (Supplementary Fig. 5 ). In brief, the NIR light source was a fibered 1-W, 885-nm diode laser (RLTMDL-885-1W, Roithner), and the visible light source was an LED (M490L4 or M530L4, Thorlabs). After collimation of the two beams and expansion of the NIR beam, they were combined using a short-pass dichroic mirror (DMSP805R, Thorlabs) inserted in a filter cube, which Brief Communication https://doi.
Image acquisition began after 4 h of incubation, when cells had reached balanced, exponential growth. Three images corresponding to three different focal planes, distant from 350 nm, were taken every minute, with 300-ms exposure time. Replisomes were segmented using BACMMAN software  29  (https://github. com/jeanollion/bacmman) with the same method used to detect fluorescent foci as in ref. 36. This method detects spots on a criterion based on both the intensity value and the Laplacian transform value. We optimized thresholds so that spots are well detected at the first frame and used the same thresholds for the whole movie in both conditions with and without NIR.
Acknowledgements This work was supported by the  Agence Nationale de la Recherche  ( ANR-19-CE29-0003  ( dISCern ),  ANR-19-CE11-0005  ( HIGHLIGHT ),  ANR-19-CE35-0003  ( TRANSMUTATOR ),  ANR-10-INBS-04  ( France Bioimaging ),  ANR-11-EQPX-0029  ( Morphoscope2 ),  ANR-10-LABX-31  ( IPGG ) and  ANR-10-IDEX-0001-02  (PSL)), the  Région Île-de-France (DIM ELICIT) ,  CNRS ,  Sorbonne Université  (Emergence  2019-2020 LIGHTNING ) and  Ecole Normale Supérieure. We thank  S. Vriz ,  M. Volovitch ,  Z. Gueroui  and  N. Peyriéras  for discussions.
, 2022). In the present case, damping was thus applied to the linear momentum balance, the angular momentum balance (for Cosserat continuum) and the return-mapping equation (for gradient regularization). Besides damping, a continuation was applied to the plastic multiplier. This allows to progressively relax the non-linearity due to plasticity throughout the iterative process in a similarly fashion to treatment of power-law viscosity in, for example,  Duretz, Räss, et al. (2018). The values of all involved numerical parameters are given in the appended code. We implement the discretized governing equations using the Julia language  (Bezanson et al. , 2017). We use the Parallelstencil. jl (Omlin & Räss, 2021b)  and ImplicitGlobalGrid. jl (Omlin & Räss, 2021a)  Julia packages which permit to write backend-agnostic high-level code for high-performance distributed stencil computations on xPUs, that is, both central processing units and graphical processing units (GPUs).
Acknowledgments The authors thanks  Daniel Kiss  and an anonymous reviewer for their constructive suggestions. TD acknowledges  Rennes Métropole  and the  French programme NEEDS  for their financial supports to the project. LR acknowledges the  Swiss Geocomputing Centre, University of Lausanne , and the  Laboratory of Hydraulics, Hydrology and Glaciology (VAW), ETH Zurich , for providing computing resources on the Octopus and Superzack GPU-powered supercomputer and server, respectively. Open Access funding enabled and organized by Projekt DEAL.
Aging is associated with a decline in the regenerative potential of stem cells. In recent years, several clinical trials have been launched in order to evaluate the efficacy of mesenchymal stem cell interventions to slow or reverse normal aging processes (aging conditions). Information concerning those clinical trials was extracted from national and international databases (United States, EU, China, Japan, and World Health Organization). Mesenchymal stem cell preparations were in development for two main aging conditions: physical frailty and facial skin aging. With regard to physical frailty, positive results have been obtained in phase II studies with intravenous Lomecel-B (an allogeneic bone marrow stem cell preparation), and a phase I/II study with an allogeneic preparation of umbilical cord-derived stem cells was recently completed.
, 2008). In recent years, several clinical trials have been launched to evaluate the efficacy and safety of SCs on aging conditions (Figure  1 ). Here, those SC preparations were identified, and trials were analyzed from information extracted from national (United States, EU, China, and Japan) and international (World Health Organization, WHO) clinical trial databases. Stem cell-based therapies for agerelated diseases are described elsewhere  (Levy et al. , 2020; Rezaie et al. , 2022).
Clinical trials databases Clinical trials databases from the US (ClinicalTrials. gov), EU (clinicaltrialsregister. eu), China (chictr. org. cn/searchprojen. aspx), Japan (https://rctportal. niph. go. jp/en/) and the World Health Organization (WHO; trialsearch. who. int) were accessed to identify recent clinical trials with SC preparations for aging conditions, using a previously developed approach  (Garay et al. , 2016; Garay, 2021)  slightly modified. The WHO Clinical Trials Search Portal provided access to trials registered in 14 primary registries  (Australia, Brazil, Cuba, Germany, India, Iran, ISRCTN, Korea, Lebanon, Netherlands, Pan African, Peru, Sri Lanka, and Thailand). For each website, the list of clinical trials was obtained by filling out the "Advanced Search" form (or "More Information" form).
Additional sources of information Relevant articles related to the selected SC interventions were searched in the following biomedical literature databases: PubMed (https://pubmed. ncbi. nlm. nih. gov), Science Direct (www. sciencedirect. com/search), Cochrane Library (www. cochranelibrary. com), and Google Scholar (https://scholar. google. com). For each website, relevant articles were found by using the name of the SC preparation, OR the clinical trial identifier number AND "aging condition". Clinical trial information was also obtained by consulting the websites of pharmaceutical and biotechnology companies working in the field of stem cells and aging.
Clinical trials with SC preparations for aging Clinical trial registries were accessed from 1 August 2022 to 16 January 2023, to identify trials with SC preparations for aging. The US database (ClinicalTrials. gov), included twenty-three clinical trials updated on 1 January 2019 or later. Of these, NCT03457870, NCT02642094, NCT04712955, NCT02456870, NCT01169831, NCT02790541, NCT03140319, NCT03535844, NCT04450602, and NCT04450589 were excluded from the present analysis because the interventions did not meet the inclusion criteria. Thirteen clinical trials met the inclusion criteria and were included in the analysis (Tables  1 2 3 ). No other clinical trials were found in the EU database (clinicaltrialsregister. eu). The Chinese database (chictr. org. cn/ searchprojen. aspx), included one clinical trial (ChiCTR2200061216) (Table  2 ).
NCT02065245 CRATUS (NCT02065245) consisted of a phase I open label, escalated dose pilot trial  (Golpanian et al. , 2017) , and a phase II randomized controlled trial (RCT) versus placebo  (Tompkins et al. , 2017)  (Table  1 ). The phase I open label trial  (Golpanian et al. , 2017)  included 15 elderly subjects (mean age: 78. 4 years) with early signs and symptoms of frailty, and a frailty score between 4 and 7 on the Clinical Frailty Scale (CFS)  (Rockwood et al. , 2005). Participants were divided in three groups (n = 5/ group) scheduled to receive 20-, 100-or 200-million hBM-MSCs, delivered via peripheral intravenous infusion  (Golpanian et al. , 2016). No therapy-related TE-SAE (treatment emergent-serious adverse event) occurred during the trial  (Golpanian et al. , 2017). There were no signs of T-cell activation (a marker of graft rejection) at 6-month.
NCT03169231 The CRATUS trial was limited by its small sample size  (Golpanian et al. , 2017; Tompkins et al. , 2017). NCT03169231 is a phase IIb multicenter RCT evaluating Lomecel-B versus placebo  (Yousefi et al. , 2022)   (Table 1 ). A total of 150 older adults with CFS scores of 5"mildly frail" or 6"moderately frail"  (Rockwood et al. , 2005) , and 6 MWD of >200 m and <400 m was included in the study. Primary outcome is the change from baseline in 6 MWD compared to placebo. Secondary outcomes are changes in overall physical function and TNF-alpha. This trial was recently completed. In September 2021, Longeveron announced preliminary biomarker results from the NCT03169231 trial  (Longeveron, 2021b). Administration of Lomecel-B was accompanied by a statistically significant reduction in serum soluble TIE-2 (sTIE-2) levels, in a dose-dependent manner, compared to placebo.
NCT02982915 HERA (NCT02982915) is a phase I/II RCT to test the safety and efficacy of intravenous Lomecel-B to improve influenza vaccine   (fluzone) responses in subjects with aging frailty (Table  1 ). Following an initial phase I safety trial (30 days), a phase II RCT will assess whether Lomecel-B may be an effective vaccine adjuvant to enhance influenza virus inactivation (assessed by hemagglutination inhibition assays) (time frame: 12 months). Primary completion date was expected for September 2021.
NCT05284604 NCT05284604 is a phase I/II RCT investigating hBM-MSCs derived from vertebrae (hvBM-MSCs, obtained from the vertebral bodies of deceased organ donors) versus placebo (Table  1 ). hvBM-MSCs are administered intravenously to older adults (65-85 years of age) who meet the following conditions: 1) Modified Physical Performance Test (mPPT) score of 18-31, 2) Clinical Frailty Scale (CFS) score of 5 or 6 and, 3) 6 MWD of >200 m and <400 m. The primary outcome is adherence (percentage of study visits attended). Secondary outcomes include: number of participants recruited, mPPT score, CFS score, and 6-min walk test (6 MWT). Other secondary outcomes include: adverse events, inflammatory markers and quality of life. The trial is not recruiting yet. Primary completion date is expected for June 2025.
NCT04314011 NCT04314011 is a phase I/II RCT evaluating the safety and efficacy of intravenous hUC-MSCs in older adults (60-80 years of age) with a frailty score of 1-4 on the Fried Phenotype Scale (Op het Veld et al. , 2015) (Table  1 ). Participants receive two intravenous infusions of hUC-MSCs (10 6 cells/kg) or saline separated by an interval of 1 month, and are followed for 6 months (after the first intervention). The primary outcome is the occurrence of serious adverse events (SAEs) during the month following the infusion. Secondary out outcomes are changes in: 1) Fried phenotype scale scores  (Op het Veld et al. , 2015) , 2) blood proinflammatory cytokines and 3) quality of life, assessed at baseline, 1 month, 3 months and 6 months. The trial was recently completed, but the results have not yet been published on ClinTrials.
NCT04919135 NCT04919135 is a phase I/II RCT investigating the safety and efficacy of adjunctive intravenous administration of allogeneic hUC-MSCs in patients receiving standard treatment for frailty in Vietnam [Hightamine (Hankook Korus Pharm, Korea), Total calcium (Nugale Pharmaceutical, Canada), and Bioflex (Ausbiomed, Australia)] (Table  1 )  (Hoang et al. , 2022). The intervention group will receive two doses of hUC-MSCs (1. 5 × 10 6 cells/kg) separated by a time interval of 3 months. The primary outcome is the occurrence of treatmentdependent SAEs. Secondary outcome measures include the 6 MWD test and CD3 + cells. The trial is not yet recruiting.
NCT05018767 NCT05018767 is a single-arm, phase I trial designed to assess the long-term safety of a single intravenous infusion of cultured allogeneic hUC-MSCs (100 million cells) in subjects with aging frailty (Table  1 ). Patients will be evaluated at baseline and at 1, 6, 12, 24, 36, and 48 months. NCT05018767 is currently recruiting participants and primary completion is expected in November 2025.
NCT03514537 NCT03514537 is an open trial to investigate the safety (and efficacy) of an autologous preparation of hAD-MSCs (cellular SVF, cSVF) for aging frailty (Table  1 ). The study includes adult and older adults (40-90 years) who have noted compromise to activities or work requirements due to increasing age and loss of energy. Participants receive intravenous infusions of cSVF isolated from subdermal adipose tissue removed from the trunk or upper thigh area. The primary outcome is the occurrence of Treatment-Emergent Adverse Events (TEAEs) during 6 months following the infusion. Secondary outcomes are changes in weight, activity level, mobility, and fatigue (at 6 months). NCT03514537 is currently recruiting participants and primary completion is expected in March 2023.
NCT03458429 NCT03458429 is a single-arm, phase I/II trial of GMFFP in elderly (55-95 years) and frail people (score of 4-7 on the Clinical Frailty Scale and/or abnormal Immune Risk Profile) (Table  1 ). Participants receive 12 once monthly transfusions of GMFFP (initial treatment period of 12 months) and are followed for a total of 24 months. The primary outcome is the number of participants with treatment-related adverse events. Secondary efficacy outcomes include frailty index (mobility, energy, strength, physical activity, nutritional status, mood, cognition, and social support), immune risk profile, and cognitive function. Primary completion date was expected for February 2023.
NCT02923219 NCT02923219 was an RCT comparing the efficacy of SVFassisted autologous fat grafting (intervention) versus fat transfer alone (control) for facial volume restoration and improvement of skin quality (Table  2 )  (Yin et al. , 2020). Fifty women (mean age: 35. 4 years) participated in the study. At 6 months: 1) Whole face volumes (assessed by 3D scanner and Geomagic software) were significantly higher in the intervention group (77. 6%) compared to the control group (56. 2%, p < 0. 001), 2) wrinkles and texture (assessed by VISIA detector) improved significantly more in the intervention group than in the control group, and 3) graft survival rate was significantly higher in the intervention group than in the control group.
NCT03928444 NCT03928444 is an RCT comparing intradermal autologous SVF injection on one side of the face versus saline injection on the other side (Table  2 ). Fifteen female participants with facial aging (35 years or older) are included in the study and will be followed for 6 months. The primary outcome is the degree of aesthetic improvement using the global aesthetic improvement GAIS 5point scale  (Savoia et al. , 2014). The trial was completed, but the results were not posted to ClinicalTrials. gov.
NCT05508191 NCT05508191 is a single-blind RCT comparing two methods of AD-MSCs "secretome" administration for facial aging (fractional CO₂ laser treatment on one side of the face and microneedle treatment on the other half) (Table  2 ; Figure  1 ). The term "secretome" designates the soluble paracrine factors produced by SCs  (Xia et al. , 2019). Thirty female participants with facial aging (35-59 years) are included in the study and will be followed for 6 weeks. Primary outcomes are: 1) Skin aging changes evaluated by dermoscopy photoaging scale and by Janus-3Ⓡ skin analyzer, 2) skin capacitance evaluated by the CorneometerⓇ and 3) total water content in the stratum corneum of the skin. Primary completion date was expected for October 2022.
NCT04174898 NCT04174898 is a single-arm, phase I trial investigating safety, quality of life and morbimortality risk of hUC-MSC and hAD-MSC infusion in adults and older adults (Table  3 ). Morbimortality risk is assessed by measuring inflammatory markers of aging (IL-6, CRP and TNF-alpha)  (Giovannini et al. , 2011; Puzianowska-Kuznicka et al. , 2016; St Sauver et al. , 2022). Primary completion was expected in April 2021. The study is not yet recruiting.
Ongoing trails with intravenous Lomecel-B The positive results obtained in the CRATUS trial  (Golpanian et al. , 2017; Tompkins et al. , 2017)  were very encouraging to continue clinical development. Therefore, two additional RCTs (phase 2b NCT03169231 and phase 2 jRCT2043200038) were launched to further assess the efficacy and safety of Lomecel-B for aging frailty. The CRATUS trial also suggested that Lomecel-B might reduce age-related chronic inflammation ("inflammaging"). Therefore, a RCT (HERA, NCT02982915) was launched to evaluate the ability of Lomecel-B to improve influenza vaccine responses in frail subjects (Table  1 ). Lomecel-B is also being evaluated in multiple clinical trials for aging-related conditions and chronic diseases (https://www. longeveron. com/clinical-pipeline). In 2021, the FDA granted Rare Pediatric Disease (RPD) designation for Lomecel-B (direct injection into the heart tissue) for the treatment of Hypoplastic Left Heart Syndrome, a rare and life-threatening congenital heart defect in infants  (Longeveron, 2022b).
hBM-MSCs derived from vertebrae from deceased donors (hvBM-MSCs) An important limitation of BM-MSC therapy is the low number of cells obtained. This requires extensive cell expansion ex vivo, with the risk of cell senescence and reduced regenerative potency  (Ganguly et al. , 2017). Barbanti Brodano et al. (  2013 ) compared the biological properties of MSCs derived from different sites in the human body, and found that hvBM-MSCs: 1) Can be maintained in culture for a greater number of passages, and 2) more efficiently generate mature cells of all mesenchymal lineages (osteogenic, adipogenic and chondrogenic differentiation). The number of hvBM-MSCs obtained from deceased donors is much higher than that obtained from traditional types of hBM-MSCs aspirated from living donors. NCT05284604 will assess the feasibility of hvBM-MSC therapy for aging frailty.
hUC-MSCs An hUC-MSC preparation investigated by the Shanghai East Hospital (China) recently completed a phase I/II study (Table  1 ). Moreover, a phase I/II RCTs (NCT04919135) and a phase I safety trial (NCT05018767) have been recently launched to evaluate the efficacy and safety of hUC-MSCs in aging frailty (Table  1 ). hUC-MSC possess several advantages compared with hBM-MSCs: 1) The UC is a waste material, while the collection of hBM-MSC involves painful invasive procedures, and 2) the UC is a source of young SCs, while adult hBM-MSCs exhibit reduced cellular regenerative potency with increasing age  (Ganguly et al. , 2017). hUC-MSC have been extensively investigated to treat hematological disorders [reviewed in  (Shang et al. , 2021) ], as well as to treat age-related or immune disorders [including metabolic and cardiovascular diseases and systemic lupus erythematosus; reviewed in  (Xie et al.
hAD-MSCs NCT03514537 is a safety trial of intravenous hAD-MSCs in frail adult and older adults (40-90 years) (Table  1 ). Comparisons with other studies are difficult to make because: 1) The doses of hAD-MSC used have not been found in the ClinicalTrials. gov database, 2) to my knowledge, no safety trial of intravenous hAD-MSC in frail subjects has been published previously, and 3) frail older people are susceptible to adverse drug reactions  (Hilmer and Kirkpatrick, 2021).
GMFFP NCT03458429 investigates whether transfusion of GMFFP (GCSF-Mobilized Fresh Frozen Plasma) from young persons may be a safe and effective treatment for frailty and immune dysfunction in older people  (Maharaj, 2020). A great advantage of GMFFP is that it is easy to collect and prepare in large quantities. However, there are some limitations regarding NCT03458429 (see Section 4. 1. 3).
Lack of consensus on efficacy outcomes The 6 MWD was one of the efficacy outcomes of the CRATUS trials with Lomecel-B  (Golpanian et al. , 2016; Golpanian et al. , 2017; Tompkins et al. , 2017) , and 6 MWD is the primary outcome measure in the current multicenter trial of Lomecel-B (NCT03169231). Some but not all ongoing trials include 6 MWD as an outcome measure (see, for example, NCT04314011 in Section 3. 1). These differences in evaluation tools do not allow for a precise comparison of efficacy results between clinical trials.
Lack of consensus on diagnostic tools A 6 MWD of >200 m and <400 m is an inclusion criterion of the current multicenter trial with Lomecel-B (NCT03169231), but this 6 MWD criterion was not included in the previous CRATUS trials (which included patients with CSF fragility scores of 4-7)  (Golpanian et al. , 2016; Golpanian et al. , 2017; Tompkins et al. , 2017). Differences in diagnostic tools are also common in ongoing trials (see Section 3. 1) and make clinical efficacy comparisons even more difficult 4. 1. 3. 3 Very few pharmacokinetic studies of intravenous MSCs in humans are available MSC distribution studies in rodents showed that 1) MSCs are transplantable by the intravenous route of administration, 2) more than 90% of intravenous MSCs are trapped in the lung and then cleared (by monocyte phagocytosis) with a half-life of 24 h and 3) local MSC administration is more appropriate for a regenerative effect in situ [for review, see  (Elman et al.
Limitations concerning NCT03458429 with GMFFP There are some limitations regarding NCT03458429 (GMFFP). First, file NCT03458429 (ClinicalTrials. gov database) assumes that GMFFP contains factors secreted by mobilized SCs, but does not specify which are present in the transfused preparations  (Maharaj, 2020). Second, nothing was found in the medical literature to clarify this issue (a PubMed search using GMFFP as a keyword returned no results). Finally, the FDA issued a statement in 2019  (FDA, 2019)  warning consumers not to receive plasma infusions from young donors that are promoted as an unproven treatment for various conditions, and NCT03458429 does not have a control (placebo) arm to assess the intervention efficacy.