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Background Host dependency factors (HDF) are essential for viral replication and are promising targets for broad-spectrum antivirals. However, most work has focused on individual viruses or individual data types, limiting our understanding of shared host mechanisms across viruses. Methods We developed a pan–viral framework that integrates multi–omics data–including genome-wide perturbation screens, single–cell transcriptomes and viral interactomes–and combines graph–based learning with classical machine–learning models to prioritize HDF for four RNA viruses (SARS-CoV–2, influenza A virus, dengue virus and Zika virus). Results Across viruses, the framework achieved high discrimination, with area under the receiver operating characteristic curve (ROC–AUC) greater than 0.90 on benchmark datasets, and identified a conserved signature of 118 genes shared by all four viruses and 427 genes shared by at least three. These genes converge on recurrent host programmes such as clathrin–mediated entry and endomembrane trafficking, nuclear transport, RNA processing and stress granules, and proteostasis and ubiquitin–proteasome signalling. The pan–viral signature generalizes beyond the training set, as genes shared by three or more viruses are strongly enriched among top–ranked Ebola virus candidates. We further provide a prioritized shortlist and an experimental validation roadmap to guide follow–up perturbation studies. Conclusions Our integrative multi-omics and machine-learning approach outlines a prediction-based, data-driven map of pan-viral host liabilities and highlights tractable opportunities for host-directed therapy against diverse RNA viruses.

Background Olfactory sensory neurons detect odourants via multiple long cilia that protrude from their dendritic endings. The G protein-coupled receptor GPRC5C was identified as part of the olfactory ciliary membrane proteome, but its function and localization is unknown. Results High-resolution confocal and electron microscopy revealed that GPRC5C is located at the base of sensory cilia in olfactory neurons, but not in primary cilia of immature neurons or stem cells. Additionally, GPRC5C localization in sensory cilia parallels cilia formation and follows the formation of the basal body. In closer examination, GPRC5C was found in the ciliary transition zone. GPRC5C deficiency altered the structure of sensory cilia and increased ciliary layer thickness. However, primary cilia were unaffected. Olfactory sensory neurons from Gprc5c -deficient mice exhibited altered localization of olfactory signalling cascade proteins, and of ciliary phosphatidylinositol-4,5-bisphosphat. Sensory neurons also exhibited increased neuronal activity as well as altered mitochondrial morphology, and knockout mice had an improved ability to detect food pellets based on smell. Conclusions Our study shows that GPRC5C regulates olfactory cilia composition and length, thereby controlling odour perception.

Olfaction depends on lifelong production of sensory neurons from CXCR4 expressing neurogenic stem cells. Signaling by CXCR4 depends on the concentration of CXCL12, CXCR4’s principal ligand. Here, we use several genetic models to investigate how regulation of CXCL12 in the olfactory stem cell niche adjusts neurogenesis. We identify subepithelial tissue and sustentacular cells, the olfactory glia, as main CXCL12 sources. Lamina propria-derived CXCL12 accumulates on quiescent gliogenic stem cells via heparan sulfate. Additionally, CXCL12 is secreted within the olfactory epithelium by sustentacular cells. Both sustentacular-cell-derived and lamina propria-derived CXCL12 are required for CXCR4 activation. ACKR3, a high-affinity CXCL12 scavenger, is expressed by mature glial cells and titrates CXCL12. The accurate adjustment of CXCL12 by ACKR3 is critical for CXCR4-dependent proliferation of neuronal stem cells and for proper lineage progression. Overall, these findings establish precise regulation of CXCL12 by glia cells as a prerequisite for CXCR4-dependent neurogenesis and identify ACKR3 as a scavenger influencing tissue homeostasis beyond embryonic development.

The purpose of this paper is to discuss methods recommended and used by the Pan American Health Organization (PAHO) to monitor the interruption of indigenous measles transmission in the Region of the Americas. The methods used include house‐to‐house monitoring of vaccination coverage as a supervisory tool during both campaigns and routine vaccination; thoroughly investigating all measles outbreaks; performing routine surveillance, including weekly reporting from at least 80% of reporting units; and validating routine surveillance through active‐case searches at health care institutions and schools and in the community. The strategies described have helped PAHO to increase the authority and accountability of vaccine program managers at the local, provincial, and national levels. Their efforts have permitted the Region of the Americas to reduce to three the number of countries with indigenous measles transmission and to reach a record low of 503 measles cases in 2001.

Snow is a vital environmental parameter and dynamically responsive to climate change, particularly in mountainous regions. Snow cover can be monitored at variable spatial scales using Earth Observation (EO) data. Long-lasting remote sensing missions enable the generation of multi-decadal time series and thus the detection of long-term trends. However, there have been few attempts to use these to model future snow cover dynamics. In this study, we, therefore, explore the potential of such time series to forecast the Snow Line Elevation (SLE) in the European Alps. We generate monthly SLE time series from the entire Landsat archive (1985–2021) in 43 Alpine catchments. Positive long-term SLE change rates are detected, with the highest rates (5–8 m/y) in the Western and Central Alps. We utilize this SLE dataset to implement and evaluate seven uni-variate time series modeling and forecasting approaches. The best results were achieved by Random Forests, with a Nash–Sutcliffe efficiency (NSE) of 0.79 and a Mean Absolute Error (MAE) of 258 m, Telescope (0.76, 268 m), and seasonal ARIMA (0.75, 270 m). Since the model performance varies strongly with the input data, we developed a combined forecast based on the best-performing methods in each catchment. This approach was then used to forecast the SLE for the years 2022–2029. In the majority of the catchments, the shift of the forecast median SLE level retained the sign of the long-term trend. In cases where a deviating SLE dynamic is forecast, a discussion based on the unique properties of the catchment and past SLE dynamics is required. In the future, we expect major improvements in our SLE forecasting efforts by including external predictor variables in a multi-variate modeling approach.

The ELIANA trial showed that 61 (81%) of 75 paediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia achieved overall remission after treatment with tisagenlecleucel, a chimeric antigen receptor targeted against the CD19 antigen. We aimed to evaluate patient-reported quality of life in these patients before and after tisagenlecleucel infusion. ELIANA, a global, single-arm, open-label, phase 2 trial, was done in 25 hospitals across Australia, Austria, Belgium, Canada, France, Germany, Italy, Japan, Norway, Spain, and the USA. Patients with B-cell acute lymphoblastic leukaemia aged at least 3 years at the time of screening and 21 years or younger at the time of initial diagnosis who were in second or greater bone marrow relapse, chemorefractory, relapsed after allogeneic stem-cell transplantation, or were otherwise ineligible for allogeneic stem-cell transplantation were enrolled. Patients received a single intravenous administration of a target dose of 0·2–5 × 106 transduced viable T cells per kg for patients weighing 50 kg or less or 0·1–2·5 × 108 transduced viable T cells for patients weighing more than 50 kg. The primary outcome, reported previously, was the proportion of patients who achieved remission. A prespecified secondary endpoint, reported here, was patient-reported quality of life measured with the Pediatric Quality of Life Inventory (PedsQL) and European Quality of Life-5 Dimensions questionnaire (EQ-5D). Patients completed the questionnaires at baseline, day 28, and months 3, 6, 9, and 12 after treatment. The data collected were summarised using descriptive statistics and post-hoc mixed models for repeated measures. Change from baseline response profiles were illustrated with cumulative distribution function plots. The proportion of patients achieving the minimal clinically important difference and normative mean value were reported. Analysis was per protocol. This study is registered with ClinicalTrials.gov, NCT02435849. Between April 8, 2015, and April 25, 2017, 107 patients were screened, 92 were enrolled, and 75 received tisagenlecleucel. 58 patients aged 8–23 years were included in the analysis of quality of life. At baseline, 50 (86%) patients had completed the PedsQL questionnaire and 48 (83%) had completed the EQ-5D VAS. Improvements in patient-reported quality-of-life scores were observed for all measures at month 3 after tisagenlecleucel infusion (mean change from baseline to month 3 was 13·3 [95% CI 8·9–17·6] for the PedsQL total score and 16·8 [9·4–24·3] for the EQ-5D visual analogue scale). 30 (81%) of 37 patients achieved the minimal clinically important difference at month 3 for the PedsQL total score and 24 (67%) of 36 patients achieved this for the EQ-5D visual analogue scale. These findings, along with the activity and safety results of ELIANA, suggest a favourable benefit–risk profile of tisagenlecleucel in the treatment of paediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia. Novartis.

Spinal cord injury (SCI) is a devastating condition with limited pharmacological treatment options to restore function. Regenerative approaches have recently attracted interest as an adjuvant to current standard of care. Adipose tissue–derived (AD) mesenchymal stem cells (MSCs) represent a readily accessible cell source with high proliferative capacity. The CELLTOP study, an ongoing multidisciplinary phase 1 clinical trial conducted at Mayo Clinic (ClinicalTrials.gov Identifier: NCT03308565), is investigating the safety and efficacy of intrathecal autologous AD-MSCs in patients with blunt, traumatic SCI. In this initial report, we describe the outcome of the first treated patient, a 53-year-old survivor of a surfing accident who sustained a high cervical American Spinal Injury Association Impairment Scale grade A SCI with subsequent neurologic improvement that plateaued within 6 months following injury. Although he improved to an American Spinal Injury Association grade C impairement classification, the individual continued to be wheelchair bound and severely debilitated. After study enrollment, an adipose tissue biopsy was performed and MSCs were isolated, expanded, and cryopreserved. Per protocol, the patient received an intrathecal injection of 100 million autologous AD-MSCs infused after a standard lumbar puncture at the L3-4 level 11 months after the injury. The patient tolerated the procedure well and did not experience any severe adverse events. Clinical signs of efficacy were observed at 3, 6, 12, and 18 months following the injection in both motor and sensory scores based on International Standards for Neurological Classification of Spinal Cord Injury. Thus, in this treated individual with SCI, intrathecal administration of AD-MSCs was feasible and safe and suggested meaningful signs of improved, rather than stabilized, neurologic status warranting further clinical evaluation.

Background The aim of this study was to evaluate the clinical implications of pathologic complete response (pCR) (i.e., T0N0M0) after neoadjuvant chemoradiation and radical surgery in patients with locally advanced rectal cancer. Materials and Methods A single-center, prospectively maintained colorectal cancer database was queried for patients with primary cII and cIII rectal cancer staged by CT and ERUS/MRI undergoing long-course neoadjuvant chemoradiation followed by proctectomy with curative intent between 1997 and 2007. Patients were stratified into pCR and no-pCR groups and compared with respect to demographics, tumor and treatment characteristics, and oncologic outcomes. Outcomes evaluated were 5-year overall survival, disease-free survival, disease-specific mortality, local recurrence, and distant recurrence. Results The query returned 238 patients (73% male), with a median age of 57 years and median follow-up of 54 months. Of these, 58 patients achieved pCR. Patients with pCR vs no-pCR were statistically comparable with respect to demographics, chemoradiation regimens, tumor distance from anal verge, clinical stage, surgical procedures performed, and follow-up time. No patient with pCR had local recurrence. Overall survival and distant recurrence were also significantly improved for patients achieving pCR. Conclusions Achievement of pCR after neoadjuvant chemoradiation is associated with greatly improved cancer outcomes in locally advanced rectal cancer. Future studies should evaluate the relationship between increases in pCR rates and improvements in cancer outcomes in this population.

Background Clinical translation of mesenchymal stromal cells (MSCs) necessitates basic characterization of the cell product since variability in biological source and processing of MSCs may impact therapeutic outcomes. Although expression of classical cell surface markers (e.g., CD90, CD73, CD105, and CD44) is used to define MSCs, identification of functionally relevant cell surface markers would provide more robust release criteria and options for quality control. In addition, cell surface expression may distinguish between MSCs from different sources, including bone marrow-derived MSCs and clinical-grade adipose-derived MSCs (AMSCs) grown in human platelet lysate (hPL). Methods In this work we utilized quantitative PCR, flow cytometry, and RNA-sequencing to characterize AMSCs grown in hPL and validated non-classical markers in 15 clinical-grade donors. Results We characterized the surface marker transcriptome of AMSCs, validated the expression of classical markers, and identified nine non-classical markers (i.e., CD36, CD163, CD271, CD200, CD273, CD274, CD146, CD248, and CD140B) that may potentially discriminate AMSCs from other cell types. More importantly, these markers exhibit variability in cell surface expression among different cell isolates from a diverse cohort of donors, including freshly prepared, previously frozen, or proliferative state AMSCs and may be informative when manufacturing cells. Conclusions Our study establishes that clinical-grade AMSCs expanded in hPL represent a homogeneous cell culture population according to classical markers,. Additionally, we validated new biomarkers for further AMSC characterization that may provide novel information guiding the development of new release criteria. Clinical trials Use of Autologous Bone Marrow Aspirate Concentrate in Painful Knee Osteoarthritis (BMAC): Clinicaltrials.gov NCT01931007 . Registered August 26, 2013. MSC for Occlusive Disease of the Kidney: Clinicaltrials.gov NCT01840540 . Registered April 23, 2013. Mesenchymal Stem Cell Therapy in Multiple System Atrophy: Clinicaltrials.gov NCT02315027 . Registered October 31, 2014. Efficacy and Safety of Adult Human Mesenchymal Stem Cells to Treat Steroid Refractory Acute Graft Versus Host Disease. Clinicaltrials.gov NCT00366145 . Registered August 17, 2006. A Dose-escalation Safety Trial for Intrathecal Autologous Mesenchymal Stem Cell Therapy in Amyotrophic Lateral Sclerosis. Clinicaltrials.gov NCT01609283 . Registered May 18, 2012.

β-carbonic anhydrases (βCA) accelerate the equilibrium formation between CO2 and carbonate. Two plant βCA isoforms are targeted to the chloroplast and represent abundant proteins in the range of >1% of chloroplast protein. While their function in gas exchange and photosynthesis is well-characterized in carbon concentrating mechanisms of cyanobacteria and plants with C4-photosynthesis, their function in plants with C3-photosynthesis is less clear. The presence of conserved and surface-exposed cysteinyl residues in the βCA-structure urged to the question whether βCA is subject to redox regulation. Activity measurements revealed reductive activation of βCA1, whereas oxidized βCA1 was inactive. Mutation of cysteinyl residues decreased βCA1 activity, in particular C280S, C167S, C230S, and C257S. High concentrations of dithiothreitol or low amounts of reduced thioredoxins (TRXs) activated oxidized βCA1. TRX-y1 and TRX-y2 most efficiently activated βCA1, followed by TRX-f1 and f2 and NADPH-dependent TRX reductase C (NTRC). High light irradiation did not enhance βCA activity in wildtype Arabidopsis, but surprisingly in βca1 knockout plants, indicating light-dependent regulation. The results assign a role of βCA within the thiol redox regulatory network of the chloroplast.