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mAb114 is a single monoclonal antibody that targets the receptor-binding domain of Ebola virus glycoprotein, which prevents mortality in rhesus macaques treated after lethal challenge with Zaire ebolavirus. Here we present expedited data from VRC 608, a phase 1 study to evaluate mAb114 safety, tolerability, pharmacokinetics, and immunogenicity. In this phase 1, dose-escalation study (VRC 608), conducted at the US National Institutes of Health (NIH) Clinical Center (Bethesda, MD, USA), healthy adults aged 18–60 years were sequentially enrolled into three mAb114 dose groups of 5 mg/kg, 25 mg/kg, and 50 mg/kg. The drug was given to participants intravenously over 30 min, and participants were followed for 24 weeks. Participants were only enrolled into increased dosing groups after interim safety assessments. Our primary endpoints were safety and tolerability, with pharmacokinetic and anti-drug antibody assessments as secondary endpoints. We assessed safety and tolerability in all participants who received study drug by monitoring clinical laboratory data and self-report and direct clinician assessment of prespecified infusion-site symptoms 3 days after infusion and systemic symptoms 7 days after infusion. Unsolicited adverse events were recorded for 28 days. Pharmacokinetic and anti-drug antibody assessments were completed in participants with at least 56 days of data. This trial is registered with ClinicalTrials.gov, number NCT03478891, and is active but no longer recruiting. Between May 16, and Sept 27, 2018, 19 eligible individuals were enrolled. One (5%) participant was not infused because intravenous access was not adequate. Of 18 (95%) remaining participants, three (17%) were assigned to the 5 mg/kg group, five (28%) to the 25 mg/kg group, and ten (55%) to the 50 mg/kg group, each of whom received a single infusion of mAb114 at their assigned dose. All infusions were well tolerated and completed over 30–37 min with no infusion reactions or rate adjustments. All participants who received the study drug completed the safety assessment of local and systemic reactogenicity. No participants reported infusion-site symptoms. Systemic symptoms were all mild and present only in four (22%) of 18 participants across all dosing groups. No unsolicited adverse events occurred related to mAb114 and one serious adverse event occurred that was unrelated to mAb114. mAb114 has linear pharmacokinetics and a half-life of 24·2 days (standard error of measurement 0·2) with no evidence of anti-drug antibody development. mAb114 was well tolerated, showed linear pharmacokinetics, and was easily and rapidly infused, making it an attractive and deployable option for treatment in outbreak settings. Vaccine Research Center, US National Institute of Allergy and Infectious Diseases, and NIH.

Assessment of measurable residual disease (often referred to as “minimal residual disease”) has emerged as a highly sensitive indicator of disease burden during and at the end of treatment and has been correlated with time-to-event outcomes in chronic lymphocytic leukemia. Undetectable-measurable residual disease status at the end of treatment demonstrated independent prognostic significance in chronic lymphocytic leukemia, correlating with favorable progression-free and overall survival with chemoimmunotherapy. Given its utility in evaluating depth of response, determining measurable residual disease status is now a focus of outcomes in chronic lymphocytic leukemia clinical trials. Increased adoption of measurable residual disease assessment calls for standards for nomenclature and outcomes data reporting. In addition, many basic questions have not been systematically addressed. Here, we present the work of an international, multidisciplinary, 174-member panel convened to identify critical questions on key issues pertaining to measurable residual disease in chronic lymphocytic leukemia, review evaluable data, develop unified answers in conjunction with local expert input, and provide recommendations for future studies. Recommendations are presented regarding methodology for measurable residual disease determination, assay requirements and in which tissue to assess measurable residual disease, timing and frequency of assessment, use of measurable residual disease in clinical practice versus clinical trials, and the future usefulness of measurable residual disease assessment. Nomenclature is also proposed. Adoption of these recommendations will work toward standardizing data acquisition and interpretation in future studies with new treatments with the ultimate objective of improving outcomes and curing chronic lymphocytic leukemia.

Here we present a sample of 12 massive quiescent galaxy candidates at z ∼ 3 - 4 observed with the James Webb Space Telescope (JWST) Near Infrared Spectrograph (NIRSpec). These galaxies were pre-selected from the Hubble Space Telescope imaging and 10 of our sources were unable to be spectroscopically confirmed by ground based spectroscopy. By combining spectroscopic data from NIRSpec with multi-wavelength imaging data from the JWST Near Infrared Camera (NIRCam), we analyse their stellar populations and their formation histories. We find that all of our galaxies classify as quiescent based on the reconstruction of their star formation histories but show a variety of quenching timescales and ages. All our galaxies are massive ( ∼ 0.1 - 1.2 × 10 11 M ⊙ ), with masses comparable to massive galaxies in the local Universe. We find that the oldest galaxy in our sample formed ∼ 1.0 × 10 11 M ⊙ of mass within the first few hundred million years of the Universe and has been quenched for more than a billion years by the time of observation at z ∼ 3.2 ( ∼ 2 billion years after the Big Bang). Our results point to very early formation of massive galaxies requiring a high conversion rate of baryons to stars in the early Universe.

We present the formation histories of 19 massive (≳3 × 1010M⊙) quiescent (specific star formation rate, sSFR < 0.15 Gyr−1) galaxy candidates at z ~ 3.0–4.5 observed using JWST/NIRSpec. This completes the spectroscopic confirmation of the 24 K-selected quiescent galaxy sample from the ZFOURGE and 3DHST surveys. Utilizing Prism 1–5 μm spectroscopy, we confirm that all 12 sources that eluded confirmation by ground-based spectroscopy lie at z > 3, resulting in a spectroscopically confirmed number density of ~1.4 × 10−5 Mpc−3 between z ~ 3 and 4. Rest-frame U − V versus V − J color selections show high effectiveness in identifying quiescent galaxies, with a purity of ~90%. Our analysis shows that parametric star formation histories (SFHs) from FAST++ and binned SFHs from Prospector on average yield consistent results, revealing diverse formation and quenching times. The oldest galaxy formed ~6 × 1010M⊙ by z ~ 10 and has been quiescent for over 1 Gyr at z ~ 3.2. We detect two galaxies with ongoing star formation and six with active galactic nuclei (AGNs). We demonstrate that the choice of stellar population models, stellar libraries, and nebular or AGN contributions does not significantly affect the derived average SFHs of the galaxies. We demonstrate that extending spectral fitting beyond the rest-frame optical regime reduces the inferred average star formation rates (SFRs) in the earliest time bins of the SFH reconstruction. The assumed SFH prior influences the SFR at early times, where spectral diagnostic power is limited. Simulated z ~ 3 quiescent galaxies from IllustrisTNG, SHARK, and Magneticum broadly match the average SFHs of the observed sample but struggle to capture the full diversity, particularly at early stages. Our results emphasize the need for mechanisms that rapidly build stellar mass and quench star formation within the first billion years of the Universe.

Masitinib is an orally administered tyrosine kinase inhibitor that targets activated cells of the innate neuroimmune system. We have studied the neuroprotective action of masitinib on the manifestations of experimental autoimmune encephalitis (EAE) induced axonal and neuronal damage. EAE is a model of neuroimmune-driven chronic neuroinflammation and therefore highly relevant to masitinib's mechanism of action in neurodegenerative diseases. Importantly, neuronal damage, or prevention thereof, can be rapidly assessed by measuring serum neurofilament light chain (NfL) concentration in EAE-induced mice. EAE induction was performed in healthy female C57BL/6 mice via active MOG 35-55 peptide immunization. Treatments were initiated 14 days post EAE induction. On day-0, 39 mice with established EAE symptoms were randomly assigned to 3 treatment groups (n = 13): EAE control, masitinib 50 mg/kg/day (M50), and masitinib 100 mg/kg/day (M100). The treatment started on day-1 and ended on day-15. Blood samples were collected on day-1 and day-8, via tail vein sampling, and on day-15, via intracardiac puncture. Assessments included quantification of serum NfL levels along the disease duration, cytokine quantification at day-15, and clinical assessments. Masitinib treatment significantly (p < 0.0001) limited NfL production with respect to control; specifically, relative change in serum NfL concentration at day-8 was 43% and 60% lower for the M50 and M100 groups, respectively. Likewise, for the assessment of absolute serum NfL at day-8 and day-15, there was a significantly lower NfL concentration for masitinib treatment as compared with control. Furthermore, EAE mice treated with masitinib showed significantly lower concentrations of several well-established pro-inflammatory cytokines relative to control at day-15. A beneficial effect of masitinib on functional performance was also observed, with both M50 and M100 groups showing significantly less relative deterioration in grip strength at day-15 as compared with control (p < 0.001). This study is the first demonstration that masitinib, a drug that targets the innate as opposed to the adaptive neuroimmune system, can lower serum NfL levels, and by extension therefore, neuronal damage, in a neuroimmune-driven neurodegenerative disease model. Overall, findings indicate that masitinib has a neuroprotective effect under conditions of chronic neuroinflammation and therefore plausible disease-modifying activity across a broad range of neurodegenerative diseases.

The formation of galaxies by gradual hierarchical co-assembly of baryons and cold dark matter halos is a fundamental paradigm underpinning modern astrophysics 1 , 2 and predicts a strong decline in the number of massive galaxies at early cosmic times 3 – 5 . Extremely massive quiescent galaxies (stellar masses of more than 10 11   M ⊙ ) have now been observed as early as 1–2 billion years after the Big Bang 6 – 13 . These galaxies are extremely constraining on theoretical models, as they had formed 300–500 Myr earlier, and only some models can form massive galaxies this early 12 , 14 . Here we report on the spectroscopic observations with the JWST of a massive quiescent galaxy ZF-UDS-7329 at redshift 3.205 ± 0.005. It has eluded deep ground-based spectroscopy 8 , it is significantly redder than is typical and its spectrum reveals features typical of much older stellar populations. Detailed modelling shows that its stellar population formed around 1.5 billion years earlier in time ( z ≈ 11) at an epoch when dark matter halos of sufficient hosting mass had not yet assembled in the standard scenario 4 , 5 . This observation may indicate the presence of undetected populations of early galaxies and the possibility of significant gaps in our understanding of early stellar populations, galaxy formation and the nature of dark matter. A massive galaxy observed with the JWST indicates that the bulk of its stars formed within the first 500 million years of the Universe.

An inability to reliably predict quantitative behaviors for novel combinations of genetic elements limits the rational engineering of biological systems. We developed an expression cassette architecture for genetic elements controlling transcription and translation initiation in Escherichia coli: transcription elements encode a common mrnA start, and translation elements use an overlapping genetic motif found in many natural systems. We engineered libraries of constitutive and repressor-regulated promoters along with translation initiation elements following these definitions. We measured activity distributions for each library and selected elements that collectively resulted in expression across a 1,000-fold observed dynamic range. We studied all combinations of curated elements, demonstrating that arbitrary genes are reliably expressed to within twofold relative target expression windows with ~93% reliability. We expect the genetic element definitions validated here can be collectively expanded to create collections of public-domain standard biological parts that support reliable forward engineering of gene expression at genome scales. One main goal of synthetic biology is to make the engineering of biology easier 1,2. DNA synthesis and assembly has progressed to the point where entire metabolic pathways, chromosomes and genomes can now be synthesized and transplanted 3-5. However, our capacity to rationally design increasingly complicated genetic systems as enabled by improvements in DNA construction methods has not kept pace 2,6. One of the greatest claimed barriers to efficient and scalable genetic design is the lack of standard parts that can be reused reliably in novel combinations 6,7. Many examples instead highlight, even within well-studied organisms such as E. coli, how seemingly simple genetic functions behave differently in different settings 8,9. For example, a prokaryotic ribosome-binding site (RBS) element that initiates translation for one coding sequence might not function at all with another coding sequence 10. If the genetic elements that encode control of central cellular processes such as transcription and translation cannot be reliably reused, then there is little chance that higher-order objects encoded from such basic elements will be reliable in larger-scale systems 6,11. Standard biological parts could, in theory, enable hierarchical abstraction of biological functions 1,2,12,13. The behavior of integrated genetic systems could then be represented via simpler models of individual elements and ultimately mapped to underlying genetic sequences whose encoded functions are dependent on a limited number of measurable or calculable intrinsic variables. Such abstraction of function seems necessary to manage biological complexity and to allow the engineering of increasingly sophisticated genetic systems 6,12,14. We engineered ~500 transcription and translation initiation elements that are compatible within a standardized genetic context, or expression operating unit (EOU), that enables predictable forward engineering of gene expression over a wide dynamic range. We characterized representative parts for each type by testing more than 1,200 part-part combinations to establish and validate functional composition rules while quantifying scores for part activity. From this data we also estimated the 'quality' of each part, a second-order statistic that represents the extent to which the activity of a part varies across changes in context 15. Our results demonstrate how, when combined with standardized transcription control elements, a more physically complex design for the control of translation initiation creates simply modeled parts enabling reliable forward engineering of gene expression. results Prioritizing part composition puzzles In related work, we systematically assembled and tested all combinations of frequently used prokaryotic transcription and translation control elements to quantify average part activities and also variation in activities as parts are reused in novel combinations 15. Here we focus on developing rules for a genetic layout architecture underlying gene expression cassettes that eliminate

Introduction There is epidemiological evidence to suggest that events in childhood influence lung growth and constitute a significant risk for adult COPD. The aim of the study is to evaluate for an association between childhood asthma and adult COPD. Methods This longitudinal, prospective study of 6–7-year-old children with asthma has been regularly reviewed every 7 years to the current analysis at 50 years of age. Participants completed respiratory questionnaires and lung function spirometry with postbronchodilator response. At the age of 50, subjects were classified to the following subgroups: non-asthmatics, asthma remission, current asthma and COPD which was defined by FEV1 to FVC ratio postbronchodilator of less than 0.7. Results Of the remaining survivors, 346 participated in the current study (participation rate of 76%) of whom 197 completed both questionnaire and lung function testing. As compared with children without symptoms of wheeze to the age of 7, (non-asthmatics) children with severe asthma had an adjusted 32 times higher risk for developing COPD (95% CI 3.4 to 269). In this cohort, 43% of the COPD group had never smoked. There was no evidence of a difference in the rate of decline in FEV1 (mL/year, 95th CI) between the COPD group (17, 10 to 23) and the other groups: non-asthmatics (16, 12 to 21), asthma remission (20, 16 to 24) and current asthma (19, 13 to 25). Conclusions Children with severe asthma are at increased risk of developing COPD.

We present spectroscopic confirmation of candidate strong gravitational lenses using the Keck Observatory and Very Large Telescope as part of our ASTRO 3D Galaxy Evolution with Lenses (AGEL) survey. We confirm that (1) search methods using convolutional neural networks (CNNs) with visual inspection successfully identify strong gravitational lenses and (2) the lenses are at higher redshifts relative to existing surveys due to the combination of deeper and higher-resolution imaging from DECam and spectroscopy spanning optical to near-infrared wavelengths. We measure 104 redshifts in 77 systems selected from a catalog in the DES and DECaLS imaging fields (r ≤ 22 mag). Combining our results with published redshifts, we present redshifts for 68 lenses and establish that CNN-based searches are highly effective for use in future imaging surveys with a success rate of at least 88% (defined as 68/77). We report 53 strong lenses with spectroscopic redshifts for both the deflector and source (z src > z defl), and 15 lenses with a spectroscopic redshift for either the deflector (z defl > 0.21) or source (z src ≥ 1.34). For the 68 lenses, the deflectors and sources have average redshifts and standard deviations of 0.58 ± 0.14 and 1.92 ± 0.59 respectively, and corresponding redshift ranges of z defl = 0.21–0.89 and z src = 0.88–3.55. The AGEL systems include 41 deflectors at z defl ≥ 0.5 that are ideal for follow-up studies to track how mass density profiles evolve with redshift. Our goal with AGEL is to spectroscopically confirm ∼100 strong gravitational lenses that can be observed from both hemispheres throughout the year. The AGEL survey is a resource for refining automated all-sky searches and addressing a range of questions in astrophysics and cosmology.

The holobiont concept was first developed for coral ecosystems but has been extended to multiple organisms, including plants and other animals. Studies on insect-associated microbial communities have produced strong evidence that symbiotic bacteria play a major role in host biology. However, the understanding of these symbiotic relationships has mainly been limited to phytophagous insects, while the role of host-associated microbiota in haematophagous insect vectors remains largely unexplored. Mosquitoes are a major global public health concern, with a concomitant increase in people at risk of infection. The global emergence and re-emergence of mosquito-borne diseases has led many researchers to study both the mosquito host and its associated microbiota. Although most of these studies have been descriptive, they have led to a broad description of the bacterial communities hosted by mosquito populations. This review describes key advances and progress in the field of the mosquito microbiota research while also encompassing other microbes and the environmental factors driving their composition and diversity. The discussion includes recent findings on the microbiota functional roles and underlines their interactions with the host biology and pathogen transmission. Insight into the ecology of multipartite interactions, we consider that conferring the term holobiont to the mosquito and its microbiota is useful to get a comprehensive understanding of the vector pathosystem functioning so as to be able to develop innovative and efficient novel vector control strategies.