Single-cell analysis of human B cell maturation predicts how antibody class switching shapes selection dynamics.

Protective humoral memory forms in secondary lymphoid organs where B cells undergo affinity maturation and differentiation into memory or plasma cells. Here, we provide a comprehensive roadmap of human B cell maturation with single-cell transcriptomics matched with bulk and single-cell antibody repertoires to define gene expression, antibody repertoires, and clonal sharing of B cell states at single-cell resolution, including memory B cell heterogeneity that reflects diverse functional and signaling states. We reconstruct gene expression dynamics during B cell activation to reveal a pre-germinal center state primed to undergo class switch recombination and dissect how antibody class-dependent gene expression in germinal center and memory B cells is linked with a distinct transcriptional wiring with potential to influence their fate and function. Our analyses reveal the dynamic cellular states that shape human B cell-mediated immunity and highlight how antibody isotype may play a role during their antibody-based selection. This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science Immunology on Science Immunology Vol. 6, Feb 2021, DOI: 10.1126/sciimmunol.abe6291

Overdose prevention for injection drug users: Lessons learned from naloxone training and distribution programs in New York City

BACKGROUND: Fatal heroin overdose is a significant cause of mortality for injection drug users (IDUs). Many of these deaths are preventable because opiate overdoses can be quickly and safely reversed through the injection of Naloxone [brand name Narcan], a prescription drug used to revive persons who have overdosed on heroin or other opioids. Currently, in several cities in the United States, drug users are being trained in naloxone administration and given naloxone for immediate and successful reversals of opiate overdoses. There has been very little formal description of the challenges faced in the development and implementation of large-scale IDU naloxone administration training and distribution programs and the lessons learned during this process. METHODS: During a one year period, over 1,000 participants were trained in SKOOP (Skills and Knowledge on Opiate Prevention) and received a prescription for naloxone by a medical doctor on site at a syringe exchange program (SEP) in New York City. Participants in SKOOP were over the age of 18, current participants of SEPs, and current or former drug users. We present details about program design and lessons learned during the development and implementation of SKOOP. Lessons learned described in the manuscript are collectively articulated by the evaluators and implementers of the project. RESULTS: There were six primary challenges and lessons learned in developing, implementing, and evaluating SKOOP. These include a) political climate surrounding naloxone distribution; b) extant prescription drug laws; c) initial low levels of recruitment into the program; d) development of participant appropriate training methodology; e) challenges in the design of a suitable formal evaluation; and f) evolution of program response to naloxone. CONCLUSION: Other naloxone distribution programs may anticipate similar challenges to SKOOP and we identify mechanisms to address them. Strategies include being flexible in program planning and implementation, developing evaluation instruments for feasibility and simplicity, and responding to and incorporating feedback from participants

Theory of high-energy emission from the pulsar/Be-star system PSR 1259−-63 I: radiation mechanisms and interaction geometry

We study the physical processes of the PSR B1259-63 system containing a 47 ms pulsar orbiting around a Be star in a highly eccentric orbit. Motivated by the results of a multiwavelength campaign during the January 1994 periastron passage of PSR B1259-63, we discuss several issues regarding the mechanism of high-energy emission. Unpulsed power law emission from the this system was detected near periastron in the energy range 1-200 keV. We find that the observed high energy emission from the PSR B1259-63 system is not compatible with accretion or propeller-powered emission. Shock-powered high-energy emission produced by the pulsar/outflow interaction is consistent with all high energy observations. By studying the evolution of the pulsar cavity we constrain the magnitude and geometry of the mass outflow outflow of the Be star. The pulsar/outflow interaction is most likely mediated by a collisionless shock at the internal boundary of the pulsar cavity. The system shows all the characteristics of a {\it binary plerion} being {\it diffuse} and {\it compact} near apastron and periastron, respectively. The PSR B1259-63 cavity is subject to different radiative regimes depending on whether synchrotron or inverse Compton (IC) cooling dominates the radiation of electron/positron pairs advected away from the inner boundary of the pulsar cavity. The highly non-thermal nature of the observed X-ray/gamma-ray emission near periastron establishes the existence of an efficient particle acceleration mechanism within a timescale shown to be less than $\sim 10^2-10^3$ s. A synchrotron/IC model of emission of e\pm-pairs accelerated at the inner shock front of the pulsar cavity and adiabatically expanding in the MHD flow provides an excellent explanation of the observed time variableX-ray flux and spectrum from the PSRComment: 68 pages, accepted for publication in the Astrophys. J. on Aug. 26, 199

Common Era sea-level budgets along the U.S. Atlantic coast

Sea-level budgets account for the contributions of processes driving sea-level change, but are predominantly focused on global-mean sea level and limited to the 20th and 21st centuries. Here we estimate site-specific sea-level budgets along the U.S. Atlantic coast during the Common Era (0-2000 CE) by separating relative sea-level (RSL) records into process-related signals on different spatial scales. Regional-scale, temporally linear processes driven by glacial isostatic adjustment dominate RSL change and exhibit a spatial gradient, with fastest rates of rise in southern New Jersey (1.6 ± 0.02 mm yr-1). Regional and local, temporally non-linear processes, such as ocean/atmosphere dynamics and groundwater withdrawal, contributed between -0.3 and 0.4 mm yr-1 over centennial timescales. The most significant change in the budgets is the increasing influence of the common global signal due to ice melt and thermal expansion since 1800 CE, which became a dominant contributor to RSL with a 20th century rate of 1.3 ± 0.1 mm yr-1

Late Glacial and Holocene records of tree-killing conifer bark beetles in Europe and North America: Implications for forest disturbance dynamics

Outbreaks of conifer bark beetles in Europe and North America have increased in scale and severity in recent decades. In this study, we identify existing fossil records containing bark beetle remains from the end of the Last Glacial Maximum (~14,000 cal. yr BP) to present day using the online databases Neotoma and BugsCEP and literature searches, and compare these data with modern distribution data of selected tree-killing species. Modern-day observational data from the Global Biodiversity Information Facility (GBIF) database was used to map recorded distributions from AD 1750 to present day. A total of 53 fossil sites containing bark beetle remains, from both geological and archeological sites, were found during our searches. Fossil sites were fewer in Europe (n = 21) than North America (n = 32). In Europe, 29% of the samples in which remains were found were younger than 1000 cal. yr BP, while in North America, remains were mainly identified from late Glacial (~14,000–11,500 cal. yr BP) sites. In total, the fossil records contained only 8 of 20 species we consider important tree-killing bark beetles in Europe and North America based on their impacts during the last 100 years. In Europe, Ips sexdentatus was absent from the fossil record. In North America, Dendroctonus adjunctus, Dendroctonus frontalis, Dendroctonus jeffreyi, Dendroctonus pseudotsugae, Dryocoetes confusus, Ips calligraphus, Ips confusus, Ips grandicollis, Ips lecontei, Ips paraconfusus, and Scolytus ventralis were absent. Overall, preserved remains of tree-killing bark beetles are rare in the fossil record. However, by retrieving bulk material from new and existing sites and combining data from identified bark beetle remains with pollen, charcoal, tree rings, and geochemistry, the occurrence and dominance of bark beetles, their outbreaks, and other disturbance events can be reconstructed

Postglacial succession of caddisfly (Trichoptera) assemblages in a central European montane lake

The Bohemian Forest lakes, situated along the Czech-German-Austrian border, were strongly affected by atmospheric acidifi- cation between the 1950s and the late 1980s. The subsequent chemical recovery of the lake water should precede and enable a biological recovery, including changes in caddisfly (Insecta: Trichoptera) assemblages. Nevertheless, local pre-acidification data and detailed knowledge of the lake district history are missing, making evaluation of lake recovery difficult. We performed high-resolution analysis of caddisfly remains in a 2.2 m long sediment profile from Prášilské Lake covering the complete history of the lake-catchment evolution. Caddisfly larvae are good indicators of environmental conditions and their subfossil remains are well preserved in unconsolidated waterlaid sediments. A total of 10 caddisfly morpho-taxa were found providing a record from 11,400 cal. yr. BP to the present. With the exception of Athripsodes aterrimus, all identified species are currently present in the Bohemian Forest glacial lakes or their inflow streams but not all of them are documented in Prášilské Lake. The caddisfly fauna consisted of acid-resistant, acid-tolerant and eurytopic species since the Early Holocene. Based on our results, the acid, dystrophic state of Prášilské Lake has been occurring since the lake formation. We conclude that the first signs of natural acidification appeared not later than during the Holocene onset in the Bohemian Forest region. Furthermore, we did not detect any abrupt changes in the species composition connected to the period of anthropogenic acidification during the twentieth century. This study provides for the first time a record of postglacial succession of caddisfly assemblages in a central European mountain lake

Community Justice and Public Safety: Assessing Criminal Justice Policy Through the Lens of the Social Contract

A reconceptualization of the idea of “community justice” is framed in the logic of the social contract and emphasizes the responsibility of the justice system for the provision of public safety. First, we illustrate the ways in which the criminal justice system has hindered the efforts of community residents to participate in the production of public safety by disrupting informal social networks. Then we turn to an examination of the compositional dynamics of California prison populations over time to demonstrate that the American justice system has failed to meet their obligations to provide public safety by incapacitating dangerous offenders. We argue that these policy failures represent a breach of the social contract and advocate for more effective collaboration between communities and the formal criminal justice system so that all parties can fulfill their obligations under the contract

Report of the 2006 ICCAT workshop for bluefin tuna direct ageing

This report provides the presentations, discussions and conclusions from the ICCAT bluefin tuna workshop for direct ageing held in Santander, Spain, in April 2006. The report summarizes the ageing criteria used in the past and the agreements on future age determination based on otoliths, vertebrae and spines. Advantages and disadvantages of each calcified structure for ageing and border interpretation were discussed. It was considered that bluefin tuna age interpretation becomes very difficult from age ten onwards using the whole vertebra and the spine sections methods, but this last technique continues to be useful for older ages. Otolith sections can be used for the whole age range. Participants agreed that none of these three structures could be excluded from routine ageing because otoliths are not easily available. Age estimations within the same structure and between different structures of the same specimen were compared for several readers. Better precision was found between spine readers compared to vertebra and otolith readers. Good age agreement was also achieved between readers of spines and vertebrae from the same bluefin for ages less than 12 years. Preliminary results from radiocarbon assays on otoliths were presented at the workshop and gave promising outcomes for bluefin tuna age validation. Also, these suggested that bluefin tuna can live longer than had previously been established and that a review is needed of the currently used asymptotic size and growth rate for both stocks. Another important contribution of the workshop was a manual for age interpretation.Le présent rapport recueille les présentations, discussions et conclusions de l’Atelier de l’ICCAT chargé de la détermination directe de l’âge du thon rouge, tenu à Santander (Espagne) au mois d’avril 2006. Le rapport résume les critères employés par le passé pour interpréter l’âge et les accords pour la détermination future de l’âge à partir des otolithes, vertèbres et épines. L’Atelier a discuté des avantages et des inconvénients de chaque structure calcifiée pour déterminer l’âge et l’interprétation du type de bord. On a abordé la difficulté de l’interprétation de l’âge des thons de plus de 10 ans au moyen de la vertèbre entière et des sections des épines, bien que cette dernière méthode continue d’être utile pour les âges avancés. Les sections d’otolithes peuvent être employées pour toute la gamme d’âges. Les participants ont convenu qu’aucune de ces trois structures ne doit être exclue pour l’interprétation de l’âge parce qu’il n’est pas toujours possible d’obtenir des otolithes. On a comparé les lectures de l’âge à l’intérieur de la même structure et entre différentes structures du même exemplaire pour divers lecteurs. On a obtenu une plus grande précision parmi les lecteurs d’épines que parmi les lecteurs de vertèbres et d’otolithes. On a également obtenu un bon accord entre les lecteurs d’épines et de vertèbres originaires du même exemplaire pour les âges inférieurs à 12 ans. Les résultats préliminaires des essais de radiocarbone dans les otolithes ont été présentés à l’Atelier, offrant de bonnes perspectives pour son utilisation dans la validation de l’âge. Ces résultats indiquent aussi que le thon rouge a une plus grande longévité que ce qui avait été auparavant établi et qu’il est nécessaire de réviser la longueur asymptotique et le taux de croissance actuellement utilisés. L’élaboration d’un manuel aux fins de l’interprétation de l’âge a constitué une autre contribution importante de l’Atelier.Este informe recoge las presentaciones, discusiones y conclusiones del congreso de ICCAT para la determinación directa de la edad de atún rojo, celebrado en Santander, España, en abril de 2006. El informe resume los criterios empleados en el pasado para interpretar la edad y los acuerdos para la determinación futura de la edad a partir de otolitos, vértebras y espinas. Se discutieron las ventajas y los inconvenientes de cada estructura calcificada para determinar la edad y la interpretación del tipo borde. Se planteó la dificultad en la interpretación de la edad de atunes mayores de 10 años utilizando la vértebra entera y las secciones de espinas, no obstante este último método continúa siendo útil para edades mayores. Las secciones de otolitos pueden ser empleadas para todo el rango de edades. Los participantes acordaron que ninguna de estas tres estructuras deben excluirse para la interpretación de la edad porque no siempre es posible obtener los otolitos. Se compararon las lecturas de edad dentro de la misma estructura y entre diferentes estructuras del mismo ejemplar para varios lectores. Se obtuvo una mayor precisión entre lectores de espinas comparada con las obtenidas por los lectores de vértebras y otolitos. También se obtuvo un buen acuerdo entre lectores de espinas y vértebras procedentes del mismo ejemplar para edades menores de 12 años. Los resultados preliminares de las pruebas de radiocarbono en otolitos fueron presentados en el congreso, proporcionando buenas expectativas para su uso en la validación de la edad. Estos resultados también indican que el atún rojo es más longevo de lo que se consideraba y que es necesaria una revisión de la longitud asintótica y de la tasa de crecimiento empleadas actualmente. Otra importante contribución del congreso fue la elaboración de un manual para la interpretación de la edad

Using citizen science data to assess the vulnerability of bottlenose dolphins to human impacts along England's South Coast

Coastal bottlenose dolphin populations are highly vulnerable due to their small population sizes and proximity to human activities. Long‐term studies in the UK have monitored populations protected within Special Areas of Conservation (SACs) since the 1990s, but a small community of bottlenose dolphins inhabiting the coastal waters of southern England has received much less attention. The English Channel is one of the most heavily impacted marine ecosystems worldwide and increasing anthropogenic pressures pose a severe threat to the long‐term viability of this population. Conservation measures to protect these animals have been hindered by a lack of knowledge of population size, distribution and ranging behaviour. This study aimed to fill these knowledge gaps. A citizen science sighting network yielded 7458 sighting reports of bottlenose dolphins between 2000 and 2020. Resightings of identified individuals were used to estimate abundance, distribution, and ranging behaviour. Social structure analysis revealed a discrete interconnected group of animals in shallow coastal waters, which did not appear to mix with conspecifics identified further offshore. A Bayesian multi‐site mark–recapture analysis estimated that this population comprises around 48 animals (CV = 0.18, 95% HPDI = 38–66). These dolphins ranged between North Cornwall and Sussex, with an average individual range of 530 km (68–760 km). Areas of high‐modelled habitat suitability were found to overlap with high levels of anthropogenic pressure, with pollution and boat traffic identified as the most pervasive threats. Although adult survival rates indicated that the population was relatively stable from 2008 to 2019 (0.945 (0.017 ± SE)), the small population size implies a significant risk to their long‐term viability and resilience to environmental change. By highlighting the most deleterious anthropogenic activities and regions of conservation significance, our results will be useful for developing management policies for threat mitigation and population conservation, to protect this vulnerable group of dolphins