Antigen escape as a shared mechanism of resistance to BCMA-directed therapies in multiple myeloma.

B-cell maturation antigen (BCMA)-targeting therapeutics have dramatically improved outcomes in relapsed/refractory multiple myeloma (RRMM). However, whether the mechanisms of resistance between these therapies are shared and how the identification of such mechanisms before therapy initiation could refine clinical decision-making remains undefined. We analyzed outcomes for 72 RRMM patients treated with teclistamab, a CD3 x BCMA bispecific antibody (BsAb), 42% (30/72) of whom had prior BCMA-directed therapy exposure. Malignant plasma cell BCMA expression was present in all BCMA therapy-naïve patients. Prior therapy-mediated loss of plasma cell BCMA expression before teclistamab treatment, measured by immunohistochemistry, was observed in 3 patients, none of whom responded to teclistamab, and one of whom also did not respond to ciltacabtagene autoleucel. Whole exome sequencing of tumor DNA from one patient revealed biallelic loss of TNFRSF17 following treatment with belantamab mafodotin. Low-to-undetectable peripheral blood soluble BCMA levels correlated with the absence of BCMA expression by bone marrow plasma cells. Thus, although rare, loss of BCMA expression following TNFRSF17 gene deletions can occur following any BCMA-directed therapy and prevents response to subsequent anti-BCMA-directed treatments, underscoring the importance of verifying the presence of a target antigen.

Global patterns of nuclear and mitochondrial genetic diversity in marine fishes.

Genetic diversity is a fundamental component of biodiversity. Examination of global patterns of genetic diversity can help highlight mechanisms underlying species diversity, though a recurring challenge has been that patterns may vary by molecular marker. Here, we compiled 6862 observations of genetic diversity from 492 species of marine fish and tested among hypotheses for diversity gradients: the founder effect hypothesis, the kinetic energy hypothesis, and the productivity-diversity hypothesis. We fit generalized linear mixed effect models (GLMMs) and explored the extent to which various macroecological drivers (latitude, longitude, temperature (SST), and chlorophyll-a concentration) explained variation in genetic diversity. We found that mitochondrial genetic diversity followed geographic gradients similar to those of species diversity, being highest near the Equator, particularly in the Coral Triangle, while nuclear genetic diversity did not follow clear geographic patterns. Despite these differences, all genetic diversity metrics were correlated with chlorophyll-a concentration, while mitochondrial diversity was also positively associated with SST. Our results provide support for the kinetic energy hypothesis, which predicts that elevated mutation rates at higher temperatures increase mitochondrial but not necessarily nuclear diversity, and the productivity-diversity hypothesis, which posits that resource-rich regions support larger populations with greater genetic diversity. Overall, these findings reveal how environmental variables can influence mutation rates and genetic drift in the ocean, caution against using mitochondrial macrogenetic patterns as proxies for whole-genome diversity, and aid in defining global gradients of genetic diversity.

"Navigating in a maze without a map". Partners' experiences of hyperemesis gravidarum- a qualitative study.

OBJECTIVE: A supportive environment for women with Hyperemesis Gravidarum is crucial but not always provided. There is a lack of research regarding Hyperemesis Gravidarum, its impact on the family, and the partner's perception of supporting their spouse. Thus, this study aims to explore partners' experiences of Hyperemesis Gravidarum during their spousés pregnancy. METHODS: Data were gathered through 13 individual, semi-structured, in-depth, digital interviews with partners of women who had experienced Hyperemesis Gravidarum and analysed with Qualitative Content Analysis. The partners were recruited through advertisement on a social media platform and were exclusively males, representing 8 of 21 Swedish regions. The mean age was 34, and they had, on average, 1 previous child. The mean time from the experience to the interview was 12 months. FINDINGS: The main theme, "Navigating in a maze without a map", explains partners' situation as stressful and demanding when their spouse suffers from Hyperemesis Gravidarum, with insufficient support and guidance from healthcare providers. The analysis resulted in three themes: "Standing alone with a demanding responsibility", "Being in a lottery when facing healthcare", and "Climbing the mountain together." The themes display challenges within everyday life and healthcare, as well as strained relations within the family. CONCLUSION: Partners experience a need to support their spouse in every aspect of daily life and advocate for adequate healthcare. Healthcare professionals must support and acknowledge the partners' struggles during the demanding situation with Hyperemesis Gravidarum.

Unscheduled healthcare interactions in multiple myeloma patients receiving T cell redirection therapies.

Outcomes for relapsed/refractory multiple myeloma (RRMM) patients have dramatically improved following the development and now growing utilization of B cell maturation antigen targeted chimeric antigen receptor (CAR) T cell therapy and bispecific antibody (BsAb) therapy. However, healthcare utilization as a quality-of-life metric in these growing populations has not been thoroughly evaluated. We performed a retrospective cohort study evaluating the frequency and cause of unscheduled healthcare interactions (UHIs) among RRMM patients responding to B-cell maturation antigen targeted BsAbs and CAR T cell therapies (N = 46). This included analysis of remote UHIs including calls to physicians' offices and messages sent through an online patient portal. Our results showed that nearly all (89%) RRMM patients receiving these therapies required a UHI during the first 125 days of treatment, with a mean of 3.7 UHIs per patient. RRMM patients responding to BsAbs were significantly more likely to remotely contact their physicians' offices (1.8-fold increase, p = 0.038) or visit an urgent care center (>3-fold increase, p = 0.012) than RRMM patients responding to CAR T cell therapies. This was largely due to increased reports of mild upper respiratory tract infections in BsAb patients. Our results underscore the need to develop preemptive management strategies for commonly reported symptoms that RRMM patients experience while receiving CAR T cell or BsAb therapies. This preemptive management may significantly reduce unnecessary healthcare utilization in this vulnerable patient population.

Bringing traits back into the equation: A roadmap to understand species redistribution.

Ecological and evolutionary theories have proposed that species traits should be important in mediating species responses to contemporary climate change; yet, empirical evidence has so far provided mixed evidence for the role of behavioral, life history, or ecological characteristics in facilitating or hindering species range shifts. As such, the utility of trait-based approaches to predict species redistribution under climate change has been called into question. We develop the perspective, supported by evidence, that trait variation, if used carefully can have high potential utility, but that past analyses have in many cases failed to identify an explanatory value for traits by not fully embracing the complexity of species range shifts. First, we discuss the relevant theory linking species traits to range shift processes at the leading (expansion) and trailing (contraction) edges of species distributions and highlight the need to clarify the mechanistic basis of trait-based approaches. Second, we provide a brief overview of range shift-trait studies and identify new opportunities for trait integration that consider range-specific processes and intraspecific variability. Third, we explore the circumstances under which environmental and biotic context dependencies are likely to affect our ability to identify the contribution of species traits to range shift processes. Finally, we propose that revealing the role of traits in shaping species redistribution may likely require accounting for methodological variation arising from the range shift estimation process as well as addressing existing functional, geographical, and phylogenetic biases. We provide a series of considerations for more effectively integrating traits as well as extrinsic and methodological factors into species redistribution research. Together, these analytical approaches promise stronger mechanistic and predictive understanding that can help society mitigate and adapt to the effects of climate change on biodiversity.

Patterns of CRS with Teclistamab in Relapsed/Refractory Multiple Myeloma patients with Prior T-Cell Redirection Therapy.

Teclistamab (Tec) is a first-in-class BCMA X CD3 bispecific T-cell engager antibody approved for treating multiple myeloma progressing after at least 4 lines of therapy. The objective of this study was to evaluate the rate of cytokine release syndrome (CRS) in patients who were treated with commercial Tec and had prior exposure to other T-cell redirection therapies. A retrospective chart review was performed to identify patients who completed the Tec step-up dosing phase between November 2022 and November 2023. Patients were divided into 2 cohorts based on prior exposure to T-cell redirection therapy (cohort 1: T-cell redirection therapy experienced; cohort 2: T-cell redirection therapy naïve). The primary objective was to compare the differences in the rates of CRS between the two cohorts. Univariate and multivariate logistic regression analyses were performed to assess the association between CRS rates with Tec and prior treatment with T-cell redirection therapy. A total of 72 patients were included in the analysis (27 in cohort 1 and 45 in cohort 2). The CRS rates were significantly lower in cohort 1 (37%, n=10) compared to cohort 2 (80%, n=36; p=0.0004). Based on multivariate logistic regression analysis, patients without prior exposure to T-cell redirection therapy (cohort 2) had about a 4-fold increase in the incidence of CRS (95% CI: 1.40-14.90, p=0.0002) with Tec. In our study, prior exposure to T-cell redirection therapy reduced the risk of CRS with Tec during the step-up dosing phase. This observation will allow for the optimization of CRS prophylactic strategies for Tec.

Influence of divalent cations on the extraction of organic acids in coffee determined by GC-MS and NMR.

The perceived flavor of coffee varies depending on the composition of the brewing water, and the influencing mechanisms are poorly understood. To investigate the effect of dissolved divalent cations on the extraction of organic acids in coffee, magnesium and calcium chloride salts were added pre- and post-brew. Citric, malic, lactic and quinic acid were analyzed using gas chromatography - mass spectrometry and nuclear magnetic resonance techniques. At concentrations typically found in drinking water, the salts resulted in limited variation of the acid content, while ten-fold higher salt concentrations produced more pronounced variations. Comparisons between pre- and post-brew additions showed similar acid content in most cases, suggesting that extraction of acids proceeds independent of the water composition. Interactions taking place post-brew may, however, influence the perceived flavor. A scientific basis for water quality recommendations in the coffee industry is long overdue and this work provides experimental and analytical contributions to continued research.

FISHGLOB_data: an integrated dataset of fish biodiversity sampled with scientific bottom-trawl surveys.

Scientific bottom-trawl surveys are ecological observation programs conducted along continental shelves and slopes of seas and oceans that sample marine communities associated with the seafloor. These surveys report taxa occurrence, abundance and/or weight in space and time, and contribute to fisheries management as well as population and biodiversity research. Bottom-trawl surveys are conducted all over the world and represent a unique opportunity to understand ocean biogeography, macroecology, and global change. However, combining these data together for cross-ecosystem analyses remains challenging. Here, we present an integrated dataset of 29 publicly available bottom-trawl surveys conducted in national waters of 18 countries that are standardized and pre-processed, covering a total of 2,170 sampled fish taxa and 216,548 hauls collected from 1963 to 2021. We describe the processing steps to create the dataset, flags, and standardization methods that we developed to assist users in conducting spatio-temporal analyses with stable regional survey footprints. The aim of this dataset is to support research, marine conservation, and management in the context of global change.

The importance of oxygen for explaining rapid shifts in a marine fish.

Large-scale shifts in marine species biogeography have been a notable impact of climate change. An effective explanation of what drives these species shifts, as well as accurate predictions of where they might move, is crucial to effectively managing these natural resources and conserving biodiversity. While temperature has been implicated as a major driver of these shifts, physiological processes suggest that oxygen, prey, and other factors should also play important roles. We expanded upon previous temperature-based distribution models by testing whether oxygen, food web productivity, salinity, and scope for metabolic activity (the Metabolic Index) better explained the changing biogeography of Black Sea Bass (Centropristis striata) in the Northeast US. This species has been expanding further north over the past 15 years. We found that oxygen improved model performance beyond a simple consideration of temperature (ΔAIC = 799, ΔTSS = 0.015), with additional contributions from prey and salinity. However, the Metabolic Index did not substantially increase model performance relative to temperature and oxygen (ΔAIC = 0.63, ΔTSS = 0.0002). Marine species are sensitive to oxygen, and we encourage researchers to use ocean biogeochemical hindcast and forecast products to better understand marine biogeographic changes.

Oxylipin profiling by LC-ESI-MS/MS in canine serum and plasma to investigate ovulation-specific changes.

New biomarkers that are directly associated with canine ovulation would be of value to ensure mating on optimal days of heat. In this study, canine plasma and serum were analyzed with liquid chromatography electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) to quantify a broad range of oxylipins for the purpose of developing a method for biomarker discovery studies in canine reproduction. A majority of the 67 oxylipins probed for were detected at comparable levels in both sample types, but more oxylipins at higher concentrations were detected in serum than in plasma. Nine of the oxylipins were detected in a pilot study of serum at levels that significantly differed (p ≤ 0.1) between time-points before (n = 10), during (n = 10) and after (n = 10) ovulation, and might serve as putative biomarkers for canine ovulation. One oxylipin (20-HETE) was significantly altered after adjusting for multiple comparisons. In conclusion, the results showed that the LC-ESI-MS/MS method was suitable for quantification of canine oxylipins, revealing important similarities and differences between plasma and serum profiles as well as preliminary ovulation-specific changes in a subset of the investigated oxylipins.

Marine heatwaves are not a dominant driver of change in demersal fishes.

Marine heatwaves have been linked to negative ecological effects in recent decades1,2. If marine heatwaves regularly induce community reorganization and biomass collapses in fishes, the consequences could be catastrophic for ecosystems, fisheries and human communities3,4. However, the extent to which marine heatwaves have negative impacts on fish biomass or community composition, or even whether their effects can be distinguished from natural and sampling variability, remains unclear. We investigated the effects of 248 sea-bottom heatwaves from 1993 to 2019 on marine fishes by analysing 82,322 hauls (samples) from long-term scientific surveys of continental shelf ecosystems in North America and Europe spanning the subtropics to the Arctic. Here we show that the effects of marine heatwaves on fish biomass were often minimal and could not be distinguished from natural and sampling variability. Furthermore, marine heatwaves were not consistently associated with tropicalization (gain of warm-affiliated species) or deborealization (loss of cold-affiliated species) in these ecosystems. Although steep declines in biomass occasionally occurred after marine heatwaves, these were the exception, not the rule. Against the highly variable backdrop of ocean ecosystems, marine heatwaves have not driven biomass change or community turnover in fish communities that support many of the world's largest and most productive fisheries.

Coral Reef Population Genomics in an Age of Global Change.

Coral reefs are both exceptionally biodiverse and threatened by climate change and other human activities. Here, we review population genomic processes in coral reef taxa and their importance for understanding responses to global change. Many taxa on coral reefs are characterized by weak genetic drift, extensive gene flow, and strong selection from complex biotic and abiotic environments, which together present a fascinating test of microevolutionary theory. Selection, gene flow, and hybridization have played and will continue to play an important role in the adaptation or extinction of coral reef taxa in the face of rapid environmental change, but research remains exceptionally limited compared to the urgent needs. Critical areas for future investigation include understanding evolutionary potential and the mechanisms of local adaptation, developing historical baselines, and building greater research capacity in the countries where most reef diversity is concentrated.

Detecting parallel polygenic adaptation to novel evolutionary pressure in wild populations: a case study in Atlantic cod (Gadus morhua).

Populations can adapt to novel selection pressures through dramatic frequency changes in a few genes of large effect or subtle shifts in many genes of small effect. The latter (polygenic adaptation) is expected to be the primary mode of evolution for many life-history traits but tends to be more difficult to detect than changes in genes of large effect. Atlantic cod (Gadus morhua) were subjected to intense fishing pressure over the twentieth century, leading to abundance crashes and a phenotypic shift toward earlier maturation across many populations. Here, we use spatially replicated temporal genomic data to test for a shared polygenic adaptive response to fishing using methods previously applied to evolve-and-resequence experiments. Cod populations on either side of the Atlantic show covariance in allele frequency change across the genome that are characteristic of recent polygenic adaptation. Using simulations, we demonstrate that the degree of covariance in allele frequency change observed in cod is unlikely to be explained by neutral processes or background selection. As human pressures on wild populations continue to increase, understanding and attributing modes of adaptation using methods similar to those demonstrated here will be important in identifying the capacity for adaptive responses and evolutionary rescue. This article is part of the theme issue 'Detecting and attributing the causes of biodiversity change: needs, gaps and solutions'.

The practice and promise of temporal genomics for measuring evolutionary responses to global change.

Understanding the evolutionary consequences of anthropogenic change is imperative for estimating long-term species resilience. While contemporary genomic data can provide us with important insights into recent demographic histories, investigating past change using present genomic data alone has limitations. In comparison, temporal genomics studies, defined herein as those that incorporate time series genomic data, utilize museum collections and repeated field sampling to directly examine evolutionary change. As temporal genomics is applied to more systems, species and questions, best practices can be helpful guides to make the most efficient use of limited resources. Here, we conduct a systematic literature review to synthesize the effects of temporal genomics methodology on our ability to detect evolutionary changes. We focus on studies investigating recent change within the past 200 years, highlighting evolutionary processes that have occurred during the past two centuries of accelerated anthropogenic pressure. We first identify the most frequently studied taxa, systems, questions and drivers, before highlighting overlooked areas where further temporal genomic studies may be particularly enlightening. Then, we provide guidelines for future study and sample designs while identifying key considerations that may influence statistical and analytical power. Our aim is to provide recommendations to a broad array of researchers interested in using temporal genomics in their work.

The sizes of life.

Recent research has revealed the diversity and biomass of life across ecosystems, but how that biomass is distributed across body sizes of all living things remains unclear. We compile the present-day global body size-biomass spectra for the terrestrial, marine, and subterranean realms. To achieve this compilation, we pair existing and updated biomass estimates with previously uncatalogued body size ranges across all free-living biological groups. These data show that many biological groups share similar ranges of body sizes, and no single group dominates size ranges where cumulative biomass is highest. We then propagate biomass and size uncertainties and provide statistical descriptions of body size-biomass spectra across and within major habitat realms. Power laws show exponentially decreasing abundance (exponent -0.9±0.02 S.D., R2 = 0.97) and nearly equal biomass (exponent 0.09±0.01, R2 = 0.56) across log size bins, which resemble previous aquatic size spectra results but with greater organismal inclusivity and global coverage. In contrast, a bimodal Gaussian mixture model describes the biomass pattern better (R2 = 0.86) and suggests small (~10-15 g) and large (~107 g) organisms outweigh other sizes by one order magnitude (15 and 65 Gt versus ~1 Gt per log size). The results suggest that the global body size-biomass relationships is bimodal, but substantial one-to-two orders-of-magnitude uncertainty mean that additional data will be needed to clarify whether global-scale universal constraints or local forces shape these patterns.

Isolation-by-distance and isolation-by-oceanography in Maroon Anemonefish (Amphiprion biaculeatus).

Obtaining dispersal estimates for a species is key to understanding local adaptation and population dynamics and to implementing conservation actions. Genetic isolation-by-distance (IBD) patterns can be used for estimating dispersal, and these patterns are especially useful for marine species in which few other methods are available. In this study, we genotyped coral reef fish (Amphiprion biaculeatus) at 16 microsatellite loci across eight sites across 210 km in the central Philippines to generate fine-scale estimates of dispersal. All sites except for one followed IBD patterns. Using IBD theory, we estimated a larval dispersal kernel spread of 8.9 km (95% confidence interval of 2.3-18.4 km). Genetic distance to the remaining site correlated strongly with the inverse probability of larval dispersal from an oceanographic model. Ocean currents were a better explanation for genetic distance at large spatial extents (sites greater than 150 km apart), while geographic distance remained the best explanation for spatial extents less than 150 km. Our study demonstrates the utility of combining IBD patterns with oceanographic simulations to understand connectivity in marine environments and to guide marine conservation strategies.

Simulation-Based Evaluation of Methods, Data Types, and Temporal Sampling Schemes for Detecting Recent Population Declines.

Understanding recent population trends is critical to quantifying species vulnerability and implementing effective management strategies. To evaluate the accuracy of genomic methods for quantifying recent declines (beginning <120 generations ago), we simulated genomic data using forward-time methods (SLiM) coupled with coalescent simulations (msprime) under a number of demographic scenarios. We evaluated both site frequency spectrum (SFS)-based methods (momi2, Stairway Plot) and methods that employ linkage disequilibrium information (NeEstimator, GONE) with a range of sampling schemes (contemporary-only samples, sampling two time points, and serial sampling) and data types (RAD-like data and whole-genome sequencing). GONE and momi2 performed best overall, with >80% power to detect severe declines with large sample sizes. Two-sample and serial sampling schemes could accurately reconstruct changes in population size, and serial sampling was particularly valuable for making accurate inferences when genotyping errors or minor allele frequency cutoffs distort the SFS or under model mis-specification. However, sampling only contemporary individuals provided reliable inferences about contemporary size and size change using either site frequency or linkage-based methods, especially when large sample sizes or whole genomes from contemporary populations were available. These findings provide a guide for researchers designing genomics studies to evaluate recent demographic declines.

Genetic decline and recovery of a demographically rebuilt fishery species.

The demographic history of a population is important for conservation and evolution, but this history is unknown for many populations. Methods that use genomic data have been developed to infer demography, but they can be challenging to implement and interpret, particularly for large populations. Thus, understanding if and when genetic estimates of demography correspond to true population history is important for assessing the performance of these genetic methods. Here, we used double-digest restriction-site associated DNA (ddRAD) sequencing data from archived collections of larval summer flounder (Paralichthys dentatus, n = 279) from three cohorts (1994-1995, 1997-1998 and 2008-2009) along the U.S. East coast to examine how contemporary effective population size and genetic diversity responded to changes in abundance in a natural population. Despite little to no detectable change in genetic diversity, coalescent-based demographic modelling from site frequency spectra revealed that summer flounder effective population size declined dramatically in the early 1980s. The timing and direction of change corresponded well with the observed decline in spawning stock census abundance in the late 1980s from independent fish surveys. Census abundance subsequently recovered and achieved the prebottleneck size. Effective population size also grew following the bottleneck. Our results for summer flounder demonstrate that genetic sampling and site frequency spectra can be useful for detecting population dynamics, even in species with large effective sizes.