White adipose tissue remodeling in Little Brown Myotis (Myotis lucifugus) with white-nose syndrome.

White-nose syndrome (WNS) is a fungal wildlife disease of bats that has caused precipitous declines in certain Nearctic bat species. A key driver of mortality is premature exhaustion of fat reserves, primarily white adipose tissue (WAT), that bats rely on to meet their metabolic needs during winter. However, the pathophysiological and metabolic effects of WNS have remained ill-defined.

Assessing scale-dependency of climate risks in coffee-based agroforestry systems.

Agroforestry is a management strategy for mitigating the negative impacts of climate and adapting to sustainable farming systems. The successful implementation of agroforestry strategies requires that climate risks are appropriately assessed. The spatial scale, a critical determinant influencing climate impact assessments and, subsequently, agroforestry strategies, has been an overlooked dimension in the literature.

Integration of ζ-deficient CARs into the CD3ζ gene conveys potent cytotoxicity in T and NK cells.

Chimeric antigen receptor (CAR)-redirected immune cells hold significant therapeutic potential for oncology, autoimmune diseases, transplant medicine, and infections. All approved CAR-T therapies rely on personalized manufacturing using undirected viral gene transfer, which results in nonphysiological regulation of CAR-signaling and limits their accessibility due to logistical challenges, high costs and biosafety requirements. Random gene transfer modalities pose a risk of malignant transformation by insertional mutagenesis.

Addressing quantum's "fine print" with efficient state preparation and information extraction for quantum algorithms and geologic fracture networks.

Quantum algorithms provide an exponential speedup for solving certain classes of linear systems, including those that model geologic fracture flow. However, this revolutionary gain in efficiency does not come without difficulty. Quantum algorithms require that problems satisfy not only algorithm-specific constraints, but also application-specific ones.

Integration of ζ-deficient CARs into the gene conveys potent cytotoxicity in T and NK cells.

Unlabelled: Chimeric antigen receptor (CAR)-reprogrammed immune cells hold significant therapeutic potential for oncology, autoimmune diseases, transplant medicine, and infections. All approved CAR-T therapies rely on personalized manufacturing using undirected viral gene transfer, which results in non-physiological regulation of CAR-signaling and limits their accessibility due to logistical challenges, high costs and biosafety requirements. Here, we propose a novel approach utilizing CRISPR-Cas gene editing to redirect T cells and natural killer (NK) cells with CARs.

Quantitative target engagement of RIPK1 in human whole blood via the cellular thermal shift assay for potential pre-clinical and clinical applications.

The cellular thermal shift assay (CETSA®) is a target engagement method widely used for preclinical characterization of small molecule compounds. CETSA® has been used for semi-quantitative readouts in whole blood with PBMC isolation, and quantitative, plate-based readouts using cell lines. However, there has been no quantitative evaluation of CETSA® in unprocessed human whole blood, which is preferred for clinical applications.

Host infection and disease-induced mortality modify species contributions to the environmental reservoir.

Environmental pathogen reservoirs exist for many globally important diseases and can fuel epidemics, influence pathogen evolution, and increase the threat of host extinction. Species composition can be an important factor that shapes reservoir dynamics and ultimately determines the outcome of a disease outbreak. However, disease-induced mortality can change species communities, indicating that species responsible for environmental reservoir maintenance may change over time.

CAR NK-92 cell-mediated depletion of residual TCR+ cells for ultrapure allogeneic TCR-deleted CAR T-cell products.

Graft-versus-host disease (GVHD) is a major risk of the administration of allogeneic chimeric antigen receptor (CAR)-redirected T cells to patients who are HLA unmatched. Gene editing can be used to disrupt potentially alloreactive T-cell receptors (TCRs) in CAR T cells and reduce the risk of GVHD. Despite the high knockout rates achieved with the optimized methods, a subsequent purification step is necessary to obtain a safe allogeneic product.

Vapour pressure deficit determines critical thresholds for global coffee production under climate change.

Our understanding of the impact of climate change on global coffee production is largely based on studies focusing on temperature and precipitation, but other climate indicators could trigger critical threshold changes in productivity. Here, using generalized additive models and threshold regression, we investigate temperature, precipitation, soil moisture and vapour pressure deficit (VPD) effects on global Arabica coffee productivity. We show that VPD during fruit development is a key indicator of global coffee productivity, with yield declining rapidly above 0.

Combining different CRISPR nucleases for simultaneous knock-in and base editing prevents translocations in multiplex-edited CAR T cells.

Background: Multiple genetic modifications may be required to develop potent off-the-shelf chimeric antigen receptor (CAR) T cell therapies. Conventional CRISPR-Cas nucleases install sequence-specific DNA double-strand breaks (DSBs), enabling gene knock-out or targeted transgene knock-in. However, simultaneous DSBs provoke a high rate of genomic rearrangements which may impede the safety of the edited cells.

Non-viral -knocked-in CD19CAR-T and gp350CAR-T cells tested against Burkitt lymphomas with type 1 or 2 EBV infection: cellular dynamics and potency.

Introduction: The ubiquitous Epstein-Barr virus (EBV) is an oncogenic herpes virus associated with several human malignancies. EBV is an immune-evasive pathogen that promotes CD8 T cell exhaustion and dysregulates CD4 T cell functions. Burkitt lymphoma (BL) is frequently associated with EBV infections.

Spatial modelling of agro-ecologically significant grassland species using the INLA-SPDE approach.

The use of spatially referenced data in agricultural systems modelling has grown in recent decades, however, the use of spatial modelling techniques in agricultural science is limited. In this paper, we test an effective and efficient technique for spatially modelling and analysing agricultural data using Bayesian hierarchical spatial models (BHSM). These models utilise analytical approximations and numerical integration called Integrated Nested Laplace Approximations (INLA).

Early flowering changes robusta coffee yield responses to climate stress and management.

A shift towards earlier flowering is a widely noted consequence of climate change for the world's plants. However, whether early flowering changes the way in which plants respond to climate stress, and in turn plant yield, remains largely unexplored. Using 10 years of flowering time and yield observations (Total N = 5580) from 558 robusta coffee (Coffea canephora) farms across Vietnam we used structural equation modelling (SEM) to examine the drivers of flowering day anomalies and the consequent effects of this on coffee climate stress sensitivity and management responses (i.

Reversible lysine-targeted probes reveal residence time-based kinase selectivity.

The expansion of the target landscape of covalent inhibitors requires the engagement of nucleophiles beyond cysteine. Although the conserved catalytic lysine in protein kinases is an attractive candidate for a covalent approach, selectivity remains an obvious challenge. Moreover, few covalent inhibitors have been shown to engage the kinase catalytic lysine in animals.

Pharmacological interventions enhance virus-free generation of -replaced CAR T cells.

Chimeric antigen receptor (CAR) redirected T cells are potent therapeutic options against hematological malignancies. The current dominant manufacturing approach for CAR T cells depends on retroviral transduction. With the advent of gene editing, insertion of a CD19-CAR into the T cell receptor (TCR) alpha constant () locus using adeno-associated viruses for gene transfer was demonstrated, and these CD19-CAR T cells showed improved functionality over their retrovirally transduced counterparts.

The scope and severity of white-nose syndrome on hibernating bats in North America.

Assessing the scope and severity of threats is necessary for evaluating impacts on populations to inform conservation planning. Quantitative threat assessment often requires monitoring programs that provide reliable data over relevant spatial and temporal scales, yet such programs can be difficult to justify until there is an apparent stressor. Leveraging efforts of wildlife management agencies to record winter counts of hibernating bats, we collated data for 5 species from over 200 sites across 27 U.

Structure-Based Drug Design and Synthesis of PI3Kα-Selective Inhibitor (PF-06843195).

The phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway is a frequently dysregulated pathway in human cancer, and PI3Kα is one of the most frequently mutated kinases in human cancer. A PI3Kα-selective inhibitor may provide the opportunity to spare patients the side effects associated with broader inhibition of the class I PI3K family. Here, we describe our efforts to discover a PI3Kα-selective inhibitor by applying structure-based drug design (SBDD) and computational analysis.

Characterizing and Controlling Nanoscale Self-Assembly of Suckerin-12.

Structural proteins such as "suckerins" present promising avenues for fabricating functional materials. Suckerins are a family of naturally occurring block copolymer-type proteins that comprise the sucker ring teeth of cephalopods and are known to self-assemble into supramolecular networks of nanoconfined β-sheets. Here, we report the characterization and controllable, nanoscale self-assembly of suckerin-12 (S12).

Not so robust: Robusta coffee production is highly sensitive to temperature.

Coffea canephora (robusta coffee) is the most heat-tolerant and 'robust' coffee species and therefore considered more resistant to climate change than other types of coffee production. However, the optimum production range of robusta has never been quantified, with current estimates of its optimal mean annual temperature range (22-30°C) based solely on the climatic conditions of its native range in the Congo basin, Central Africa. Using 10 years of yield observations from 798 farms across South East Asia coupled with high-resolution precipitation and temperature data, we used hierarchical Bayesian modeling to quantify robusta's optimal temperature range for production.

A gatekeeping function of the replicative polymerase controls pathway choice in the resolution of lesion-stalled replisomes.

DNA lesions stall the replisome and proper resolution of these obstructions is critical for genome stability. Replisomes can directly replicate past a lesion by error-prone translesion synthesis. Alternatively, replisomes can reprime DNA synthesis downstream of the lesion, creating a single-stranded DNA gap that is repaired primarily in an error-free, homology-directed manner.

Target engagement approaches for pharmacological evaluation in animal models.

The field of chemical biology has introduced several approaches, typically using chemical probes, to measure the direct binding interaction of a small molecule with its biological target in cells. The use of these direct target engagement assays in pharmaceutical development can support mechanism of action hypothesis testing, rank ordering of compounds, and iterative improvements of chemical matter. This Feature Article highlights a newer application of these approaches: the quantification of target engagement in animal models to support late stage preclinical development and the nomination of a drug candidate to clinical trials.