Miracle-dz/UniFAR-FTUs huggingface dataset:
PTPRZ1-targeting RNA CAR-T cells exert antigen-specific and bystander antitumor activity in glioblastoma

The great success of chimeric antigen receptor (CAR)-T cell therapy in B-cell malignancies has prompted its translation to solid tumors. In the case of glioblastoma (GBM), clinical trials have shown modest efficacy, but anti-GBM CAR-T cells are being intensely developed. In this study, we selected PTPRZ1 as an attractive new target for GBM treatment. We isolated six anti-human PTPRZ1 scFv from a human phage display library and produced 2nd generation CAR-T cells in an RNA format. Patient-derived GBM PTPRZ1-knock-in cell lines were used to select the CAR construct (471_28z), which showed high cytotoxicity while consistently displaying high CAR expression. CAR-T cells incorporating 471_28z were able to release IFN-γ, IL-2, TNF-α, Granzyme B, IL-17A, IL-6, and soluble FasL, and displayed low tonic signaling. Additionally, they maintained an effector memory phenotype after in vitro killing. Importantly, 471_28z CAR-T cells displayed strong bystander killing against PTPRZ1-negative cell lines after pre-activation by PTPRZ1-positive tumor cells, but did not kill antigen-negative non-tumor cells. In an orthotopic xenograft tumor model using NSG mice, a single dose of anti-PTPRZ1 CAR-T cells significantly delayed tumor growth. Taken together, these results validate the use of PTPRZ1 as a new GBM target and prompt the use of anti-PTPRZ1 CAR-T cells for clinical translation.
The expression of congenital Shoc2 variants induces AKT-dependent feedback activation of the ERK1/2 pathway

The Shoc2 scaffold protein is crucial in transmitting signals within the Epidermal Growth Factor Receptor (EGFR)-mediated Extracellular signal-regulated Kinase (ERK1/2) pathway. While the significance of Shoc2 in this pathway is well-established, the precise mechanisms through which Shoc2 governs signal transmission remain to be fully elucidated. Hereditary mutations in Shoc2 are responsible for Noonan Syndrome with Loose anagen Hair (NSLH). However, due to the absence of known enzymatic activity in Shoc2, directly assessing how these mutations affect its function is challenging. ERK1/2 phosphorylation is used as a primary parameter of Shoc2 function, but the impact of Shoc2 mutants on the pathway activation is unclear. This study investigates how the NSLH-associated Shoc2 variants influence EGFR signals in the context of the ERK1/2 and AKT downstream signaling pathways. We show that when the ERK1/2 pathway is a primary signaling pathway activated downstream of EGFR, Shoc2 variants cannot upregulate ERK1/2 phosphorylation to the level of the WT Shoc2. Yet, when the AKT and ERK1/2 pathways were activated, in cells expressing Shoc2 variants, ERK1/2 phosphorylation was higher than in cells expressing WT Shoc2. We found that, in cells expressing the Shoc2 NSLH mutants, the AKT signaling pathway triggers the PAK activation, followed by phosphorylation and Raf-1/MEK1/2 /ERK1/2 signaling axis activation. Hence, our studies reveal a previously unrecognized feedback regulation downstream of the EGFR and provide evidence for the Shoc2 role as a “gatekeeper” in controlling the selection of downstream effectors within the EGFR signaling network.
Unsupervised mapping of causal relations between brain and behavior

Studies of patients with focal brain lesions provided the historical foundation for cognitive neuroscience, but how to identify a precise mapping between specific brain regions and the cognitive variables affected remains unclear. The challenge lies both in identifying anatomical regions wherein lesions have a shared causal effect, as well as in the precise delineation of the behavioral outcome. Currently, either the relevant brain region or the dimensionality of the behavior being mapped are pre-specified by the investigators rather than both being informed by optimal brain-behavior relationships. Here we apply a novel data-driven causal aggregation algorithm, Causal Feature Learning (CFL) to tackle this challenge in 520 individuals with focal brain lesions. CFL simultaneously constructs macro-level summaries of the spatial distribution of brain lesions and the itemized responses on psychometric tests to optimally characterize the causal brain-behavior relationships. Focusing on the domains of language, visuospatial ability, and depression, we recapitulate established findings, provide new and more precise anatomical results, and present an aggregation of item-wise data that provides an empirical test of extant behavioral scores and can be used to identify novel, psychologically meaningful factors. Future work could use our approach to construct entirely new psychometric variables that might cut across established categories.
Evolution of Multicellularity Genes in the Lead Up to the Great Oxidation Event

Cyanobacteria are among the most morphologically diverse prokaryotic phyla on Earth. Their morphotypes range from unicellular to multicellular filaments, yet mechanisms underlying the evolution of filamentous morphologies remain unknown. Here, we implement phylogenomic, Bayesian molecular clock and gene-tree-species-tree reconciliation analyses to estimate when genes encoding cell-cell joining structures first evolved. We also characterise septal structures and measure intercellular communication rates in non-model and early-branching filamentous strains. Our results suggest that genes encoding septal proteins (namely sepJ, sepI, and fraE) and potentially pattern formation (hetR) evolved in the Neoarchaean ∼2.6-2.7 billion years (Ga) ago. Later, at the start of the Great Oxygenation Event ∼2.5 Ga, genes involved in cellular differentiation (namely hetZ, patU3 and hglK) appeared. Our results predict that early-branching lineages like Pseudanabaena were capable of intercellular communication, but further innovations in cellular differentiation were needed to drive ecological expansion on a scale large enough to permanently oxygenate Earth’s atmosphere.
Presenilin-dependent regulation of tau pathology via the autophagy/proteasome pathway

Autosomal dominant inherited mutations in the presenilin (PS/PSEN) genes cause early-onset familial Alzheimer’s disease (AD) by enhancing cerebral accumulation of amyloid-β (Aβ) and microtubule-associated protein tau, although the precise cellular mechanisms by which PS dysfunction drives neuronal tau pathology remain still unclear. Here, we investigated the mechanisms linking PS/γ-secretase-dependent tau pathology and autophagy by using molecular, imaging and pathological approaches in brains, fibroblasts and induced pluripotent stem cells (iPSCs)-derived neurons from mutant PSEN1 carriers, as well as in a novel tauopathy mouse model lacking PS in glutamatergic neurons. We found colocalization of phosphorylated tau with the autophagy marker p62 in the hippocampus of tauopathy patients with PSEN1 mutations, corticobasal degeneration and Pick’s disease. Remarkably, disrupted autophagic clearance of pathological tau was evidenced by increased autophagy markers and accumulation of total and AD-associated phosphorylated tau species (pTau 181, 202, 217) in hippocampal lysates and autophagosomes of familial AD-linked PSEN1 patients and PS-deficient tau transgenic mice. Human iPSC-derived neurons harboring the familial AD-linked PSEN1 G206D mutation are less sensitive to autophagy inhibition, reduce tau release and accumulate intracellular tau oligomers. Human primary fibroblasts from PSEN1 G206D and/or L286P carriers show elevated LC3 and autolysosomes indicating that these familial AD-linked PSEN1 mutations disrupt autophagy flux. PS is required for efficient autophagy-mediated tau degradation in neurons through a dual mechanism involving autophagy induction via blockage of Akt/PRAS40-dependent mTORC1 activation and promoting autophagosome/lysosome fusion. Surprisingly, pharmacological proteasome inhibition decreases tau accumulation in neurons by promoting tau release through a mechanism that requires functional PS. In conclusion, PS is required for autophagy/proteasome-mediated tau elimination in neurons, while familial AD-linked PSEN mutations cause progressive tau pathology by disrupting autophagy. These findings may impact on the development of new therapeutic targets for tauopathy dementias.
Switching perspective: Comparing ground-level and bird’s-eye views for bees navigating clutter

Animals navigating in three dimensions encounter different perspectives of their world, often transitioning from bird’s eye views at higher altitudes to frog’s-eye views closer to the ground. How they integrate this information to pinpoint a goal location is virtually unknown. Here we tested the ability of bumblebees to use both types of views when homing in a cluttered environment. While prior research emphasised ground-level cues, recent evidence suggests bees incorporate bird’s-eye perspectives at higher altitudes for long-distance navigation. This raises the question of whether bird’s-eye views also aid local homing, especially in environments where nest entrances are concealed by undergrowth. Our combined modelling and experimental approach examined various views for goal location in cluttered settings. Whereas, bird’s-eye views performed best in simulations of current snapshot homing models, behavioural experiments revealed that bumblebees predominantly relied on frog’s eye views when pinpointing nest entrances in cluttered environments. These findings reveal the limitations of snapshot-homing models and suggest that bumblebees use a mix of navigational tools to successfully find their way home in cluttered environments. This is not only relevant for understanding bee movements, but also for other animals and humans navigating in 3D as well as the development of technologies inspired by natural systems, such as autonomous flying robots. Significance statement Navigation in three dimensions is essential for animals especially for those that swim or fly, like fish, birds, or bees. Moving at different altitudes relative to the destination, animals undergo a range of perspectives, transitioning from aerial, bird’s eye views to goal-level perspectives as they approach their goal. We investigated if bumblebees utilise both perspectives when homing in cluttered environments. While past studies focused on ground-level cues, recent findings suggest bees incorporate bird’s-eye views for long-distance navigation. Our study explores whether these views also aid local homing, particularly for visually concealed goals. The results challenge existing models, revealing that bumblebees employ a combination of navigational strategies in cluttered settings, impacting our understanding of 3D navigation in animals and technology development.
Harnessing Bilayer Biomaterial Delivery of FTY720 as an Immunotherapy to Accelerate Oral Wound Healing

Orofacial clefts are the most common craniofacial congenital anomaly. Following cleft palate repair, up to 60% of surgeries have wound healing complications leading to oronasal fistula (ONF), a persistent connection between the roof of the mouth and the nasal cavity. The current gold standard methods for ONF repair use human allograft tissues; however, these procedures have risks of graft infection and/or rejection, requiring surgical revisions. Immunoregenerative therapies present a novel alternative approach to harness the body’s immune response and enhance the wound healing environment. We utilized a repurposed FDA-approved immunomodulatory drug, FTY720, to reduce the egress of lymphocytes and induce immune cell fate switching toward pro-regenerative phenotypes. Here, we engineered a bilayer biomaterial system using Tegaderm™, a liquid-impermeable wound dressing, to secure and control the delivery of FTY720- nanofiber scaffolds (FTY720-NF). We optimized release kinetics of the bilayer FTY720-NF to sustain drug release for up to 7d with safe, efficacious transdermal absorption and tissue biodistribution. Through comprehensive immunophenotyping, our results illustrate a pseudotime pro-regenerative state transition in recruited hybrid immune cells to the wound site. Additional histological assessments established a significant difference in full thickness ONF closure in mice on Day 7 following treatment with bilayer FTY720-NF, compared to controls. These findings demonstrate the utility of immunomodulatory strategies for oral wound healing, better positing the field to develop more efficacious treatment options for pediatric patients. One Sentence Summary Local delivery of bilayer FTY720-nanofiber scaffolds in an ONF mouse model promotes complete wound closure through modulation of pro-regenerative immune and stromal cells.
When Culture Matters : Frame Resonance and Protests against Femicide in Ciudad Juarez , Mexico Chelsea Starr

Framing theory in social movements is an analytical tool for examining the symbols, slogans, and underlying messages that provide the public with a way to interpret, or frame, a movement resonant with the host culture. The questions I pursue: Looking at how frame resonance varies between movements on the same issue, is there a difference in the movement’s success and failures based on use of different frames? Do frames matter? Using qualitative content analysis as a method and framing theory as an analytical perspective to guide the method, I examine the frames of five movement organizations protesting femicide in Ciudad Juarez, Mexico. Multiple datasets were triangulated to provide greater qualitative validity, along with a coding strategy that utilized grounded theory to allow for maximum control of coder bias. Organizations using frames with lower cultural resonance did not have success on the scale of the organization that used resonant frames, and in some cases caused conflict between local and international anti-femicide movements operating in Ciudad Juarez.
Acclimation Capacity to Global Warming of Amphibians and Freshwater Fishes: Drivers, Patterns, and Data Limitations

Amphibians and fishes play a central role in shaping the structure and function of freshwater environments. These organisms have a limited capacity to disperse across different habitats and the thermal buffer offered by freshwater systems is small. Understanding determinants and patterns of their physiological sensitivity across life history is, therefore, imperative to predicting the impacts of climate change in freshwater systems. Based on a systematic literature review including 345 studies with 998 estimates on 96 amphibian and 93 freshwater fish species, we conducted a meta-analysis to explore phylogenetic, ontogenetic, and biogeographic (i.e. thermal adaptation) patterns in upper thermal tolerance (CTmax) and thermal acclimation capacity (Acclimation Response Ratio, ARR) as well as the influence of the methodology used to assess these thermal traits using a conditional inference tree analysis. We found CTmax and ARR differed between taxa, pre- and post-metamorphic life stages as well as with thermal adaptation. The ARR of freshwater fishes exceeded that of amphibians by more than twice across life stages. In amphibians, CTmax decreased throughout early development, with juveniles exhibiting the lowest heat tolerance, potentially representing a life history bottleneck if other strategies to reach thermal refugia, e.g. through behavioral thermoregulation, would also be constrained. In contrast to the broader literature, CTmax was not generally higher in low latitude populations but also varied with ontogeny, emphasizing the importance of assessing life stage- specific sensitivity to thermal stress. Importantly, the application of different methods (e.g. acclimation duration, ramping rates) changed life stage, phylogeny, and thermal adaptation patterns in CTmax and ARR. Our analyses highlight biases and data limitations with respect to coverage in taxonomy, biogeographic distribution of species, life stage, and study design. We propose methods to improve robustness and comparability of thermal sensitivity knowledge needed to adopt interventions to safeguard freshwater biodiversity in a future climate.
Analysis of the Geoelectric Field in Sweden Over Solar Cycles 23 and 24: Spatial and Temporal Variability During Strong GIC Events

Geomagnetic storms can produce large perturbations on the Earth magnetic field. Through complex magnetosphere‐ionosphere coupling, the geoelectric field (E) and geomagnetic field (B) are highly perturbed. The E is the physical driver of geomagnetically induced currents. However, a statistical study of the E in Sweden has never been done before. We combined geomagnetic data from the International Monitor for Auroral Geomagnetic Effects network in Northern Europe with a 3‐D structure of Earth's electrical conductivity in Sweden as the input of a 1‐D model to compute the E between 2000 and 2018. Northwestern Sweden presents statistically larger E magnitudes due to larger |dB/dt| variations in the north than in the south of Sweden and relative lower conductivity in the west compared to central and eastern Sweden. In contrast, the 15 strongest daily maximum |E| events present more frequently a maximum magnitude in central Sweden (62.25°N) and their relative strengths are not the same for all latitudes. These results highlight the different regional response to geomagnetic storms, which can be related to ground conductivity variability and the complex magnetosphere‐ionosphere coupling mechanisms.
Colon Cancer Cells Evade Drug Action by Enhancing Drug Metabolism

Colorectal cancer (CRC) is the second most deadly cancer worldwide. One key reason is the failure of therapies that target RAS proteins, which represent approximately 40% of CRC cases. Despite the recent discovery of multiple alternative signalling pathways that contribute to resistance, durable therapies remain an unmet need. Here, we use liquid chromatography/ mass spectrometry (LC/MS) analyses on Drosophila CRC tumour models to identify multiple metabolites in the glucuronidation pathway—a toxin clearance pathway—as upregulated in trametinib-resistant RAS/APC/P53 (“RAP”) tumours compared to trametinib-sensitive RASG12V tumours. Elevating glucuronidation was sufficient to direct trametinib resistance in RASG12Vanimals while, conversely, inhibiting different steps along the glucuronidation pathway strongly reversed RAP resistance to trametinib. For example, blocking an initial HDAC1-mediated deacetylation step with the FDA-approved drug vorinostat strongly suppressed trametinib resistance in Drosophila RAP tumours. We provide functional evidence that pairing oncogenic RAS with hyperactive WNT activity strongly elevates PI3K/AKT/GLUT signalling, which in turn directs elevated glucose and subsequent glucuronidation. Finally, we show that this mechanism of trametinib resistance is conserved in an KRAS/APC/TP53 mouse CRC tumour organoid model. Our observations demonstrate a key mechanism by which oncogenic RAS/WNT activity promotes increased drug clearance in CRC. The majority of targeted therapies are glucuronidated, and our results provide a specific path towards abrogating this resistance in clinical trials.s
Decoding Pain: Uncovering the Factors that Affect Performance of Neuroimaging-Based Pain Models

Neuroimaging-based pain biomarkers, when combined with machine learning techniques, have demonstrated potential in decoding pain intensity and diagnosing clinical pain conditions. However, a systematic evaluation of how different modeling options affect model performance remains unexplored. This study presents results from a comprehensive literature survey and benchmarking analysis. We conducted a survey of 57 previously published articles that included neuroimaging-based predictive modeling of pain, comparing classification and prediction performance based on the following modeling variables—the levels of data, spatial scales, idiographic vs. population models, and sample sizes. The findings revealed a preference for population-level modeling with brain-wide features, aligning with the goal of clinical translation of neuroimaging biomarkers. However, a systematic evaluation of the influence of different modeling options was hindered by a limited number of independent test results. This prompted us to conduct benchmarking analyses using a locally collected functional Magnetic Resonance Imaging (fMRI) dataset (N = 124) involving an experimental thermal pain task. The results clearly demonstrated that data levels, spatial scales, and sample sizes significantly impact model performance. Specifically, incorporating more pain-related brain regions, increasing sample sizes, and using less data averaging in training while increasing it in testing enhanced performance. These findings provide a useful reference for decision-making in the development of neuroimaging-based biomarkers, highlighting the importance of the careful selection of modeling strategies and options to build better-performing neuroimaging pain biomarkers. These findings offer useful guidance for developing neuroimaging-based biomarkers, underscoring the importance of strategic selection of modeling approaches to build better-performing neuroimaging pain biomarkers.
Distinct ancient structural polymorphisms control heterodichogamy in walnuts and hickories

The maintenance of stable mating type polymorphisms is a classic example of balancing selection, underlying the nearly ubiquitous 50/50 sex ratio in species with separate sexes. One lesser known but intriguing example of a balanced mating polymorphism in angiosperms is heterodichogamy – polymorphism for opposing directions of dichogamy (temporal separation of male and female function in hermaphrodites) within a flowering season. This mating system is common throughout Juglandaceae, the family that includes globally important and iconic nut and timber crops – walnuts (Juglans), as well as pecan and other hickories (Carya). In both genera, heterodichogamy is controlled by a single dominant allele. We fine-map the locus in each genus, and find two ancient (>50 Mya) structural variants involving different genes that both segregate as genus-wide trans-species polymorphisms. The Juglans locus maps to a ca. 20 kb structural variant adjacent to a probable trehalose phosphate phosphatase (TPPD-1), homologs of which regulate floral development in model systems. TPPD-1 is differentially expressed between morphs in developing male flowers, with increased allele-specific expression of the dominant haplotype copy. Across species, the dominant haplotype contains a tandem array of duplicated sequence motifs, part of which is an inverted copy of the TPPD-1 3’ UTR. These repeats generate various distinct small RNAs matching sequences within the 3’ UTR and further downstream. In contrast to the single-gene Juglans locus, the Carya heterodichogamy locus maps to a ca. 200-450 kb cluster of tightly linked polymorphisms across 20 genes, some of which have known roles in flowering and are differentially expressed between morphs in developing flowers. The dominant haplotype in pecan, which is nearly always heterozygous and appears to rarely recombine, shows markedly reduced genetic diversity and is over twice as long as its recessive counterpart due to accumulation of various types of transposable elements. We did not detect either genetic system in other heterodichogamous genera within Juglandaceae, suggesting that additional genetic systems for heterodichogamy may yet remain undiscovered.