julilili42/papers huggingface dataset:
Autologous T cell therapy for PRAME+ advanced solid tumors in HLA-A*02+ patients: a phase 1 trial
2025-04-09

In contrast to chimeric antigen receptor T cells, T cell receptor (TCR)-engineered T cells can target intracellular tumor-associated antigens crucial for treating solid tumors. However, most trials published so far show limited clinical activity. Here we report interim data from a first-in-human, multicenter, open-label, 3 + 3 dose-escalation/de-escalation phase 1 trial studying IMA203, an autologous preferentially expressed antigen in melanoma (PRAME)-directed TCR T cell therapy in HLA-A*02<sup>+</sup> patients with PRAME<sup>+</sup> recurrent and/or refractory solid tumors, including melanoma and sarcoma. Primary objectives include the evaluation of safety and tolerability and the determination of the maximum tolerated dose (MTD) and/or recommended dose for extension. Secondary objectives include the evaluation of IMA203 TCR-engineered T cell persistence in peripheral blood, tumor response as well as duration of response. A total of 27 patients were enrolled in the phase 1a dose escalation and 13 patients in the phase 1b dose extension. IMA203 T cells were safe, and the MTD was not reached. Of the 41 patients receiving treatment (that is, who started lymphodepletion), severe cytokine release syndrome was observed in 4.9% (2/41), and severe neurotoxicity did not occur. In the 40 patients treated with IMA203, an overall response rate consisting of patients with unconfirmed or confirmed response (u/cORR) of 52.5% (21/40) and a cORR of 28.9% (11/38) was observed with a median duration of response of 4.4 months (range, 2.4-23.0, 95% confidence interval: 2.6-not reached) across multiple indications. Rapid T cell engraftment and long-term persistence of IMA203 T cells were observed. IMA203 T cells trafficked to all organs, and confirmed responses were more frequent in patients with higher dose. T cell exhaustion was not observed in the periphery; deep responses were enriched at higher PRAME expression; and higher T cell infiltration resulted in longer progression-free survival. Overall, IMA203 showed promising anti-tumor activity in multiple solid tumors, including refractory melanoma. ClinicalTrials.gov identifier: NCT03686124 .
An unsupervised map of excitatory neuron dendritic morphology in the mouse visual cortex
2025-04-09

Abstract Neurons in the neocortex exhibit astonishing morphological diversity, which is critical for properly wiring neural circuits and giving neurons their functional properties. However, the organizational principles underlying this morphological diversity remain an open question. Here, we took a data-driven approach using graph-based machine learning methods to obtain a low-dimensional morphological “bar code” describing more than 30,000 excitatory neurons in mouse visual areas V1, AL, and RL that were reconstructed from the millimeter scale MICrONS serial-section electron microscopy volume. Contrary to previous classifications into discrete morphological types (m-types), our data-driven approach suggests that the morphological landscape of cortical excitatory neurons is better described as a continuum, with a few notable exceptions in layers 5 and 6. Dendritic morphologies in layers 2–3 exhibited a trend towards a decreasing width of the dendritic arbor and a smaller tuft with increasing cortical depth. Inter-area differences were most evident in layer 4, where V1 contained more atufted neurons than higher visual areas. Moreover, we discovered neurons in V1 on the border to layer 5, which avoided deeper layers with their dendrites. In summary, we suggest that excitatory neurons’ morphological diversity is better understood by considering axes of variation than using distinct m-types.
MyoGestic: EMG interfacing framework for decoding multiple spared motor dimensions in individuals with neural lesions
2025-04-09

Restoring motor function in individuals with spinal cord injuries (SCIs), strokes, or amputations is a crucial challenge. Recent studies show that spared motor neurons can still be voluntarily controlled using surface electromyography (EMG), even without visible movement. To harness these signals, we developed a wireless, high-density EMG bracelet and a software framework, MyoGestic. Our system enables rapid adaptation of machine learning models to users’ needs, allowing real-time decoding of spared motor dimensions. In our study, we successfully decoded motor intent from two participants with traumatic SCI, two with spinal stroke, and three with amputations in real time, achieving multiple controllable motor dimensions within minutes. The decoded neural signals could control a digitally rendered hand, an orthosis, a prosthesis, or a two-dimensional cursor. MyoGestic’s participant-centered approach allows a collaborative and iterative development of myocontrol algorithms, bridging the gap between researcher and participant, to advance intuitive EMG interfaces for neural lesions.
The Simple Essence of Monomorphization
2025-04-09

Monomorphization is a common implementation technique for parametric type-polymorphism, which avoids the potential runtime overhead of uniform representations at the cost of code duplication. While important as a folklore implementation technique, there is a lack of general formal treatments in the published literature. Moreover, it is commonly believed to be incompatible with higher-rank polymorphism. In this paper, we formally present a simple monomorphization technique based on a type-based flow analysis that generalizes to programs with higher-rank types, existential types, and arbitrary combinations. Inspired by algebraic subtyping, we track the flow of type instantiations through the program. Our approach only supports monomorphization up to polymorphic recursion, which we uniformly detect as cyclic flow. Treating universal and existential quantification uniformly, we identify a novel form of polymorphic recursion in the presence of existential types, which we coin polymorphic packing. We study the meta-theory of our approach, showing that our translation is type-preserving and preserves semantics step-wise.
Look What You Made Me Do: Discerning Feature for Classification of Endocrine-Disrupting Chemical Binding to Steroid Hormone Receptors
2025-04-09

Exposure to metabolism-disrupting chemicals, which are a specific type of endocrine-disrupting chemical (EDC), is linked to metabolic problems such as dyslipidemia, insulin resistance, and hepatic steatosis. Steroid hormone receptors (SHRs) within the nuclear receptor superfamily are well-known targets for EDCs in reproductive tissues and, to a lesser extent, in liver. In this study, we investigated how five well-established SHR ligands and eight EDCs including pesticides, plasticizers, pharmaceuticals, flame retardants, industrial chemicals, and their metabolites affect estrogen (ERα in reproductive tissues) and glucocorticoid (GR in liver) receptors. We investigated the utility of structural molecular modeling to classify EDC binding to ERα and GR. To this end, we modeled a set of EDC binding to ER and GR using unbiased all-atom long-time scale molecular dynamics (MD) simulations and compared them against known established SHR agonists and antagonists. We systematically evaluated MD-derived variables such as protein-ligand interactions and binding energy, folding secondary structure elements, distances, and angles as relevant parameters. Our findings suggest that the well-established H12 folding and conformational angles can be discerning features for binding of EDCs to SHRs. Although SHR activation often involves changes in H12 folding and geometry, GR displayed less flexibility in this region, suggesting that protein-ligand interaction and binding energy are more relevant for its classification. We show that MD simulations combined with experimental assays can be a useful tool for studying novel EDCs by providing relevant structural features for their classification.
Compiling Classical Sequent Calculus to Stock Hardware: The Duality of Compilation
2025-04-09

Compiler intermediate representations have to strike a balance between being high-level enough to allow for easy translation of surface languages into them and being low-level enough to make code generation easy. An intermediate representation based on a logical system typically has the former property and additionally satisfies several meta-theoretical properties which are valuable when optimizing code. Recently, classical sequent calculus, which is widely recognized and impactful within the fields of logic and proof theory, has been proposed as a natural candidate in this regard, due to its symmetric treatment of data and control flow. For such a language to be useful, however, it must eventually be compiled to machine code. In this paper, we introduce an intermediate representation that is based on classical sequent calculus and demonstrate that this language can be directly translated to conventional hardware. We provide both a formal description and an implementation. Preliminary performance evaluations indicate that our approach is viable.
The TetR-like regulator Sco4385 and Crp-like regulator Sco3571 modulate heterologous production of antibiotics in Streptomyces coelicolor M512
2025-04-09

ABSTRACT Heterologous expression in well-studied model strains is a routinely applied method to investigate biosynthetic pathways. Here, we pursue a comparative approach of large-scale DNA-affinity-capturing assays (DACAs) coupled with semi-quantitative mass spectrometry (MS) to identify putative regulatory proteins from Streptomyces coelicolor M512, which bind to the heterologously expressed biosynthetic gene clusters (BGCs) of the liponucleoside antibiotics caprazamycin and liposidomycin. Both gene clusters share an almost identical genetic arrangement, including the location of promoter regions, as detected by RNA sequencing. A total of 2,214 proteins were trapped at the predicted promoter regions, with only three binding to corresponding promoters in both gene clusters. Among these, the overexpression of a yet uncharacterized TetR-family regulator (TFR), Sco4385, increased caprazamycin but not liposidomycin production. Protein–DNA interaction experiments using biolayer interferometry confirmed the binding of Sco4385 to P cpz10 and P lpmH at different locations within both promoter regions, which might explain its functional variance. Sequence alignment allowed the determination of a consensus sequence present in both promoter regions, to which Sco4385 was experimentally shown to bind. Furthermore, we found that the overexpression of the Crp regulator, Sco3571, leads to a threefold increase in caprazamycin and liposidomycin production yields, possibly due to an increased expression of a precursor pathway. IMPORTANCE Streptomycetes are well-studied model organisms for the biosynthesis of pharmaceutically, industrially, and biotechnologically valuable metabolites. Their naturally broad repertoire of natural products can be further exploited by heterologous expression of biosynthetic gene clusters (BGCs) in non-native host strains. This approach forces the host to adapt to a new regulatory and metabolic environment. In our study, we demonstrate that a host regulator not only interacts with newly incorporated gene clusters but also regulates precursor supply for the produced compounds. We present a comprehensive study of regulatory proteins that interact with two genetically similar gene clusters for the biosynthesis of liponucleoside antibiotics. Thereby, we identified regulators of the heterologous host that influence the production of the corresponding antibiotic. Surprisingly, the regulatory interaction is highly specific for each biosynthetic gene cluster, even though they encode largely structurally similar metabolites.
An informed deep learning model of the Omicron wave and the impact of vaccination
2025-04-09

The Omicron (B.1.1.529) variant of SARS-CoV-2 emerged in November 2021 and has since evolved into multiple lineages. Understanding its transmission, vaccine efficacy, and potential for reinfection is crucial. This study examines the dynamics of Omicron in Germany, France, and Italy by employing Physics-Informed Neural Networks to estimate the temporal parameters influencing its spread. We validated the performance of our model using the Root Mean Squared Percent Error (RMSPE). Our analysis revealed significant correlations between specific viral mutations-S371F, T376A, D405N, and R408S-and increased transmission rates in all three countries. These mutations, prevalent in the Omicron BA.2 and BA.3 sublineages, are linked to immune evasion and heightened transmissibility.
Evaluating Pre-Interventional Administration of a Liver-Specific Contrast Agent During MRI-Guided Thermal Ablation of Malignant Liver Lesions
2025-04-09

Background/Objectives: Hepatocyte-specific contrast agent (Gd-EOB-DTPA) can improve the detection of liver lesions during MRI-guided thermal ablation. This study aimed to assess the impact of contrast agent administration on the delineation of the ablation zone during therapy monitoring. Methods: From 2010 to 2020, 358 patients with primary and secondary hepatic malignancies underwent MRI-guided thermoablation. A total of 27 patients with 30 liver lesions received Gd-EOB-DTPA during the procedure to improve target lesion visibility (Group 1), while 30 patients with 30 lesions underwent MRI-guided thermoablation without contrast administration (Group 2). T1-weighted volumetric interpolated breath-hold examination (VIBE) sequences were used for intraprocedural imaging, and post-procedural control imaging involved intravenous Gadobutrol administration in both groups. The contrast-to-noise ratio (CNR) was assessed for three key structures: the target lesion before applicator placement, the ablation zone during unenhanced therapy monitoring, and the ablation zone in contrast-enhanced control imaging. A statistical comparison of CNR values between the two groups was performed using the non-parametric Wilcoxon test (p &lt; 0.05). Results: The CNR of lesions in group 1 significantly increased following the administration of Gd-EOB-DTPA. During therapy monitoring, the ablation zone in group 2 exhibited a significantly higher CNR compared to group 1 (median: 7.9 vs. 2.1; p &lt; 0.001). Similarly, at the contrast-enhanced final control, the CNR of the ablation zone remained significantly greater in group 2 than in group 1 (median: 7.7 vs. 2.0; p &lt; 0.001). Conclusions: The administration of a hepatocyte-specific contrast agent (Gd-EOB-DTPA) prior to intervention improves the visualization of liver lesions that are poorly demarcated but significantly reduces the contrast of the ablation zone during intra- and post-procedural imaging. Therefore, its use should be reserved for cases in which the target lesion cannot be sufficiently delineated without contrast.
Returners and New Arrivals After the Crash: Intermediate Hosts and Global Invaders Dominate Gastropod Fauna of Lake Naivasha, Kenya
2025-04-09

Aquatic alien species (AAS) have had a major impact on freshwater ecosystems, including Lake Naivasha in Kenya. Here, the ecosystem has undergone tremendous changes and multiple species introductions over the past 100 years, and molluscs have experienced a major decline in species diversity. The East African Rift Lakes have experienced a steady rise in lake levels since 2010. We investigated the impact of recent ecosystem changes on the lakes’ molluscs by determining the current mollusc diversity and its composition. We also reconstruct the history of faunal change and turnover over the last 100 years and discuss the future of molluscs in the lake and the implications in a One Health context. The combined effects of rising water levels and the decline of the crayfish Procambarus clarkii are likely to be responsible for the resurgence of Lake Naivasha’s mollusc fauna. The current fauna consists of three global invaders of American origin, one of which is new to East Africa (Pseudosuccinea columella) and another of which has only recently begun to spread (Pomacea canaliculata). A further three species are native to Africa, two of which are known from historical records, while one is new to Lake Naivasha (Bulinus forskalii). All native species are of public health (Biomphalaria sudanica) and veterinary health (Bulinus tropicus, Bulinus forskalii) concern. The current biodiversity of molluscs has reached the same level as in historical times, but the species composition is remarkably different.
Second trimester soft markers: still worth to be mentioned?
2025-04-09

Despite the widespread use of cell-free DNA in screening for trisomy 21, soft markers continue to be assessed in the second trimester, leading to confusion about how they affect the risk of trisomy 21, especially after an earlier screening test such as cell-free DNA screening. In this review, we provide an overview of commonly used second trimester soft markers, explain how they can be used to calculate the risk for trisomy 21, and discuss what other chromosomal or structural abnormalities might be associated with these markers. We especially focus on pathogenic copy number variants as these, in aggregate, are common and are very difficult to detect using cfDNA or even standard karyotyping.
Designer tetrazine probes for chemical labeling of isocyanide-containing natural products
2025-04-09

The identification of novel antibacterial natural products (NPs) is paramount in confronting the global threat of antimicrobial resistance. New NPs with novel core structures and mechanisms of action (MoA) have become significantly more difficult to discover, as modern methods remain largely similar to those employed for decades. An alternative approach to classical bioactivity-guided isolation of NPs is chemical reactivity-guided isolation of NPs. Here, the reactivity of isocyanides with tetrazines via a [4+1] click reaction was exploited to establish a protocol for the detection and isolation of novel isocyanide-containing NPs using carefully designed tetrazine-based probes and contemporary metabolomics methods. Notably, these chemical probes can be used for the direct detection and isolation of primary, secondary, and tertiary isocyanides. Proof-of-concept was achieved, with the help of genome-mining, through the discovery of hazimycin in Kitasatospora purpeofusca. For this underexplored antibacterial agent, we further report on the biosynthesis, total synthesis, structure-activity relationship, metal-binding properties and antibacterial mechanism.
The Outcome of Cell Therapy Treating Urinary Incontinence Correlates with Precise Cell Localization in the Sphincter Complex
2025-04-09

Background/Objectives: Urethral sphincter muscle deficiency is the leading cause of stress urinary incontinence. Preclinical and clinical studies suggested that cell therapy may improve the situation. However, the overall efficacy of cell therapies did often not satisfy the patient’s needs. We, therefore, investigated in a large animal model of incontinence if the localization of injected regenerative cells in the deficient urethral sphincter muscle correlated with the outcome. Methods: Urethral sphincter insufficiency was induced in three cohorts of pigs and confirmed by urodynamics. Then, either myogenic progenitor cells (MPCs) or adipose tissue-derived stromal cells (ADSCs) were injected into the injured sphincter complex by Williams needle under visual using a cystoscope. Sham-treated animals served as controls. Functional sphincter muscle regeneration was monitored by urodynamics over 5 weeks of follow-up. The localization of the injected cells was investigated by histology of cryosections of the tissue targeted. Results: Injection of MPCs near the sphincter muscle yielded better functional recovery when compared to MPC injections in adjacent sides. By contrast, injection of ADSCs in the submucosal tissue adjacent to the muscle led to better regeneration when compared to ADSC injections into the sphincter muscle. After five weeks of follow-up, MPCs yielded an overall robust but not significant improvement when compared to mock-treated controls, while ADSC injections reached significance. Conclusions: This small proof-of-principle study suggests that the clinical outcome of cell therapy for urinary incontinence depends on the choice of therapeutic cells and the precise localization of the cells in the tissue targeted as well.
Physical Contact between Bacteria and Carbonaceous Materials: The Key Switch Triggering Activated Carbon and Biochar to Promote Microbial Iron Reduction
2025-04-10

Carbonaceous materials, including activated carbon and pyrolytic carbon, have been recognized for about over a decade as effective electron shuttles or conductive materials in promoting microbial Fe(III) mineral reduction. However, recent studies reveal inhibitory effects, sparking debates about their overall impact. We hypothesized that the physical contact between bacteria and carbon is an overlooked yet critical factor in determining whether carbon promotes or inhibits microbial Fe(III) reduction. Using systems containing <i>Shewanella oneidensis</i> MR-1, activated carbon, and ferrihydrite, we investigated how carbon-iron oxide aggregate structure affects Fe(III) reduction kinetics. At low activated carbon-to-iron oxide ratios (C/Fe = 5:7 by mass), ferrihydrite aggregated with carbon, forming carbon-encapsulated particles that suppressed Fe(III) reduction rates. Conversely, at higher ratios (C/Fe = 100:7), the ferrihydrite dispersed on the carbon surface, enhancing both the rate and extent of Fe(III) reduction. Tests with 11 different carbonaceous materials (activated carbon and biochar) all confirmed that the microstructure of iron oxides─whether encapsulating or dispersed─on carbon surfaces is critical for determining Fe(III) reduction rates. This insight resolves the debate on whether carbonaceous materials promote or inhibit Fe(III) mineral reduction and enhances our understanding of their roles in biogeochemical processes and environmental remediation.
Pre-trained molecular representations enable antimicrobial discovery
2025-04-10

Abstract The rise in antimicrobial resistance poses a worldwide threat, reducing the efficacy of common antibiotics. Determining the antimicrobial activity of new chemical compounds through experimental methods remains time-consuming and costly. While compound-centric deep learning models promise to accelerate this search and prioritization process, current strategies require large amounts of custom training data. Here, we introduce a lightweight computational strategy for antimicrobial discovery that builds on MolE (Molecular representation through redundancy reduced Embedding), a self-supervised deep learning framework that leverages unlabeled chemical structures to learn task-independent molecular representations. By combining MolE representation learning with available, experimentally validated compound-bacteria activity data, we design a general predictive model that enables assessing compounds with respect to their antimicrobial potential. Our model correctly identifies recent growth-inhibitory compounds that are structurally distinct from current antibiotics. Using this approach, we discover de novo, and experimentally confirm, three human-targeted drugs as growth inhibitors of Staphylococcus aureus . This framework offers a viable, cost-effective strategy to accelerate antibiotic discovery.