julilili42/papers huggingface dataset:
Clinical Implementation of Pharmacogenomics and Drug–Drug Interaction Screening in a German Academic Teaching Hospital and Outpatient Follow‐Up
2025-10-11

Pharmacogenomics (PGx) helps to explain variability in drug response, including adverse drug reactions. Functional variants in genes affecting drug absorption, distribution, metabolism, and excretion (ADME) have been described. Despite PGx guidelines (e.g., CPIC and DPWG) enabling genotype‐guided drug and dose selection, preemptive implementation remains challenging due to various issues including standardized result communication and integration into electronic health record (EHR) systems. We implemented PGx testing as well as drug–drug interaction (DDI) screening in a German academic hospital and assessed their impact on physicians, general practitioners (GPs), and patients. A novel PGx workflow was established using a 60‐genetic variant panel. CPIC/DPWG guideline‐based PGx reports were integrated into the EHR system and provided as a mobile and web application for patients through a genetic information system. Medication profiles and questionnaires evaluated PGx‐based decisions 3 months post‐discharge. Among 255 patients, 95% had at least one actionable PGx variant, most commonly affecting statins, 5‐fluorouracil, irinotecan, and pantoprazole. Actionable recommendations were provided in 21.5%, with hospital physicians modifying treatment subsequently in 75.5%. We identified 57 clinically significant DDIs, including PGx drugs in 21%. GPs maintained optimized treatment in 77% of those patients with a medication change initiated during hospitalization. One in 10 patients discussed results with their GPs. GPs favored PGx for future prescriptions and requested training. We showed that preemptive PGx testing can be successfully implemented in a German hospital with high acceptance among physicians and GPs, and that PGx integration into the EHR supports broader adoption in precision medicine.
A POSSIBLE CONNECTION BETWEEN VERTICAL TRANSHUMANCE AND TEMPORARY PLAGUE RESERVOIRS DURING THE SECOND PLAGUE EPIDEMIC
2025-10-11

The Second Plague Pandemic (SPP) ravaged large parts of Eurasia and North Africa between the 14th and 19th centuries. Today, plague is still active in parts of Asia, Africa, and America. One of the hotly debated topics in plague studies is the geographic origins of the recurrent plague waves in Europe after the Black Death (1338-1353): Were they being repeatedly introduced from outside, or did they originate in domestic reservoirs? Here, we build upon recent work arguing for the existence of domestic reservoirs, by exploring a possibility that vertical transhumance by pastoralists could have been a conduit between temporary plague reservoirs and human population centers in Europe. We argue that aspects of pastoral movement and practice, including the utilization of marginal areas and of caves, account for some aspects of plague outbreaks both in the present and in the past. We support this hypothesis using historical sources from the Second Plague Pandemic in Central Europe, and suggest an association between recent and historical land use for pasture and plague outbreaks data.
DB-OTO Gene Therapy for Inherited Deafness
2025-10-12

DB-OTO gene therapy improved hearing in patients with <i>OTOF</i>-related deafness, enabling natural acoustic hearing and normalizing hearing sensitivity in 3 of 12 treated patients. (Funded by Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT05788536.).
Engineered pattern recognition receptors enhance broad-spectrum plant resistance
2025-10-13

Abstract Conventional plant resistance breeding has primarily focused on intracellular immune receptors, while cell-surface pattern recognition receptors (PRRs) have been underexplored because of their comparatively modest contributions to resistance. However, PRRs offer untapped potential for crop improvement. Here we demonstrate that the Arabidopsis receptor-like protein RLP23, which recognizes molecular patterns from three distinct microbial kingdoms, confers broad-spectrum resistance when introduced into the Solanaceae crop tomato. We also identify the C-terminal domain of RLPs as crucial for ensuring compatibility and efficacy during heterologous expression. Targeted engineering of the C-terminal domain significantly enhances RLP23 and its use, enabling transfer of robust resistance against bacterial, fungal and oomycete pathogens to tomato plants without compromising yield. We extend this RLP engineering strategy to rice and poplar, highlighting its broad applicability. These findings establish a versatile framework for PRR-based engineering, opening additional avenues for sustainable crop protection.
Language contact and creolization
2025-10-13

Abstract Creole languages offer a fascinating insight into the (re)structuring of argument structure constructions (hereafter ASCs) in language contact situations involving genetically unrelated languages. So far, however, research on ASCs in creoles has been strongly biased towards the search for so-called African ‘substrate’ influence. In the present contribution, I propose a more nuanced perspective that is consistent with findings from usage-based and/or constructionist studies on motion encoding among bilingual speakers and in second language learning. These show the adoption or retention of L2 lexical items and of (both lexically bound and more abstract) ASCs, but also fine-grained constructional differences in comparison to monolingual speakers. Drawing on lexicographic sources and quantitative corpus data from oral folktales, I provide a usage-based and cognitive-constructionist analysis of self-motion constructions in Guianese French Creole, which emerged at the turn of the 17th to the 18th century from contact between French-speaking colonists and the (predominantly) West-African slave population. My case study shows that verb-framed intransitive motion constructions with path verbs of (Colonial) French origin are by far the most frequent and productive construction type, similar to French. Moreover, I find more subtle ‘hybrid’ characteristics in Creole self-motion constructions (e.g. with regard to prepositional uses and restrictions on specific lexical fillers) that can be related to contact-induced and/or convergence-driven developments involving multiple source constructions. This is in sharp contrast to previous research suggesting that creole ASCs are overwhelmingly of non-French origin and shows interesting parallels with research on typological tendencies and bilingual speakers and learners.
Absence of Systematic Effects of Internalizing Psychopathology on Learning Under Uncertainty
2025-10-13

Abstract Difficulties in adapting learning to meet the challenges of uncertain and changing environments are widely thought to play a central role in internalizing psychopathology, including anxiety and depression. This view stems from findings linking trait anxiety and transdiagnostic internalizing symptoms to learning impairments in laboratory tasks often used as proxies for real-world behavioral flexibility. These tasks typically require learners to adjust learning rates dynamically in response to uncertainty, for instance, increasing learning from prediction errors in volatile environments. However, prior studies have produced inconsistent and sometimes contradictory findings regarding the nature and extent of learning impairments in populations with internalizing disorders. To address this, we conducted eight experiments (N = 820) using predictive inference and reversal learning tasks, and applied a bi-factor analysis to capture internalizing symptom variance shared across and differentiated between anxiety and depression. While we observed robust evidence for adaptive learning-rate modulation across participants, we found no convincing evidence of a systematic relationship between internalizing symptoms and either learning rates or task performance. These findings challenge prominent claims that learning difficulties are a hallmark feature of internalizing psychopathology and suggest that the relationship between these traits and adaptive behavior under uncertainty may be more subtle than previously thought.
Mechanisms and reversibility of glyphosate and phosphorus ligands sorption on Al2O3: Experimental evidence and computational modeling
2025-10-13

The environmental fate and risk of glyphosate (Gly) are critically influenced by its retention at soil-water interfaces. While aluminum (oxyhydr)oxides (Al<sub>2</sub>O<sub>3</sub>, Al(OH)<sub>3</sub>, AlOOH) are abundant in soils, their adsorption mechanisms for Gly have received considerably less attention than iron (hydr)oxides in geochemical modeling. This work employs a combined experimental-surface complexation model (SCM)-density functional theory (DFT) approach to systematically investigate the complexation of Gly and various phosphorus ligands (individually and competitively) on Al<sub>2</sub>O<sub>3</sub>. Beyond the widely studied phosphate (PO<sub>4</sub>), we also introduce the aminomethylphosphonic acid (AMPA) and phosphonic acid (HPO<sub>3</sub>), both containing phosphonate groups (-PO<sub>3</sub>), into the framework. For individual adsorptions, SCM and DFT results consistently reveal pH- and loading-dependent complexation structures, comparable to iron mineral studies while filling Al<sub>2</sub>O<sub>3</sub>-specific knowledge gaps. DFT provides a full-pH energy analysis for Gly and PO<sub>4</sub> on the Al<sub>2</sub>O<sub>3</sub>(110) surface, specifically indicating the superior stability of Gly via carboxylate (-COO) monodentate complexation under high pH. Crucially, our SCM model, as first applied in such competitive organic-inorganic systems, identifies the adsorption irreversibility for weakly adsorbed species (Gly, AMPA) and explicitly links monodentate coordination to irreversibility at high loadings. DFT results elucidate the thermodynamic competition mechanisms at low loadings. These insights pave the way in precisely predicting and elucidating the environmental adsorption behavior of Gly at aluminum-rich soil matrix.
Reliability of blood inflammatory markers at constant real-life workloads over time: Study protocol
2025-10-13

Background Work-related musculoskeletal disorders (WMSDs) are prevalent in occupations characterised by high repetition and high force demands. Both factors not only evoke inflammatory and degenerative processes in affected musculoskeletal tissue, but also systemic responses identified by biomarkers in blood serum. Clarifying methodological aspects of biomarkers may provide insights into their predictive role in the pathway of developing WMSDs. This study will primarily assess reliability of systemic inflammatory biomarkers (CRP, TNF-α, IL-6, IL-1β) and immune cell reactivity by repeated measures in workers with constant workloads over time. Methods This observational cross-sectional study will include two groups of workers: exposed group including workers exposed to higher upper-extremity physical workloads, especially affecting the elbow/forearm/hand-area; unexposed group, including office workers exposed to lower upper-extremity physical workloads. Recruited persons are screened against eligibility criteria followed by a medical anamnesis and blood analysis. Enrolled participants undergo nine repeated measurements once every two weeks, taking blood among others. Blood analyses will determine values of systemic inflammatory biomarkers and reactivity of immune cells. The absolute test-retest reliability of biomarkers and immune cell reactivity over time is assessed by the intra-class correlation coefficient applying two-way mixed-effects models. The relative test-retest reliability is assessed by the standard error of measurement. Discussion Knowledge of and models currently describing the pathological role of systemic inflammatory biomarkers are based on highly-controlled laboratory rat experiments. This study has the strength of assessing a human population under real-life conditions. The major challenge is in participant recruitment given the intensive and complex study design. The results of this study could provide fundamentals for initiating a cohort study and be used for developing work-related stress-recovery concepts for occupations with different physical demands to identify workers who may be at risk for developing WMSDs. German Clinical Trials Register ( DRKS00031872 , 25 May 2023).
Precision medicine in cutaneous melanoma—A comprehensive review
2025-10-13

Abstract Precision medicine aims to tailor medical treatment to the individual characteristics of each patient, beginning with detailed diagnostic assessments. In cutaneous melanoma, precision medicine has made considerable progress, with some approaches already implemented in clinical practice and guidelines. For instance, testing for BRAF mutations to guide the use of targeted BRAF/MEK inhibitor therapy is an established standard of care. Even melanoma with rarer genetic alterations, such as NTRK fusions or KIT mutations, can increasingly be treated with specific targeted therapies. These advancements have translated into significant improvements in overall survival, especially in patients with metastatic disease. Other innovative approaches, such as gene expression profiling (GEP) and the use of circulating tumour DNA (ctDNA) for monitoring treatment response, are already available. However, they are not yet part of routine clinical care or broadly recommended in guidelines. Likewise, the use of tumour‐infiltrating lymphocytes (TIL) remains limited to specialized centres, and tailor‐made mRNA vaccines are still in the investigational phase but hold great promise for the future of melanoma therapy. This review provides an overview of current and emerging approaches in precision therapy and diagnostics for melanoma, encompassing key areas such as molecular and genomic profiling, advanced imaging techniques, biomarker‐based stratification and AI‐driven technologies.
PDE4D and PDE3B orchestrate distinct cAMP microdomains in 3T3‐L1 adipocytes
2025-10-13

Abstract Background and Purpose Lipolysis is tightly regulated by pro‐lipolytic β ‐adrenoceptor signalling, which activates the cAMP/PKA pathway, and by antilipolytic hormones like insulin and FGF1, which counter‐regulate lipolysis through cAMP‐degrading phosphodiesterases (PDEs). While the spatial compartmentalization of cAMP signalling is recognized, comparisons between distinct cAMP pools remain under‐investigated in adipocytes. Moreover, the dynamics of cAMP around lipid droplets (LD) where lipolysis occurs, are particularly intriguing. Thus, we studied whether adipose FGF1/PDE4D and insulin/PDE3B pathways regulate distinct cAMP microdomains to execute their antilipolytic actions. Experimental Approach We evaluated the role of subcellular cAMP pools in lipolysis regulation by PDEs, or antilipolytic hormones, by utilizing EPAC1‐based FRET cAMP biosensors specifically designed to localize in the cytoplasm or at the plasma membrane of living cells. Additionally, we developed the first LD‐associated cAMP biosensor by fusing the lipid droplet‐associated protein perilipin‐1 to the EPAC1‐based probe. Key Results We identified previously unrecognized cAMP pools surrounding LDs that are distinct from cytoplasmic cAMP and resistant to PDE inhibition or antilipolytic stimuli. PDE4D exhibits a stronger effect on all three cAMP pools investigated than PDE3B. FGF1 mainly inhibits the cAMP in the initiation of the signalling at the plasma membrane, whereas insulin targets mainly cytoplasmic cAMP pools. Conclusion and Implications The discovery of LD‐associated cAMP as a distinct subcellular pool suggests that cAMP signalling in adipocytes is more compartmentalized than previously recognized. The distinct pathways by which FGF1 and insulin regulate adipose cell cAMP levels highlight that antilipolytic signalling is not uniform, refining our understanding of lipolysis regulation.
Excited State Dynamics of the Carbazolato‐Carbene Chromium(III) Complex [Cr(bimca)2]+
2025-10-13

Efficient near‐infrared spin‐flip luminescence from molecular chromium(III) complexes is challenging to achieve due to the presence of various nonradiative excited state decay pathways. General design principles for efficient spin‐flip emission, especially in the near‐infrared spectral region, are not yet well established. Small structural modifications can unexpectedly suppress spin‐flip luminescence completely, as found for the amido/carbene complex [Cr(bimca) 2 ] + (bimca – = 1,8‐bis(3‐methylimidazolin‐2‐ylidene‐1‐yl)carbazolido). To better understand these apparently unforeseeable effects, static and time‐resolved spectroscopy with quantum chemical calculations is combined to elucidate the excited state dynamics of [Cr(bimca) 2 ] + . Weak high‐energy fluorescence is observed, yet low‐energy spin‐flip emission is not detected. In this particular N ‐heterocyclic carbene complex, efficient nonradiative decay via CH overtones of the carbene's N ‐methyl substituents impedes the spin‐flip phosphorescence.
High‐resolution deuterium metabolic imaging of the human brain at 9.4 T using phase‐cycled balanced SSFP spectral–spatial acquisitions
2025-10-13

Abstract Purpose The aim was to improve the sensitivity and robustness against B 0 inhomogeneities of deuterium metabolic imaging (DMI) using phase‐cycled balanced SSFP (bSSFP) methods at 9.4 T. Methods We investigated two variants of phase‐cycled bSSFP acquisitions, namely uniformly weighted multi‐echo and acquisition‐weighted chemical shift imaging (CSI) to improve the SNR of DMI in the brain after oral [6,6′‐ 2 H 2 ]‐glucose intake. Phase‐cycling was introduced to reduce the off‐resonance sensitivity of bSSFP, incurring a moderate SNR loss. Two SNR optimal methods for obtaining metabolite amplitudes from the phase‐cycled bSSFP data were proposed. The SNR performance of the two bSSFP variants was compared with the SNR‐optimized vendor's standard CSI. Additionally, in vivo T 1 and T 2 of deuterium metabolites were estimated. Results High‐resolution whole‐brain dynamic DMI maps were obtained for all acquisitions. The CSI variant of phase‐cycled bSSFP achieved an average SNR increase of 16% and 25% for glucose and glutamate + glutamine (Glx), respectively, compared to the SNR‐optimized vendor's standard CSI. Phase‐cycling improved the bSSFP metabolite estimation and provided additional spectral encoding at the cost of a 10% to 20% SNR loss. Compared to the CSI variant of bSSFP acquisition, the multi‐echo variant exhibited up to 35% lower SNR performance because of uniform k‐space weighting and less efficient readout. However, it achieved higher resolutions than acquisition‐weighted CSI protocols and showed several qualitative improvements. Conclusion We demonstrated the feasibility of using two phase‐cycled bSSFP acquisitions for off‐resonance insensitive high‐resolution [6,6′‐ 2 H 2 ]‐glucose DMI studies in the human brain. bSSFP acquisitions have potential to improve the sensitivity of DMI despite the SNR loss of phase‐cycling and other human scanner constraints.
Out in the cold? A review of Early Middle Palaeolithic settlements in northern Central Europe, age data and geological preconditions for site formation and preservation
2025-10-13

The characteristics of settlement of Neanderthals in northern Central Europe during the earlier phases of the Middle Palaeolithic (Marine Isotope Stage 8–6) have been a matter of debate for decades, specifically regarding the population dynamics at such latitudes during the coldest phases. In this paper, we review the known archaeological record of the study region, focusing on 10 sites with available numerical dating and discussing their lithic assemblages and chronological attribution, together with the geological preconditions for the formation and preservation of archaeological sites. The results of our review show that our current knowledge remains affected by several issues, as for instance difficulties in interpreting the depositional setting and taphonomic processes at play, as well as the complexities regarding the dating. A proper understanding of the site formation and sedimentological background is therefore required to evaluate the reliability of the numerical ages. According to the data collected here, it is evident that currently known sites attributed to interglacial/interstadial stages within the early Middle Palaeolithic are neither more numerous nor located further north than during the previous and subsequent colder phases. Whether this reflects climate‐independent demographic fluxes or is instead related to the non‐preservation of interglacial/interstadial sediments, has to remain undetermined at present. Limitations of the applied dating techniques (error ranges covering several Marine Isotope Stages) do not currently allow us to establish how ephemeral the human presence was at such latitudes, in terms of both population size and duration. Following such reasoning, we think that proposing a continent void of population for tens of thousands of years as the main working hypothesis is not scientifically valid. Instead, we suggest including in the future discussion on the early Middle Palaeolithic settlement strategies an ‘out in the cold’ hypothesis, alongside the currently existing ones.
Advanced investigation of the suitability of confocal Raman spectroscopy for dermatological bioequivalence assessments using caffeine and 1,2-pentanediol
2025-10-13

Since the European Medicines Agency released its "Guideline on quality and equivalence of locally applied, locally acting cutaneous products", the interest in bioequivalence studies especially in relation to the approval of generics has grown. The guideline provides a framework for the methodology of such studies with the specification of tape stripping as the sole method for skin penetration tests and the vague requirements for a control formulation presenting slight shortcomings in this context. Thus, the aim of this study was to broaden the understanding of what constitutes a suitable control formulation as well as showing the suitability of confocal Raman spectroscopy (CRS) as an alternative method to tape stripping. Validation of CRS results was achieved by performing tape stripping and CRS experiments using caffeine as a model API consecutively on the same skin samples. In order to investigate a suitable control formulation, the effect of different concentrations of 1,2-pentanediol as a penetration enhancer on thermodynamic activity and thus penetrated API amount was examined. We established that CRS is appropriate for both quantitative skin penetration testing as well as in depth bioequivalence testing by demonstrating that the findings of tape stripping and CRS were extremely similar in terms of both the total amounts of detected API as well as the outcomes of bioequivalence testing. Furthermore, we could show that high concentrations of 1,2-pentanediol, by improving the solubility of caffeine, reduce the thermodynamic activity sufficiently to obtain a suitable control formulation. Lower concentrations achieved the expected penetration enhancement but not to a sufficient degree that the formulation can be used as a control. Finally, against the background of these findings, the penetration-enhancing effect of 1,2-pentanediol was investigated, whereby effects on the lipid structure of the stratum corneum and a water-binding effect in the skin were observed.