julilili42/papers huggingface dataset:
Outer retina micro-inflammation is driven by T cell responses prior to retinal degeneration in early age-related macular degeneration
2025-02-05

Introduction Age-related macular degeneration (AMD) is a leading cause of blindness with limited treatment options. Dysfunction of the retinal pigment epithelium (RPE) is a unifying salient feature of the pathology and a primary end-point damage leading to complications such as geographic atrophy (GA), which represents the most common end-stage of AMD. Methods Human and murine ocular tissues were used for histological examinations. Furthermore, flow cytometry and gene expression analysis were used on ocular and splenic tissues of Cx3cr1 GFP/GFP and C57BL/6J mice at 8 and 12 months of age to characterize the dynamics of local and systemic T cell populations. Results We show the presence of memory T cells such as CD45RO + cells in the choroid and retina of patients with AMD with a peak of abundance in early stages of AMD. As further evidence for the contribution of the adaptive immune system to GA we identified an increased frequency of CD44 + CD69 + KLRG1 + T cells and para-inflammation of the retina in a mouse model that mimics features of GA. Importantly, the activation of T cells found at early AMD-like stages prior to degeneration possessed long-lasting cytotoxic properties and adopted typical features of senescent immune cells. T cells were intimately associated with the RPE, suggesting transmigration and participating in local micro-inflammation. Discussion Our data support that activation and accumulation of memory T cells can be considered as a hallmark of early AMD, and that adaptive immunosenescence likely to contribute to the chronic inflammation associated with RPE damage and the progression to large lesions as seen in GA.
Robot-Based Procedure for 3D Reconstruction of Abdominal Organs Using the Iterative Closest Point and Pose Graph Algorithms
2025-02-05

Image-based 3D reconstruction enables robot-assisted interventions and image-guided navigation, which are emerging technologies in laparoscopy. When a robotic arm guides a laparoscope for image acquisition, hand–eye calibration is required to know the transformation between the camera and the robot flange. The calibration procedure is complex and must be conducted after each intervention (when the laparoscope is dismounted for cleaning). In the field, the surgeons and their assistants cannot be expected to do so. Thus, our approach is a procedure for a robot-based multi-view 3D reconstruction without hand–eye calibration, but with pose optimization algorithms instead. In this work, a robotic arm and a stereo laparoscope build the experimental setup. The procedure includes the stereo matching algorithm Semi Global Matching from OpenCV for depth measurement and the multiscale color iterative closest point algorithm from Open3D (v0.19), along with the multiway registration algorithm using a pose graph from Open3D (v0.19) for pose optimization. The procedure is evaluated quantitatively and qualitatively on ex vivo organs. The results are a low root mean squared error (1.1–3.37 mm) and dense point clouds. The proposed procedure leads to a plausible 3D model, and there is no need for complex hand–eye calibration, as this step can be compensated for by pose optimization algorithms.
Social context affects sequence modification learning in birdsong
2025-02-05

Social interactions are crucial for imitative vocal learning such as human speech learning or song learning in songbirds. Recently, introducing specific learned modifications into adult song by experimenter-controlled reinforcement learning has emerged as a key protocol to study aspects of vocal learning in songbirds. This form of adult plasticity does not require conspecifics as a model for imitation or to provide social feedback on song performance. We therefore hypothesized that social interactions are irrelevant to, or even inhibit, song modification learning. We tested whether social context affects song sequence learning in adult male Bengalese finches ( Lonchura striata domestica ). We targeted specific syllable sequences in adult birds’ songs with negative auditory feedback, which led the birds to reduce the targeted syllable sequence in favor of alternate sequences. Changes were apparent in catch trials without feedback, indicating a learning process. Each experiment was repeated within subjects with three different social contexts (male–male, MM; male–female, MF; and male alone, MA) in randomized order. We found robust learning in all three social contexts, with a nonsignificant trend toward facilitated learning with social company (MF, MM) compared to the single-housed (MA) condition. This effect could not be explained by the order of social contexts, nor by different singing rates across contexts. Our results demonstrate that social context can influence degree of learning in adult birds even in experimenter-controlled reinforcement learning tasks, and therefore suggest that social interactions might facilitate song plasticity beyond their known role for imitation and social feedback.
Parkinson’s disease mutant Miro1 causes mitochondrial dysfunction and dopaminergic neuron loss
2025-02-06

Abstract The complex and heterogeneous nature of Parkinson's disease (PD) is still not fully understood. However, increasing evidence supports mitochondrial impairment as a major driver of neurodegeneration. Miro1, a mitochondrial GTPase encoded by the RHOT1 gene, is involved in mitochondrial transport, mitophagy and mitochondrial calcium buffering, and is therefore essential for maintaining mitochondrial homeostasis. Recently, Miro1 has been linked genetically and pathophysiologically to PD, further supported by the identification of heterozygous variants of Miro1 in patients. Herein, we used patient-derived cellular models alongside knock-in mice to investigate Miro1-dependent pathophysiological processes and molecular mechanisms underlying neurodegeneration in PD. Experimental work performed in induced pluripotent stem cell (iPSC)-derived models, including midbrain organoids and dopaminergic neuronal cell cultures from a PD patient carrying the p.R272Q Miro1 mutation as well as healthy and isogenic controls, indicated that the p.R272Q Miro1 mutation leads to increased oxidative stress, disrupted mitochondrial bioenergetics and altered cellular metabolism. These changes were accompanied by increased α-synuclein levels and a significant reduction of dopaminergic neurons. Moreover, the p.R272Q Miro1 mutation—located in the calcium-binding domain of the GTPase—disrupted calcium homeostasis, resulting in calcium-dependent activation of calpain proteases and the subsequent cleavage of α-synuclein. Knock-in mice expressing p.R285Q Miro1 (the murine orthologue of the human p.R272Q mutation) displayed accumulation of phosphorylated α-synuclein in the striatum and a significant loss of dopaminergic neurons in the substantia nigra pars compacta, accompanied by behavioural alterations. These findings demonstrate that mutant Miro1 is sufficient to comprehensively model PD-relevant phenotypes in vitro and in vivo, reinforcing its pivotal role in PD pathogenesis.
Characteristics and prognosis of patients with primary metastatic disease vs. recurrent HER2-negative, hormone receptor-positive advanced breast cancer
2025-02-06

HRpos/HER2neg first-line MBC patients have a more favorable prognosis if the disease was previously not treated. This difference was similar across all examined clinicopathological parameters. It may therefore be beneficial to incorporate MBC categories as a stratification factor in clinical trials.
On the Inconsistency of the “Suid Gap” Hypothesis and Its Inappropriate Biochronological Use in Dating the Localities of Orce (Venta Micena, Barranco León D, and Fuente Nueva 3). Reply to Martínez-Navarro et al. Comment on “Iannucci, A. The Occurrence of Suids in the Post-Olduvai to Pre-Jaramillo Pleistocene of Europe and Implications for Late Villafranchian Biochronology and Faunal Dynamics. Quaternary 2024, 7, 11”
2025-02-06

According to the “suid gap” hypothesis, suids (Suidae, Mammalia) would have been absent from Europe between 1.8 and 1.2 Ma. This hypothesis has been influential owing to its putative implications for biochronology and paleoecology—Sus scrofa (the modern wild boar) would appear 1.2 Ma in a period of climatic and environmental changes, coinciding with the beginning of the Epivillafranchian and the Early–Middle Pleistocene Transition, and hominins—the arrival of Homo in western Europe would precede the “return” of pigs. However, the “suid gap” hypothesis is based on the wrong premises that suids are abundantly represented in the European fossil record before and after the “suid gap”, that this purported abundance is linked to the suid reproductive potential, and that the paleontological sites dated within the 1.8–1.2 Ma interval yielded enough remains to exclude the notion that the absence of suid is merely accidental. In a recent paper, it is shown that all these assumptions are erroneous and suid material is described from Peyrolles (France), which is dated at 1.47 ± 0.01 Ma, hence perfectly “filling the suid gap”. Some proposers of the “suid gap” hypothesis have now provided comments to this recent paper, casting doubt on the age of Peyrolles and reiterating the arbitrary statement that suids were commonly recorded and abundantly represented in the Pleistocene of Europe. There is no valid reason to question the homogeneity of the faunal assemblage of Peyrolles, which is indeed a key locality for the mammal biochronology of Europe, being the reference for MNQ 19. Suids of comparable chronology have also been found in Krimni (Greece). Moreover, the “suid gap” proposers are basically advocating the use of an interval biozone based on the temporary absence of Sus strozzii—a species not common in the Pleistocene of Europe—providing no ecological explanation for this gap, apart from speculating it would be due to competition with Homo. The defense of the “suid gap” seems motivated by its use from the “suid gap” proposers as a biochronological argument to contend that the localities of Orce in Spain (Barranco León D, Fuente Nueva 3, and Venta Micena) are older than 1.2 Ma, when they postulated suids would “reappear” in the fossil record. However, since the “suid gap” hypothesis was primarily proposed based on the absence of suids from the Orce sites (and, secondarily, from other sites biochronologically correlated with the localities of Orce, like Pirro Nord in Italy), this represents an evident example of circular reasoning.
The AMD-associated genetic polymorphism CFH Y402H confers vulnerability to Hydroquinone-induced stress in iPSC-RPE cells
2025-02-06

Introduction Age-related macular degeneration (AMD), a degenerative disease of the macula, is caused by an interplay of diverse risk factors (genetic predisposition, age and lifestyle habits). One of the main genetic risks includes the Y402H polymorphism in complement Factor H (FH), an inhibitor of complement system activation. There has been, and continues to be, much discussion around the functional consequences of this Y402H polymorphism, whether the soluble FH protein confers its risk association, or if the cells expressing the protein themselves are affected by the genetic alteration. In our study, we examined the cell characteristics of the retinal pigment epithelium (RPE) cells, which play a major role in retinal homeostasis and stability and which are synonymously linked to AMD. Methods Here, we employ RPE cells derived from induced pluripotent stem cells (iPSC) generated from donors, carrying either homozygous 402Y (low risk) or 402H (high risk) variants of the CFH gene. RPE cells were treated with Hydroquinone (HQ), a component of cigarette smoke, to induce oxidative damage. Results Intriguingly, RPE cells carrying high genetic risk proved more vulnerable to oxidative insult when exposed to HQ, as demonstrated by increased cytotoxicity and caspase activation, compared to the low-risk RPE cells. The exposure of RPE cells to RPE conditioned medium, normal human serum (NHS) and inactivated NHS (iNHS) had minimal impact on cell cytotoxicity and caspase activation, nor did the presence of purified soluble FH rescue the observed effects. Considering the known connection of oxidative stress to proteotoxic stress and degrading processes, we investigated the unfolded protein response (UPR) and autophagy. When exposed to HQ, RPE cells showed an increase in autophagy markers; however, iPSC-RPE cells carrying high genetic risk showed an overall reduced autophagic flux. Discussion Our findings suggest that the degree of cellular susceptibility to oxidative stress is not conferred by soluble FH protein and other complement sources, but intercellularly because of the corresponding genetic risk predisposition. Our data support the hypothesis that RPE cells carrying high genetic risk are less resilient to oxidative stress.
Unraveling the Impact of Drug Metabolism on Tamoxifen Response in Breast Cancer
2025-02-06

Abstract The selective estrogen receptor modulator tamoxifen is a mainstay of endocrine breast cancer therapy. However, the clinical response rates of tamoxifen are inferior to those of aromatase inhibitors, which may be partially explained by variable drug exposure due to the pharmacogenetics of the drug-metabolizing enzyme cytochrome P450 (CYP) 2D6. Clinical trials investigating the association between CYP2D6 impairment and tamoxifen outcomes have yielded conflicting results. The results of a comprehensive meta-analysis of 33 single-center tamoxifen trials reported here address this inconsistency by adjusting for two biases that may affect the validity of previous association studies: allele coverage of CYP2D6 genotyping and loss of heterozygosity of the CYP2D6 locus in tumor-derived DNA. After adjustment for bias, meta-analyses show significantly reduced study heterogeneity and a higher risk of recurrence or death in patients with impaired CYP2D6 metabolism compared with those with normal activity. These data may support the use of pharmacogenetics-guided tamoxifen therapy to improve outcomes in patients with CYP2D6-compromised breast cancer. Prospective studies should be considered. See related article by MacLehose et al., p. 224
Comparing apples to oranges: Consumer ambivalence regarding an eco-innovation – laser marking of organic fruits
2025-02-06

Laser marking is an innovative and eco-friendly alternative to plastic sticker labeling of organic fruits, with no known negative side effects. Still, based on Ram and Sheth’s innovation resistance theory, we predict that this food eco-innovation applied to the produce may lead to ambivalent responses, with consumers valuing its eco-friendliness but fearing health risks. Drawing on Festinger’s cognitive dissonance theory, we predict that consumers actively attempt to resolve the ambivalence by adapting their beliefs about laser marking to situation-specific realities. Finally, based on Nemeroff and Rozin’s contagion theory, we predict that an important situation-specific reality for this eco-innovation is fruit peel edibility, which moderates the found relationships. These hypotheses are tested in three between-subjects experiments (Study 1 – 396 participants; Study 2 – 390 participants; Study 3 – 346 participants). Participants were exposed to scenarios presenting an organic fruit with a laser-marked or plastic sticker label, on an edible or non-edible peel. As predicted, we find that laser marking decreases perceived eco-friendliness, because of anticipation of food waste, and reduces perceived healthfulness, because of fear of contamination, both depending on whether the fruit’s peel is edible or not. Implications for managers include the need to educate consumers about the benefits and risks of this technology. For a start, laser marking should probably be limited to fruits with non-edible peels.
Residents as learning facilitators inside and outside of interprofessional education: a faculty development program in postgraduate pediatric training
2025-02-06

Introduction Changing learning environments in health professions are an important challenge of interprofessional education (IPE). When students experience IPE activities during their undergraduate training, they are often guided by trained learning facilitators. Students still spend more time in non-IPE settings, often guided by residents. Residents rarely undergo specific training for core teaching competencies that are crucial in both IPE and non-IPE contexts. At our pediatric hospital, some residents were trained as learning facilitators on an interprofessional training ward. To bridge the gap between IPE and non-IPE learning facilitation for the other residents, we developed the resident-as-teachers course “How to teach pediatrics.” Methods “How to teach pediatrics” was implemented as a 4-week blended learning program based on the framework of Core Competencies for Medical Teachers (KLM). The intended learning outcomes were to reflect on residents’ role modelling and professionalism as well as personal teaching practice, emphasize learner centeredness and foster social and communicative competencies. Participants self-assessed their teaching competencies pre/post-course using a validated questionnaire (FKM_L). Oral feedback was gathered by group reflection and qualitative feedback by open-ended survey questions. Results 26 residents participated in the course, of which N = 22 qualified for the pre/post-course self-assessment via the FKM_L (return rate: n = 9; 40.9%). Participants reported an increase in the competency fields of “didactical activities in medicine,” “social and communicative competence,” “role model and professional behavior” as well as “reflection and further development of own teaching practice.” Participants evaluated the course overall as “very good,” stated a high learning gain and estimated the course to be a good preparation for teaching students. Discussion “How to teach pediatrics” shows the feasibility of integrating faculty development as part of resident training. We observed a self-assessed increase in core competencies for medical teachers after participating in the course. Although more participants need to be included and long-lasting effects still need to be proven, such faculty development programs for learning facilitators might be an opportunity to ensure a more consistent and high-quality learning experience for students in both IPE and non-IPE teaching and learning activities.
Model‐Based Prediction of Clinically Relevant Thrombocytopenia after Allogeneic Hematopoietic Stem Cell Transplantation
2025-02-06

Platelet reconstitution after allogeneic hematopoietic cell transplantation (allo‐HCT) is heterogeneous and influenced by various patient‐ and transplantation‐related factors, associated with poor prognoses for poor graft function (PGF) and isolated thrombocytopenia. Tailored interventions could improve the outcome of patients with PGF and post‐HCT thrombocytopenia. To provide individual predictions of 180‐day platelet counts from early phase data, we developed a model of long‐term platelet reconstitution after allo‐HCT. A large cohort ( n = 1949) of adult patients undergoing their first allo‐HCT was included. Real‐world data from 1,048 retrospective patients were used for non‐linear mixed‐effects model development. Bayesian forecasting was used to predict platelet–time profiles for 518 retrospective and 383 prospective patients during internal and external model validation, respectively. Thrombocytopenia was defined as mean platelet count &lt; 75 × 10 9 /L, derived from the last 12 platelet measurements within the first 180 days post‐HCT. Thrombocytopenia affected 37% of all patients and was associated with significantly reduced overall survival ( P ‐value &lt; 0.0001). On days +7, +14, +21, and +28, the developed model achieved areas under the receiver‐operating characteristic of ≥ 0.68, ≥ 0.75, ≥ 0.78, and 0.81 for the prediction of post‐HCT thrombocytopenia, respectively, with anti‐thymocyte globulin, donor relation, and total protein measurements representing prognostic markers for post‐HCT platelet kinetics. A publicly accessible web‐based demonstrator of the model was established ( https://hsct.precisiondosing.de ). In summary, the developed model predicts individual platelet counts from day +28 post‐HCT adequately, utilizing internal and external datasets. The web‐based demonstrator provides a basis to implement model‐based predictions in clinical practice and to confirm these findings in future clinical studies.
TIMS2Rescore: A Data Dependent Acquisition-Parallel Accumulation and Serial Fragmentation-Optimized Data-Driven Rescoring Pipeline Based on MS2Rescore
2025-02-07

The high throughput analysis of proteins with mass spectrometry (MS) is highly valuable for understanding human biology, discovering disease biomarkers, identifying therapeutic targets, and exploring pathogen interactions. To achieve these goals, specialized proteomics subfields, including plasma proteomics, immunopeptidomics, and metaproteomics, must tackle specific analytical challenges, such as an increased identification ambiguity compared to routine proteomics experiments. Technical advancements in MS instrumentation can mitigate these issues by acquiring more discerning information at higher sensitivity levels. This is exemplified by the incorporation of ion mobility and parallel accumulation and serial fragmentation (PASEF) technologies in timsTOF instruments. In addition, AI-based bioinformatics solutions can help overcome ambiguity issues by integrating more data into the identification workflow. Here, we introduce TIMS<sup>2</sup>Rescore, a data-driven rescoring workflow optimized for DDA-PASEF data from timsTOF instruments. This platform includes new timsTOF MS<sup>2</sup>PIP spectrum prediction models and IM2Deep, a new deep learning-based peptide ion mobility predictor. Furthermore, to fully streamline data throughput, TIMS<sup>2</sup>Rescore directly accepts Bruker raw mass spectrometry data and search results from ProteoScape and many other search engines, including Sage and PEAKS. We showcase TIMS<sup>2</sup>Rescore performance on plasma proteomics, immunopeptidomics (HLA class I and II), and metaproteomics data sets. TIMS<sup>2</sup>Rescore is open-source and freely available at https://github.com/compomics/tims2rescore.
Clinical characteristics, metastasis patterns, and treatment outcomes of HER2-low breast cancer
2025-02-07

Breast cancer (BC) is a heterogeneous disease, traditionally classified by hormone receptor and HER2 (human epidermal growth factor receptor 2) status. HER2-low, characterized by low HER2 expression without gene amplification, recently gained attention. While new therapies are promising, its clinical significance remains unclear. We analysed 241,510 BC patients diagnosed between 2000 and 2020 in Germany using data from the German Cancer Registry Group. HER2 status was determined using immunohistochemistry and fluorescence in situ hybridization results, and patients were classified as HER2-positive, HER2-low or HER2-zero. Clinical features, chemosensitivity and long-term outcomes - metastasis-free survival (MFS), recurrence-free survival (RFS), and overall survival (OS) - were analysed using Cox models. HER2-low comprised 42% of female and 47% of male patients, predominantly hormone receptor positive. Metastatic patterns in HER2-low and HER2-zero were similar but differed from HER2-positive, which showed more liver metastasis and multiple metastatic sites. HER2-positive showed worse MFS, RFS, and OS than HER2-zero and HER2-low subtypes. Pathological complete response (pCR) rates after neoadjuvant chemotherapy were highest in HER2-positive. HER2-low has higher hormone receptor positivity, distinguishing it from HER2-zero. While metastatic behaviour, treatment and long-term response in HER2-low were comparable to HER2-zero, the hormone receptor status seems to play a critical role in these outcomes.