julilili42/papers huggingface dataset:
The remains of a large cercopithecid from the Lower Pleistocene locality of Karnezeika (southern Greece)
2022-11-07

ABSTRACT The Lower Pleistocene Karnezeika locality, lies in the Peloponnese, southern Greece, and its fauna corresponds to the Middle Villafranchian biochronological unit (MN17). The recovered mammal assemblage includes, among others, a few remains of a large Cercopithecid. Herein, we describe this material, including an upper second molar, a partially preserved proximal radius and, possibly, an upper first incisor. The teeth show advanced stages of wear but retain their typical papionin characters, such as a strong lingual cleft and four bilophodont cusps in the molar. The general morphology and wear pattern of the teeth rules out the possibility that the remains belong to the genus Theropithecus , while the general size of the corresponding material excludes the possibility of a Macaca representative as well. On the contrary, the studied material better fits the size range of Paradolichopithecus . Even though this genus is likely represented in the Villafranchian of Europe by a single species, Par. arvernensis , the scarcity of the studied material imposes reservations and thus the Karnezeika papionin is referred at the moment to cf. Paradolichopithecus sp. As in the rest of Europe, the Paradolichopithecus record is rare in Greece, having been found in only two localities, Vatera and Dafnero. Despite its scarcity, the new material from Karnezeika indicates a wide distribution of this important taxon in the Greek peninsula.
Immunogenicity of non-canonical HLA-I tumor ligands identified through proteogenomics
2022-11-07

Abstract Tumor antigens are central to antitumor immunity. Recent evidence suggests that peptides from non-canonical (nonC) aberrantly translated proteins can be presented on HLA-I by tumor cells. Here, we investigated the immunogenicity of nonC tumor HLA-I ligands (nonC-TL) to better understand their contribution to cancer immunosurveillance and their therapeutic applicability. Using proteogenomics, we identified 517 nonC-TL from 9 patients with melanoma, gynecological, and head and neck cancer. We found no recognition of the 507 nonC-TL tested by autologous ex vivo expanded tumor reactive T-cell cultures while the same cultures demonstrated reactivity to mutated, cancer-germline, or melanocyte differentiation antigens. However, in vitro sensitization of donor peripheral blood lymphocytes against 170 selected nonC-TL, led to the identification of T-cell receptors (TCRs) specific to three nonC-TL, two of which mapped to the 5’ UTR regions of HOXC13 and ZKSCAN1, and one mapping to a non-coding spliced variant of C5orf22C. T cells targeting these nonC-TL recognized cancer cell lines naturally presenting their corresponding antigens. Expression of the three immunogenic nonC-TL was shared across tumor types and barely or not detected in normal cells. Our findings predict a limited contribution of nonC-TL to cancer immunosurveillance but demonstrate they may be attractive novel targets for widely applicable immunotherapies.
Do Go Chasing Waterfalls: Enoyl Reductase (FabI) in Complex with Inhibitors Stabilizes the Tetrameric Structure and Opens Water Channels
2022-11-07

The enzyme enoyl-ACP reductase (FabI) is the limiting step of the membrane's fatty acid biosynthesis in bacteria and a druggable target for novel antibacterial agents. The FabI active form is a homotetramer, which displays the highest affinity to inhibitors. Herein, molecular dynamics studies were carried out using the structure of FabI in complex with known inhibitors to investigate their effects on tetramerization. Our results suggest that multimerization is essential for the integrity of the catalytic site and that inhibitor binding enables the multimerization by stabilizing the substrate binding loop (SBL, L:195-200) coupled with changes in the H4/5 (QR interface). We also observed that AFN-1252 (naphtpyridinone derivative) promotes unique conformational changes affecting monomer-monomer interfaces. These changes are induced by AFN-1252 interaction with key residues in the binding sites (Ala95, Tyr146, and Tyr156). In addition, the analysis of water trajectories indicated that AFN-1252 complexes allow more water molecules to enter the binding site than triclosan and MUT056399 complexes. FabI-AFN-1252 simulations show accumulation of water molecules near the Tyr146/147 pocket, which can become a hotspot to the design of novel FabI inhibitors.
4’-Fluorouridine mitigates lethal infection with pandemic human and highly pathogenic avian influenza viruses
2022-11-07

Abstract Influenza outbreaks are associated with substantial morbidity, mortality and economic burden. Next generation antivirals are needed to treat seasonal infections and prepare against zoonotic spillover of avian influenza viruses with pandemic potential. Having previously identified oral efficacy of the nucleoside analog 4’-Fluorouridine (4’-FlU, EIDD-2749) against SARS-CoV-2 and respiratory syncytial virus, we explored activity of the compound against seasonal and highly pathogenic influenza (HPAI) viruses in cell culture, human airway epithelium organoids, and/or two animal models, ferrets and mice, that assess IAV transmission and lethal viral pneumonia, respectively. 4’-FlU inhibited a panel of relevant influenza A and B viruses with nanomolar potency in organoids. In vitro polymerase assays revealed immediate chain termination of IAV polymerase after 4’-FlU incorporation, in contrast to delayed chain termination of SARS-CoV-2 and RSV polymerase. Once-daily oral treatment of ferrets with 2 mg/kg 4’-FlU initiated 12 hours after infection rapidly stopped virus shedding and prevented direct-contact transmission to untreated sentinels. Treatment of mice infected with a lethal inoculum of pandemic A/CA/07/2009 (H1N1)pdm09 (Ca09) with 2 mg/kg 4’-FlU alleviated pneumonia. Three doses mediated complete survival when treatment was initiated up to 60 hours after infection, indicating an unusually broad window for effective intervention. Therapeutic oral 4’-FlU ensured survival of animals infected with HPAI A/VN/12/2003 (H5N1) and of immunocompromised mice infected with pandemic Ca09. Recoverees were fully protected against homologous reinfection. This study defines the mechanistic foundation for high sensitivity of influenza viruses to 4’-FlU and supports 4’-FlU as developmental candidate for the treatment of seasonal and pandemic influenza. Author Summary Next-generation antiviral therapeutics are needed to better mitigate seasonal influenza and prepare against zoonotic virus spillover from animal reservoirs. At greatest risk are the immunocompromised and patients infected with highly pathogenic influenza viruses. In this study, we have demonstrated efficacy of a broad-spectrum nucleoside analog, 4’-fluorouridine, against a representative panel of influenza viruses in cell culture, human organoids, and two animal models, ferrets and mice. Acting as an immediate chain terminator of the influenza virus polymerase, once-daily oral treatment protected against lethal infection with seasonal and highly pathogenic avian influenza viruses, prevented direct-contact transmission to untreated sentinels, and mitigated lethal infection of immunocompromised hosts. These results support the developmental potential of 4’-fluorouridine for treatment of vulnerable patient groups and mitigation of pandemic influenza, providing a much-needed additional therapeutic option for improved disease management.
Periodic neglect after frontoparietal lesions provides causal evidence for rhythmic attention sampling
2022-11-07

Summary Contemporary models conceptualize spatial attention as a blinking spotlight that sequentially samples visual space. Hence, behavior fluctuates over time even in states of presumed ‘sustained’ attention. Recent evidence suggested that rhythmic neural activity in the frontoparietal network constitutes the functional basis of rhythmic attentional sampling. However, causal evidence to support this notion remains absent. Using a lateralized spatial attention task, we addressed this issue in patients with focal lesions in the frontoparietal attention network. Our results uncovered that frontoparietal lesions introduce periodic neglect, i.e., temporally-specific behavioral deficits that were aligned with the underlying neural oscillations. Attention-guided perceptual sensitivity was on par with healthy controls during optimal phases but attenuated during the less excitable sub-cycles. Theta-dependent sampling (3 – 8 Hz) was causally dependent on prefrontal cortex, while alpha-band sampling (8 – 14 Hz) emerged from parietal areas. Collectively, our findings reveal that lesion-induced high amplitude, low frequency brain activity is not epiphenomenal, but has immediate behavioral consequences. More generally, these results provide causal evidence for the hypothesis that the functional architecture of attention is inherently rhythmic.
Associations of sleep and emotion regulation processes in childhood and adolescence - a systematic review, report of methodological challenges and future directions
2022-11-08

Sleep and emotions are closely associated; however, the methodological challenges in the examination of sleep and the processes of emotion regulation in children and adolescents have not been investigated so far. Additionally, there is the demand to identify the levels of emotion regulating processes in which problematic or restricted sleep causes effect. Experimental sleep deprivation as well as prevalent sleep problems have been found to have negative influence on mental health and regulating functions. This review focuses first on the methodological protocols of the included studies. Subsequently, the results are summarized in the context of a multilevel model of emotion regulation. Thereafter, suggestions for future directions are given. Sleep problems and sleep deprivation are associated with a decrease of functional emotion regulating behavior and impaired emotion generation, and prolonged sleep enhances better mood and affect states, positive emotion expression, and faster sensory processing in response to emotional stimuli. This literature review highlights the limitations in current research, focusing on types of measurements, task characteristics, and data analysis. At the conclusion, suggestions are given for the future research direction in the field of sleep and emotion regulation in children and adolescents.
Influence of Staphylococcus aureus Strain Background on Sa3int Phage Life Cycle Switches
2022-11-08

Staphylococcus aureus asymptomatically colonizes the nasal cavity of mammals, but it is also a leading cause of life-threatening infections. Most human nasal isolates carry Sa3 phages, which integrate into the bacterial hlb gene encoding a sphingomyelinase. The virulence factor-encoding genes carried by the Sa3-phages are highly human-specific, and most animal strains are Sa3 negative. Thus, both insertion and excision of the prophage could potentially confer a fitness advantage to S. aureus. Here, we analyzed the phage life cycle of two Sa3 phages, Φ13 and ΦN315, in different phage-cured S. aureus strains. Based on phage transfer experiments, strains could be classified into low (8325-4, SH1000, and USA300c) and high (MW2c and Newman-c) transfer strains. High-transfer strains promoted the replication of phages, whereas phage adsorption, integration, excision, or recA transcription was not significantly different between strains. RNASeq analyses of replication-deficient lysogens revealed no strain-specific differences in the CI/Mor regulatory switch. However, lytic genes were significantly upregulated in the high transfer strain MW2c Φ13 compared to strain 8325-4 Φ13. By transcriptional start site prediction, new promoter regions within the lytic modules were identified, which are likely targeted by specific host factors. Such host-phage interaction probably accounts for the strain-specific differences in phage replication and transfer frequency. Thus, the genetic makeup of the host strains may determine the rate of phage mobilization, a feature that might impact the speed at which certain strains can achieve host adaptation.
Adjuvant Treatment for Breast Cancer Patients Using Individualized Neoantigen Peptide Vaccination—A Retrospective Observation
2022-11-08

Breast cancer is a tumor entity that is one of the leading causes of mortality among women worldwide. Although numerous treatment options are available, current explorations of personalized vaccines have shown potential as promising new treatment options to prevent the recurrence of cancer. Here we present a small proof of concept study using a prophylactic peptide vaccination approach in four female breast cancer patients who achieved remission after standard treatment. The patients were initially analyzed for somatic tumor mutations and then treated with personalized neoantigen-derived peptide vaccines. These vaccines consisted of HLA class I and class II peptides and were administered intracutaneously followed by subcutaneous application of sargramostim and/or topical imiquimod as an immunological adjuvant. After an initial priming phase of four vaccinations within two weeks, patients received monthly boosting/maintenance vaccinations. Chemotherapy or checkpoint inhibition was not performed during vaccination. One patient received hormone therapy. The vaccines were well tolerated with no serious adverse events. All patients displayed vaccine-induced CD4+ and/or CD8+ T-cell responses against various neoantigens. Furthermore, all patients remained tumor-free and had persistent T-cell responses, even several months after the last vaccination, suggesting the potential of peptide vaccines as an immunosurveillance and long term prophylaxis option.
Parasympathetic Versus Sympathetic Changes in Heart Rate Variability After a Multimodal Integrative Medicine Intervention for Frontline COVID-19 Personnel
2022-11-08

ABSTRACT Objective Frontline healthcare providers (HCPs) working in COVID-19 hospital departments need to deal with considerable physical and emotional stress on a daily basis. We conducted a pilot study to examine changes in heart rate variability (HRV) in frontline COVID-19 personnel after an integrative medicine (IM) intervention. Methods HCPs working in isolated COVID-19 inpatient departments underwent a single 30-minute individually tailored IM sessions combining various IM modalities (acupuncture, mind-body, and/or manual-movement modalities, including anthroposophic medicine). HRV parameters were compared during the first IM session at 3-minute intervals, at the beginning of treatments, and after 20 minutes. Root mean square of successive RR interval differences (RMSSD) was measured, as were domains of time (standard deviation of NN intervals, percentage of successive RR intervals that differ by more than 50 milliseconds) and frequency (low frequency/high frequency [LF/HF] ratio). Preintervention and postintervention concerns were assessed using the Measure Yourself Concerns and Well-being questionnaire, with posttreatment free-text narratives analyzed for clusters of emotional- and spiritual-related keywords (ESKs). Results A total of 114 HCPs underwent an IM treatment session, and their HRV values were measured, of which 75 (65.8%) expressed ESKs. The RMSSD increased only in the ESK-expressing group ( p &lt; .001). LF/HF ratios decreased in both groups, with HF power increasing in the ESK-expressing ( p = .043) and LF power decreasing in the non–ESK-expressing groups ( p = .004). Conclusions Increased parasympathetic activity was observed in all HCPs after the IM intervention, particularly among those expressing ESKs. LF/HF parameters suggest different relaxation-associated mechanisms, with increased HF (regulated predominantly by parasympathetic tone) in the ESK-expressing and decreased LF (regulated partially by sympathetic tone) in the nonexpressing group. Additional research needs to explore the relationship between subjective effects of the IM intervention and physiological mechanisms of relaxation in HCPs working in stressful environments. Trial Registration ClinicalTrials.gov identifier NCT05104827.
Clinical Importance of PGRMC1 in Hormone Responsive Breast Cancer
2022-11-08

Background: For the development of PGRMC1, a multifunctional receptor belonging to membrane-associated progesterone receptor proteins (MAPR) family, as possible predictive marker for increased hormone-dependent breast cancer (BC) risk, a systematic research program has been performed, starting with different BC cells, continued with animal studies and finally with clinical studies with BC patients. Summary: In vitro studies showed dose- and time-dependent BC cell proliferations with all available synthetic progestogens (not with progesterone), but mostly significant only in the presence of PGRMC1. Different animal (xenograft) studies confirmed that synthetic progestogens, but not progesterone and dydrogesterone, increased the estradiol-induced tumor proliferation, although with dydrogesterone, a small time-dependent increase could be seen. Clinical studies with hormone replacement therapy (HRT) to confirm these results are still running. In patients with BC expression of PGRMC1 in BC tissue was correlated to tumor characteristics like diameter, grade, and metastatic status. BC patients with PGRMC1 in the tumors had poorer disease-free and overall survival. After developing of an assay, blood levels could be correlated to the expression in BC tissue showing PGRMC1 superior to tumor markers such as CEA, CA125, CA153, and TPS. Key Messages: This review is summarizing two different functions of PGRMC1: (1) to predict the prognosis of BC patients, already well demonstrated in BC patients and (2) being a possible predictive marker for BC risk during HRT as suggested from in vitro and animal research.
T1 Mapping MOLLI 5(3)3 Acquisition Scheme Yields High Accuracy in 1.5 T Cardiac Magnetic Resonance
2022-11-08

Objectives: To systematically compare two modified Look-Locker inversion recovery (MOLLI) T1 mapping sequences and their impact on (1) myocardial T1 values native, (2) post-contrast and (3) extracellular volume (ECV). Methods: 200 patients were prospectively included for 1.5 T CMR for work-up of ischemic or non-ischemic cardiomyopathies. To determine native and post-contrast T1 for ECV calculation, two different T1 mapping MOLLI acquisition schemes, 5(3)3 (designed for native scans with long T1) and 4(1)3(1)2 (designed for post-contrast scans with short T1), were acquired in identical mid-ventricular short-axis slices. Both schemes were acquired in native and post-contrast scans. Results: Datasets from 163 patients were evaluated (age 55 ± 17 years; 38% female). Myocardial T1 native for 5(3)3 was 1017 ± 42 ms vs. 956 ± 40 ms for 4(1)3(1)2, with mean intraindividual difference −61 ms (p &lt; 0.0001). Post-contrast myocardial T1 in patients was similar for both acquisition schemes, with 494 ± 48 ms for 5(3)3 and 490 ± 45 ms for 4(1)3(1)2 and mean intraindividual difference −4 ms. Myocardial ECV for 5(3)3 was 27.6 ± 4% vs. 27 ± 4% for 4(1)3(1)2, with mean difference −0.6 percentage points (p &lt; 0.0001). Conclusions: The T1 MOLLI 5(3)3 acquisition scheme provides a reliable estimation of myocardial T1 for the clinically relevant range of long and short T1 values native and post-contrast. In contrast, the T1 MOLLI 4(1)3(1)2 acquisition scheme may only be used for post-contrast scans according to its designed purpose.
Abstract 14714: Marked Gradient Reduction Through a Transcoronary Alcohol Ablation of Septal Hypertrophy in a Patient With Cardiac Amyloidosis and Hypertrophic Cardiomyopathy
2022-11-08

A 66-year-old male with a history of carpal tunnel syndrome and hypertension presented with dyspnea (NYHA III), angina pectoris, and sinus bradycardia. On clinical examination, the patient was stable and euvolemic. A systolic murmur (III/VI) was audible in the 4th left intercostal space laterally, augmented after a Valsalva maneuver. An electrocardiogram revealed normal sinus rhythm, heart rate of 81 bpm, normal voltage, and non-specific ST-changes in I, II, III, aVF, V5, and V6. The patient underwent a transthoracic echocardiography, which revealed thickened ventricular walls (IVSd 23 mm, PWd 20 mm), hyperdynamic left ventricular ejection fraction (LVEF 75%), LVOT gradient of 150 mmHg maximum (after Valsalva maneuver), apical sparing on strain analysis, and a dilated atria. A coronary angiography ruled out coronary artery disease. A endomyocardial biopsy revealed hypertrophic cardiomyopathy combined with focal cardiac amyloidosis (Figure 1). Subtyping and genetic analysis revealed transthyretin (ATTR) wild-type amyloidosis. Accordingly, therapy with Tafamidis 61 mg daily was initiated. Given the relevant amount of hypertrophy depicted on the biopsy samples, the high LVOT gradient, and the patient’s debilitating symptoms despite maximal medical therapy, the decision was made to attempt a transcoronary alcohol ablation of the septal hypertrophy (TASH). The TASH reduced the LVOT gradient from 150 mmHg to 35 mmHg. After the procedure, the patient experienced significant symptom improvement (NYHA II) and was discharged the next day. This case illustrates the feasibility of marked LVOT gradient reduction in patients with amyloidosis and hypertrophic cardiomyopathy through a TASH procedure. Figure 1: Histology reveals hypertrophic cardiomyocytes and cardiac amyloidosis on Congo red staining.
Abstract 13986: Efficacy and Safety of Cangrelor in Patients Undergoing PCI After Cardio-Pulmonary Resuscitation and/or Cardiogenic Shock. Results of the CAN-SHOCK Registry
2022-11-08

Background. Cangrelor is an intravenous P2Y12 inhibitor with an immediate onset of action and a short half-life. Its use seems especially attractive in patients who cannot swallow oral drugs, e.g. after CPR or in cardiogenic shock. Purpose. To determine the efficacy and safety of the intravenous P2Y12 inhibitor cangrelor undergoing PCI after prehospital cardiopulmonary resuscitation (CPR) and/or cardiogenic shock (CS) in real life. Methods: The CAN-SHOCK registry included patients undergoing PCI for acute myocardial infarction after CPR. Baseline characteristics, procedural features, and in-hospital outcomes were centrally collected and analysed. The primary endpoint was the incidence of stent thrombosis and/or myocardial reinfarction until 48 hours after PCI. Results. A total of 303 patients were included in 10 centers in Austria and Germany. The inclusion criteria were CPR before PCI (n=169, 55.8 %), cardiogenic shock (n=68, 22.4 %) and CPR and cardiogenic shock (n=59, 19.5 %). The baseline characteristics, in-hospital procedures and outcomes are listed in the table. Conclusions. In this large multicentre registry cangrelor in patients undergoing PCI after CPR and/or CS cangrelor was effective in preventing stent thrombosis and re-infarction and associated with an acceptable bleeding rate.