Miracle-dz/UniFAR-FTUs huggingface dataset:
Variation in actuarial senescence does not reflect life span variation across mammals

The concept of actuarial senescence (defined here as the increase in mortality hazards with age) is often confounded with life span duration, which obscures the relative role of age-dependent and age-independent processes in shaping the variation in life span. We use the opportunity afforded by the Species360 database, a collection of individual life span records in captivity, to analyze age-specific mortality patterns in relation to variation in life span. We report evidence of actuarial senescence across 96 mammal species. We identify the life stage (juvenile, prime-age, or senescent) that contributes the most to the observed variation in life span across species. Actuarial senescence only accounted for 35%–50% of the variance in life span across species, depending on the body mass category. We computed the sensitivity and elasticity of life span to five parameters that represent the three stages of the age-specific mortality curve—namely, the duration of the juvenile stage, the mean juvenile mortality, the prime-age (i.e., minimum) adult mortality, the age at the onset of actuarial senescence, and the rate of actuarial senescence. Next, we computed the between-species variance in these five parameters. Combining the two steps, we computed the relative contribution of each of the five parameters to the variance in life span across species. Variation in life span was increasingly driven by the intensity of actuarial senescence and decreasingly driven by prime-age adult mortality from small to large species because of changes in the elasticity of life span to these parameters, even if all the adult survival parameters consistently exhibited a canalization pattern of weaker variability among long-lived species than among short-lived ones. Our work unambiguously demonstrates that life span cannot be used to measure the strength of actuarial senescence, because a substantial and variable proportion of life span variation across mammals is not related to actuarial senescence metrics.
CD8+ T-cells of CLL-bearing mice acquire a transcriptional program of T-cell activation and exhaustion

Abstract Chronic lymphocytic leukemia (CLL) is associated with an accumulation of oligoclonal CD8+ effector T-cells, which control leukemia progression in mice, but gradually acquire a dysfunctional phenotype along with disease progression. Exhaustion of CD8+ T-cells is characterized by increased expression of inhibitory receptors like PD-1, decreased proliferation, and reduced effector function such as cytokine production, which reduces anti-tumor control. Despite the accumulation of exhausted PD-1+ CD8+ T-cells in secondary lymphoid organs of CLL patients, immune checkpoint blockade as a means to reinvigorate anti-tumor T-cell activity has not shown the expected efficacy. This highlights the need for a better understanding of T-cell exhaustion in CLL. Here, we uncover the transcriptional program of T-cell exhaustion in CLL by comparing naïve with dysfunctional effector CD8+ T-cells with high PD-1 expression from mice after adoptive transfer of Eµ-TCL1 leukemic cells. Our data provide clear evidence for activation-induced dysfunction of CD8+ T-cells in the CLL microenvironment and assess the heterogeneity in the expression of functionally relevant proteins in specific clusters of CD8+ T-cells at a single-cell level.
Functional conservation of lncRNA JPX despite sequence and structural divergence

Long noncoding RNAs (lncRNAs) have been identified in all eukaryotes and are most abundant in the human genome. However, the functional importance and mechanisms of action for human lncRNAs are largely unknown. Using comparative sequence, structural, and functional analyses, we characterize the evolution and molecular function of human lncRNA JPX. We find that human JPX and its mouse homolog, lncRNA Jpx, have deep divergence in their nucleotide sequences and RNA secondary structures. Despite such differences, both lncRNAs demonstrate robust binding to CTCF, a protein that is central to Jpx’s role in X chromosome inactivation. In addition, our functional rescue experiment using Jpx-deletion mutant cells, shows that human JPX can functionally complement the loss of Jpx in mouse embryonic stem cells. Our findings support a model for functional conservation of lncRNAs independent from sequence and structural changes. The study provides mechanistic insight into the evolution of lncRNA function.
Impact of uncertainties in range and RBE on small field proton therapy

The objective of this paper is to evaluate the clinical impact of biological uncertainties in small field proton therapy due to the assumption of using a constant relative biological effectiveness (RBE) value of 1.1 (RBE-fixed) compared to a variable RBE (RBE-weighted). In this context the impact of the applied range margin was investigated. Eight patients with arteriovenous malformation (AVM) treated with proton radiosurgery were selected due to the small target volume. Dose distributions were compared for RBE-weighted and RBE-fixed. The impact of RBE was assessed using Monte Carlo (MC) dose calculations for stereotactic doses and doses of 2 Gy(RBE). Four different α/β ratios were investigated. Additionally, dose distributions were recalculated with reduced range margins. Applying variable RBE values for stereotactic doses resulted in an increase in the mean dose of 1.6% for a low α/β of 2 Gy, but a decrease of 2.6% for an α/β of 10 Gy. However, the mean dose increased to 17.1% and 2.1% for doses of 2 Gy(RBE) and α/β of 2 Gy and 10 Gy, respectively. Reducing range margins from 3.5% + 1 mm to 2.5% + 1 mm resulted in negligible difference in the mean RBE within the target, or 0.1% for stereotactic doses and 0.3% for doses of 2 Gy(RBE). Larger differences were seen for a range reduction to 0% + 1 mm, i.e. 1.1% and 3.0% for stereotactic doses and doses of 2 Gy(RBE), respectively. Because potential RBE effects are typically more pronounced in the distal part of a field, a bigger clinical impact of RBE uncertainties in small fields is expected. Our study shows that this could be significant for tissues with low α/β and a small dose per fraction. The uncertainty in RBE due to the uncertainty associated with the α/β ratio seems larger than the impact of the applied range uncertainty margin on RBE.
Big Data and Artificial Intelligence Modeling for Drug Discovery.

Due to the massive data sets available for drug candidates, modern drug discovery has advanced to the big data era. Central to this shift is the development of artificial intelligence approaches to implementing innovative modeling based on the dynamic, heterogeneous, and large nature of drug data sets. As a result, recently developed artificial intelligence approaches such as deep learning and relevant modeling studies provide new solutions to efficacy and safety evaluations of drug candidates based on big data modeling and analysis. The resulting models provided deep insights into the continuum from chemical structure to in vitro, in vivo, and clinical outcomes. The relevant novel data mining, curation, and management techniques provided critical support to recent modeling studies. In summary, the new advancement of artificial intelligence in the big data era has paved the road to future rational drug development and optimization, which will have a significant impact on drug discovery procedures and, eventually, public health. Expected final online publication date for the Annual Review of Psychology, Volume 71 is January 4, 2020. Please see http://www.annualreviews. org/page/journal/pubdates for revised estimates.
Cultural differences in the use of acoustic cues for musical emotion experience

Does music penetrate cultural differences with its ability to evoke emotion? The ragas of Hindustani music are specific sequences of notes that elicit various emotions: happy, romantic, devotion, calm, angry, longing, tension and sad. They can be presented in two modes, alaap and gat, which differ in rhythm, but match in tonality. Participants from Indian and Non-Indian cultures (N = 144 and 112, respectively) rated twenty-four pieces of Hindustani ragas on eight dimensions of emotion, in a free response task. Of the 192 between-group comparisons, ratings differed in only 9% of the instances, showing universality across multiple musical emotions. Robust regression analyses and machine learning methods revealed tonality best explained emotion ratings for Indian participants whereas rhythm was the primary predictor in Non-Indian listeners. Our results provide compelling evidence for universality in emotions in the auditory domain in the realm of musical emotion, driven by distinct acoustic features that depend on listeners’ cultural backgrounds.
Predictive rules for optical diagnosis of < 10-mm colorectal polyps based on a dedicated software

Abstract Background The BASIC classification for predicting in vivo colorectal polyp histology incorporates both surface and pit/vessel descriptor domains. This study aimed to define new BASIC classes for adenomatous and hyperplastic polyps. Methods A video library (102 still images/videos of < 10-mm polyps using white-light [WLI] and blue-light imaging [BLI]) was reviewed by seven expert endoscopists. Polyps were rated according to the individual descriptors of the three BASIC domains (surface/pit/vessel). A model to predict polyp histology (adenomatous or hyperplastic) was developed using multivariable logistic regression and subsequent “leave-one-out” cross-validation. New BASIC rules were then defined by Delphi agreement. The overall accuracy of these rules when used by experts was evaluated according to the level of confidence and light type. Results The strength of prediction for adenomatous histology from 2175 observations assessed by area under the curve (AUC; 95 % confidence interval) was poor-to-fair for the surface descriptors (0.50 [0.33 – 0.69] for mucus; 0.68 [0.57 – 0.79] for irregular surface), but stronger for pits (0.87 [0.80 – 0.96] for featureless/round/not round) and vessels (0.80 [0.65 – 0.87] for not present/lacy/pericryptal). By combining the domains, a good-to-excellent prediction was shown (AUC 0.89 [0.81 – 0.96]). After the definition of new BASIC rules for adenomatous and hyperplastic polyps, accuracy for high confidence BLI predictions was 90.3 % (86.3 % – 93.2 %), which was superior to high confidence WLI (83.7 % [77.3 % – 87.7 %]) and low confidence BLI predictions (77.7 % [61.1 % – 88.6 %]). Conclusions Based on the strength of prediction, the new BASIC classes for adenomatous and hyperplastic histology show favorable results for accuracy and confidence levels.
Low-level sensory processes play a more crucial role than high-level cognitive ones in the size-weight illusion

The size-weight illusion (SWI) pertains to the experience of perceiving the smaller of two equally weighted objects as heavier. Competing theories to explain the illusion can be generally grouped into cognitive and sensory theories, which place more importance on top-down processing of cognitive expectations and bottom-up processing of sensory information about the size and weight of objects, respectively. The current study examined the relative contribution of these two general explanations. This was done by varying the amounts of cognitive load in a dual-task and the quality of somatosensory feedback by wearing or not wearing gloves. Participants placed their hands through a curtain inside a box so they could not see the test objects. Inside the box, they were presented with either a small or large sphere of varying weights, which they explored manually without vision. Participants provided magnitude estimates about each object’s weight in four experimental conditions (no-load with gloves, no-load without gloves, low-load without gloves, and high-load without gloves). The dual-task involved the visual presentation of a cross on a computer monitor that changed in both colour and orientation. With foot pedals, the participants responded to a target colour and / or orientation, which varied across conditions, while they hefted an object. Some conditions were designed to be more cognitively taxing than others (high-load > low-load > no-load conditions). The results revealed that the strength of the SWI diminished when participants wore the gloves but did not change as cognitive load increased on the dual-task. We conclude that the illusion is more influenced by bottom-up sensory than top-down cognitive processes.
Cholecystokinin 2 Receptor Agonist 177Lu-PP-F11N for Radionuclide Therapy of Medullary Thyroid Carcinoma: Results of the Lumed Phase 0a Study

Treatment of patients with advanced medullary thyroid carcinoma (MTC) is still a challenge. For more than 2 decades, it has been known that the cholecystokinin 2 receptor is a promising target for the treatment of MTC with radiolabeled minigastrin analogs. Unfortunately, kidney toxicity has precluded their therapeutic application so far. In 6 consecutive patients, we evaluated with advanced 3-dimensional dosimetry whether improved minigastrin analog 177Lu-DOTA-(d-Glu)6-Ala-Tyr-Gly-Trp-Nle-Asp-PheNH2 (177Lu-PP-F11N) is a suitable agent for the treatment of MTC. Methods: Patients received 2 injections of about 1 GBq (∼80 μg) of 177Lu-PP-F11N with and without a solution of succinylated gelatin (SG, a plasma expander used for nephroprotection) in a random crossover sequence to evaluate biodistribution, pharmacokinetics, and tumor and organ dosimetry. An electrocardiogram was obtained and blood count and blood chemistry were measured up to 12 wk after the administration of 177Lu-PP-F11N to assess safety. Results: In all patients, 177Lu-PP-F11N accumulation was visible in tumor tissue, stomach, and kidneys. Altogether, 13 tumors were eligible for dosimetry. The median absorbed doses for tumors, stomach, kidneys, and bone marrow were 0.88 (interquartile range [IQR]: 0.85–1.04), 0.42 (IQR: 0.25–1.01), 0.11 (IQR: 0.07–0.13), and 0.028 (IQR: 0.026–0.034) Gy/GBq, respectively. These doses resulted in median tumor-to-kidney dose ratios of 11.6 (IQR: 8.11–14.4) without SG and 13.0 (IQR: 10.2–18.6) with SG; these values were not significantly different (P = 1.0). The median tumor-to-stomach dose ratio was 3.34 (IQR: 1.14–4.70). Adverse reactions (mainly hypotension, flushing, and hypokalemia) were self-limiting and not higher than grade 1. Conclusion: 177Lu-PP-F11N accumulates specifically in MTC at a dose that is sufficient for a therapeutic approach. With a low kidney and bone marrow radiation dose, 177Lu-PP-F11N shows a promising biodistribution. The dose-limiting organ is most likely the stomach. Further clinical studies are necessary to evaluate the maximum tolerated dose and the efficacy of 177Lu-PP-F11N.
A Screen of the Conserved Kinome for Negative Regulators of LIN-12 Negative Regulatory Region (“NRR”)-Missense Activity in Caenorhabditis elegans

Genetic analysis of LIN-12/Notch signaling in C. elegans has provided many insights into human biology. Activating missense mutations in the Negative Regulatory Region (NRR) of the ectodomain of LIN-12/Notch were first described in C. elegans, and similar mutations in human Notch were later found to cause T-cell acute lymphoblastic leukemia (T-ALL). The ubiquitin ligase sel-10/Fbw7 is the prototype of a conserved negative regulator of lin-12/Notch that was first defined by loss-of-function mutations that enhance lin-12 NRR-missense activity in C. elegans, and then demonstrated to regulate Notch activity in mammalian cells and to be a bona fide tumor suppressor in T-ALL. Here, we report the results of an RNAi screen of 248 C. elegans protein kinase-encoding genes with human orthologs for enhancement of a weakly activating NRR-missense mutation of lin-12 in the Vulval Precursor Cells. We identified, and validated, thirteen kinase genes whose loss led to increase lin-12 activity; eleven of these genes have never been implicated previously in regulating Notch activity in any system. Depleting the activity of five kinase genes (cdk-8, wnk-1, kin-3, hpo-11, and mig-15) also significantly enhanced the activity of a transgene in which heterologous sequences drive expression of the untethered intracellular domain of LIN-12, suggesting that they increase the activity or stability of the signal-transducing form of LIN-12/Notch. Precedents set by other regulators of lin-12/Notch defined through genetic interactions in C. elegans suggest that this new set of genes may include negative regulators that are functionally relevant to mammalian development and cancer.
Music notes to amino acid sequence: A STEAM approach to study protein structure

Recently, manuscripts that use bioinformatics tools to convert proteins and other biological materials into music have appeared in several journals. The authors claim that this type of studies adds joy to education of life sciences and attract public attention to biochemistry education along with other uses. We thought the reverse of the process might also be possible for the purpose. We converted notes into amino acids depending on the decreasing hydrophobicity and by using the famous nursery song “Twinkle, Twinkle, Little Star” notes, a hypothetical protein sequence was obtained. Three‐dimensional structures were modeled by I‐Tasser Protein Structure and Function Prediction server and the structure of the possible models were investigated. This Science, Technology, Engineering, Arts and Math (STEAM) approach may bring fun to protein structure education. © 2019 International Union of Biochemistry and Molecular Biology, 47(6):669–671, 2019.
The Role of Personality in Retirement Adjustment: Longitudinal Evidence for the Effects on Life Satisfaction.

OBJECTIVE Research on retirement suggests that personality can influence the adjustment process, but the mechanisms involved remain still largely unknown. In the present study we investigate direct and indirect associations between the Big Five personality traits and life satisfaction over the retirement transition. Indirect effects were evaluated through the role of personality for levels and changes in self-esteem, autonomy, social support, self-rated physical health, self-rated cognitive ability, and financial satisfaction. METHOD Our sample consisted of 796 older adults (age 60-66) and four annual measurement waves from the longitudinal population-based HEalth, Ageing, and Retirement Transitions in Sweden (HEARTS) study, including individuals retiring during the study period. RESULTS Results from multivariate latent growth curve analysis revealed multiple indirect associations between personality and life satisfaction. Extraversion, agreeableness, and conscientiousness were positively related to life satisfaction through higher levels of self-esteem, autonomy, and social support. Neuroticism was negatively associated with life satisfaction through lower levels of self-esteem and lower levels and negative changes in autonomy and social support. CONCLUSIONS Our findings suggest that retirees with higher levels of neuroticism are more vulnerable in the transition process and they are also more likely to experience adjustment problems resulting from negative changes in key resources.
Hypoxic drive caused Type 3 neovascularization in a preclinical model of exudative age-related macular degeneration.

Hypoxia associated with the high metabolic demand of rods has been implicated in the pathology of age-related macular degeneration (AMD), the most common cause of adult blindness in the developed world. The majority of AMD-associated severe vision loss cases are due to exudative AMD, characterized by neovascularization. To further investigate the causes and histopathology of exudative AMD, we conditionally induced hypoxia in a novel preclinical AMD model (Pde6gcreERT2/+;Vhl-/-) by targeting Vhl and used multimodal imaging and immunohistochemistry to track the development of hypoxia-induced neovascularization. In addition to developing a preclinical model that phenocopies exudative AMD, our studies revealed that the photoreceptor hypoxic response initiates and drives Type 3 neovascularization, mainly in the outer retina. Activation of the VHL-HIF1a-VEGF-EPO pathway in the adult retina led to long-term neovascularization, retinal hemorrhages, and compromised retinal layers. Our novel preclinical model would accelerate the testing of therapies that use metabolomic approaches to ameliorate AMD.
Unmanipulated haploidentical peripheral blood stem cell transplantation for patients with Philadelphia-negative acute lymphoblastic leukaemia in first complete remission

Abstract Haploidentical peripheral blood stem cell transplantation (Haplo-PBSCT) is a promising treatment option for patients with Ph-negative acute lymphoblastic leukemia (ALL). In this study, we retrospectively analyzed data from Ph-negative ALL patients who underwent haplo-PBSCT during their first complete remission (CR1), and compared the long-term outcomes between the standard-risk and high-risk patients. The 3-year probability of relapse was 7.6% and 16.7% for the standard- and high-risk group (p = .274). The 3-year probability of disease-free survival (DFS) and overall survival (OS) for the standard-risk versus high-risk groups were 84.6% versus 50% (p = .0063) and 92.3% versus 61.1% (p = .046), respectively. Univariate analysis showed that a diagnosis of high risk with fusion/mutation genes were associated with worse outcomes, which was confirmed by multivariate analysis (p = .016). In summary, haplo-PBSCT may be a promising alternative for patients with Ph-negative ALL in CR1, although the fusion/mutation genes in high-risk patients may relatively impair the long-term efficacy compared with standard-risk patients.
Long-range order imposed by short-range interactions in methylammonium lead iodide: Comparing point-dipole models to machine-learning force fields

The crystal structure of the MAPbI$_3$ hybrid perovskite forms an intricate electrostatic puzzle with different ordering patterns of the MA molecules at elevated temperatures. For this perovskite three published model Hamiltonians based on the point-dipole (pd) approximation combined with short-range effective interactions are compared to a recently developed machine-learning force field. A molecular order parameter is used to consistently compare the transformation of the anti-ferroelectric ordering in the orthorhombic phase upon raising the temperature. We show that the ground states and the order-disorder transition of the three models are completely different. Our analysis indicates that the long-range order in the low-temperature orthorhombic phase can be captured by pd-based models with a short cutoff radius, including the nearest and next-nearest neighbor molecules. By constructing effective atomic interactions the ordering can already be described within 6 A radius. By extracting the coupling energetics of the molecules from density functional theory calculations on MA$_x$Cs$_{1-x}$PbI$_3$ test systems, we show that the pd-approximation holds at least for static structures. To improve the accuracy of the pd-interaction an Ewald summation is applied combined with a distance dependent electronic screening function.