julilili42/papers huggingface dataset:
An unconventional robust integrator for dynamical low-rank approximation
2021-05-10

Abstract We propose and analyse a numerical integrator that computes a low-rank approximation to large time-dependent matrices that are either given explicitly via their increments or are the unknown solution to a matrix differential equation. Furthermore, the integrator is extended to the approximation of time-dependent tensors by Tucker tensors of fixed multilinear rank. The proposed low-rank integrator is different from the known projector-splitting integrator for dynamical low-rank approximation, but it retains the important robustness to small singular values that has so far been known only for the projector-splitting integrator. The new integrator also offers some potential advantages over the projector-splitting integrator: It avoids the backward time integration substep of the projector-splitting integrator, which is a potentially unstable substep for dissipative problems. It offers more parallelism, and it preserves symmetry or anti-symmetry of the matrix or tensor when the differential equation does. Numerical experiments illustrate the behaviour of the proposed integrator.
Targeting Lyn Kinase in Chorea-Acanthocytosis: A Translational Treatment Approach in a Rare Disease
2021-05-10

Chorea-acanthocytosis (ChAc) is a neurodegenerative disease caused by mutations in the VPS13A gene. It is characterized by several neurological symptoms and the appearance of acanthocytes. Elevated tyrosine kinase Lyn activity has been recently identified as one of the key pathophysiological mechanisms in this disease, and therefore represents a promising drug target. Methods: We evaluated an individual off-label treatment with the tyrosine kinase inhibitor dasatinib (100 mg/d, 25.8–50.4 weeks) of three ChAc patients. Alongside thorough safety monitoring, we assessed motor and non-motor scales (e.g., MDS-UPDRS, UHDRS, quality of life) as well as routine and experimental laboratory parameters (e.g., serum neurofilament, Lyn kinase activity, actin cytoskeleton in red blood cells). Results: Dasatinib appeared to be reasonably safe. The clinical parameters remained stable without significant improvement or deterioration. Regain of deep tendon reflexes was observed in one patient. Creatine kinase, serum neurofilament levels, and acanthocyte count did not reveal consistent effects. However, a reduction of initially elevated Lyn kinase activity and accumulated autophagy markers, as well as a partial restoration of the actin cytoskeleton, was found in red blood cells. Conclusions: We report on the first treatment approach with disease-modifying intention in ChAc. The experimental parameters indicate target engagement in red blood cells, while clinical effects on the central nervous system could not be proven within a rather short treatment time. Limited knowledge on the natural history of ChAc and the lack of appropriate biomarkers remain major barriers for “clinical trial readiness”. We suggest a panel of outcome parameters for future clinical trials in ChAc.
The genetic architecture of phenotypic diversity in the betta fish (Betta splendens)
2021-05-10

Summary The Betta fish displays a remarkable variety of phenotypes selected during domestication. However, the genetic basis underlying these traits remain largely unexplored. Here, we report a high-quality genome assembly and re-sequencing of 727 individuals representing diverse morphologies of the betta fish. We show that current breeds have a complex domestication history with extensive introgression with wild species. Using GWAS, we identify the genetic basis of multiple traits, including several coloration phenotypes, sex-determination which we map to DMRT1 , and the long-fin phenotype which maps to KCNJ15 . We identify a polygenic signal related to aggression with many similarities to human psychiatric traits, involving genes such as CACNB2 and DISC1 . Our study provides a resource for developing the Betta fish as a genetic model for morphology and behavior in vertebrates.
Intact prioritization of fearful faces during continuous flash suppression in psychopathy
2021-05-10

Affective state recognition and in particular the identification of fear is known to be impaired in psychopathy. It is unclear, however, whether this reflects a deficit in basic perception (‘fear blindness’) or a deficit in later cognitive processing. To test for a perceptual deficit, 63 male incarcerated offenders, assessed with the Hare Psychopathy Checklist-Revised (PCL-R), and 59 age-matched control participants detected fearful, neutral, and happy facial expressions rendered invisible through continuous flash suppression (CFS), a strong interocular suppression technique. Consistent with previous CFS studies on children, student and community samples, fearful faces were detected faster than neutral faces, which were detected faster than happy faces. Detection of emotional faces was unimpaired in offenders, with strong evidence for a full-blown fear advantage. Moreover, the fear advantage was not reduced in the 20 offenders qualifying as psychopaths according to the PCL-R, and there was no correlation between the fear advantage and PCL-R scores in the 63 incarcerated offenders. These results show that basic visual detection of fearful faces is unimpaired in psychopathy. Deficits in the processing of fearful facial expressions in psychopathy may thus not reflect fear blindness, but impairments at later post-perceptual processing stages related to attention, memory, decision-making, or language.
Magnetic Resonance Guided Radiation Therapy for Pancreatic Adenocarcinoma, Advantages, Challenges, Current Approaches, and Future Directions
2021-05-11

Introduction Pancreatic adenocarcinoma (PAC) has some of the worst treatment outcomes for any solid tumor. PAC creates substantial difficulty for effective treatment with traditional RT delivery strategies primarily secondary to its location and limited visualization using CT. Several of these challenges are uniquely addressed with MR-guided RT. We sought to summarize and place into context the currently available literature on MR-guided RT specifically for PAC. Methods A literature search was conducted to identify manuscript publications since September 2014 that specifically used MR-guided RT for the treatment of PAC. Clinical outcomes of these series are summarized, discussed, and placed into the context of the existing pancreatic literature. Multiple international experts were involved to optimally contextualize these publications. Results Over 300 manuscripts were reviewed. A total of 6 clinical outcomes publications were identified that have treated patients with PAC using MR guidance. Successes, challenges, and future directions for this technology are evident in these publications. MR-guided RT holds theoretical promise for the treatment of patients with PAC. As with any new technology, immediate or dramatic clinical improvements associated with its use will take time and experience. There remain no prospective trials, currently publications are limited to small retrospective experiences. The current level of evidence for MR guidance in PAC is low and requires significant expansion. Future directions and ongoing studies that are currently open and accruing are identified and reviewed. Conclusions The potential promise of MR-guided RT for PAC is highlighted, the challenges associated with this novel therapeutic intervention are also reviewed. Outcomes are very early, and will require continued and long term follow up. MR-guided RT should not be viewed in the same fashion as a novel chemotherapeutic agent for which dosing, administration, and toxicity has been established in earlier phase studies. Instead, it should be viewed as a novel procedural intervention which must be robustly tested, refined and practiced before definitive conclusions on the potential benefits or detriments can be determined. The future of MR-guided RT for PAC is highly promising and the potential implications on PAC are substantial.
Frictional Segmentation of the Chilean Megathrust From a Multivariate Analysis of Geophysical, Geological, and Geodetic Data
2021-05-11

Abstract We present a formal seismic segmentation model of the Chile Margin derived from a multivariate analysis of gravity anomalies, basal friction and interplate locking from GPS velocities. These independent proxies of the frictional structure along the megathrust integrate over timescales of 10 1 –10 7 years. We analyze their covariance using Principal Component Analysis (PCA) and extracting the Empirical Orthogonal Functions (EOFs) and Principal Components (PCs). We find that (a) the first and first + second PCA modes for the triple combination of the proxies explain (respectively) 41.4% and 69.4% of the total variance and (b) the first‐order spatial pattern of each isolated proxy is largely reproduced when it is combined with the other two proxies. This suggests that the three proxies share a first order along‐trench tendency that must be connected through a common physical process. Comparing our results with rupture areas of earthquakes and using the rate‐and‐state friction theory, we infer that trench‐perpendicular PCs reflect the limits of the velocity‐weakening (VW) seismogenic zone. Polarity changes in along‐trench EOFs (mostly for gravity) mark changes between unstable and conditionally stable frictional regimes inside the VW zone and we used them to define the boundaries of 17 unitary segments. These segments correlate with first‐order tectonic features of the Andes at &gt;10 3 ‐km scales as well as with zones of multi‐segment ruptures at 10 2 ‐km scale. We analyze the combined influence of subducting and upper‐plate geologic features on the nature of persistent seismic barriers. Our results have implications for understanding seismotectonic processes along the Andean margin and elsewhere.
Intermediate-size fullerenes as degradation products of interstellar polycyclic aromatic hydrocarbons
2021-05-11

The high interstellar abundances of polycyclic aromatic hydrocarbons (PAHs) and their size distribution are the result of complex chemical processes implying dust, UV radiation, and the main gaseous components (H, C + , and O). These processes must explain the high abundance of relatively small PAHs in the diffuse interstellar medium (ISM) and imply the continuous formation of some PAHs that are small enough (number of carbon atoms N C &lt; ~35–50) to be completely dehydrogenated by interstellar UV radiation. The carbon clusters C n thus formed are constantly exposed to the absorption of ~10–13.6 eV UV photons, allowing isomerization and favoring the formation of the most stable isomers. They might tend to form irregular carbon cages. The frequent accretion of interstellar C + ions could favor further cage isomerization, as is known in the laboratory for C 60 , possibly yielding most stable fullerenes, such as C 40 , C 44 , and C 50 . These fullerenes are expected to be very stable in the diffuse ISM because C 2 ejection is not possible by single UV photon absorption, but could need rare two-photon absorption. It is possible that at least one of these fullerenes or its cation is as abundant as C 60 or C 60 + in the diffuse ISM, although this abundance is limited by the lack of observed matching features in observed mid-infrared spectra. B3LYP calculations of the visible spectrum for a number of fullerene isomers with 40 ≤ N C ≤ 50 show that they generally have a few spectral bands in the visible range, with f-values in the range of a few 10 −2 . This could make such fullerenes interesting candidates for the carriers of some diffuse interstellar bands.
Design and Synthesis of Highly Selective Brain Penetrant p38α Mitogen-Activated Protein Kinase Inhibitors
2021-05-11

Stress-induced p38α mitogen-activated protein (MAP) kinase activation modulates cytokine overproduction and is associated with neuroinflammation and neurodegeneration. As a potential therapeutic approach, novel Skepinone-based p38α MAP kinase inhibitors were optimized to cross the blood-brain barrier via either amino acid transporters or hydrophobic diffusion. To enhance absorption from the oral route, we used methyl ester prodrugs of the active carboxy analogs. Of these, 3-(8-((2,4-difluorophenyl)amino)-5-oxo-10,11-dihydro-<i>5H</i>-dibenzo[<i>a</i>,<i>d</i>][7]annulene-3-carboxamido)propanoic acid (<b>43</b>; p38α, IC<sub>50</sub> = 5.5 nM) and 4-(8-((2,4-difluorophenyl)amino)-5-oxo-10,11-dihydro-5<i>H</i>-dibenzo[<i>a</i>,<i>d</i>][7]annulene-3-carboxamido)butanoic acid (<b>44</b>; p38α, IC<sub>50</sub> = 12 nM) had brain-to-plasma ratios of 1.4 and 4.4, respectively. Compound <b>70</b>, 3-(8-((2-aminophenyl)amino)-5-oxo-10,11-dihydro-5<i>H</i>-dibenzo[<i>a</i>,<i>d</i>][7]annulene-3-carboxamido)propanoic acid (p38α, IC<sub>50</sub> = 1.0 nM), the Skepinone-N counterpart of <b>43</b>, was most present in the mouse brain (brain-to-plasma ratio of 4.7; 0.4 mg/kg p.o., 2 h, 580 nmol/kg). Compounds <b>43</b>, <b>44</b>, and <b>70</b> were p38α-MAP-kinase-selective, metabolically stable, hERG nonbinding, and able to modulate IL-6 and TNF-α production in cell-based assays.
Form-factor-independent test of lepton universality in semileptonic heavy meson and baryon decays
2021-05-11

In the semileptonic decays of heavy mesons and baryons the lepton-mass\\ndependence factors out in the quadratic coefficient of the\\ndifferential distribution. We call the corresponding normalized\\ncoefficient the convexity parameter. This observation opens the path to a test\\nof lepton universality in semileptonic heavy meson and baryon decays that is\\nindependent of form-factor effects. By projecting out the quadratic rate\\ncoefficient, dividing out the lepton-mass-dependent factor and restricting the\\nphase space integration to the lepton phase space, one can define\\noptimized partial rates which, in the Standard Model, are the same for all\\nthree modes in a given semileptonic decay process. We discuss\\nhow the identity is spoiled by New Physics effects. We discuss semileptonic\\nheavy meson decays such as and\\n , and semileptonic heavy baryon\\ndecays such as for each\\n .\\n
Peril, Prudence and Planning as Risk, Avoidance and Worry
2021-05-11

Risk occupies a central role in both the theory and practice of decision-making. Although it is deeply implicated in many conditions involving dysfunctional behavior and thought, modern theoretical approaches to understanding and mitigating risk, in either one-shot or sequential settings, have yet to permeate fully the fields of neural reinforcement learning and computational psychiatry. Here we use one prominent approach, called conditional value-at-risk (CVaR), to examine optimal risk-sensitive choice and a form of optimal, risk-sensitive offline planning. We relate the former to both a justified form of the gambler’s fallacy and extremely risk-avoidant behavior resembling that observed in anxiety disorders. We relate the latter to worry and rumination.
Risk Factors for Delirium Are Different in the Very Old: A Comparative One-Year Prospective Cohort Study of 5,831 Patients
2021-05-11

Background: In an ever-aging society, health care systems will be confronted with an increasing number of patients over 80 years (“the very old”). Currently, knowledge about and recommendations for delirium management are often based on studies in patients aged 60 to 65 years. It is not clear whether these findings apply to patients ≥80 years. Aim: Comparison of younger and older patients with delirium, especially regarding risk factors. Methods: In this prospective cohort study, within 1-year, 5,831 patients (18–80 years: n = 4,730; ≥80: n = 1,101) with delirium were enrolled. The diagnosis of delirium was based on the Delirium Observation screening scale (DOS), Intensive Care Delirium Screening Checklist (ICDSC) and a DSM (Diagnostic and Statistical Manual)-5 construct of nursing instrument. Sociodemographic trajectories, as well as the relevant predisposing and precipitating factors for delirium, were assessed via a multiple regression analysis. Results: The very old were more commonly admitted as emergencies (OR 1.42), had a greater mortality risk (OR 1.56) and displayed fewer precipitating risk factors for the development of a delirium, although the number of diagnoses were not different ( p = 0.325). Predisposing factors were sufficient almost alone for the development of delirium in patients ≥ 80 years of age; in 18–80 years of age, additional precipitating factors had to occur to make a delirium possible. Conclusion: When relevant predisposing factors for delirium are apparent, patients over 80 years of age require comparatively few or no precipitating factors to develop delirium. This finding should be taken into account at hospitalization and may allow better treatment of delirium in the future.
Platelet-Expressed Synaptophysin (pSyn) as Novel Biomarker in Neuroendocrine Malignancies
2021-05-11

Neuroendocrine neoplasms (NENs) encompass a heterogeneous group of tumors. Whereas low-grade neuroendocrine tumors (NETs) are histologically well-differentiated, highly aggressive neuroendocrine carcinomas (NECs) are characterized by a high proliferation rate and a worse clinical outcome. Since most NEN patients need monitoring of tumor progress and response to treatment for a long period of time, especially in metastatic disease, reliable, dynamic, and easy-to-assess biomarkers are needed. In this prospective study, we identified platelet-expressed synaptophysin (pSyn) as a novel biomarker in NENs. The level of pSyn in NENs was significantly upregulated compared to healthy donors. pSyn was positively correlated with higher tumor stages, the occurrence of metastasis, histological grading, and higher tumor proliferation (Ki67). Most importantly, high pSyn expression in our NEN cohort was shown to predict shorter progression-free survival (PFS). In conclusion, our data highlight the potential of pSyn as a novel biomarker in NENs reflecting tumor stages, grading, and prognosis.
Neogene hyperaridity in Arabia drove the directions of mammalian dispersal between Africa and Eurasia
2021-05-11

The evolution of the present-day African savannah fauna has been substantially influenced by the dispersal of Eurasian ancestors into Africa. The ancestors evolved endemically, together with the autochthonous taxa, into extant Afrotropical clades during the last 5 million years. However, it is unclear why Eurasian ancestors moved into Africa. Here we use sedimentological observations and soluble salt geochemical analyses of samples from a sedimentary sequence in Western Iran to develop a 10-millionyear long proxy record of Arabian climate. We identify transient periods of Arabian hyperaridity centred 8.75, 7.78, 7.50 and 6.25 million years ago, out of-phase with Northern African aridity. We propose that this relationship promoted unidirectional mammalian dispersals into Africa. This was followed by a sustained hyperarid period between 5.6 and 3.3 million years ago which impeded dispersals and allowed African mammalian faunas to endemically diversify into present-day clades. After this, the mid-Piacenzian warmth<br> enabled bi-directional fauna exchange between Africa and Eurasia, which continued during the Pleistocene.
Staphylococcus epidermidis Phages Transduce Antimicrobial Resistance Plasmids and Mobilize Chromosomal Islands
2021-05-12

Multidrug-resistant strains of S. epidermidis emerge in both nosocomial and livestock environments as the most important pathogens among coagulase-negative staphylococcal species. The study of transduction by phages is essential to understanding how virulence and antimicrobial resistance genes spread in originally commensal bacterial populations.
Tools for optimising pharmacotherapy in psychiatry (therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests): focus on antidepressants
2021-05-12

<b>Objectives:</b> More than 40 drugs are available to treat affective disorders. Individual selection of the optimal drug and dose is required to attain the highest possible efficacy and acceptable tolerability for every patient.<b>Methods:</b> This review, which includes more than 500 articles selected by 30 experts, combines relevant knowledge on studies investigating the pharmacokinetics, pharmacodynamics and pharmacogenetics of 33 antidepressant drugs and of 4 drugs approved for augmentation in cases of insufficient response to antidepressant monotherapy. Such studies typically measure drug concentrations in blood (i.e. therapeutic drug monitoring) and genotype relevant genetic polymorphisms of enzymes, transporters or receptors involved in drug metabolism or mechanism of action. Imaging studies, primarily positron emission tomography that relates drug concentrations in blood and radioligand binding, are considered to quantify target structure occupancy by the antidepressant drugs in vivo. <b>Results:</b> Evidence is given that in vivo imaging, therapeutic drug monitoring and genotyping and/or phenotyping of drug metabolising enzymes should be an integral part in the development of any new antidepressant drug.<b>Conclusions:</b> To guide antidepressant drug therapy in everyday practice, there are multiple indications such as uncertain adherence, polypharmacy, nonresponse and/or adverse reactions under therapeutically recommended doses, where therapeutic drug monitoring and cytochrome P450 genotyping and/or phenotyping should be applied as valid tools of precision medicine.
Factors Influencing the Adjuvant Therapy Decision: Results of a Real-World Multicenter Data Analysis of 904 Melanoma Patients
2021-05-12

Adjuvant treatment of melanoma patients with immune-checkpoint inhibition (ICI) and targeted therapy (TT) significantly improved recurrence-free survival. This study investigates the real-world situation of 904 patients from 13 German skin cancer centers with an indication for adjuvant treatment since the approval of adjuvant ICI and TT. From adjusted log-binomial regression models, we estimated relative risks for associations between various influence factors and treatment decisions (adjuvant therapy yes/no, TT vs. ICI in BRAF mutant patients). Of these patients, 76.9% (95% CI 74–80) opted for a systemic adjuvant treatment. The probability of starting an adjuvant treatment was 26% lower in patients &gt;65 years (RR 0.74, 95% CI 68–80). The most common reasons against adjuvant treatment given by patients were age (29.4%, 95% CI 24–38), and fear of adverse events (21.1%, 95% CI 16–28) and impaired quality of life (11.9%, 95% CI 7–16). Of all BRAF-mutated patients who opted for adjuvant treatment, 52.9% (95% CI 47–59) decided for ICI. Treatment decision for TT or ICI was barely associated with age, gender and tumor stage, but with comorbidities and affiliated center. Shortly after their approval, adjuvant treatments have been well accepted by physicians and patients. Age plays a decisive role in the decision for adjuvant treatment, while pre-existing autoimmune disease and regional differences influence the choice between TT or ICI.