julilili42/papers huggingface dataset:
Climate change and state evolution
2021-03-31

Despite the vast evidence on the short-run effects of adverse climate shocks on the economy, our understanding of their long-run impact on institutions is limited. To tackle such a key issue, a vast body of research has focused on ancient societies because of the limited complexity of their economies and their unparalleled experience with environmental and institutional change. Notably, the “collapse archaeology” literature has reported countless correlations consistent with the mantra that severe droughts are bound to trigger institutional crises. This conclusion, however, has been recently challenged by a stream of papers that, building on more detailed data on Bronze Age Mesopotamia and a more credible theory-based empirical strategy, have yielded the following two results. First, severe droughts pushed the elites to grant strong political and property rights to the nonelites to convince them that a sufficient part of the returns on joint investments would be shared via public good provision and, thus, to cooperate and accumulate a culture of cooperation. Second, a more favorable climate allowed the elites to elicit cooperation under less inclusive political regimes as well as a weaker culture of cooperation and, possibly, incomplete property rights. These patterns emphasize the importance of considering the asymmetric effect of droughts and, more generally, combining natural and social sciences for the evaluation of climate-related policies.
Differences Sustained Between Diffuse and Limited Forms of Juvenile Systemic Sclerosis in an Expanded International Cohort
2021-03-31

Objective To evaluate the baseline clinical characteristics of juvenile systemic sclerosis (SSc) patients in the international juvenile SSc inception cohort, and to compare these characteristics between the classically defined juvenile diffuse cutaneous SSc (dcSSc) and limited cutaneous SSc (lcSSc) subtypes and among those with overlap features. Methods A cross‐sectional study was performed using baseline visit data. Information on demographic characteristics, organ system evaluation, treatment, and patient‐ and physician‐reported outcomes was extracted and summary statistics applied. Comparisons between juvenile dcSSc and lcSSc subtypes and patients with and without overlap features were performed using chi‐square and Mann‐Whitney U tests. Results At data extraction, 150 juvenile SSc patients were enrolled across 42 centers; 83% were White, 80% were female, juvenile dcSSc predominated (72%), and 17% of the cohort had overlap features. Significant differences were found between juvenile dcSSc and juvenile lcSSc regarding modified Rodnan skin thickness score, the presence of Gottron's papules, digital tip ulceration, results of the 6‐minute walk test, and composite pulmonary and cardiac involvement. All of these were more frequent in dcSSc except for cardiac involvement. Juvenile dcSSc patients had significantly worse scores for physician‐rated disease activity and damage. A significantly higher occurrence of Gottron's papules and musculoskeletal and composite pulmonary involvement, and a significantly lower frequency of Raynaud's phenomenon, were seen in those with overlap features. Conclusion Results from a large international juvenile SSc cohort demonstrate significant differences between juvenile dcSSc and juvenile lcSSc patients, including more globally severe disease and increased frequency of interstitial lung disease in juvenile dcSSc patients, while those with lcSSc have more frequent cardiac involvement. Those with overlap features had an unexpected higher frequency of interstitial lung disease.
Identification of Substandard and Falsified Medicines: Influence of Different Tolerance Limits and Use of Authenticity Inquiries
2021-03-31

ABSTRACT Substandard and falsified medicines have severe public health and socioeconomic effects, especially in low- and middle-income countries. The WHO has emphasized the need for reliable estimates of the prevalence of such medicines to efficiently respond to this problem. In the present study, we used 601 medicine samples collected in Cameroon, the DR Congo, and Malawi to assess the rates of substandard and falsified medicines based on different criteria. Based on the specifications of the U.S. Pharmacopoeia for the amount of the active pharmaceutical ingredients, the rate of out-of-specification medicines was 9.3%. By contrast, this rate ranged from 3.3% up to 35.0% if the tolerance limits of other pharmacopoeias or recently published medicine quality studies were used. This shows an urgent need for harmonization. Principal methods to assess the rate of falsified medicines are packaging analysis, chemical analysis, and authenticity inquiries. In the present study, we carried out an authenticity inquiry for the aforementioned medicine samples, contacting 126 manufacturers and 42 distributors. Response rates were higher for samples stated to be manufactured in Asia (52.4%) or Europe (53.8%) than for samples manufactured in Africa (27.4%; P &lt; 0.001). One sample had been identified as falsified by packaging analysis by the local researchers and two additional ones by chemical analysis. Notably, seven additional falsified samples were identified by the authenticity inquiries. The total rate of falsified medicines resulted as 1.7%. Considerations are discussed for assessing the rates of “substandard” and “falsified” medicines in future medicine quality studies.
Pancreatic fat cells of humans with type 2 diabetes display reduced adipogenic and lipolytic activity
2021-03-31

Obesity, especially visceral fat accumulation, increases the risk of type 2 diabetes (T2D). The purpose of this study was to investigate the impact of T2D on the pancreatic fat depot. Pancreatic fat pads from 17 partial pancreatectomized patients (PPP) were collected, pancreatic preadipocytes isolated, and in vitro differentiated. Patients were grouped using HbA1c into normal glucose tolerant (NGT), prediabetic (PD), and T2D. Transcriptome profiles of preadipocytes and adipocytes were assessed by RNAseq. Insulin sensitivity was estimated by quantifying AKT phosphorylation on Western blots. Lipogenic capacity was assessed with oil red O staining, lipolytic activity via fatty acid release. Secreted factors were measured using ELISA. Comparative transcriptome analysis of preadipocytes and adipocytes indicates defective upregulation of genes governing adipogenesis ( NR1H3), lipogenesis ( FASN, SCD, ELOVL6, and FADS1), and lipolysis ( LIPE) during differentiation of cells from T2D–PPP. In addition, the ratio of leptin/adiponectin mRNA was higher in T2D than in NGT–PPP. Preadipocytes and adipocytes of NGT–PPP were more insulin sensitive than T2D–PPP cells in regard to AKT phosphorylation. Triglyceride accumulation was similar in NGT and T2D adipocytes. Despite a high expression of the receptors NPR1 and NPR2 in NGT and T2D adipocytes, lipolysis was stimulated by ANP 1.74-fold in NGT cells only. This stimulation was further increased by the PDE5 inhibitor dipyridamole (3.09-fold). Dipyridamole and forskolin increased lipolysis receptor independently 1.88-fold and 1.48-fold, respectively, solely in NGT cells. In conclusion, the metabolic status persistently affects differentiation and lipolysis of pancreatic adipocytes. These alterations could aggravate the development of T2D.
Estimating smooth and sparse neural receptive fields with a flexible spline basis
2021-03-31

ABSTRACT Spatio-temporal receptive field (STRF) models are frequently used to approximate the computation implemented by a sensory neuron. Typically, such STRFs are assumed to be smooth and sparse. Current state-of-the-art approaches for estimating STRFs based empirical Bayes estimation encode such prior knowledge into a prior covariance matrix, whose hyperparameters are learned from the data, and thus provide STRF estimates with the desired properties even with little or noisy data. However, empirical Bayes methods are often not computationally efficient in high-dimensional settings, as encountered in sensory neuroscience. Here we pursued an alternative approach and encode prior knowledge for estimation of STRFs by choosing a set of basis function with the desired properties: a natural cubic spline basis. Our method is computationally efficient, and can be easily applied to Linear-Gaussian and Linear-Nonlinear-Poisson models as well as more complicated Linear-Nonlinear-Linear-Nonlinear cascade model or spike-triggered clustering methods. We compared the performance of spline-based methods to no-spline ones on simulated and experimental data, showing that spline-based methods consistently outperformed the no-spline versions. We provide a Python toolbox for all suggested methods ( https://github.com/berenslab/RFEst/ ).
An integrative skeletal and paleogenomic analysis of prehistoric stature variation suggests relatively reduced health for early European farmers
2021-03-31

Abstract Human culture, biology, and health were shaped dramatically by the onset of agriculture ~12,000 years before present (BP). Subsistence shifts from hunting and gathering to agriculture are hypothesized to have resulted in increased individual fitness and population growth as evidenced by archaeological and population genomic data alongside a simultaneous decline in physiological health as inferred from paleopathological analyses and stature reconstructions of skeletal remains. A key component of the health decline inference is that relatively shorter statures observed for early farmers may (at least partly) reflect higher childhood disease burdens and poorer nutrition. However, while such stresses can indeed result in growth stunting, height is also highly heritable, and substantial inter-individual variation in the height genetic component within a population is typical. Moreover, extensive migration and gene flow were characteristics of multiple agricultural transitions worldwide. Here, we consider both osteological and ancient DNA data from the same prehistoric individuals to comprehensively study the trajectory of human stature variation as a proxy for health across a transition to agriculture. Specifically, we compared ‘predicted’ genetic contributions to height from paleogenomic data and ‘achieved’ adult osteological height estimated from long bone measurements on a per-individual basis for n=160 ancient Europeans from sites spanning the Upper Paleolithic to the Iron Age (~38,000-2,400 BP). We found that individuals from the Neolithic were shorter than expected (given their individual polygenic height scores) by an average of −4.47 cm relative to individuals from the Upper Paleolithic and Mesolithic (P=0.016). The average osteological vs. expected stature then increased relative to the Neolithic over the Copper (+2.67 cm, P=0.052), Bronze (+3.33 cm, P=0.032), and Iron Ages (+3.95 cm, P=0.094). These results were partly attenuated when we accounted for genome-wide genetic ancestry variation in our sample (which we note is partly duplicative with the individual polygenic score information). For example, in this secondary analysis Neolithic individuals were −3.48 cm shorter than expected on average relative to individuals from the Upper Paleolithic and Mesolithic (P=0.056). We also incorporated observations of paleopathological indicators of non-specific stress that can persist from childhood to adulthood in skeletal remains (linear enamel hypoplasia, cribra orbitalia, and porotic hyperostosis) into our model. Overall, our work highlights the potential of integrating disparate datasets to explore proxies of health in prehistory.
Bromine Isotope Variations in Magmatic and Hydrothermal Sodalite and Tugtupite and the Estimation of Br Isotope Fractionation between Melt and Sodalite
2021-03-31

We determined the bromine isotope compositions of magmatic and hydrothermal sodalite (Na8Al6Si6O24Cl2) and tugtupite (Na8Al2Be2Si8O24Cl2) from the Ilímaussaq intrusion in South Greenland, in order to constrain the Br isotope composition of the melt and hydrothermal fluids from which these minerals were formed. Early formed magmatic sodalite has high Br contents (138 ± 10 μg/g, n = 5) and low δ81Br values (+0.23 ± 0.07‰). Late stage hydrothermal sodalite has lower Br contents (53±10 μg/g, n = 5) and higher δ81Br values (+0.36 ± 0.08‰). Tugtupite that forms at even later stages shows the lowest Br contents (26 ± 2 μg/g, n = 2) and the highest δ81Br values (+0.71 ± 0.17‰). One hydrothermal sodalite has a Br concentration of 48 ± 9 μg/g and an exceptionally high δ81Br of 0.82 ± 0.12‰, very similar to the δ81Br of tugtupites. We suggest that this may be a very late stage sodalite that possibly formed under Be deficient conditions. The data set suggests that sodalite crystallises with a negative Br isotope fractionation factor, which means that the sodalite has a more negative δ81Br than the melt, of −0.3 to −0.4‰ from the melt. This leads to a value of +0.5 to +0.6‰ relative to SMOB for the melt from which sodalite crystallises. This value is similar to a recently published δ81Br value of +0.7‰ for very deep geothermal fluids with very high R/Ra He isotope ratios, presumably derived from the mantle. During crystallisation of later stage hydrothermal sodalite and the Be mineral tugtupite, δ81Br of the residual fluids (both melt and hydrothermal fluid) increases as light 79Br crystallises in the sodalite and tugtupite. This results in increasing δ81Br values of later stage minerals that crystallise with comparable fractionation factors from a fluid with increasingly higher δ81Br values.
Deceleration capacity for rapid risk stratification in patients suffering from acute ischemic stroke
2021-03-31

Abstract Deceleration capacitiy for rapid risk stratification in stroke patients Cerebral ischemia is a major cause of neurologic deficit and patients suffering from ischemic stroke bear a relevant risk of mortality. Identifying stroke patients at high mortality risk is of crucial clinical relevance. Deceleration capacity of heart rate (DC) as a parameter of cardiac autonomic function is an excellent predictor of mortality in myocardial infarction and heart failure patients. The aim of our study was to evaluate whether DC provides prognostic information regarding mortality risk in patients with acute ischemic stroke. From September 2015 to March 2018 we prospectively enrolled consecutive patients presenting at the Stroke Unit of our university hospital with acute ischemic stroke who were in sinus rhythm. In these patients 24 hours-Holter-ECG recordings and evaluation of National Institute of Health Stroke Scale (NIHSS) were performed. DC was calculated according to a previously published algorithm. Primary endpoint was intrahospital mortality. Eight hundred seventy eight stroke patients were included in the study. Intrahospital mortality was 2.8% (25 patients). Both DC and NIHSS were significantly different between non-survivors and survivors (Mean ± SD: DC: 4.1 ± 2.8 ms vs 6.3 ± 3.3 ms, P &lt; .001) (NIHSS: 7.6 ± 7.1 vs 4.3 ± 5.5, P = .02). DC achieved an area under the curve value (AUC) of 0.708 for predicting intrahospital mortality, while the AUC value of NIHSS was 0.641. In a binary logistic regression analysis, DC, NIHSS and age were independent predictors for intrahospital mortality (DC: HR CI 95%: 0.88 (0.79–0.97); P = .01; NIHSS: HR CI 95%: 1.08 (1.02–1.15); P = .01; Age: HR CI 95%: 1.07 (1.02–1.11); P = .004. The combination of NIHSS, age and DC in a prediction model led to a significant improvement of the AUC, which was 0.757 ( P &lt; .001, incremental development index [IDI] 95% CI: 0.037 (0.018–0.057)), compared to the individual risk parameters. Our study demonstrated that DC is suitable for both objective and independent risk stratification in patients suffering from ischemic stroke. The application of a prediction model combining NIHSS, age and DC is superior to the single markers in identifying patients at high mortality risk.
Synthesis, Characterization, and in vivo Distribution of Intracellular Delivered Macrolide Short‐Chain Fatty Acid Derivatives
2021-03-31

Abstract Short‐chain fatty acids (SCFAs) have a range of effects in metabolism and immune regulation. We have observed that delivery of SCFAs to lysosomes has potent immune regulatory effects, possibly as a surrogate signal for the presence of anaerobic organisms. To better understand the pharmacology of lysosomal SCFA donors, we investigated the distribution and metabolism of propionate and butyrate donors. Each analog ( 1 a and 2 a ) can donate three SCFA equivalents via ester hydrolysis through six intermediate metabolites. The compounds are stabilized by low pH, and stability in cells is usually higher than in medium, but is cell‐type specific. Butyrate derivatives were found to be more stable than propionates. Tri‐esters were more stable than di‐ or mono‐esters. The donors were surprisingly stable in vivo, and hydrolysis of each position was organ specific. Jejunum and liver caused rapid loss of 4’’ esters. The gut metabolite pattern by i. v. differed from that of p.o. application, suggesting luminal and apical enzyme effects in the gut epithelium. Central organs could de‐esterify the 11‐position. Levels in lung relative to other organs were higher by p.o. than via i. v., suggesting that delivery route can influence the observed pharmacology and that gut metabolites distribute differently. The donors were largely eliminated by 24 h, following near linear decline in organs. The observed levels and distribution were found to be consistent with pharmacodynamic effects, particularly in the gut.
Neuropathogenesis caused by Trypanosoma brucei, still an enigma to be unveiled
2021-03-31

Trypanosoma brucei is one of the protozoa parasites that can enter the brain and cause injury associated with toxic effects of parasite-derived molecules or with immune responses against infection. Other protozoa parasites with brain tropism include Toxoplasma, Plasmodium, Amoeba, and, eventually, other Trypano-somatids such as T. cruzi and Leishmania. Together, these parasites affect billions of people worldwide and are responsible for more than 500.000 deaths annually. Factors determining brain tropism, mechanisms of in-vasion as well as processes ongoing inside the brain are not well understood. But, they depend on the par-asite involved. The pathogenesis caused by T. brucei initiates locally in the area of parasite inoculation, soon trypanosomes rich the blood, and the disease enters in the so-called early stage. The pathomecha-nisms in this phase have been described, even mole-cules used to combat the disease are effective during this period. Later, the disease evolves towards a late-stage, characterized by the presence of parasites in the central nervous system (CNS), the so-called meningo-encephalitic stage. This phase of the disease has not been sufficiently examined and remains a matter of investigation. Here, I stress the importance of delve into the study of the neuropathogenesis caused by T. brucei, which will enable the identification of path-ways that may be targeted to overcome parasites that reached the CNS. Finally, I highlight the impact that the application of tools developed in the last years in the field of neuroscience will have on the study of neglect-ed tropical diseases.
Boundary Conditions that Remove Certain Ultraviolet Divergences
2021-03-31

In quantum field theory, Hamiltonians contain particle creation and annihilation terms that are usually ultraviolet (UV) divergent. It is well known that these divergences can sometimes be removed by adding counter-terms and by taking limits in which a UV cutoff tends toward infinity. Here, I review a novel way of removing UV divergences: by imposing a type of boundary condition on the wave function. These conditions, called interior-boundary conditions (IBCs), relate the values of the wave function at two configurations linked by the creation or annihilation of a particle. They allow for a direct definition of the Hamiltonian without renormalization or limiting procedures. In the last section, I review another boundary condition that serves to determine the probability distribution of detection times and places on a time-like 3-surface.
Effect of Substituents of Cerium Pyrazolates and Pyrrolates on Carbon Dioxide Activation
2021-03-31

Homoleptic ceric pyrazolates (pz) Ce(RR’pz)4 (R = R’ = tBu; R = R’ = Ph; R = tBu, R’ = Me) were synthesized by the protonolysis reaction of Ce[N(SiHMe2)2]4 with the corresponding pyrazole derivative. The resulting complexes were investigated in their reactivity toward CO2, revealing a significant influence of the bulkiness of the substituents on the pyrazolato ligands. The efficiency of the CO2 insertion was found to increase in the order of tBu2pz &lt; Ph2pz &lt; tBuMepz &lt; Me2pz. For comparison, the pyrrole-based ate complexes [Ce2(pyr)6(μ-pyr)2(thf)2][Li(thf)4]2 (pyr = pyrrolato) and [Ce(cbz)4(thf)2][Li(thf)4] (cbz = carbazolato) were obtained via protonolysis of the cerous ate complex Ce[N(SiHMe2)2]4Li(thf) with pyrrole and carbazole, respectively. Treatment of the pyrrolate/carbazolate complexes with CO2 seemed promising, but any reversibility could not be observed.
Pitfalls in Genetic Diagnostics: Why Phenotyping is Essential
2021-03-31

Abstract New genetic testing technologies have revolutionized medicine within the past years. It is foreseeable that the development will continue with the introduction of new techniques. Nevertheless, despite improved technology, an exact clinical description of the phenotype is still necessary and it is important to critically question findings, both before initiating genetic testing and when interpreting the results. We present four brief case vignettes to point out difficulties associated with correctly interpreting genetic findings.
Addressing a Trapped High-Energy Water: Design and Synthesis of Highly Potent Pyrimidoindole-based GSK-3β inhibitors.
2021-03-31

Raw concatenated trajectoriesof the molecular dynamics simulations and WaterMap-output files related to publication: Addressing a Trapped High-Energy Water: Design and Synthesis of Highly Potent Pyrimidoindole-Based Glycogen Synthase Kinase-3&amp;beta; Inhibitors J Med Chem (2021):https://doi.org/10.1021/acs.jmedchem.0c02146 Compounds (S)-5c and (S)-15 trajectories are provided in a single concatenated Desmondtrajectory file (Both: 1 &amp;micro;s +1 &amp;micro;s +1 &amp;micro;s +1 &amp;micro;s +1 &amp;micro;s +1 &amp;micro;s +1 &amp;micro;s +1 &amp;micro;s +1 &amp;micro;s +1 &amp;micro;s =10 &amp;micro;s in total) (S)-5c = Files named: M_CL_all-out.cms; M_CL_all_trj/ (S)-15= Files named: M_CC_all-out.cms; M_CC_all_trj/ WaterMap-output files (.zip) (S)-5c = watermap_5c_wm.zip (S)-5m = watermap_5c_wm.zip (S)-15= watermap_15_wm.zip; MD-derived (#1-5):MD_derived_watermap_15_?_wm.zip