Miracle-dz/UniFAR-FTUs huggingface dataset:
Glacial to Holocene changes in trans-Atlantic Saharan dust transport and dust-climate feedbacks

Variations in long-range Saharan dust transport may have amplified past Atlantic ITCZ and West African monsoon changes. Saharan mineral dust exported over the tropical North Atlantic is thought to have significant impacts on regional climate and ecosystems, but limited data exist documenting past changes in long-range dust transport. This data gap limits investigations of the role of Saharan dust in past climate change, in particular during the mid-Holocene, when climate models consistently underestimate the intensification of the West African monsoon documented by paleorecords. We present reconstructions of African dust deposition in sediments from the Bahamas and the tropical North Atlantic spanning the last 23,000 years. Both sites show early and mid-Holocene dust fluxes 40 to 50% lower than recent values and maximum dust fluxes during the deglaciation, demonstrating agreement with records from the northwest African margin. These quantitative estimates of trans-Atlantic dust transport offer important constraints on past changes in dust-related radiative and biogeochemical impacts. Using idealized climate model experiments to investigate the response to reductions in Saharan dust’s radiative forcing over the tropical North Atlantic, we find that small (0.15°C) dust-related increases in regional sea surface temperatures are sufficient to cause significant northward shifts in the Atlantic Intertropical Convergence Zone, increased precipitation in the western Sahel and Sahara, and reductions in easterly and northeasterly winds over dust source regions. Our results suggest that the amplifying feedback of dust on sea surface temperatures and regional climate may be significant and that accurate simulation of dust’s radiative effects is likely essential to improving model representations of past and future precipitation variations in North Africa.
Taking the Load Off a Learner's Mind: Instructional Design for Complex Learning

Complex learning aims at the integration of knowledge, skills, and attitudes; the coordination of qualitatively different constituent skills; and the transfer of what is learned to daily life or work settings. Recent instructional theories stress authentic learning tasks as the driving force for learning; but due to the complexity of those tasks, learning may be hampered by the limited processing capacity of the human mind. In this article we present a framework for scaffolding practice and just-in-time information presentation, aiming to control cognitive load effectively. We briefly describe a design model for complex learning consistent with cognitive load theory. Theoretical and practical implications of the presented framework are discussed.
Hepatic protein phosphatase 1 regulatory subunit 3B (Ppp1r3b) promotes hepatic glycogen synthesis and thereby regulates fasting energy homeostasis

Maintenance of whole-body glucose homeostasis is critical to glycemic function. Genetic variants mapping to chromosome 8p23.1 in genome-wide association studies have been linked to glycemic traits in humans. The gene of known function closest to the mapped region, PPP1R3B (protein phosphatase 1 regulatory subunit 3B), encodes a protein (GL) that regulates glycogen metabolism in the liver. We therefore sought to test the hypothesis that hepatic PPP1R3B is associated with glycemic traits. We generated mice with either liver-specific deletion (Ppp1r3bΔhep) or liver-specific overexpression of Ppp1r3b. The Ppp1r3b deletion significantly reduced glycogen synthase protein abundance, and the remaining protein was predominantly phosphorylated and inactive. As a consequence, glucose incorporation into hepatic glycogen was significantly impaired, total hepatic glycogen content was substantially decreased, and mice lacking hepatic Ppp1r3b had lower fasting plasma glucose than controls. The concomitant loss of liver glycogen impaired whole-body glucose homeostasis and increased hepatic expression of glycolytic enzymes in Ppp1r3bΔhep mice relative to controls in the postprandial state. Eight hours of fasting significantly increased the expression of two critical gluconeogenic enzymes, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, above the levels in control livers. Conversely, the liver-specific overexpression of Ppp1r3b enhanced hepatic glycogen storage above that of controls and, as a result, delayed the onset of fasting-induced hypoglycemia. Moreover, mice overexpressing hepatic Ppp1r3b upon long-term fasting (12–36 h) were protected from blood ketone-body accumulation, unlike control and Ppp1r3bΔhep mice. These findings indicate a major role for Ppp1r3b in regulating hepatic glycogen stores and whole-body glucose/energy homeostasis.
Improved Bioavailability of the mGlu2/3 Receptor Agonist LY354740 Using a Prodrug Strategy: In Vivo Pharmacology of LY544344

Numerous studies have indicated that selective agonists of group II metabotropic glutamate (mGlu) receptors, such as LY354740 [(1S,2S,5R,6S)-2-aminobicyclo[3.1. 0]hexane-2,6-dicarboxylate monohydrate] and LY379268 [(-)-2-oxa-4-aminobicyclo[3.1. 0]hexane-4,6-dicarboxylate], may be useful in the treatment of many psychiatric disorders, including psychosis, anxiety, and drug withdrawal. Although animal and human studies demonstrate potential therapeutic utility, poor oral bioavailability is a limiting factor in the clinical development of these compounds. Therefore, a novel prodrug approach is being pursued to increase exposure levels of active compound after oral administration. Here, we demonstrate a 10-fold increase in brain, plasma, and cerebrospinal fluid levels of LY354740 after oral prodrug administration. Furthermore, we compare the oral efficacy of the mGlu2/3 receptor agonist LY354740 and its prodrug LY544344 [(1S,2S,5R,6S)-2-[(2′S)-(2′-amino)propionyl]aminobicyclo[3.1. 0]hexane-2,6-dicarboxylic acid hydrochloride] in rodent models of psychosis and anxiety. Phencyclidine (PCP)-induced hyperlocomotion was dose dependently inhibited in rats receiving oral administration of 30 or 100 mg/kg LY544344, whereas LY354740 did not significantly reverse PCP-mediated behaviors at doses up to 100 mg/kg. Orally administered LY544344 (30 mg/kg) and subcutaneously administered LY354740 (10 mg/kg) attenuated stress-induced hyperthermia in DBA/2 mice, with the prodrug producing anxiolytic effects at lower oral doses than the parent compound. Although oral administration of LY354740 did not significantly affect fear-induced suppression of operant responding in rats, subcutaneously administered LY354740 (10 or 20 mg/kg) and orally administered LY544344 (10 or 30 mg/kg) produced significant anxiolytic effects in this model. The present data confirm that mGlu2/3 receptor agonists produce antipsychotic and anxiolytic effects in animal behavioral models and demonstrate that oral bioavailability of LY354740 was substantially increased using a prodrug strategy.
Effects of Pre-Aging and Natural Aging on Bake Hardening Behavior in Al-Mg-Si Alloys

The effects of pre-aging and natural aging on the bake hardening behavior of Al-0.62Mg-0.93Si (mass%) alloy with multi-step aging process were investigated by means of Vickers hardness test, tensile test, differential scanning calorimetry analysis (DSC) and transmission electron microscopy (TEM). The characteristics of nanoclusters (nano scale solute atom clusters) formed during pre-aging and natural aging were also investigated using the three dimensional atom probe (3DAP) analysis. The results revealed the occurrence of natural age hardening and that the bake hardening response was decreased after the extended natural aging even though the pre-aging was conducted before natural aging. Since the 3DAP results exhibited the Si-rich clusters were newly formed during extended natural aging, it was assumed that the Si-rich clusters caused the natural age hardening and the reduced bake hardening response corresponding to Cluster(1). The decrease of the bake hardening response was markedly higher in the later stage of bake hardening than in the early stage. The size of the β’’ precipitates were reduced with increasing the natural aging time. Exothermic peaks of Peak 2 and Peak 2’ were observed in the DSC curves for the alloys pre-aged at 363K. Peak 2’ became larger with the natural aging time. This is well understood by the following model. The transition from Cluster(2) to the β’’ phase occurs preferentially at the early stage of the bake hardening. Then the growth of the β’’ phase is inhibited by the presence of Cluster(1) at the later stage of bake hardening. The combined formation of Cluster(1) and Cluster(2) by the multi-step aging essentially affects the bake hardening response and the β’’ precipitates in the Al-Mg-Si alloys.
More than One Sense Per Discourse

Previous research has indicated that when a polysemous word appears two or more times in a discourse, it is extremely likely that they will all share the same sense [Gale et al. 92]. However, those results were based on a coarse-grained distinction between senses (e.g, sentence in the sense of a ‘prison sentence’ vs. a ‘grammatical sentence’). We report on an analysis of multiple senses within two sense-tagged corpora, Semcor and DSO. These corpora used WordNet for their sense inventory. We found significantly more occurrences of multiple-senses per discourse than reported in [Gale et al. 92] (33% instead of 4%). We also found classes of ambiguous words in which as many as 45% of the senses in the class co-occur within a document. We discuss the implications of these results for the task of word-sense tagging and for the way in which senses should be represented.
Identification of Neuromedin U as the Cognate Ligand of the Orphan G Protein-coupled Receptor FM-3*

Neuromedin U is a bioactive peptide first isolated from porcine spinal cord. In this paper, we demonstrate that neuromedin U is the cognate ligand for the orphan G protein-coupled receptor, FM-3, isolated originally as a homologue of neurotensin and growth hormone secretogogue receptors. Neuromedin U induced specific and evident elevation of extracellular acidification rates, arachidonic acid metabolite release, and intracellular Ca2+mobilization in Chinese hamster ovary cells expressing human FM-3. In addition, radiolabeled neuromedin U specifically bound to membrane fractions prepared from these cells with high affinity. We subsequently analyzed the tissue distribution of neuromedin U and FM-3 mRNAs in rats using quantitative reverse transcription-polymerase chain reaction. Neuromedin U mRNA was highly expressed in the gastrointestinal tract, and the highest expression was detected in the pituitary gland. On the other hand, FM-3 mRNA was highly expressed in the small intestine and lung, suggesting that neuromedin U plays important roles in these tissues. The identification of a specific and functional receptor for neuromedin U will facilitate studies on their physiological roles and the search for receptor agonists and antagonists.
A Systematic Review of Dynamic Cerebral and Peripheral Endothelial Function in Lacunar Stroke Versus Controls

Background and Purpose— The etiology of cerebral small vessel disease is unknown. An association with endothelial dysfunction has been suggested. We systematically assessed all relevant studies of dynamic endothelial function in patients with lacunar stroke as a marker of small vessel disease. Methods— We searched for studies of cerebral or peripheral vascular reactivity in patients with lacunar or cortical (ie, large artery atheromatous) ischemic stroke or nonstroke control subjects. We calculated standardized mean difference (SMD) in vascular reactivity±95% CIs between small vessel disease and control groups. Results— Sixteen publications (974 patients) were included. In lacunar stroke, cerebrovascular reactivity (n=534) was reduced compared with age-matched normal (SMD −0.94, 95% CI −1.17 to −0.70), but not age+risk factor-matched control subjects (SMD 0.08, 95% CI −0.36 to 0.53) or cortical strokes (SMD −0.29, 95% CI −0.69 to 0.11); forearm flow-mediated dilatation (n=401) was reduced compared with age-matched normal control subjects (SMD −1.04, 95% CI −1.33 to −0.75) and age+risk factor-matched control subjects (SMD −0.94, 95% CI −1.26 to −0.61), but not cortical strokes (SMD −0.23, 95% CI −0.55 to 0.08). Conclusions— Endothelial dysfunction is present in patients with lacunar stroke but may simply reflect exposure to vascular risk factors and having a stroke, because a similar degree of dysfunction is found in cortical (large artery atheromatous) stroke. Current data do not confirm that endothelial dysfunction is specific to small vessel stroke. Future studies should include control subjects with nonlacunar stroke.
A regulatory calcium-binding site at the subunit interface of CLC-K kidney chloride channels

The two human CLC Cl− channels, ClC-Ka and ClC-Kb, are almost exclusively expressed in kidney and inner ear epithelia. Mutations in the genes coding for ClC-Kb and barttin, an essential CLC-K channel β subunit, lead to Bartter syndrome. We performed a biophysical analysis of the modulatory effect of extracellular Ca2+ and H+ on ClC-Ka and ClC-Kb in Xenopus oocytes. Currents increased with increasing [Ca2+]ext without full saturation up to 50 mM. However, in the absence of Ca2+, ClC-Ka currents were still 20% of currents in 10 mM [Ca2+]ext, demonstrating that Ca2+ is not strictly essential for opening. Vice versa, ClC-Ka and ClC-Kb were blocked by increasing [H+]ext with a practically complete block at pH 6. Ca2+ and H+ act as gating modifiers without changing the single-channel conductance. Dose–response analysis suggested that two protons are necessary to induce block with an apparent pK of ∼7.1. A simple four-state allosteric model described the modulation by Ca2+ assuming a 13-fold higher Ca2+ affinity of the open state compared with the closed state. The quantitative analysis suggested separate binding sites for Ca2+ and H+. A mutagenic screen of a large number of extracellularly accessible amino acids identified a pair of acidic residues (E261 and D278 on the loop connecting helices I and J), which are close to each other but positioned on different subunits of the channel, as a likely candidate for forming an intersubunit Ca2+-binding site. Single mutants E261Q and D278N greatly diminished and the double mutant E261Q/D278N completely abolished modulation by Ca2+. Several mutations of a histidine residue (H497) that is homologous to a histidine that is responsible for H+ block in ClC-2 did not yield functional channels. However, the triple mutant E261Q/D278N/H497M completely eliminated H+ -induced current block. We have thus identified a protein region that is involved in binding these physiologically important ligands and that is likely undergoing conformational changes underlying the complex gating of CLC-K channels.
Lack of response to unaligned chromosomes in mammalian female gametes

Chromosome segregation errors are highly frequent in mammalian female meiosis, and their incidence gradually increases with maternal age. The fate of aneuploid eggs is obviously dependent on the stringency of mechanisms for detecting unattached or repairing incorrectly attached kinetochores. In case of their failure, the newly formed embryo will inherit the impaired set of chromosomes, which will have severe consequences for its further development. Whether spindle assembly checkpoint (SAC) in oocytes is capable of arresting cell cycle progression in response to unaligned kinetochores was discussed for a long time. It is known that abolishing SAC increases frequency of chromosome segregation errors and causes precocious entry into anaphase; SAC, therefore, seems to be essential for normal chromosome segregation in meiosis I. However, it was also reported that for anaphase-promoting complex (APC) activation, which is a prerequisite for entering anaphase; alignment of only a critical mass of kinetochores on equatorial plane is sufficient. This indicates that the function of SAC and of cooperating chromosome attachment correction mechanisms in oocytes is different from somatic cells. To analyze this phenomenon, we used live cell confocal microscopy to monitor chromosome movements, spindle formation, APC activation and polar body extrusion (PBE) simultaneously in individual oocytes at various time points during first meiotic division. Our results, using oocytes from aged animals and interspecific crosses, demonstrate that multiple unaligned kinetochores and severe congression defects are tolerated at the metaphase to anaphase transition, although such cells retain sensitivity to nocodazole. This indicates that checkpoint mechanisms, operating in oocytes at this point, are essential for accurate timing of APC activation in meiosis I, but they are insufficient in detection or correction of unaligned chromosomes, preparing thus conditions for propagation of the aneuploidy to the embryo.
Use of the Theoretical Domains Framework to Develop an Intervention to Improve Physical Therapist Management of the Risk of Falls After Discharge

Background and Purpose Older adults have an increased risk of falls after discharge from the hospital. Guidelines to manage this risk of falls are well documented but are not commonly implemented. The aim of this case report is to describe the novel approach of using the Theoretical Domains Framework (TDF) to develop an intervention to change the clinical behavior of physical therapists. Case Description This project had 4 phases: identifying the evidence-practice gap, identifying barriers and enablers that needed to be addressed, identifying behavior change techniques to overcome the barriers, and determining outcome measures for evaluating behavior change. Outcomes The evidence-practice gap was represented by the outcome that few patients who had undergone surgery for hip fracture were recognized as having a risk of falls or had a documented referral to a community agency for follow-up regarding the prevention of falls. Project aims aligned with best practice guidelines were established; 12 of the 14 TDF domains were considered to be relevant to behaviors in the project, and 6 behavior change strategies were implemented. Primary outcome measures included the proportion of patients who had documentation of the risk of falls and were referred for a comprehensive assessment of the risk of falls after discharge from the hospital. Discussion A systematic approach involving the TDF was useful for designing a multifaceted intervention to improve physical therapist management of the risk of falls after discharge of patients from an acute care setting in South Australia, Australia. This framework enabled the identification of targeted intervention strategies that were likely to influence health care professional behavior. Early case note audit results indicated that positive changes were being made to reduce the evidence-practice gap.
Communication-Efficient Distributed Statistical Inference

ABSTRACT We present a communication-efficient surrogate likelihood (CSL) framework for solving distributed statistical inference problems. CSL provides a communication-efficient surrogate to the global likelihood that can be used for low-dimensional estimation, high-dimensional regularized estimation, and Bayesian inference. For low-dimensional estimation, CSL provably improves upon naive averaging schemes and facilitates the construction of confidence intervals. For high-dimensional regularized estimation, CSL leads to a minimax-optimal estimator with controlled communication cost. For Bayesian inference, CSL can be used to form a communication-efficient quasi-posterior distribution that converges to the true posterior. This quasi-posterior procedure significantly improves the computational efficiency of Markov chain Monte Carlo (MCMC) algorithms even in a nondistributed setting. We present both theoretical analysis and experiments to explore the properties of the CSL approximation. Supplementary materials for this article are available online.
Measles hotspots and epidemiological connectivity

SUMMARY Though largely controlled in developed countries, measles remains a major global public health issue. Regional and local transmission patterns are rooted in human mixing behaviour across spatial scales. Identifying spatial interactions that contribute to recurring epidemics helps define and predict outbreak patterns. Using spatially explicit reported cases from measles outbreaks in Niger, we explored how regional variations in movement and contact patterns relate to patterns of measles incidence. Because we expected to see lower rates of re-introductions in small, compared to large, populations, we measured the population-size corrected proportion of weeks with zero cases across districts to understand relative rates of measles re-introductions. We found that critical elements of spatial disease dynamics in Niger are agricultural seasonality, transnational contact clusters, and roads networks that facilitate host movement and connectivity. These results highlight the need to understand local patterns of seasonality, demographic characteristics, and spatial heterogeneities to inform vaccination policy.
Association of a Genetic Variation in a miR-191 Binding Site in MDM4 with Risk of Esophageal Squamous Cell Carcinoma

As an oncoprotein, MDM4 plays a key part in P53 tumor suppressor pathway through negatively regulating P53 function. It has been reported that an rs4245739 A>C polymorphism locating in the MDM4 3′-untranslated region creates a miR-191 target site and results in decreased MDM4 expression. Therefore, we investigated the association between this polymorphism and esophageal squamous cell carcinoma (ESCC) risk as well as its biological function in vivo. Genotypes were determined in two independent case-control sets consisted of 1128 ESCC cases and 1150 controls from two regions of China. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression. The impact of the polymorphism on MDM4 expression was examined with esophagus tissues. Our results demonstrated that the MDM4 rs4245739 AC and CC genotypes were significantly associated with decreased ESCC risk compared with the AA genotype in both case-control sets (Jinan set: OR = 0.54, 95% CI = 0.35–0.82, P = 0.004; Huaian set: OR = 0.68, 95% CI = 0.45–0.99, P = 0.049). Stratified analyses revealed that a multiplicative interaction between rs4245739 and smoking or drinking was evident (Gene-smoking: P interactioin = 0.022; gene-drinking: P interactioin = 0.032). After detecting In vivo MDM4 mRNA expression, we found that the rs4245739 AC and CC genotype carriers had significantly decreased MDM4 expression in normal esophagus tissues compared with AA genotype carriers, indicating a consistent genotype-phenotype correlation. Our results elucidate that the MDM4 rs4245739 polymorphism contributes to susceptibility of ESCC and support the hypothesis that genetic variants, interrupting miRNA-mediated gene regulation, may modify cancer risk.