Miracle-dz/UniFAR-FTUs huggingface dataset:
Lung ultrasound assessment of response to antibiotic therapy in cystic fibrosis exacerbations: a study of two cases

1. Departamento de Pediatria, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas (SP) Brasil. 2. Centro de Investigação em Pediatria, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas (SP) Brasil. 3. Unidade de Urgência e Emergência, Hospital de Clínicas, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas (SP) Brasil. 4. Departamento de Genética Médica e Medicina Genômica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas (SP) Brasil. 5. Programa de Pós-Graduação em Ciências da Saúde, Universidade São Francisco, Bragança Paulista (SP) Brasil. 6. Unidade de Terapia Intensiva Pediátrica, Hospital de Clínicas, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas (SP) Brasil. Financial support: The following authors received financial support: Peixoto AO, Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, National Council for Scientific and Technological Development; Grant no. 407364/2016-1); Marson FAL, Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, São Paulo Research Foundation; Grant nos. 2011/12939-4, 2011/18845-1, 2015/12183-8, and 2015/12858-5) and State University at Campinas Fundo de Apoio à Pesquisa ao Ensino e à Extensão (FAEPEX, Fund for the Support of Research, Teaching, and Extension; Grant no. 0648/2015); and Ribeiro JD, FAPESP (Grant nos. 2011/18845-1 and 2015/12183-8) and CNPq (Grant no. 407364/2016-1). a. http://orcid.org/0000-0002-8407-4087; b. http://orcid.org/0000-0003-4955-4234; c. http://orcid.org/0000-0001-6944-0221; d. http://orcid.org/0000-0003-0999-5350; e. http://orcid.org/0000-0002-3387-5642 TO THE EDITOR:
Multiple distinct pathways lead to hyperubiquitylated insoluble TDP-43 protein independent of its translocation into stress granules

Insoluble, hyperubiquitylated TAR DNA-binding protein of 43 kDa (TDP-43) in the central nervous system characterizes frontotemporal dementia and ALS in many individuals with these neurodegenerative diseases. The causes for neuropathological TDP-43 aggregation are unknown, but it has been suggested that stress granule (SG) formation is important in this process. Indeed, in human embryonic kidney HEK293E cells, various SG-forming conditions induced very strong TDP-43 ubiquitylation, insolubility, and reduced splicing activity. Osmotic stress–induced SG formation and TDP-43 ubiquitylation occurred rapidly and coincided with colocalization of TDP-43 and SG markers. Washout experiments confirmed the rapid dissolution of SGs, accompanied by normalization of TDP-43 ubiquitylation and solubility. Surprisingly, interference with the SG process using a protein kinase R–like endoplasmic reticulum kinase inhibitor (GSK2606414) or the translation blocker emetine did not prevent TDP-43 ubiquitylation and insolubility. Thus, parallel pathways may lead to pathological TDP-43 modifications independent of SG formation. Using a panel of kinase inhibitors targeting signaling pathways of the osmotic shock inducer sorbitol, we could largely rule out the stress-activated and extracellular signal–regulated protein kinase modules and glycogen synthase kinase 3β. For arsenite, but not for sorbitol, quenching oxidative stress with N-acetylcysteine did suppress both SG formation and TDP-43 ubiquitylation and insolubility. Thus, sodium arsenite appears to promote SG formation and TDP-43 modifications via oxidative stress, but sorbitol stimulates TDP-43 ubiquitylation and insolubility via a novel pathway(s) independent of SG formation. In conclusion, pathological TDP-43 modifications can be mediated via multiple distinct pathways for which SGs are not essential.
Sinorhizobium meliloti succinylated high‐molecular‐weight succinoglycan and the Medicago truncatula LysM receptor‐like kinase MtLYK10 participate independently in symbiotic infection

Summary The formation of nitrogen‐fixing nodules on legume hosts is a finely tuned process involving many components of both symbiotic partners. Production of the exopolysaccharide succinoglycan by the nitrogen‐fixing bacterium Sinorhizobium meliloti 1021 is needed for an effective symbiosis with Medicago spp. , and the succinyl modification to this polysaccharide is critical. However, it is not known when succinoglycan intervenes in the symbiotic process, and it is not known whether the plant lysin‐motif receptor‐like kinase MtLYK10 intervenes in recognition of succinoglycan, as might be inferred from work on the Lotus japonicus MtLYK10 ortholog, LjEPR3. We studied the symbiotic infection phenotypes of S. meliloti mutants deficient in succinoglycan production or producing modified succinoglycan, in wild‐type Medicago truncatula plants and in Mtlyk10 mutant plants. On wild‐type plants, S. meliloti strains producing no succinoglycan or only unsuccinylated succinoglycan still induced nodule primordia and epidermal infections, but further progression of the symbiotic process was blocked. These S. meliloti mutants induced a more severe infection phenotype on Mtlyk10 mutant plants. Nodulation by succinoglycan‐defective strains was achieved by in trans rescue with a Nod factor‐deficient S. meliloti mutant. While the Nod factor‐deficient strain was always more abundant inside nodules, the succinoglycan‐deficient strain was more efficient than the strain producing only unsuccinylated succinoglycan. Together, these data show that succinylated succinoglycan is essential for infection thread formation in M. truncatula, and that MtLYK10 plays an important, but different role in this symbiotic process. These data also suggest that succinoglycan is more important than Nod factors for bacterial survival inside nodules.
QSAR Models for Predicting Five Levels of Cellular Accumulation of Lysosomotropic Macrocycles

Drugs that accumulate in lysosomes reach very high tissue concentrations, which is evident in the high volume of distribution and often lower clearance of these compounds. Such a pharmacokinetic profile is beneficial for indications where high tissue penetration and a less frequent dosing regime is required. Here, we show how the level of lysosomotropic accumulation in cells can be predicted solely from molecular structure. To develop quantitative structure–activity relationship (QSAR) models, we used cellular accumulation data for 69 lysosomotropic macrocycles, the pharmaceutical class for which this type of prediction model is extremely valuable due to the importance of cellular accumulation for their anti-infective and anti-inflammatory applications as well as due to the fact that they are extremely difficult to model by computational methods because of their large size (Mw > 500). For the first time, we show that five levels of intracellular lysosomotropic accumulation (as measured by liquid chromatography coupled to tandem mass spectrometry—LC-MS/MS), from low/no to extremely high, can be predicted with 60% balanced accuracy solely from the compound’s structure. Although largely built on macrocycles, the eight non-macrocyclic compounds that were added to the set were found to be well incorporated by the models, indicating their possible broader application. By uncovering the link between the molecular structure and cellular accumulation as the key process in tissue distribution of lysosomotropic compounds, these models are applicable for directing the drug discovery process and prioritizing the compounds for synthesis with fine-tuned accumulation properties, according to the desired pharmacokinetic profile.
Advancements to the Axolotl Model for Regeneration and Aging

Loss of regenerative capacity is a normal part of aging. However, some organisms, such as the Mexican axolotl, retain striking regenerative capacity throughout their lives. Moreover, the development of age-related diseases is rare in this organism. In this review, we will explore how axolotls are used as a model system to study regenerative processes, the exciting new technological advancements now available for this model, and how we can apply the lessons we learn from studying regeneration in the axolotl to understand, and potentially treat, age-related decline in humans.
NTRC and Thioredoxin f Overexpression Differentially Induces Starch Accumulation in Tobacco Leaves

Thioredoxin (Trx) f and NADPH-dependent Trx reductase C (NTRC) have both been proposed as major redox regulators of starch metabolism in chloroplasts. However, little is known regarding the specific role of each protein in this complex mechanism. To shed light on this point, tobacco plants that were genetically engineered to overexpress the NTRC protein from the chloroplast genome were obtained and compared to previously generated Trx f-overexpressing transplastomic plants. Likewise, we investigated the impact of NTRC and Trx f deficiency on starch metabolism by generating Nicotiana benthamiana plants that were silenced for each gene. Our results demonstrated that NTRC overexpression induced enhanced starch accumulation in tobacco leaves, as occurred with Trx f. However, only Trx f silencing leads to a significant decrease in the leaf starch content. Quantitative analysis of enzyme activities related to starch synthesis and degradation were determined in all of the genotypes. Zymographic analyses were additionally performed to compare the amylolytic enzyme profiles of both transplastomic tobacco plants. Our findings indicated that NTRC overexpression promotes the accumulation of transitory leaf starch as a consequence of a diminished starch turnover during the dark period, which seems to be related to a significant reductive activation of ADP-glucose pyrophosphorylase and/or a deactivation of a putative debranching enzyme. On the other hand, increased starch content in Trx f-overexpressing plants was connected to an increase in the capacity of soluble starch synthases during the light period. Taken together, these results suggest that NTRC and the ferredoxin/Trx system play distinct roles in starch turnover.
The autonomic nervous system and the brainstem: A fundamental role or the background actors for consciousness generation? Hypothesis, evidence, and future directions for rehabilitation and theoretical approaches

One of the hardest challenges of the third century is to develop theories that could joint different results for a global explanation of human consciousness. Some important theories have been proposed, trying to explain the emergence of consciousness as the result of different progressive changes in the elaboration of information during brain processing, giving particular attention to the thalamocortical system.
It’s politics, stupid! A political analysis of the HIV/AIDS Trust Fund in Uganda

The role of trust funds in the practice of and the policy discourse on the sustainable financing for health and HIV is growing. However, there is a paucity of political analyses on implementing trust fund arrangements. Drawing on a novel meta-framework – connecting multiple streams and advocacy coalition frameworks to policy cycle models of analysis – to politically analyse HIV financing policy design, adoption and implementation as well as insights from public finance literature, this article critically analyses the politics of the AIDS Trust Fund (ATF) in Uganda. We find that politics was the most fundamental driver for the establishment of the ATF. Whereas HIV financing is inherently both technical and political, enacting the ATF was largely a geopolitical positioning policy instrument that entailed navigating political economy challenges in managing multiple stakeholder groups’ politics. With the mandated tax revenues earmarked to capitalise the ATF covering only 0.5% of the annual resource needs, we find a very insignificant potential to contribute to financial sustainability of the national HIV response per se. As good ideas and evidence alone often do not necessarily produce desired results, we conclude that systematic and continuous political analysis can bring meaningful insights to our understanding of political economy dimensions of the ATF as an innovative financing policy instrument, thereby helping drive technically sound health financing policy proposals into practice more effectively. For Uganda, while proponents have invested a considerable amount of hope in the ATF as a source of sustainable domestic funding for the HIV response, substantial work remains to be done to address a number of questions that continue to beguile the current ATF architecture. Regarding global health financing policy, the findings suggest the need to pay attention to the position, power and interests of stakeholders as a powerful lever in health financing policy reforms.
CSPG4 as Target for CAR-T-Cell Therapy of Various Tumor Entities–Merits and Challenges

Targeting cancer cells using chimeric-antigen-receptor (CAR-)T cells has propelled adoptive T-cell therapy (ATT) to the next level. A plentitude of durable complete responses using CD19-specific CAR-T cells in patients suffering from various lymphoid malignancies resulted in the approval by the food and drug administration (FDA) of CD19-directed CAR-T cells for the treatment of acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL). A substantial portion of this success in hematological malignancies can be traced back to the beneficial properties of the target antigen CD19, which combines a universal presence on target cells with no detectable expression on indispensable host cells. Hence, to replicate response rates achieved in ALL and DLBCL in the realm of solid tumors, where ideal target antigens are scant and CAR-T cells are still lagging behind expectations, the quest for appropriate target antigens represents a crucial task to expedite the next steps in the evolution of CAR-T-cell therapy. In this review, we want to highlight the potential of chondroitin sulfate proteoglycan 4 (CSPG4) as a CAR-target antigen for a variety of different cancer entities. In particular, we discuss merits and challenges associated with CSPG4-CAR-T cells for the ATT of melanoma, leukemia, glioblastoma, and triple-negative breast cancer.
The Usefulness of Respiratory Mechanic Instability in Evaluating the Effect of Continuous Positive Airway Pressure for Obstructive Sleep Apnea

Objectives: Respiratory mechanics instability (RMI) based on paradoxical movement is correlated with respiratory disturbance such as apnea-hypopnea index (AHI) and reflects the severity of obstructive sleep apnea (OSA). The purpose of this study was to identify RMI as a method for assessing the effectiveness of continuous positive airway pressure (CPAP) in the management for OSA. Methods: A total of 71 consecutive OSA patients with CPAP titration were included in this study. We compared sleep (sleep efficiency, arousal index, and sleep stages), respiratory (AHI, oxygen desaturation index ≥3% [ODI3], and lowest oxygen saturation), and RMI parameters (events, index, duration, and % of stage duration) between diagnostic polysomnography and CPAP titration data. Results: All RMI parameters (events [157.5 ± 80.9 vs 80.0 ± 47.1; P < .001], index [25.3 ± 12.4 vs 12.7 ± 7.0; P < .001], duration [182.6 ± 96.2 vs 79.8 ± 88.9; P < .001], and % of stage duration [49.0 ± 24.4 vs 20.5 ± 21.3; P < .001]) were significantly improved by the alleviation of obstructive respiratory disturbance parameters (AHI [45.1 ± 23.0 vs 4.2 ± 4.3; P < .001], ODI3 [44.9 ± 22.6 vs 4.8 ± 4.6; P < .001], and lowest oxygen saturation [77.7 ± 7.3 vs 89.3 ± 3.8; P < .001]) compared to diagnostic polysomnography and CPAP titration data. Conclusion: RMI may be a useful method for evaluating the effect of CPAP in OSA patients.
Paternal—but Not Maternal—Autistic Traits Predict Frontal EEG Alpha Asymmetry in Infants with Later Symptoms of Autism

Previous research found that the parental autism phenotype is associated with child autism spectrum disorder (ASD), even if the pathway between autistic traits in parents and child ASD is still largely unknown. Several studies investigated frontal asymmetry in alpha oscillation (FAA) as an early marker for ASD. However, no study has examined the mediational effect of FAA between parental autistic traits and child ASD symptoms in the general population. We carried out a prospective study of 103 typically developing infants and measured FAA as a mediator between both maternal and paternal autistic traits and child ASD traits. We recorded infant baseline electroencephalogram (EEG) at 6 months of age. Child ASD symptoms were measured at age 24 months by the Child Behavior Checklist 1½–5 Pervasive Developmental Problems Scale, and parental autistic traits were scored by the Autism spectrum Quotient questionnaire. The mediation model showed that paternal vs. maternal autistic traits are associated with greater left FAA which, in turn, is associated with more child ASD traits with a significant indirect effect only in female infants vs. male infants. Our findings show a potential cascade of effects whereby paternal autistic traits drive EEG markers contributing to ASD risk.
Amyloid, APP, and Electrical Activity of the Brain

The Amyloid Precursor Protein (APP) is infamous for its proposed pivotal role in the pathogenesis of Alzheimer’s disease (AD). Much research on APP focusses on potential contributions to neurodegeneration, mostly based on mouse models with altered expression or mutated forms of APP. However, cumulative evidence from recent years indicates the indispensability of APP and its metabolites for normal brain physiology. APP contributes to the regulation of synaptic transmission, plasticity, and calcium homeostasis. It plays an important role during development and it exerts neuroprotective effects. Of particular importance is the soluble secreted fragment APPsα which mediates many of its physiological actions, often counteracting the effects of the small APP-derived peptide Aβ. Understanding the contribution of APP for normal functions of the nervous system is of high importance, both from a basic science perspective and also as a basis for generating new pathophysiological concepts and therapeutic approaches in AD. In this article, we review the physiological functions of APP and its metabolites, focusing on synaptic transmission, plasticity, calcium signaling, and neuronal network activity.
Comments on the article “Optimum waist circumference‐height indices for evaluating adult adiposity: An analytic review”: Relationships to previous studies

To the editor The recent review of Hwaung et al provides a detailed and valuable account of the history and rationale of the body mass index (BMI) and of indices relating waist circumference (WC) to body height that take the form WC/height. I show here how their evidence and analysis are usefully supplemented with those of earlier studies. The ratio WC/height, with α = 1, is widely used, but the authors have concluded that the optimum value of α is approximately 0.5, with this giving the strongest association with adiposity and the weakest correlation with height for men and women of four race/ethnic groups. Burton also considered 0.5 to be an appropriate round‐number value. On dimensional grounds, one might choose a value of 1 for α, making the index dimensionless, but data scatter associated with variable body shape must lower values of α as estimated by regression analysis—just as it lowers the height exponent, p, of the Benn index, (body mass)/height. (Here, I am applying the symbol “α” just to WC and not also to body mass as in the review.) Both α and p necessarily correlate strongly with the respective correlation coefficients for WC and height and for body mass and height. The negative value of α for Korean women (−0.43)—unadjusted for age—must be associated with a negative correlation between WC and height (though R is positive). These negative values were also found by Han et al for Europeans. This, as well as Table 1, illustrates the importance of age in considering the height dependences of WC and body mass and therefore both α and p. In contrast, Table S9 indicates that there is conveniently little influence of age on correlations between WC and % fat and between body mass and % fat. With increasing age, body mass tends generally to increase and height tends to decrease. Figure 2 of Burton shows a strong correlation between p and α (with α there denoted q) with most of the points being for data that were age‐adjusted or grouped for age. The tabulated results of Hwaung et al show similar relationships, for values both unadjusted and adjusted for age. Moreover, their eight age‐adjusted values, together with eight age‐adjusted values of Han et al., show a single clear straight‐line relationship, with a correlation coefficient of 0.91. This suggests a link beyond the obvious between WC/height and (body mass)/height that has yet to be elucidated. The reduced major axis regression equation is:
Incoherent strange metal sharply bounded by a critical doping in Bi2212

A sharp boundary in the cuprates Many physicists working on cuprate superconductors believe that the so-called strange metal phase in the cuprate phase diagram is associated with a quantum critical point. Within this picture, the quantum critical point gives rise to a V-shaped region in the doping-temperature phase diagram of the cuprates: the strange metal phase. Chen et al. used angle-resolved photoemission spectroscopy in the cuprate family Bi2212 to challenge this view. By taking comprehensive measurements as a function of doping and temperature—and making sure that the signal was not affected by environmental conditions—they found an incoherent strange metal phase that was sharply separated from a conventional phase by a temperature-independent vertical line in the phase diagram. Science, this issue p. 1099 Angle-resolved photoemission indicates a temperature-independent boundary between the strange metal and conventional phases. In normal metals, macroscopic properties are understood using the concept of quasiparticles. In the cuprate high-temperature superconductors, the metallic state above the highest transition temperature is anomalous and is known as the “strange metal. ” We studied this state using angle-resolved photoemission spectroscopy. With increasing doping across a temperature-independent critical value pc ~ 0.19, we observed that near the Brillouin zone boundary, the strange metal, characterized by an incoherent spectral function, abruptly reconstructs into a more conventional metal with quasiparticles. Above the temperature of superconducting fluctuations, we found that the pseudogap also discontinuously collapses at the very same value of pc. These observations suggest that the incoherent strange metal is a distinct state and a prerequisite for the pseudogap; such findings are incompatible with existing pseudogap quantum critical point scenarios.