Miracle-dz/UniFAR-FTUs huggingface dataset:
Hookworm recombinant protein promotes regulatory T cell responses that suppress experimental asthma

A secreted hookworm protein in recombinant form acts on dendritic cells to drive the expansion and mucosal homing of regulatory T cells that protect against airway inflammation in mice, and also dampens human dendritic cell and T cell activation. Airway allergy alleviated by hookworm protein One reason for allergy prevalence in the developed world may be a lack of exposure to parasites, which can influence immune development and function. Because administering live parasites to people might pose safety issues, Navarro et al. tested the ability of the hookworm protein AIP-2 to treat airway allergic sensitization. Administration of AIP-2 could prevent or treat asthma symptoms in a mouse model, in a mechanism that was dependent on dendritic cells and regulatory T cells. Encouragingly, AIP-2 also reduced activation of human dendritic cells and T cells, indicating that these findings may readily translate to the clinic. In the developed world, declining prevalence of some parasitic infections correlates with increased incidence of allergic and autoimmune disorders. Moreover, experimental human infection with some parasitic worms confers protection against inflammatory diseases in phase 2 clinical trials. Parasitic worms manipulate the immune system by secreting immunoregulatory molecules that offer promise as a novel therapeutic modality for inflammatory diseases. We identify a protein secreted by hookworms, anti-inflammatory protein-2 (AIP-2), that suppressed airway inflammation in a mouse model of asthma, reduced expression of costimulatory markers on human dendritic cells (DCs), and suppressed proliferation ex vivo of T cells from human subjects with house dust mite allergy. In mice, AIP-2 was primarily captured by mesenteric CD103+ DCs and suppression of airway inflammation was dependent on both DCs and Foxp3+ regulatory T cells (Tregs) that originated in the mesenteric lymph nodes (MLNs) and accumulated in distant mucosal sites. Transplantation of MLNs from AIP-2–treated mice into naïve hosts revealed a lymphoid tissue conditioning that promoted Treg induction and long-term maintenance. Our findings indicate that recombinant AIP-2 could serve as a novel curative therapeutic for allergic asthma and potentially other inflammatory diseases.
HPLC-MS/MS Analyses Show That the Near-Starchless aps1 and pgm Leaves Accumulate Wild Type Levels of ADPglucose: Further Evidence for the Occurrence of Important ADPglucose Biosynthetic Pathway(s) Alternative to the pPGI-pPGM-AGP Pathway

In leaves, it is widely assumed that starch is the end-product of a metabolic pathway exclusively taking place in the chloroplast that (a) involves plastidic phosphoglucomutase (pPGM), ADPglucose (ADPG) pyrophosphorylase (AGP) and starch synthase (SS), and (b) is linked to the Calvin-Benson cycle by means of the plastidic phosphoglucose isomerase (pPGI). This view also implies that AGP is the sole enzyme producing the starch precursor molecule, ADPG. However, mounting evidence has been compiled pointing to the occurrence of important sources, other than the pPGI-pPGM-AGP pathway, of ADPG. To further explore this possibility, in this work two independent laboratories have carried out HPLC-MS/MS analyses of ADPG content in leaves of the near-starchless pgm and aps1 mutants impaired in pPGM and AGP, respectively, and in leaves of double aps1/pgm mutants grown under two different culture conditions. We also measured the ADPG content in wild type (WT) and aps1 leaves expressing in the plastid two different ADPG cleaving enzymes, and in aps1 leaves expressing in the plastid GlgC, a bacterial AGP. Furthermore, we measured the ADPG content in ss3/ss4/aps1 mutants impaired in starch granule initiation and chloroplastic ADPG synthesis. We found that, irrespective of their starch contents, pgm and aps1 leaves, WT and aps1 leaves expressing in the plastid ADPG cleaving enzymes, and aps1 leaves expressing in the plastid GlgC accumulate WT ADPG content. In clear contrast, ss3/ss4/aps1 leaves accumulated ca. 300 fold-more ADPG than WT leaves. The overall data showed that, in Arabidopsis leaves, (a) there are important ADPG biosynthetic pathways, other than the pPGI-pPGM-AGP pathway, (b) pPGM and AGP are not major determinants of intracellular ADPG content, and (c) the contribution of the chloroplastic ADPG pool to the total ADPG pool is low.
A Brazilian Population of the Asexual Fungus-Growing Ant Mycocepurus smithii (Formicidae, Myrmicinae, Attini) Cultivates Fungal Symbionts with Gongylidia-Like Structures

Attine ants cultivate fungi as their most important food source and in turn the fungus is nourished, protected against harmful microorganisms, and dispersed by the ants. This symbiosis evolved approximately 50–60 million years ago in the late Paleocene or early Eocene, and since its origin attine ants have acquired a variety of fungal mutualists in the Leucocoprineae and the distantly related Pterulaceae. The most specialized symbiotic interaction is referred to as “higher agriculture” and includes leafcutter ant agriculture in which the ants cultivate the single species Leucoagaricus gongylophorus. Higher agriculture fungal cultivars are characterized by specialized hyphal tip swellings, so-called gongylidia, which are considered a unique, derived morphological adaptation of higher attine fungi thought to be absent in lower attine fungi. Rare reports of gongylidia-like structures in fungus gardens of lower attines exist, but it was never tested whether these represent rare switches of lower attines to L. gonglyphorus cultivars or whether lower attine cultivars occasionally produce gongylidia. Here we describe the occurrence of gongylidia-like structures in fungus gardens of the asexual lower attine ant Mycocepurus smithii. To test whether M. smithii cultivates leafcutter ant fungi or whether lower attine cultivars produce gongylidia, we identified the M. smithii fungus utilizing molecular and morphological methods. Results shows that the gongylidia-like structures of M. smithii gardens are morphologically similar to gongylidia of higher attine fungus gardens and can only be distinguished by their slightly smaller size. A molecular phylogenetic analysis of the fungal ITS sequence indicates that the gongylidia-bearing M. smithii cultivar belongs to the so-called “Clade 1”of lower Attini cultivars. Given that M. smithii is capable of cultivating a morphologically and genetically diverse array of fungal symbionts, we discuss whether asexuality of the ant host maybe correlated with low partner fidelity and active symbiont choice between fungus and ant mutualists.
Reactive oxygen species affect spinal cell type-specific synaptic plasticity in a model of neuropathic pain

Abstract Spinal synaptic plasticity is believed to drive central sensitization that underlies the persistent nature of neuropathic pain. Our recent data showed that synaptic plasticity in the dorsal horn is cell type specific: intense afferent stimulation produced long-term potentiation (LTP) in excitatory spinothalamic tract neurons (STTn), whereas it produced long-term depression (LTD) in inhibitory GABAergic interneurons (GABAn). In addition, reactive oxygen species (ROS) were shown to be involved in LTP in STTn (STTn-LTP) and in LTD in GABAn (GABAn-LTD). This study examined the roles of 2 biologically important ROS––superoxide [·O2] and hydroxyl radicals [·OH]––in neuropathic mechanical hyperalgesia and cell type-specific spinal synaptic plasticity. The [·O2] donor induced stronger mechanical hyperalgesia than the [·OH] donor in naive mice. The [·O2] scavenger showed greater antihyperalgesic effect than [·OH] scavengers in the spinal nerve ligation (SNL) mouse model of neuropathic pain. In addition, the [·O2] donor induced both STTn-LTP and GABAn-LTD, but the [·OH] donor induced only GABAn-LTD. On the other hand, the [·O2] scavenger inhibited STTn-LTP and GABAn-LTD induction in naive mice and alleviated SNL-induced potentiation in STTn and depression in GABAn. The [·OH] scavenger, however, inhibited depression in GABAn but did not interfere with potentiation in STTn. These results indicate that mechanical hyperalgesia in SNL mice is the result of the combination of STTn-LTP and GABAn-LTD. Behavioral outcomes compliment electrophysiological results which suggest that [·O2] mediates both STTn-LTP and GABAn-LTD, whereas [·OH] is involved primarily in GABAn-LTD.
Perceptions of Hospital‐Dependent Patients on Their Needs for Hospitalization

&NA; In the United States, older adults account for a significant proportion of hospitalizations, and a subset become hospital‐dependent, for reasons that are unclear. We conducted a qualitative study to explore these individuals' perspectives on their need for hospitalizations. Twenty patients hospitalized at an academic medical center underwent semistructured qualitative interviews. Criteria for selection included age 65 and older, at least three hospitalizations over six months, admission to the medical service at the time of the study, did not meet criteria for chronic critical illness, was not comfort measures only, and did not have a conservator. Interviews were audiotaped, transcribed, and inductively analyzed. The major themes derived were the necessity and inevitability of hospitalizations (“You have to bring me in here”), feeling safe in the hospital (“It makes me feel more secure”), patients hospitalized despite having outside medical and social support (“I have everything”), and inadequate goals‐of‐care discussions (“It just doesn't occur to me”). Results suggested that candid discussions about health trajectories are needed to ensure hospitalization is consistent with the patient's realistic health priorities.
Relationship between Physicians’ Uncertainty about Clinical Assessments and Patient-Centered Recommendations for Colorectal Cancer Screening in the Elderly

Objective. The goal of this study was to examine associations between physicians’ clinical assessments, their certainty in these assessments, and the likelihood of a patient-centered recommendation about colorectal cancer (CRC) screening in the elderly. Methods. Two hundred seventy-six primary care physicians in the United States read 3 vignettes about an 80-year-old female patient and answered questions about her life expectancy, their confidence in their life expectancy estimate, the balance of benefits/downsides of CRC screening, their certainty in their benefit/downside assessment, and the best course of action regarding CRC screening. We used logistic regression to determine the relationship between these variables and patient-centered recommendations about CRC screening. Results. In bivariate analyses, physicians had higher odds of making a patient-centered recommendation about CRC screening when their clinical assessments did not lead to a clear screening recommendation or when they experienced uncertainty in their clinical assessments. However, in a multivariate regression model, only benefit/downside assessment and best course of action remained statistically significant predictors of a patient-centered recommendation. Conclusions. Our findings demonstrate that when the results of clinical assessments do not lead to obvious screening decisions or when physicians feel uncertain about their clinical assessments, they are more likely to make patient-centered recommendations. Existing uncertainty frameworks do not adequately describe the uncertainty associated with patient-centered recommendations found in this study. Adapting or modifying these frameworks to better reflect the constructs associated with uncertainty and the interactions between uncertainty and the complexity inherent in clinical decisions will facilitate a more complete understanding of how and when physicians choose to include patients in clinical decisions.
Mechanistic modeling of hemoglobin glycation and red blood cell kinetics enables personalized diabetes monitoring

On the basis of first principles, a model of hemoglobin glycation yields a personalized, more accurate estimate of average glucose for diabetics. A better estimate of blood glucose For optimal medical care, diabetics and their doctors need to know exactly the patient’s recent average blood glucose. Malka and colleagues have developed a mathematical model to this end by integrating the mechanisms of hemoglobin glycation (an indication of blood glucose concentrations) and red blood cell kinetics. Combining the modeling with routine clinical measurements yielded personalized estimates of a patient’s average blood glucose that reduced diagnostic errors by more than 50% compared to the current method. The amount of glycated hemoglobin (HbA1c) in diabetic patients’ blood provides the best estimate of the average blood glucose concentration over the preceding 2 to 3 months. It is therefore essential for disease management and is the best predictor of disease complications. Nevertheless, substantial unexplained glucose-independent variation in HbA1c makes its reflection of average glucose inaccurate and limits the precision of medical care for diabetics. The true average glucose concentration of a nondiabetic and a poorly controlled diabetic may differ by less than 15 mg/dl, but patients with identical HbA1c values may have true average glucose concentrations that differ by more than 60 mg/dl. We combined a mechanistic mathematical model of hemoglobin glycation and red blood cell kinetics with large sets of within-patient glucose measurements to derive patient-specific estimates of nonglycemic determinants of HbA1c, including mean red blood cell age. We found that between-patient variation in derived mean red blood cell age explains all glucose-independent variation in HbA1c. We then used our model to personalize prospective estimates of average glucose and reduced errors by more than 50% in four independent groups of greater than 200 patients. The current standard of care provided average glucose estimates with errors >15 mg/dl for one in three patients. Our patient-specific method reduced this error rate to 1 in 10. Our personalized approach should improve medical care for diabetes using existing clinical measurements.
Decoding the centromeric nucleosome through CENP-N

Centromere protein (CENP) A, a histone H3 variant, is a key epigenetic determinant of chromosome domains known as centromeres. Centromeres nucleate kinetochores, multi-subunit complexes that capture spindle microtubules to promote chromosome segregation during mitosis. Two kinetochore proteins, CENP-C and CENP-N, recognize CENP-A in the context of a rare CENP-A nucleosome. Here, we reveal the structural basis for the exquisite selectivity of CENP-N for centromeres. CENP-N uses charge and space complementarity to decode the L1 loop that is unique to CENP-A. It also engages in extensive interactions with a 15-base pair segment of the distorted nucleosomal DNA double helix, in a position predicted to exclude chromatin remodelling enzymes. Besides CENP-A, stable centromere recruitment of CENP-N requires a coincident interaction with a newly identified binding motif on nucleosome-bound CENP-C. Collectively, our studies clarify how CENP-N and CENP-C decode and stabilize the non-canonical CENP-A nucleosome to enforce epigenetic centromere specification and kinetochore assembly.
Precision medicine screening using whole-genome sequencing and advanced imaging to identify disease risk in adults

Significance Advances in technology are enabling evaluation for prevention and early detection of age-related chronic diseases associated with premature mortality, such as cancer and cardiovascular diseases. These diseases kill about one-third of men and one-quarter of women between the ages of 50 and 74 years old in the United States. We used whole-genome sequencing, advanced imaging, and other clinical testing to screen 209 active, symptom-free adults. We identified a broad set of complementary age-related chronic disease risks associated with premature mortality. Reducing premature mortality associated with age-related chronic diseases, such as cancer and cardiovascular disease, is an urgent priority. We report early results using genomics in combination with advanced imaging and other clinical testing to proactively screen for age-related chronic disease risk among adults. We enrolled active, symptom-free adults in a study of screening for age-related chronic diseases associated with premature mortality. In addition to personal and family medical history and other clinical testing, we obtained whole-genome sequencing (WGS), noncontrast whole-body MRI, dual-energy X-ray absorptiometry (DXA), global metabolomics, a new blood test for prediabetes (Quantose IR), echocardiography (ECHO), ECG, and cardiac rhythm monitoring to identify age-related chronic disease risks. Precision medicine screening using WGS and advanced imaging along with other testing among active, symptom-free adults identified a broad set of complementary age-related chronic disease risks associated with premature mortality and strengthened WGS variant interpretation. This and other similarly designed screening approaches anchored by WGS and advanced imaging may have the potential to extend healthy life among active adults through improved prevention and early detection of age-related chronic diseases (and their risk factors) associated with premature mortality.
Anal, Penile, and Oral High-Risk HPV Infections and HPV Seropositivity in HIV-Positive and HIV-Negative Men Who Have Sex with Men

The effects of single or multiple concordant HPV infections at various anatomical sites on type-specific HPV seropositivity are currently unknown. In this cross-sectional study we assessed whether high-risk HPV infections at various anatomical sites (i.e., anal canal, penile shaft, and oral cavity), as well as concordant infections at multiple anatomical sites, were associated with type-specific seropositivity in HIV-positive and HIV-negative MSM. MSM aged ≥18 years were recruited in Amsterdam, the Netherlands (2010–2011). Baseline anal, penile, and oral samples were analyzed for HPV DNA and genotyped using a highly sensitive PCR and reverse line blot assay. Virus-like particle (VLP) based multiplex immunoassay was used to asses HPV-specific serum antibodies against L1 VLPs. The associations between HPV infections and type-specific seropositivity of seven high-risk HPV types (7-hrHPV: types 16, 18, 31, 33, 45, 52, 58) were estimated using logistic regression analyses with generalized estimating equations. We found that 86% of 306 HIV-positive MSM and 62% of 441 HIV-negative MSM were seropositive for at least one 7-hrHPV type. 69% of HIV-positive and 41% of HIV-negative MSM were infected with at least one 7-hrHPV type at the anus, penis, or oral cavity. In multivariable analyses, 7-hrHPV seropositivity was associated with type-specific anal (and not penile) 7-hrHPV infection, and did not significantly increase with a higher number of infected anatomical sites. Oral 7-hrHPV infection showed a positive, albeit non-significant, association with seropositivity. In conclusion, seropositivity among MSM appears to be largely associated with anal HPV infection, irrespective of additionally infected anatomical sites.
Mother-Child Positivity and Negativity: Family-Wide and Child-Specific Main Effects and Interactions Predict Child Adjustment

Links between positive and negative aspects of the parent-child relationship and child adjustment are undisputed. Scholars recognize the importance of parental differential treatment (PDT) of siblings, yet, less is known about PDT in the context of the shared (family-wide) parent-child relationship climate, or about the extent to which positivity may buffer children’s adjustment from negativity. Controlling for behavioral stability, we examined the potential for positive and negative parent-child processes to interact across and between child-specific and family-wide levels in the prediction of children’s adjustment. Specifically, in a sample of 2,039 United Kingdom families, we used multilevel models to examine child-specific and family-wide mother-child relationships (at 4 years)—including interactive processes—in the prediction of prosocial behavior and conduct problems (at 7 years). The majority of variance in children’s adjustment resided within-families: siblings were strikingly different. Accounting for behavioral stability, family-wide negativity and negative PDT associated with both prosociality and conduct problems. More important, we demonstrated interactions between, (a) family-wide negativity and negative PDT for conduct problems, as well as, (b) positive and negative PDT in the prediction of both prosocial behavior and conduct problems. Results suggest negative PDT associates with increased conduct problems over time, even when the overall family climate is low in negativity. They also indicate a buffering role of positive PDT on the deleterious effects of negative PDT for children’s adjustment. Implications for both research and practice are discussed, including the importance of information gained by considering more than one child in the family.
Improved Methods for Capture, Extraction, and Quantitative Assay of Environmental DNA from Asian Bigheaded Carp (Hypophthalmichthys spp.)

Indirect, non-invasive detection of rare aquatic macrofauna using aqueous environmental DNA (eDNA) is a relatively new approach to population and biodiversity monitoring. As such, the sensitivity of monitoring results to different methods of eDNA capture, extraction, and detection is being investigated in many ecosystems and species. One of the first and largest conservation programs with eDNA-based monitoring as a central instrument focuses on Asian bigheaded carp (Hypophthalmichthys spp.), an invasive fish spreading toward the Laurentian Great Lakes. However, the standard eDNA methods of this program have not advanced since their development in 2010. We developed new, quantitative, and more cost-effective methods and tested them against the standard protocols. In laboratory testing, our new quantitative PCR (qPCR) assay for bigheaded carp eDNA was one to two orders of magnitude more sensitive than the existing endpoint PCR assays. When applied to eDNA samples from an experimental pond containing bigheaded carp, the qPCR assay produced a detection probability of 94.8% compared to 4.2% for the endpoint PCR assays. Also, the eDNA capture and extraction method we adapted from aquatic microbiology yielded five times more bigheaded carp eDNA from the experimental pond than the standard method, at a per sample cost over forty times lower. Our new, more sensitive assay provides a quantitative tool for eDNA-based monitoring of bigheaded carp, and the higher-yielding eDNA capture and extraction method we describe can be used for eDNA-based monitoring of any aquatic species.