Miracle-dz/UniFAR-FTUs huggingface dataset:
Vaccination with early ferroptotic cancer cells induces efficient antitumor immunity

Background Immunotherapy represents the future of clinical cancer treatment. The type of cancer cell death determines the antitumor immune response and thereby contributes to the efficacy of anticancer therapy and long-term survival of patients. Induction of immunogenic apoptosis or necroptosis in cancer cells does activate antitumor immunity, but resistance to these cell death modalities is common. Therefore, it is of great importance to find other ways to kill tumor cells. Recently, ferroptosis has been identified as a novel, iron-dependent form of regulated cell death but whether ferroptotic cancer cells are immunogenic is unknown. Methods Ferroptotic cell death in murine fibrosarcoma MCA205 or glioma GL261 cells was induced by RAS-selective lethal 3 and ferroptosis was analyzed by flow cytometry, atomic force and confocal microscopy. ATP and high-mobility group box 1 (HMGB1) release were detected by luminescence and ELISA assays, respectively. Immunogenicity in vitro was analyzed by coculturing of ferroptotic cancer cells with bone-marrow derived dendritic cells (BMDCs) and rate of phagocytosis and activation/maturation of BMDCs (CD11c+CD86+, CD11c+CD40+, CD11c+MHCII+, IL-6, RNAseq analysis). The tumor prophylactic vaccination model in immune-competent and immune compromised (Rag-2−/−) mice was used to analyze ferroptosis immunogenicity. Results Ferroptosis can be induced in cancer cells by inhibition of glutathione peroxidase 4, as evidenced by confocal and atomic force microscopy and inhibitors’ analysis. We demonstrate for the first time that ferroptosis is immunogenic in vitro and in vivo. Early, but not late, ferroptotic cells promote the phenotypic maturation of BMDCs and elicit a vaccination-like effect in immune-competent mice but not in Rag-2−/− mice, suggesting that the mechanism of immunogenicity is very tightly regulated by the adaptive immune system and is time dependent. Also, ATP and HMGB1, the best-characterized damage-associated molecular patterns involved in immunogenic cell death, have proven to be passively released along the timeline of ferroptosis and act as immunogenic signal associated with the immunogenicity of early ferroptotic cancer cells. Conclusions These results pave the way for the development of new therapeutic strategies for cancers based on induction of ferroptosis, and thus broadens the current concept of immunogenic cell death and opens the door for the development of new strategies in cancer immunotherapy.
Pedigree-Based Gene Mapping Supports Previous Loci and Reveals Novel Suggestive Loci in Specific Language Impairment

Purpose Specific language impairment (SLI) is characterized by a delay in language acquisition despite a lack of other developmental delays or hearing loss. Genetics of SLI is poorly understood. The purpose of this study is to identify SLI genetic loci through family-based linkage mapping. Method We performed genome-wide parametric linkage analysis in six families segregating with SLI. An age-appropriate standardized omnibus language measure was used to categorically define the SLI phenotype. Results A suggestive linkage region replicated a previous region of interest with the highest logarithm of odds (LOD) score of 2.40 at 14q11.2-q13.3 in Family 489. A paternal parent-of-origin effect associated with SLI and language phenotypes on a nonsynonymous single nucleotide polymorphism (SNP) in NOP9 (14q12) was reported previously. Linkage analysis identified a new SLI locus at 15q24.3-25.3 with the highest parametric LOD score of 3.06 in Family 315 under a recessive mode of inheritance. Suggestive evidence of linkage was also revealed at 4q31.23-q35.2 in Family 300, with the highest LOD score of 2.41. Genetic linkage was not identified in the other three families included in parametric linkage analysis. Conclusions These results are the first to report genome-wide suggestive linkage with a total language standard score on an age-appropriate omnibus language measure across a wide age range. Our findings confirm previous reports of a language-associated locus on chromosome 14q, report new SLI loci, and validate the pedigree-based parametric linkage analysis approach to mapping genes for SLI. Supplemental Material https://doi.org/10.23641/asha.13203218
A role for calcium-dependent protein kinases in differential CO2 - and ABA-controlled stomatal closing and low CO2 -induced stomatal opening in Arabidopsis.

- Low concentrations of CO2 cause stomatal opening, whereas [CO2 ] elevation signals stomatal closure. Classical studies have suggested a role for Ca2+ and protein phosphorylation in CO2 -induced stomatal closing. Calcium-dependent protein kinases (CPKs) and calcineurin-B-like proteins (CBLs) can sense and translate cytosolic elevation of the second messenger Ca2+ into specific phosphorylation events. Yet, Ca2+ -binding proteins that function in the stomatal CO2 response remain unknown. - Time-resolved stomatal conductance measurements using intact plants and guard cell patch-clamp experiments were pursued. - We isolated cpk quintuple mutants and analyzed stomatal movements in response to CO2 , light and abscisic acid (ABA). Interestingly, we found that cpk3/5/6/11/23 quintuple mutant plants, but not other analyzed cpk quadruple/quintuple mutants, were defective in high CO2 -induced stomatal closure and unexpectedly also in low CO2 -induced stomatal opening. Furthermore, K+ -uptake-channel activities were reduced in cpk3/5/6/11/23 quintuple mutants, in correlation with the stomatal opening phenotype. However, light-mediated stomatal opening remained unaffected and ABA responses showed slowing in some experiments. In contrast, quintuple mutant plants in the plasma membrane-targeted cbl1/4/5/8/9 did not clearly affect CO2 regulated stomatal movement kinetics. - These findings reveal combinatorial cpk mutants that function in CO2 control of stomatal movements and support classical studies showing a role for Ca2+ in this response.
Mechanisms of EGFR Resistance in Glioblastoma

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. Despite numerous efforts to target epidermal growth factor receptor (EGFR), commonly dysregulated in GBM, approaches directed against EGFR have not achieved the same degree of success as seen in other tumor types, particularly as compared to non-small cell lung cancer (NSCLC). EGFR alterations in glioblastoma lie primarily in the extracellular domain, unlike the kinase domain alterations seen in NSCLC. Small molecule inhibitors are difficult to develop for the extracellular domain. Monoclonal antibodies can be developed to target the extracellular domain but must contend with the blood brain barrier (BBB). We review the role of EGFR in GBM, the history of trialed treatments, and the potential paths forward to target the pathway that may have greater success.
Distinct inflammatory profiles distinguish COVID-19 from influenza with limited contributions from cytokine storm

Immunologic evaluation shows that most COVID-19 patients exhibit targeted immunosuppression compared to patients with influenza. We pursued a study of immune responses in coronavirus disease 2019 (COVID-19) and influenza patients. Compared to patients with influenza, patients with COVID-19 exhibited largely equivalent lymphocyte counts, fewer monocytes, and lower surface human leukocyte antigen (HLA)–class II expression on selected monocyte populations. Furthermore, decreased HLA-DR on intermediate monocytes predicted severe COVID-19 disease. In contrast to prevailing assumptions, very few (7 of 168) patients with COVID-19 exhibited cytokine profiles indicative of cytokine storm syndrome. After controlling for multiple factors including age and sample time point, patients with COVID-19 exhibited lower cytokine levels than patients with influenza. Up-regulation of IL-6, G-CSF, IL-1RA, and MCP1 predicted death in patients with COVID-19 but were not statistically higher than patients with influenza. Single-cell transcriptional profiling revealed profound suppression of interferon signaling among patients with COVID-19. When considered across the spectrum of peripheral immune profiles, patients with COVID-19 are less inflamed than patients with influenza.
Humoral and Cell-Mediated Immune Response Validation in Calves after a Live Attenuated Vaccine of Babesia bigemina

The current vaccines to control bovine Babesia bigemina (B. bigemina) infection are not fully protective and vaccination failures incur heavy losses to the cattle industry around the world. Using modified micro-aerophilous stationary phase, we developed a culture-derived attenuated live vaccine against B. bigemina and tested a single subcutaneous inoculation of 2 × 108 infected erythrocytes in calves. The protection was measured after a lethal intravenous challenge with 5 × 108 virulent calf-derived B. bigemina. Our results demonstrated that a single shot of attenuated vaccine was capable of inducing robust humoral and cell-mediated immune responses in calves. We found a significant increase in the IgG antibody titers post-challenge and a strong proliferation of both CD4+ and CD8+ T cells contributing towards the protection. Our vaccine provided complete protection and parasitic clearance, which was followed for more than 100 days post-challenge. This immunity against babesiosis was directly linked to strong humoral responses; however, the parasitic clearance was attributed to significant T cells effector responses in vaccinated calves as compared to the infected control calves. We anticipate that these results will be helpful in the development of more efficient culture-derived vaccines against Babesia infections, thus reducing significant global economic losses to farmers and the cattle industry.
On uncorrelated inter-monomer Förster energy transfer in Fenna–Matthews–Olson complexes

The Fenna–Matthews–Olson (FMO) light-harvesting antenna protein of green sulfur bacteria is a long-studied pigment–protein complex which funnels energy from the chlorosome to the reaction centre where photochemistry takes place. The structure of the FMO protein from Chlorobaculum tepidum is known as a homotrimeric complex containing eight bacteriochlorophyll a per monomer. Owing to this structure FMO has strong intra-monomer and weak inter-monomer electronic coupling constants. While long-lived (sub-picosecond) coherences within a monomer have been a prevalent topic of study over the past decade, various experimental evidence supports the presence of subsequent inter-monomer energy transfer on a picosecond time scale. The latter has been neglected by most authors in recent years by considering only sub-picosecond time scales or assuming that the inter-monomer coupling between low-energy states is too weak to warrant consideration of the entire trimer. However, Förster theory predicts that energy transfer of the order of picoseconds is possible even for very weak (less than 5 cm–1) electronic coupling between chromophores. This work reviews experimental data (with a focus on emission and hole-burned spectra) and simulations of exciton dynamics which demonstrate inter-monomer energy transfer. It is shown that the lowest energy 825 nm absorbance band cannot be properly described by a single excitonic state. The energy transfer through FMO is modelled by generalized Förster theory using a non-Markovian, reduced density matrix approach to describe the electronic structure. The disorder-averaged inter-monomer transfer time across the 825 nm band is about 27 ps. While only isolated FMO proteins are presented, the presence of inter-monomer energy transfer in the context of the overall photosystem is also briefly discussed.
Sarcopenia Severity Based on Computed Tomography Image Analysis in Patients with Cirrhosis

Standardized sex-specific cut-offs for sarcopenia in cirrhosis are needed to identify the risk of clinical complications and to discriminate the severity of sarcopenia. We aimed to compare clinical characteristics between patients with cirrhosis categorized according to the severity of sarcopenia. Computed tomography images were taken at the 3rd lumbar vertebra from 603 patients with cirrhosis and 129 adult donors for living liver transplantation. Patients with skeletal muscle index (SMI) two standard deviations (SD) below the sex-specific mean value of young donors (18–40 years old) were categorized as having severe sarcopenia whereas patients with SMI between −1 and −2 SD of the sex-specific young adult mean values were categorized as having sarcopenia. In the cirrhosis group, 408 patients (68%) were male with the mean age of 57 ± 0.4 years, and MELD score of 14 ± 0.4. Patients were divided into three groups: severe-sarcopenic (SMI < 30 cm2/m2 in females and <42 cm2/m2 in males), sarcopenic (30 ≤ SMI < 37 cm2/m2 in females and 42 ≤ SMI < 50 cm2/m2 in males) and non-sarcopenic (SMI ≥ 37 cm2/m2 in females and ≥50 cm2/m2 in males). Patients with cirrhosis and severe sarcopenia had lower muscle radiodensity and higher plasma neutrophil as well as neutrophil to lymphocyte ratio levels than both non- and sarcopenic groups. The frequency of alcohol-induced cirrhosis, refractory ascites, hepatic encephalopathy, CRP > 20 mg/mL, and severe malnutrition was also higher in severe-sarcopenic patients. The interval between sarcopenia and severe sarcopenia may reflect a window of opportunity in which to intervene and mitigate muscle wasting to improve patient outcomes.
Minor Changes in the Composition and Function of the Gut Microbiota During a 12-Week Whole Grain Wheat or Refined Wheat Intervention Correlate with Liver Fat in Overweight and Obese Adults

ABSTRACT Background Whole grain wheat (WGW) products are advocated as a healthy choice when compared with refined wheat (RW). One proposed mechanism for these health benefits is via the microbiota, because WGW contains multiple fibers. WGW consumption has been proposed to ameliorate nonalcoholic fatty liver disease, in which microbiota might play a role. Objectives We investigated the effect of WGW compared with RW intervention on the fecal microbiota composition and functionality, and correlated intervention-induced changes in bacteria with changes in liver health parameters in adults with overweight or obesity. Methods We used data of a 12-wk double-blind, randomized, controlled, parallel trial to examine the effects of a WGW (98 g/d) or RW (98 g/d) intervention on the secondary outcomes fecal microbiota composition, predicted microbiota functionality, and stool consistency in 37 women and men (aged 45–70 y, BMI 25–35 kg/m2). The changes in microbiota composition, measured using 16S ribosomal RNA gene sequencing, after a 12-wk intervention were analyzed with nonparametric tests, and correlated with changes in liver fat and circulating concentrations of liver enzymes including alanine transaminase, aspartate transaminase, γ-glutamyltransferase, and serum amyloid A. Results The WGW intervention increased the mean (± SD) relative abundances of Ruminococcaceae_UCG-014 (baseline: 2.2 ± 4.6%, differential change over time (Δ) 0.51 ± 4.2%), Ruminiclostridium_9 (baseline: 0.065 ± 0.11%, Δ 0.054 ± 0.14%), and Ruminococcaceae_NK4A214_group (baseline: 0.37 ± 0.56%, Δ 0.17 ± 0.83%), and also the predicted pathway acetyl-CoA fermentation to butyrate II (baseline: 0.23 ± 0.062%, Δ 0.035 ± 0.059%), compared with the RW intervention (P values <0.05). A change in Ruminococcaceae_NK4A214_group was positively correlated with the change in liver fat, in both the WGW (ρ = 0.54; P = 0.026) and RW (ρ = 0.67; P = 0.024) groups. Conclusions In middle-aged overweight and obese adults, a 12-wk WGW intervention increased the relative abundance of a number of bacterial taxa from the family Ruminococcaceae and increased predicted fermentation pathways when compared with an RW intervention. Potential protective health effects of replacement of RW by WGW on metabolic organs, such as the liver, via modulation of the microbiota, deserve further investigation. This trial was registered at clinicaltrials.gov as NCT02385149.
The impact of neonatal nutrition on the growth, fertility, health, milk yield and day old calf performances of Holstein dairy heifers

Neonatal nutrition may influence performance in later life in many species; however, there have been a few studies of this phenomenon in cattle. Determining if there are direct and residual effects of nutrition during the first 60 days of life may help optimise lifetime productivity. Underfeeding reduces calf weaning weight and delays puberty, which reduces the potential lifetime productivity of the dairy heifers. As well as repercussions on calf health, growth and welfare; many studies in human suggest that underfeeding of the newborn is a major risk factor for metabolic diseases in the adult. The aims of this study were to investigate the performances of Holstein heifers that were fed increased milk replacer compared to restricted volumes during their early life and to determine the impact of this on key performance indicators of these animals as future potential the best cows in the herd. Thus, a total of eighty eight heifers were included in this study, which forty seven heifers were in Group A (ad libitum milk replacer fed group) and forty one heifers were in Group R (restricted milk replacer fed group). They were enrolled 8 weeks prior to predicted calving based on artificial insemination dates of pregnancies confirmed by per rectum ultrasound examination of the uterus and 282 days of gestation period. The body weight, body condition score, withers and loin height, heart and belly girth, crown to rump length and hock fetlock length were recorded from 8 weeks prior to predicted calving until 30 weeks of postpartum. Blood samples were collected for β-hydroxybutyrate (BHB) concentration measurements and milk samples were collected for pregnane profiles analysis. Data on physical measurements (heifers and calves), pregnane profiles, reproductive parameters, BHB concentration values, health parameters, milk yield and milk components were analysed. The MilkBot parameters were used to describe the lactation curve between the 2 groups. There was no large effect of different pre-weaning feeding strategies during early life of heifers on their growth, fertility, health, milk yield and day old calf performances between Group A and Group R during first lactation period. There were no differences in MilkBot parameters; estimated scale, decay, persistence, peak milk and peak day between the 2 groups. However, several significant findings were observed; heifers in Group A had higher milk protein percentage and higher in somatic cell counts (SCC). Meanwhile, heifers in Group R had higher number of delayed ovulation type 1 (DOV1) profile, higher incidence of subclinical ketosis (SCK) and higher in estimated ramp. Another finding was heifers produced more milk following birth of a bull calf regardless of groups.
Oviposition, Feeding Preferences and Distribution of Delia Species (Diptera: Anthomyiidae) in Eastern Canadian Onions

Simple Summary Delia root maggot species are commonly found in onions. It is unclear which species affects onions most and how they are distributed among the major onion growing regions in Eastern Canada. Through oviposition and feeding preference bioassays, we determined that all species can similarly affect onion crops. We also determined that proportions of Delia species differ between the growing regions. Abstract Delia antiqua, Delia platura and Delia florilega are three root maggot species commonly considered pests in Eastern Canadian onions. The onion maggot, D. antiqua, is considered the primary root maggot pest in onion but it remains unclear whether the other two species are also causing damage. In order to develop updated management strategies for root maggot, we tested adult oviposition and feeding preference by Delia larvae on four growth stages of onion using bioassays and we determined the Delia species composition across the four major onion growing regions in eastern Canada. Delia species oviposit readily on onion at the 5–7 true leaf growth stage but damage on onions is not statistically different between Delia species in our zero-inflated models. The four eastern Canadian onion growing regions have different proportions of Delia species. Southern Ontario and Quebec were the only two regions where Delia antiqua was collected. The highest average numbers of Delia spp. were caught in Quebec and Nova Scotia. Our study shows that timing is important in implementation of management strategies for root maggot in Eastern Canadian onions.
Controlled drinking - non-abstinent versus abstinent treatment goals in alcohol use disorder: A Systematic Review, Meta-Analysis and Meta-Regression.

BACKGROUND AND AIMS The proportion of untreated patients with alcohol use disorder (AUD) exceeds that of any other mental health disorder and treatment alternatives are needed. A widely discussed strategy is to depart from the abstinence paradigm as part of controlled drinking approaches. This first systematic review with meta-analysis aims to assess the efficacy of non-abstinent treatment strategies compared with abstinence-based strategies. METHODS CENTRAL, PubMed, PsycINFO, and Embase databases were searched until February 2019 for controlled (randomized and non-randomized) clinical trials (RCTs and non-RCTs) among adult AUD populations, including an intervention group aiming at controlled drinking and a control group aiming for abstinence. Following PRISMA and Cochrane guidelines, literature search, data collection and risk of bias assessment were carried out independently by two reviewers (PROSPERO Registration-No.: CRD42019128716). The primary outcome was the proportion of participants consuming alcohol at or below the recommended threshold. Secondary outcomes were social functioning, drinking reductions, abstinence rates and dropouts. Using random effects models, RCTs and non-RCTs were analyzed separately. Sensitivity and subgroup analyses accounted for methodological rigor, inclusion of goal-specific treatment, length of follow-up and AUD severity. RESULTS Twenty-two studies (including five RCTs) with 4,204 patients were selected. There was no statistically significant difference between both treatment paradigms in RCTs [odds ratio: 1.32 (95%CI: 0.51-3.39)]. Nonrandomized studies of free goal-choice favored abstinence-orientation [0.60 (0.40-0.90)], unless goal-specific treatment was provided [0.79 (0.40-1.56)] or in studies of low risk of bias [0.73 (0.49-1.09)] or with long follow-up [1.49 (0.78-2.85)]. Effect sizes were not clearly dependent on AUD severity. Abstinence- and controlled drinking interventions did not clearly differ in their effect on social functioning and drinking reductions. CONCLUSIONS Available evidence does not support abstinence as the only approach in the treatment of alcohol use disorder. Controlled drinking, particularly if supported by specific psychotherapy, appears to be a viable option where an abstinence-oriented approach is not applicable.