Miracle-dz/UniFAR-FTUs huggingface dataset:
Short-Term Physiological Effects of a Very Low-Calorie Ketogenic Diet: Effects on Adiponectin Levels and Inflammatory States

Adipose tissue is a multifunctional organ involved in many physiological and metabolic processes through the production of adipokines and, in particular, adiponectin. Caloric restriction is one of the most important strategies against obesity today. The very low-calorie ketogenic diet (VLCKD) represents a type of caloric restriction with very or extremely low daily food energy consumption. This study aimed to investigate the physiological effects of a VLCKD on anthropometric and biochemical parameters such as adiponectin levels, as well as analyzing oligomeric profiles and cytokine serum levels in obese subjects before and after a VLCKD. Twenty obese subjects were enrolled. At baseline and after eight weeks of intervention, anthropometric and biochemical parameters, such as adiponectin levels, were recorded. Our findings showed a significant change in the anthropometric and biochemical parameters of these obese subjects before and after a VLCKD. We found a negative correlation between adiponectin and lipid profile, visceral adipose tissue (VAT), C-reactive protein (CRP), and pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), which confirmed the important involvement of adiponectin in metabolic and inflammatory diseases. We demonstrated the beneficial short-term effects of a VLCKD not only in the treatment of obesity but also in the establishment of obesity-correlated diseases.
A Genome-scale CRISPR Screen Identifies the ERBB and mTOR Signaling Networks as Key Determinants of Response to PI3K Inhibition in Pancreatic Cancer

KRAS mutation is a key driver of pancreatic cancer and PI3K pathway activity is an additional requirement for Kras-induced tumorigenesis. Clinical trials of PI3K pathway inhibitors in pancreatic cancer have shown limited responses. Understanding the molecular basis for this lack of efficacy may direct future treatment strategies with emerging PI3K inhibitors. We sought new therapeutic approaches that synergize with PI3K inhibitors through pooled CRISPR modifier genetic screening and a drug combination screen. ERBB family receptor tyrosine kinase signaling and mTOR signaling were key modifiers of sensitivity to alpelisib and pictilisib. Inhibition of the ERBB family or mTOR was synergistic with PI3K inhibition in spheroid, stromal cocultures. Near-complete loss of ribosomal S6 phosphorylation was associated with synergy. Genetic alterations in the ERBB–PI3K signaling axis were associated with decreased survival of patients with pancreatic cancer. Suppression of the PI3K/mTOR axis is potentiated by dual PI3K and ERBB family or mTOR inhibition. Surprisingly, despite the presence of oncogenic KRAS, thought to bestow independence from receptor tyrosine kinase signaling, inhibition of the ERBB family blocks downstream pathway activation and synergizes with PI3K inhibitors. Further exploration of these therapeutic combinations is warranted for the treatment of pancreatic cancer.
Impaired angiogenesis and extracellular matrix metabolism in Autosomal-Dominant Hyper-IgE Syndrome.

There are more than 7000 described rare diseases, most lacking specific treatment. Autosomal-dominant hyper-IgE syndrome (AD-HIES, Job's syndrome) is caused by mutations in signal transducer and activator of transcription 3 (STAT3). These patients present with immunodeficiency accompanied by severe non-immunological features including skeletal, connective tissue and vascular abnormalities, poor post-infection lung healing, and subsequent pulmonary failure. No specific therapies are available for these abnormalities. Here we investigated underlying mechanisms in order to identify therapeutic targets. Histological analysis of skin wounds demonstrated delayed granulation tissue formation and vascularization during skin wound healing in AD-HIES patients. Global gene expression analysis in AD-HIES patient skin fibroblasts identified deficiencies in a STAT3 controlled transcriptional network regulating extracellular matrix (ECM) remodeling and angiogenesis, with hypoxia inducible factor 1α (HIF1α) being a major contributor. Consistent with this, histological analysis of skin wounds and coronary arteries from AD-HIES patients showed decreased HIF1α expression, and revealed abnormal organization of the ECM and altered formation of the coronary vasa vasorum. Disease modeling utilizing cell culture and mouse models of angiogenesis and wound healing confirmed these predicted deficiencies and demonstrated therapeutic benefit of HIF1α stabilizing drugs. The study provides mechanistic insights into AD-HIES pathophysiology and finds new treatment option for this rare disease.
A venous mechanism of ventriculomegaly shared between traumatic brain injury and normal ageing

Age-related ventricular dilatation is considered a consequence of tissue atrophy, distinct from the ventriculomegaly seen in idiopathic normal pressure hydrocephalus. Aso et al. show that an age-related venous perfusion timing shift may be another factor driving ventricular enlargement in both normal ageing and pathology.
Towards the routine use of in silico screenings for drug discovery using metabolic modelling

Currently, the development of new effective drugs for cancer therapy is not only hindered by development costs, drug efficacy, and drug safety but also by the rapid occurrence of drug resistance in cancer. Hence, new tools are needed to study the underlying mechanisms in cancer. Here, we discuss the current use of metabolic modelling approaches to identify cancer-specific metabolism and find possible new drug targets and drugs for repurposing. Furthermore, we list valuable resources that are needed for the reconstruction of cancer-specific models by integrating various available datasets with genome-scale metabolic reconstructions using model-building algorithms. We also discuss how new drug targets can be determined by using gene essentiality analysis, an in silico method to predict essential genes in a given condition such as cancer and how synthetic lethality studies could greatly benefit cancer patients by suggesting drug combinations with reduced side effects.
Black-Si as a Photoelectrode

The fabrication and characterization of photoanodes based on black-Si (b-Si) are presented using a photoelectrochemical cell in NaOH solution. B-Si was fabricated by maskless dry plasma etching and was conformally coated by tens-of-nm of TiO2 using atomic layer deposition (ALD) with a top layer of CoOx cocatalyst deposited by pulsed laser deposition (PLD). Low reflectivity R<5% of b-Si over the entire visible and near-IR (λ<2 μm) spectral range was favorable for the better absorption of light, while an increased surface area facilitated larger current densities. The photoelectrochemical performance of the heterostructured b-Si photoanode is discussed in terms of the n-n junction between b-Si and TiO2.
Impact of a 25% Salt Reduction on the Microbial Load, Texture, and Sensory Attributes of a Traditional Dry-Cured Sausage

Catalão is a Portuguese dry-cured traditional sausage, highly appreciated for its distinctive sensory properties. The aim of this study was to evaluate the impact of a 25% salt reduction on Catalão manufactured with either purebred Alentejano (Al) or crossbred Iberian × Duroc (IDr) pork meat, on its physicochemical and microbiological stability, texture parameters, and sensory attributes. No significant effect of salt reduction or genotype was observed for pH, aW, and microbiological parameters. PUFA content was significantly higher for Al Catalão, particularly due to the content in linoleic and linolenic fatty acids. IDr 3% NaCl samples had the highest mean n6/n3 PUFA ratio, and the highest mean values for the atherogenicity and thrombogenicity indices, showing that both genotype and salt content influence these nutritional indices. Texture profile of Catalão was significantly influenced by salt content and genotype. Al samples were less adhesive, cohesive, and easier to chew. Low-salt Catalão was harder, more adhesive, and less cohesive, with lower resilience and higher chewiness values. Regarding sensory attributes, salt content influenced the product aroma, with reduced-salt sausages being evaluated as significantly less aromatic. Overall, a 25% salt reduction did not have a significant impact on the quality, stability, and sensory evaluation of Catalão.
Pancreatic cancer triggers diabetes through TGF-β–mediated selective depletion of islet β-cells

Pancreatic ductal adenocarcinoma formation culminates in hyperactivation of transforming growth factor β signaling, which in turn induces selective depletion of β-cell mass and thereby leading to new-onset diabetes. Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease that remains incurable because of late diagnosis, which renders any therapeutic intervention challenging. Most PDAC patients develop de novo diabetes, which exacerbates their morbidity and mortality. How PDAC triggers diabetes is still unfolding. Using a mouse model of KrasG12D-driven PDAC, which faithfully recapitulates the progression of the human disease, we observed a massive and selective depletion of β-cells, occurring very early at the stages of preneoplastic lesions. Mechanistically, we found that increased TGF beta (TGF-β) signaling during PDAC progression caused erosion of β-cell mass through apoptosis. Suppressing TGF-β signaling, either pharmacologically through TGF-β immunoneutralization or genetically through deletion of Smad4 or TGF-β type II receptor (TβRII), afforded substantial protection against PDAC-driven β-cell depletion. From a translational perspective, both activation of TGF-β signaling and depletion of β-cells frequently occur in human PDAC, providing a mechanistic explanation for the pathogenesis of diabetes in PDAC patients, and further implicating new-onset diabetes as a potential early prognostic marker for PDAC.
Childhood overweight and obesity and timing of puberty in boys and girls: cohort and sibling-matched analyses

Abstract Background Early puberty is a risk indicator for adult diseases. Identification of modifiable causes of earlier puberty is, therefore, warranted. We estimate the association between childhood body mass index (BMI) and pubertal timing in a cohort study and in a sibling-matched study to adjust for unobserved time-stable confounders shared within families. Methods For the cohort study, 11 046 of 22 439 (49%) invited children, born 2000–203, from the Danish National Birth Cohort (DNBC) had information on childhood BMI at 7 years and self-reported, half-yearly puberty information from 11 years on Tanner stages, menarche, voice break, first ejaculation, acne, and axillary hair. For the sibling-matched study, 1700 brothers and sisters were included among 86 820 live-born singletons from the DNBC. Results Childhood overweight (85th ≤ BMI < 95th percentile) and obesity (BMI ≥ 95th percentile) were associated with earlier age attaining the pubertal milestones in a dose-dependent manner in boys and girls. When modelling all pubertal milestones simultaneously, the pubertal milestones were attained earlier in: overweight boys: −3.1 [95% confidence interval (CI): −4.5, −1.7] months, overweight girls: −5.5 (95% CI: −7.1, −3.9) months, obese boys: −3.5 (95% CI: −5.1, −2.0) months, obese girls: −5.2 (95% CI: −7.1, −3.4) months compared with normal weight (BMI < 85th percentile) children. In the sibling-matched study, higher BMI was associated with earlier age at attaining most pubertal milestones in girls, but only a tendency toward earlier pubertal timing was observed in boys. Conclusions Childhood overweight and obesity were associated with earlier pubertal timing even after adjustment for unobserved time-stable confounders shared within families.
Hybrid Imaging Agents for Pretargeting Applications Based on Fusarinine C—Proof of Concept

Hybrid imaging combining the beneficial properties of radioactivity and optical imaging within one imaging probe has gained increasing interest in radiopharmaceutical research. In this study, we modified the macrocyclic gallium-68 chelator fusarinine C (FSC) by conjugating a fluorescent moiety and tetrazine (Tz) moieties. The resulting hybrid imaging agents were used for pretargeting applications utilizing click reactions with a trans-cyclooctene (TCO) tagged targeting vector for a proof of principle both in vitro and in vivo. Starting from FSC, the fluorophores Sulfocyanine-5, Sulfocyanine-7, or IRDye800CW were conjugated, followed by introduction of one or two Tz motifs, resulting in mono and dimeric Tz conjugates. Evaluation included fluorescence microscopy, binding studies, logD, protein binding, in vivo biodistribution, µPET (micro-positron emission tomography), and optical imaging (OI) studies. 68Ga-labeled conjugates showed suitable hydrophilicity, high stability, and specific targeting properties towards Rituximab-TCO pre-treated CD20 expressing Raji cells. Biodistribution studies showed fast clearance and low accumulation in non-targeted organs for both SulfoCy5- and IRDye800CW-conjugates. In an alendronate-TCO based bone targeting model the dimeric IRDye800CW-conjugate resulted in specific targeting using PET and OI, superior to the monomer. This proof of concept study showed that the preparation of FSC-Tz hybrid imaging agents for pretargeting applications is feasible, making such compounds suitable for hybrid imaging applications.
Zinc ions differentially affect chitin synthase gene expression in an ericoid mycorrhizal fungus

Two chitin synthase (Chs) genes (class II and class IV, respectively) were identified in the mycelium of strain PSIV, a sterile ascomycete capable of establishing ericoid mycorrhiza. Both genes were constitutively expressed during mycelial growth in liquid medium. However, when the fungus was challenged with toxic amounts of zinc ions, the accumulation of class II, but not class IV, Chs mRNAs was inhibited. To our knowledge, this is the first report on the differential expression of distinct Chs mRNAs following exposure to heavy metals.
Assessment of vegetation and naturalness: a study case in Southern Italy

Abstract: The study of vegetation and naturalness in the province of Benevento (southern Italy) was conducted through a series of complementary steps starting from a preliminary phase of bibliographical research. To draw up the theme map, after the preparatory phase of GIS-based cartographic support, a photo-interpretation phase was conducted for the whole province of Benevento on the basis of orthophotos at a scale of 1:10.000 taken in 1997-1998 supplied by the Provincial Authority. We produced a map which chiefly takes account of the physiognomic features of vegetation alongside floristic data. Throughout the province of Benevento we identified 21 main floristic types grouped into four categories, which include three physiognomic categories and one category grouping the areas greatly affected by human impact. For each vegetation type we calculated the percentage of the area against the whole surface area of the province. Starting from the vegetation map, the vegetation types in the area were reclassified according to the scale of naturalness ordered according to the criterion of proximity to the mature vegetation phase. The conservation status of the plant landscape in the province of Benevento was thus assessed by using the ILC (Index of Landscape Conservation).
A Qualitative Transcriptional Signature for Predicting Prognosis and Response to Bevacizumab in Metastatic Colorectal Cancer

Bevacizumab is the molecular-targeted agent used for the antiangiogenic therapy of metastatic colorectal cancer. But some patients are resistant to bevacizumab, it needs an effective biomarker to predict the prognosis and responses of metastatic colorectal cancer (mCRC) to bevacizumab therapy. In this work, we developed a qualitative transcriptional signature to individually predict the response of bevacizumab in patients with mCRC. First, using mCRC samples treated with bevacizumab, we detected differentially expressed genes between response and nonresponse groups. Then, the gene pairs, consisting of at least one differentially expressed gene, with stable relative expression orderings in the response samples but reversal stable relative expression orderings in the nonresponse samples were identified, denoted as pairs-bevacizumab. Similarly, we screened the gene pairs significantly associated with primary tumor locations, donated as pairs-LR. Among the overlapped gene pairs between the pairs-bevacizumab and pairs-LR, we adopted a feature selection process to extract gene pairs that reached the highest F-score for predicting bevacizumab response status in mCRC as the final gene pair signature (GPS), denoted as 64-GPS. In two independent datasets, the predicted response group showed significantly better overall survival than the nonresponse group (P = 6.00e−4 in GSE72970; P = 0.04 in TCGA). Genomic analyses showed that the predicted response group was characterized by frequent copy number alternations, whereas the nonresponse group was characterized by hypermutation. In conclusion, 64-GPS was an objective and robust predictive signature for patients with mCRC treated with bevacizumab, which could effectively assist in the decision of clinical therapy.
Clinical Characteristics and Disability Progression of Early- and Late-Onset Multiple Sclerosis Compared to Adult-Onset Multiple Sclerosis

Background: Compared to the adult onset of multiple sclerosis (AOMS), both early-onset (EOMS) and late-onset (LOMS) are much less frequent, but are often under- or misdiagnosed. The aims of the present study were: 1. To compare demographic and clinical features of individuals with EOMS, AOMS and LOMS, and 2. To identify predictors for disability progression from relapsing remitting MS (RRMS) to secondary progressive MS (SPMS). Method: Data were taken from the Isfahan Hakim MS database. Cases were classified as EOMS (MS onset ≤18 years), LOMS (MS onset >50 years) and AOMS (MS >18 and ≤50 years). Patients’ demographic and clinical (initial symptoms; course of disease; disease patterns from MRI; disease progress) information were gathered and assessed. Kaplan–Meier and Cox proportional hazard regressions were conducted to determine differences between the three groups in the time lapse in conversion from relapsing remitting MS to secondary progressive MS. Results: A total of 2627 MS cases were assessed; of these 127 were EOMS, 84 LOMS and 2416 AOMS. The mean age of those with EOMS was 14.5 years; key symptoms were visual impairments, brain stem dysfunction, sensory disturbances and motor dysfunctions. On average, 24.6 years after disease onset, 14.2% with relapsing remitting MS (RRMS) were diagnosed with secondary progressive MS (SPMS). The key predictor variable was a higher Expanded Disability Status Scale (EDSS) score at disease onset. Compared to individuals with AOMS and LOMS, those with EOMS more often had one or two relapses in the first two years, and more often gadolinium-enhancing brain lesions. For individuals with AOMS, mean age was 29.4 years; key symptoms were sensory disturbances, motor dysfunctions and visual impairments. On average, 20.5 years after disease onset, 15.6% with RRMS progressed to SPMS. The key predictors at disease onset were: a higher EDSS score, younger age, a shorter inter-attack interval and spinal lesions. Compared to individuals with EOMS and LOMS, individuals with AOMS more often had either no or three and more relapses in the first two years. For individuals with LOMS, mean age was 53.8 years; key symptoms were motor dysfunctions, sensory disturbances and visual impairments. On average, 14 years after disease onset, 25.3% with RRMS switched to an SPMS. The key predictors at disease onset were: occurrence of spinal lesions and spinal gadolinium-enhancement. Compared to individuals with EOMS and AOMS, individuals with LOMS more often had no relapses in the first two years, and higher EDSS scores at disease onset and at follow-up. Conclusion: Among a large sample of MS sufferers, cases with early onset and late onset are observable. Individuals with early, adult and late onset MS each display distinct features which should be taken in consideration in their treatment.
Etiology of Autism Spectrum Disorders and Autistic Traits Over Time.

Importance The frequency with which autism spectrum disorders (ASDs) are diagnosed has shown a marked increase in recent years. One suggestion is that this is partly because of secular changes in the environment, yet to our knowledge this hypothesis lacks evidence. Objective To assess whether the relative importance of genetic and environmental associations with ASD and autistic traits has changed over a 16-year and 26-year period. Design, Setting, and Participants A twin design was used to assess whether the heritability of ASD and autistic traits has changed over time. Data from 2 nationwide Swedish twin cohorts was used: the Swedish Twin Registry (STR; participants born between January 1982 and December 2008) and the Child and Adolescent Twin Study in Sweden (CATSS; participants born between January 1992 and December 2008). Autism spectrum disorder diagnoses were identified for twins in the STR, with follow-up to 2013. Questionnaires assigned screening diagnoses of ASD to CATSS participants and assessed autistic traits. Analyses were performed from September 1, 2018, to March 31, 2019. Exposures Each sample was divided into several birth cohorts covering 1982 to 1991 (for the STR only), 1992-1995, 1996-1999, 2000-2003, and 2004-2008. Outcomes We assessed whether the genetric and environment variance underlying autistic traits changed across birth cohorts and examined whether the relative contribution of genetics and environment to liability for autism changed across birth cohorts. Results Data were available for 22 678 twin pairs (5922 female same-sex pairs [26.1%], 5563 male same-sex pairs [24.5%], and 11193 opposite-sex pairs [49.4%]) in the STR and 15 280 pairs (4880 female same-sex pairs [31.9%], 5092 male same-sex pairs [33.3%], and 5308 opposite-sex pairs [34.7%]) in CATSS. The heritability of ASD diagnoses in the STR ranged from 0.88 (95% CI, 0.74-0.96) to 0.97 (95% CI, 0.89-0.99). The heritability of screening diagnoses in CATSS varied from 0.75 (95% CI, 0.58-0.87) to 0.93 (95% CI, 0.84-0.98). Autistic traits showed a modest variance increase over time that was associated with increases in genetic and environmental variance, with the total variance increasing from 0.95 (95% CI, 0.92-0.98) to 1.17 (95% CI, 1.13-1.21) over time. Conclusions and Relevance Weak evidence was found for changes in the genetic and environmental factors underlying ASD and autistic traits over time. Genetic factors played a consistently larger role than environmental factors. Environmental factors are thus unlikely to explain the increase in the prevalence of ASD.