Miracle-dz/UniFAR-FTUs huggingface dataset:
Advanced Microscopy for Liver and Gut Ultrastructural Pathology in Patients with MVID and PFIC Caused by MYO5B Mutations

Mutations in the actin motor protein myosinVb (myo5b) cause aberrant apical cargo transport and the congenital enteropathy microvillus inclusion disease (MVID). Recently, missense mutations in myo5b were also associated with progressive familial intrahepatic cholestasis (MYO5B-PFIC). Here, we thoroughly characterized the ultrastructural and immuno-cytochemical phenotype of hepatocytes and duodenal enterocytes from a unique case of an adult MYO5B-PFIC patient who showed constant hepatopathy but only periodic enteric symptoms. Selected data from two other patients supported the findings. Advanced methods such as cryo-fixation, freeze-substitution, immuno-gold labeling, electron tomography and immuno-fluorescence microscopy complemented the standard procedures. Liver biopsies showed mislocalization of Rab11 and bile canalicular membrane proteins. Rab11-positive vesicles clustered around bile canaliculi and resembled subapical clusters of aberrant recycling endosomes in enterocytes from MVID patients. The adult patient studied in detail showed a severe, MVID-specific enterocyte phenotype, despite only a mild clinical intestinal presentation. This included mislocalization of numerous proteins essential for apical cargo transport and morphological alterations. We characterized the heterogeneous population of large catabolic organelles regarding their complex ultrastructure and differential distribution of autophagic and lysosomal marker proteins. Finally, we generated duodenal organoids/enteroids from biopsies that recapitulated all MVID hallmarks, demonstrating the potential of this disease model for personalized medicine.
Sex Differences in Autism Spectrum Disorder: Repetitive Behaviors and Adaptive Functioning

Sex differences in restricted and repetitive behaviors (RRBs) in individuals with Autism Spectrum Disorder (ASD) have been explored with mixed findings. We aimed to investigate sex differences in RRBs through a specific measure—i.e., the Repetitive Behavior Scale Revised (RBS-R)—in a sample of preschool-age and school-age children with ASD. Additionally, we evaluated if RRBs were differently related to adaptive functioning within the male and the female age groups. A sample of 210 ASD individuals (3–18 years; 145 males, 65 females) underwent an in-depth assessment including a cognitive, adaptive functioning evaluation (i.e., the Adaptive Behavior Assessment System, Second Edition (ABAS-II)) and RRBs assessment (i.e., RBS-R). No significant sex differences on the RBS-R total score or any RBS-R subscale emerged. Within the group of older participants, RRBs were negatively associated with all adaptive skill domains independently from sex and age. Our results suggest a lack of sex differences in RRBs in our sample. Additionally, our findings highlight the possible negative impact of RRBs on adaptive skills in older individuals with autism, emphasizing the need for autistic individuals of both sexes to undergo an early intervention targeting RRBs, in order to improve their adaptive skills.
Serine/Threonine Kinase 11 Plays a Canonical Role in Malignant Progression of KRAS-Mutant and GNAS-Wild-Type Intraductal Papillary Mucinous Neoplasms of the Pancreas

Objective: We aimed to elucidate the clinicopathobiological significance of Serine/Threonine Kinase 11 (STK11) in pancreatic intraductal papillary mucinous neoplasms (IPMNs). Background: STK11 is a tumor suppressor involved in certain IPMNs; however, its significance is not well known. Methods: In 184 IPMNs without Peutz-Jeghers syndrome, we analyzed expression of STK11 and phosphorylated-AMPKa in all cases, and p16, p53, SMAD4, and β-catenin in 140 cases by immunohistochemistry; and we analyzed mutations in 37 genes, including whole coding exons of STK11, CDKN2A, TP53, and SMAD4, and hotspots of KRAS, BRAF, and GNAS in 64 cases by targeted sequencing. KRAS and GNAS were additionally analyzed in 86 STK11-normal IPMNs using digital-PCR. Results: Consistent loss or reduction of STK11 expression was observed in 26 of 184 (14%) IPMNs. These STK11-aberrant IPMNs were 17 of 45 (38%) pancreatobiliary, 8 of 27 (30%) oncocytic, 1 of 54 (2%) gastric, and 0 of 58 (0%) intestinal subtypes (P = 8.5E-11), and 20 of 66 (30%) invasive, 6 of 74 (8%) high-grade, and 0 of 44 (0%) low-grade (P = 3.9E-06). Sixteen somatic STK11 mutations (5 frameshift, 6 nonsense, 1 splicing, and 4 missense) were detected in 15/26 STK11-aberrant IPMNs (P = 4.1E-06). All STK11-aberrant IPMNs were GNAS-wild-type and 96% of them were KRAS or BRAF-mutant. Morphologically, STK11-aberrant IPMNs presented “fern-like” arborizing papillae with thin fibrovascular core. Phosphorylated-AMPKa was down-regulated in STK11-aberrant IPMNs (92%, P = 6.8E-11). Patients with STK11-aberrant IPMNs showed poorer survival than patients with STK11-normal IPMNs (P = 3.6E-04 overall; P = 6.1E-04 disease-free). Conclusion: STK11 may play a canonical role in malignant progression and poor survival of patients with IPMNs. Aberrant STK11-driven phosphorylated AMPK downregulation may provide therapeutic opportunities with mTOR inhibitors/AMPK activators.
The Effects of Internal Attention on Knee Biomechanics in Volleyball Spike Jump through Augmented Video Feedback

Poor knee biomechanics in a volleyball spike jump generally result in a higher knee injury risk, which can be altered by an internal focus of attention (FOA). The constrained action hypothesis (CAH) purports that the FOA inhibits sports performance whereas no ecologically valid evidence has been found in previous studies. The purpose of this research is to explore the effect of video feedback on knee biomechanics in a volleyball spike jump including landing and take-off phases. The video feedback was performed in a natural way. Fourteen volleyball male players were recruited in this study. A paired t-test was used to detect the effect of the feedback; meanwhile, statistical parameter mapping (SPM) statistics were used for the continuum differences during movement. After biofeedback, the initial contact flexion angle of the knee (t = 2.179, p = 0.049), the maximal flexion angle of the knee (t = 3.242, p = 0.006) and the maximal internal rotation angular velocity of the knee (t = 5.209, p = 0.003) increased significantly; the maximal extension moment of the knee (t = 3.962, p < 0.001) and the maximal flexion moment of the knee (t = −3.711, p = 0.002) significantly decreased; the maximal abduction moment significantly decreased (t = 3.069, p = 0.037) but the maximal internal rotation moment significantly increased (t = 2.813, p = 0.018); the first peak of the vertical ground reaction force (vGRF) (t = 7.618, p < 0.001) and the average loading rate to the first peak (t = 4.205, p = 0.004) significantly decreased; the other peaks of the vGRF were not found to have differences; a larger knee flexion was found during the phase from 31.17 to 73.19% (t = 2.611, p = 0.012); a larger adduction angular velocity was found during the phase from 49.07 to 62.46% (t = 3.148, p = 0.004); a smaller external rotational angular velocity was found during the phase from 45.85 to 49.96% (t = 5.011 p = 0.017); there was an increased flexion moment of the knee during the phase from 19.72 to 21.38% (t = 0.029, p = 0.029) and an external moment of the knee during the phase from 85.55 to 95.06% (t = 4.214, p < 0.001); the vGRF significantly decreased during the phase from 3.13 to 5.94% (t = 4.096, p = 0.014) and 19.83–21.97% (t = 4.096, p = 0.024) but significantly increased in the phase of 91.43–100% (t = 4.096, p < 0.001). The impulse of the vGRF and knee power were not found to be different compared with before biofeedback. Therefore, our study suggests video feedback in a natural practice has the potential to improve knee movement whilst not altering the performance in a volleyball spike jump. This indicates that the CAH theory is possibly not suitable in a real competition. Due to the complexity of human movements and the limitations of this study, muscle activities must be considered in the future.
Incidence and Clinical Implications of Autoimmune Thyroiditis in the Development of Acne in Young Patients

Autoimmune thyroiditis (AIT) is on the rise among the population, and is frequently associated with patients with acne vulgaris, especially females aged between 18–55 years old. The connection between the two is not fully elucidated. In this study, 236 patients diagnosed with acne in the dermatological office of the private Pelican Hospital and in few private dermatological offices from Oradea, Romania, during January 2018–December 2020, aged between 12 and 55 years old, were endocrinologically investigated to determine AIT and its influence on the severity of the acne. The values for the thyroid antibodies and thyroid-stimulating hormone (TSH) were determined for all of the subjects. The frequency of AIT in the study group was 72% and was associated with severe acne (p < 0.001). Patients with AIT with normal or hypofunction had more frequent severe acne than those with hyperfunction (p < 0.001, p = 0.002). The TSH and anti thyroidperoxidase (TPO) values did not influence the severity of the acne (p = 0.494; p = 0.111), while the anti-TG values were associated with severe acne (p = 0.007). The risk analysis indicated that raised values of anti-TPO (2.91 times greater) correlated with high anti-thyroglobulin (TG) values (4.36 times greater) doubled the risk of developing severe acne in patients. In acne evolution, the existence of AIT involves significant modifications.
Inflammasomes in Teleosts: Structures and Mechanisms That Induce Pyroptosis during Bacterial Infection

Pattern recognition receptors (PRRs) play a crucial role in inducing inflammatory responses; they recognize pathogen-associated molecular patterns, damage-associated molecular patterns, and environmental factors. Nucleotide-binding oligomerization domain-leucine-rich repeat-containing receptors (NLRs) are part of the PRR family; they form a large multiple-protein complex called the inflammasome in the cytosol. In mammals, the inflammasome consists of an NLR, used as a sensor molecule, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) as an adaptor protein, and pro-caspase1 (Casp1). Inflammasome activation induces Casp1 activation, promoting the maturation of proinflammatory cytokines, such as interleukin (IL)-1β and IL-18, and the induction of inflammatory cell death called pyroptosis via gasdermin D cleavage in mammals. Inflammasome activation and pyroptosis in mammals play important roles in protecting the host from pathogen infection. Recently, numerous inflammasome-related genes in teleosts have been identified, and their conservation and/or differentiation between their expression in mammals and teleosts have also been elucidated. In this review, we summarize the current knowledge of the molecular structure and machinery of the inflammasomes and the ASC-spec to induce pyroptosis; moreover, we explore the protective role of the inflammasome against pathogenic infection in teleosts.
Photosynthetic Responses of Anthurium × ‘Red’ under Different Light Conditions

Light is an essential energy source for plant photosynthesis, although it can also be a stress-causing element. Therefore, the current research was aimed to compare photosynthetic responses of Anthurium × ‘Red’ leaves at different positions (bottom old leaf, 1; center mature leaf, 2; top expanded leaf, 3) established under three photosynthetic photon flux densities (PPFDs): 550 μmol·m−2·s−1 as high (H), 350 μmol·m−2·s−1 as medium (M), and 255 μmol·m−2·s−1 as low (L). After six months, all the replicates were relocated to interior rooms with a PPFD of 30 μmol·m−2·s−1. There were no significant differences in chlorophyll concentration of the old leaf among treatments, before (Day 0) and after shifting the plants to interior rooms (Day 30). The total chlorophyll concentrations of the mature and top leaves increased significantly. In greenhouse conditions, H and M treatments did not show any significant change for net photosynthetic rate (Pn) at various leaf positions. However, M2 exhibited an improved Pn in the interior conditions. Plants grown under M treatment were greener and had bigger leaves compared to other treatments. Our study reveals that Anthurium × ‘Red’ photosynthesis responses to different light conditions varied distinctly. However, M treatment can keep the plants looking green by accumulating enough energy for indoor conditions, and middle and lower leaves may be triggered to restore photosynthetic activity under low light or indoor conditions.
Selection, Expansion, and Unique Pretreatment of Allogeneic Human Natural Killer Cells with Anti-CD38 Monoclonal Antibody for Efficient Multiple Myeloma Treatment

Cellular immunotherapy is becoming a new pillar in cancer treatment after recent striking results in different clinical trials with chimeric antigen receptor T cells. However, this innovative therapy is not exempt from challenges such as off-tumor toxicity, tumor recurrence in heterogeneous tumors, and affordability. To surpass these limitations, we exploit the unique anti-tumor characteristics of natural killer (NK) cells. In this study, we aimed to obtain a clinically relevant number of allogeneic NK cells derived from peripheral blood (median of 14,050 million cells from a single donor) to target a broad spectrum of solid and liquid tumor types. To boost their anti-tumor activity, we combined allogeneic NK cells with the approved anti-cluster of differentiation 38 (CD-38) monoclonal antibody Daratumumab to obtain a synergistic therapeutic effect against incurable multiple myeloma. The combination therapy was refined with CD16 polymorphism donor selection and uncomplicated novel in vitro pretreatment to avoid undesired fratricide, increasing the in vitro therapeutic effect against the CD-38 positive multiple myeloma cell line by more than 20%. Time-lapse imaging of mice with established human multiple myeloma xenografts revealed that combination therapy of selected and pretreated NK cells with Daratumumab presented tumor volumes 43-fold smaller than control ones. Combination therapy with an allogeneic source of fully functional NK cells could be beneficial in future clinical settings to circumvent monoclonal antibodies’ low therapeutic efficiency due to NK cell dysfunctionality in MM patients.
The Challenge of Diagnosing Constitutional Mismatch Repair Deficiency Syndrome in Brain Malignancies from Young Individuals

Biallelic germline mismatch repair (MMR) gene (MLH1, MSH2, MSH6, and PMS2) mutations are an extremely rare event that causes constitutional mismatch repair deficiency (CMMRD) syndrome. CMMRD is underdiagnosed and often debuts with pediatric malignant brain tumors. A high degree of clinical awareness of the CMMRD phenotype is needed to identify new cases. Immunohistochemical (IHC) assessment of MMR protein expression and analysis of microsatellite instability (MSI) are the first tools with which to initiate the study of this syndrome in solid malignancies. MMR IHC shows a hallmark pattern with absence of staining in both neoplastic and non-neoplastic cells for the biallelic mutated gene. However, MSI often fails in brain malignancies. The aim of this report is to draw attention to the peculiar IHC profile that characterizes CMMRD syndrome and to review the difficulties in reaching an accurate diagnosis by describing the case of two siblings with biallelic MSH6 germline mutations and brain tumors. Given the difficulties involved in early diagnosis of CMMRD we propose the use of the IHC of MMR proteins in all malignant brain tumors diagnosed in individuals younger than 25 years-old to facilitate the diagnosis of CMMRD and to select those neoplasms that will benefit from immunotherapy treatment.
Silicon Effects on the Root System of Diverse Crop Species Using Root Phenotyping Technology

Roots play an essential function in the plant life cycle, as they utilize water and essential nutrients to promote growth and plant productivity. In particular, root morphology characteristics (such as length, diameter, hairs, and lateral growth) and the architecture of the root system (spatial configuration in soil, shape, and structure) are the key elements that ensure growth and a fine-tuned response to stressful conditions. Silicon (Si) is a ubiquitous element in soil, and it can affect a wide range of physiological processes occurring in the rhizosphere of various crop species. Studies have shown that Si significantly and positively enhances root morphological traits, including root length in rice, soybean, barley, sorghum, mustard, alfalfa, ginseng, and wheat. The analysis of these morphological traits using conventional methods is particularly challenging. Currently, image analysis methods based on advanced machine learning technologies allowed researchers to screen numerous samples at the same time considering multiple features, and to investigate root functions after the application of Si. These methods include root scanning, endoscopy, two-dimensional, and three-dimensional imaging, which can measure Si uptake, translocation and root morphological traits. Small variations in root morphology and architecture can reveal different positive impacts of Si on the root system of crops, with or without exposure to stressful environmental conditions. This review comprehensively illustrates the influences of Si on root morphology and root architecture in various crop species. Furthermore, it includes recommendations in regard to advanced methods and strategies to be employed to maintain sustainable plant growth rates and crop production in the currently predicted global climate change scenarios.
Valutazione della qualità dell'olio extra vergine di oliva mediante naso elettronico a sensori MOS

Electronic noses are becoming a valuable tool for the organoleptic evaluation of food freshness, seasoning, geographical origin and shelf-life. This article reports a series of experiments aimed to highlight potentials and limits of MOS electronic noses for detecting defects present in extra virgin olive oil. The instrument is also able to discriminate olive oils obtained from the same fruits using respectively milling of stoned olives and traditional milling.
Anti-Angiogenic Therapy: Albumin-Binding Proteins Could Mediate Mechanisms Underlying the Accumulation of Small Molecule Receptor Tyrosine Kinase Inhibitors in Normal Tissues with Potential Harmful Effects on Health

Simple Summary In the last five decades the tumor microvascular endothelium has been, and still remains, an object of sustained interest in biomedical research. This interest is undoubtedly connected with the importance of blood microvessels in cancer cell proliferation, tumor growth, and metastasis. Depriving a tumor of its oxygen and nutrients by preventing the formation of new vessels with anti-angiogenic drugs including small molecule receptor tyrosine kinase inhibitors (RTKIs) is a common treatment in oncology. However, resistance to treatment, insufficient efficacy, and high toxicity limit the success of this antivascular therapy. Cellular and molecular mechanisms mediated by several albumin-binding proteins (ABPs) expressed in normal tissues and organs seem to be responsible for the side effects and toxicity associated with this type of anti-angiogenic therapy. Abstract Anti-angiogenics currently used in cancer therapy target angiogenesis by two major mechanisms: (i) neutralizing angiogenic factors or their receptors by using macromolecule anti-angiogenic drugs (e.g., therapeutic antibodies), and (ii) blocking intracellularly the activity of receptor tyrosine kinases with small molecule (Mr < 1 kDa) inhibitors. Anti-angiogenics halt the growth and spread of cancer, and significantly prolong the disease-free survival of the patients. However, resistance to treatment, insufficient efficacy, and toxicity limit the success of this antivascular therapy. Published evidence suggests that four albumin-binding proteins (ABPs) (gp18, gp30, gp60/albondin, and secreted protein acidic and cysteine-rich (SPARC)) could be responsible for the accumulation of small molecule receptor tyrosine kinase inhibitors (RTKIs) in normal organs and tissues and therefore responsible for the side effects and toxicity associated with this type of cancer therapy. Drawing attention to these studies, this review discusses the possible negative role of albumin as a drug carrier and the rationale for a new strategy for cancer therapy based on follicle-stimulating hormone receptor (FSHR) expressed on the luminal endothelial cell surface of peritumoral blood vessels associated with the major human cancers. This review should be relevant to the audience and the field of cancer therapeutics and angiogenesis/microvascular modulation-based interventions.
Isolation and Characterization of Strain Exiguobacterium sp. KRL4, a Producer of Bioactive Secondary Metabolites from a Tibetan Glacier

Extremophilic microorganisms represent a unique source of novel natural products. Among them, cold adapted bacteria and particularly alpine microorganisms are still underexplored. Here, we describe the isolation and characterization of a novel Gram-positive, aerobic rod-shaped alpine bacterium (KRL4), isolated from sediments from the Karuola glacier in Tibet, China. Complete phenotypic analysis was performed revealing the great adaptability of the strain to a wide range of temperatures (5–40 °C), pHs (5.5–8.5), and salinities (0–15% w/v NaCl). Genome sequencing identified KRL4 as a member of the placeholder genus Exiguobacterium_A and annotation revealed that only half of the protein-encoding genes (1522 of 3079) could be assigned a putative function. An analysis of the secondary metabolite clusters revealed the presence of two uncharacterized phytoene synthase containing pathways and a novel siderophore pathway. Biological assays confirmed that the strain produces molecules with antioxidant and siderophore activities. Furthermore, intracellular extracts showed nematocidal activity towards C. elegans, suggesting that strain KRL4 is a source of anthelmintic compounds.
A Complementary Herbal Product for Controlling Giardiasis

Giardiasis is an intestinal protozoal disease caused by Giardia lamblia. The disease became a global health issue due to development of resistance to commonly used drugs. Since many plant-derived products have been used to treat many parasitic infestations, we aimed to assess the therapeutic utility of Artemisia annua (A. annua) for giardiasis. We showed that NO production was significantly reduced whereas serum levels of IL-6, IFN-γ, and TNF-α were elevated in infected hamsters compared to uninfected ones. Additionally, infection resulted in increased numbers of intraepithelial lymphocytes and reduced villi heights, goblet cell numbers, and muscularis externa thickness. We also showed that inducible NO synthase (iNOS) and caspase-3 were elevated in the intestine of infected animals. However, treatment with A. annua significantly reduced the intestinal trophozoite counts and IEL numbers, serum IL-6, IFN-γ, and TNF-α, while increasing NO and restoring villi heights, GC numbers, and ME thickness. Moreover, A. annua treatment resulted in lower levels of caspase-3, which indicates a protective effect from apoptotic cell death. Interestingly, A. annua therapeutic effects are comparable to metronidazole. In conclusion, our results show that A. annua extract is effective in alleviating infection-induced intestinal inflammation and pathological effects, which implies its potential therapeutic utility in controlling giardiasis.