We present phenomenological study of the most minimal realistic SU(5) model that owns its predictivity solely to the gauge symmetry and the representational content. The model is built entirely out of the fields residing in the first five lowest dimensional representations that transform non-trivially under the SU(5) gauge group. It has eighteen real parameters and fourteen phases, all in all, to address experimental observables of the Standard Model fermions and accomplishes that via simultaneous use of three different mass generation mechanisms. Furthermore, it inextricably links the origin of the neutrino mass to the experimentally observed difference between the down-type quark and charged lepton masses. The main predictions of the model are that (i) the neutrinos are Majorana particles, (ii) one neutrino is massless, (iii) the neutrinos have normal mass ordering, and (iv) there are four new scalar multiplets at or below a 120TeV mass scale. A one-loop analysis demonstrates that an improvement of the current p→ πe partial lifetime limit by a factor of 2, 15, and 96 would require these four scalar multiplets to reside at or below the 100TeV, 10TeV, and 1TeV mass scales, respectively.

Introduction: Rapid-onset obesity, hypoventilation, hypothalamic dysfunction and autonomic dysregulation (ROHHAD) is a rare syndrome beginning at 3-6 years of age with approximately 150 cases described. Additional features include eye abnormalities, neurobehavioral dysfunction and paraneoplastic tumors. The etiology of the complex phenotype remains unknown. Methods: This study aims to investigate the genetic landscape of this complex phenotype by whole exome sequencing (WES) and copy number variation (CNV) analysis. We recruited 33 families (27 trios, 1 duo and 5 singletons) with a proband with ROHHAD syndrome (Ize-Ludlow 2007, Pediatrics). WES of 89 individuals was performed at the Center for Mendelian Genomics, Broad Institute. The Illumina platform with a mean coverage of ~100X (> 90% targets 20x) and Infinium Global Screening Array BeadChip 24v1.0 were used. Results: This report includes 28 probands (female = 18, 64%) with rapid onset obesity (100%), hypoventilation (88%), hypothalamic dysfunction (69%), eye disorders (62%) and neurobehavioral abnormalities (76%). Neuroendocrine tumor, ganglioneuroblastoma, was present in 38% (n=13). No unifying causative single gene or CNV was identified, but a number of sequence variants are prioritized. ARNT2, which encodes for a helix-loop-helix transcription factor, plays a role in the development of the hypothalamic-pituitary axis, postnatal brain growth, and visual and renal function. The de novo monoallelic missense variant was found in a 14-year old white girl (BMIz +3.25) with extreme obesity and a neurobehavioral phenotype. OCRL1, a multi-domain protein involved in cytoskeleton-plasma membrane adhesion, endosomal trafficking and in primary cilium assembly. Mutations in this gene have also been known to cause Lowe syndrome. A hemizygous X-linked frameshift variant in a 5-year old white boy with extreme obesity (BMIz +5.48), central hypoventilation neurobehavioral dysfunction and ganglioneuroblastoma. A monoallelic missense variant in NSD1, a transcriptional intermediary factor acting as a histone methyltransferase, was identified in a 8-year old Hispanic girl with severe obesity (BMIz +2.91), neurobehavioral disorder, pituitary and eye dysfunction and ganglioneuroblastoma. NSD1 is known to cause Sotos and Beckwith-Wiedemann. Compound heterozygous variants in KIF7, a key component of the Hedgehog signaling pathway, were identified in a 14-year old white girl with severe obesity (BMIz +3.00), autistic behavior, pituitary dysfunction and central hypoventilation. This gene is known to cause autosomal recessive hydrolethalis and acroscallosal syndromes with mutations also noted in Bardet-Biedl, Meckel and Joubert syndromes. Conclusion: While no unifying genetic cause has been identified in ROHHAD syndrome, it is possible that the phenotype represents a collection of complex genetic syndromes.

By successfully solving the problem of forecasting, the processes in the work of various companies are optimized and savings are achieved. In this process, the analysis of time series data is of particular importance. Since the creation of Facebook’s Prophet, and Amazon’s DeepAR+ and CNN-QR forecasting models, algorithms have attracted a great deal of attention. The paper presents the application and comparison of the above algorithms for sales forecasting in distribution companies. A detailed comparison of the performance of algorithms over real data with different lengths of sales history was made. The results show that Prophet gives better results for items with a longer history and frequent sales, while Amazon’s algorithms show superiority for items without a long history and items that are rarely sold.

Self‐rating scales are frequently used to screen for anxiety and depression in patients with irritable bowel syndrome (IBS). Different cutoff values are recommended in literature, and guidelines have suggested the use of other screening instruments over time. The aim of this study was to assess the correlation between the most commonly used psychological screening instruments for anxiety and depression in IBS and to compare custom cutoff scores for these instruments.

Replication is an important tool used to test and develop scientific theories. Areas of biomedical and psychological research have experienced a replication crisis, in which many published findings failed to replicate. Following this, many other scientific disciplines have been interested in the robustness of their own findings. This chapter examines replication in primate cognitive studies. First, it discusses the frequency and success of replication studies in primate cognition and explores the challenges researchers face when designing and interpreting replication studies across the wide range of research designs used across the field. Next, it discusses the type of research that can probe the robustness of published findings, especially when replication studies are difficult to perform. The chapter concludes with a discussion of different roles that replication can have in primate cognition research.

Replications are widely considered an essential tool to evaluate scientific claims. However, many fields have recently reported that replication rates are low and - when they are conducted - many findings do not successfully replicate. These circumstances have led to widespread debates about the value of replications for research quality, credibility of research findings, and factors contributing to current problems with replicability. This special issue brings together researchers from various areas within the field of animal behavior to offer their perspective on the status and value of replications in animal behavior science.

While the COVID-19 pandemic continues to spread globally, with relistic hope that will be solved with adequate vacination, more and more evidences are collected about the presence of psychi-atric and neurological manifestations and symptoms associated with this diseas. Neurological manifestations, are part of the COVID-19 clinical picture, but questions remain regarding the frequency and severity of centra nervous system symptoms, the mechanism of action underlying neurological symptoms, and the relationship of symptoms with the course and severity of COVID-19. The review of the so far published papers shows that although more and more papers are reporting neuro-logical and psyhiatric manifestations associated with COVID-19, many items remain unclear. The long-term psychological implications of this infectious diseases should not be ignored. In this paper, we aim to present a some of psychological consequences and neurological disorders associat-ed with the SARS-CoV-2 infection, and to emphasize the need a global action that requires close coordination and open-data sharing between hospitals, academic and public health institutions and the fast establishment of harmonised research priorities to face acut and long-term the neurological and psychological consequences.

Head and neck cancers (HNC) occur in the upper aerodigestive tract and are among the most common cancers. The etiology of HNC is complex, involving many factors, including excessive tobacco and alcohol consumption; over the last two decades, oncogenic viruses have also been recognized as an important cause of HNC. Major etiological agents of nasopharynx carcinoma and oropharyngeal carcinoma include Epstein-Barr virus (EBV) and human papillomaviruses (HPVs), both of which are able to interfere with cell cycle control. Additionally, the association of hepatitis C and hepatitis B infection was observed in oral cavity, oropharyngeal, laryngeal, and nasopharyngeal cancers. Overall prognoses depend on anatomic site, stage, and viral status. Current treatment options, including radiotherapy, chemotherapy, targeted therapies and immunotherapies, are distributed in order to improve overall patient prognosis and survival rates. However, the interplay between viral genome sequences and the health, disease, geography, and ethnicity of the host are crucial for understanding the role of viruses and for development of potential personalized treatment and prevention strategies. This review provides the most comprehensive analysis to date of a vast field, including HNC risk factors, as well as viral mechanisms of infection and their role in HNC development. Additionally, currently available treatment options investigated through clinical practice are emphasized in the paper.

The antidiabetic drug gliclazide is partly metabolized by CYP2C19, the main enzyme involved in omeprazole metabolism. The aim of the study was to explore the interaction between omeprazole and gliclazide in relation to CYP2C19 phenotype using physiologically based pharmacokinetic (PBPK) modeling approach. Developed PBPK models were verified using in vivo pharmacokinetic profiles obtained from a clinical trial on omeprazole-gliclazide interaction in healthy volunteers, CYP2C19 normal/rapid/ultrarapid metabolizers (NM/RM/UM). In addition, the association of omeprazole cotreatment with gliclazide-induced hypoglycemia was explored in 267 patients with type 2 diabetes (T2D) from the GoDARTS cohort, Scotland. The PBPK simulations predicted 1.4–1.6-fold higher gliclazide area under the curve (AUC) after 5-day treatment with 20 mg omeprazole in all CYP2C19 phenotype groups except in poor metabolizers. The predicted gliclazide AUC increased 2.1 and 2.5-fold in intermediate metabolizers, and 2.6- and 3.8-fold in NM/RM/UM group, after simulated 20-day dosing with 40 mg omeprazole once and twice daily, respectively. The predicted results were corroborated by findings in patients with T2D which demonstrated 3.3-fold higher odds of severe gliclazide-induced hypoglycemia in NM/RM/UM patients concomitantly treated with omeprazole. Our results indicate that omeprazole may increase exposure to gliclazide and thus increase the risk of gliclazide-associated hypoglycemia in the majority of patients.

Cytokines and other immune regulatory molecules are critical players in the immune response against cancer. There is growing interest in testing the potential utility of systemic immune biomarkers to track cancer progression and to use them as predictors of effective responses to cancer therapy. The central hypothesis guiding this project is that specific immune biomarkers will serve as predictors of effective vs. ineffective immunotherapy in patients with malignant diseases. The objective of this study was to establish baseline of immune markers in patients already started treatment with immunotherapy (n=10) (T), patients starting, but not yet treated (S) with immunotherapy (n=10) and subjects without diagnosed malignant disease (W) (n=10). Blood was collected and plasma was isolated and used in the biomarker (100 markers) analysis using a protein microarray method (RayBiotech). The biomarkers in the three groups were analyzed by Principal Component Analysis, heat map with clustering, and differential expression based on p value, and Significance Analysis of Microarrays (SAM). Although 15 biomarkers were significantly different between S vs. W groups, based on SAM, only seven were found differentially expressed. Similarly, although 10 biomarkers were significantly different between T vs. W groups, based on SAM, only one biomarker was found differentially expressed. Furthermore, SAM revealed that responders (n=4) vs. stable (n=5) subgroup of patients within the T group exhibited 22 differentially expressed biomarkers. Future larger studies will be needed to evaluate whether immune markers will be able to predict effective vs. ineffective responses to immunotherapy and whether they may have therapeutic potential.

Artificial Intelligence (AI) has been drawing attention in the field of medical devices. However, due to system complexity, the variability of their architecture, as well as ethical and regulatory concerns there is an ongoing need to analyze its application and performance.This study presents a narrative commentary on the applications of artificial neural networks (ANN) and machine learning (ML) algorithms in medical devices, past, current and future perspectives of application. One research focus of this study was on identifying problems and issues related to the implementation of AI in medical devices. The commentary is based on scientific articles published in PubMed, Scopus ad ScienceDirect databases, official publications of international organizations: European Comission (EC), Food and Drug Administration (FDA), and World Health Organisation (WHO) published in 2009 - 2020 period. AI is revolutionizing healthcare, from medical applications to clinical engineering. However, before grasp-ing the full potential ethical, legal and social concerns need to be resolved and its application needs to be harmonized and regulated regarding equitable access, privacy, appropriate uses and users, liability and bias and inclusiveness.

Acacetin, apigenin, chrysin, and pinocembrin are flavonoid aglycones found in foods such as parsley, honey, celery, and chamomile tea. Flavonoids can act as substrates and inhibitors of the CYP3A4 enzyme, a heme containing enzyme responsible for the metabolism of one third of drugs on the market. The aim of this study was to investigate the inhibitory effect of selected flavonoids on the CYP3A4 enzyme, the kinetics of inhibition, the possible covalent binding of the inhibitor to the enzyme, and whether flavonoids can act as pseudo-irreversible inhibitors. For the determination of inhibition kinetics, nifedipine oxidation was used as a marker reaction. A hemochromopyridine test was used to assess the possible covalent binding to the heme, and incubation with dialysis was used in order to assess the reversibility of the inhibition. All the tested flavonoids inhibited the CYP3A4 enzyme activity. Chrysin was the most potent inhibitor: IC50 = 2.5 ± 0.6 µM, Ki = 2.4 ± 1.0 µM, kinact = 0.07 ± 0.01 min−1, kinact/Ki = 0.03 min−1 µM−1. Chrysin caused the highest reduction of heme (94.5 ± 0.5% residual concentration). None of the tested flavonoids showed pseudo-irreversible inhibition. Although the inactivation of the CYP3A4 enzyme is caused by interaction with heme, inhibitor-heme adducts could not be trapped. These results indicate that flavonoids have the potential to inhibit the CYP3A4 enzyme and interact with other drugs and medications. However, possible food–drug interactions have to be assessed clinically.

OBJECTIVE   We aimed to confirm whether serum on admission homocysteine level (HCY) and red cell distribution width (RDW) value are independent risk factors for MACE incidence in patients with STEMI myocardial infarction treated by percutaneous coronary intervention (PCI), as well as the possibility of their joint assessment in order to enhance the risk stratification for major adverse cardiac events (MACE). PATIENTS AND METHODS A total of 80 patients with acute myocardial infarction (AMI) were included in the study and tested for blood HCY and RDW values. Patients were followed up for six months after discharge and evaluated for MACE occurrence. RESULTS The RDW value was significantly associated with HCY level (r=0.267, p=0.026). Univariate logistic regression analysis identified both the RDW and HCY as independent predictors of MACE (OR 2.179; CI 95% 1.250 to 3.797; p=0.006 and OR 1.108; CI 95% 1.013 to 1.213; p=0.025, respectively), naming RDW as a stronger predictor of unfavorable prognosis in AMI patients. Addition of HCY to RDW value in receiver operating characteristic (ROC) curve analysis increased the area under the curve (AUC) from 0.705 to 0.730 (p=0.007), while risk prediction model, which also included traditional risk factors, increased AUC up to 0.806, implying this model as good predictor of MACE both in low-risk and high-risk STEMI patients. CONCLUSIONS A high baseline HCY level and RDW value in patients with STEMI undergoing PCI is independently associated with increased risk for MACE outcome. Their joint assessment increases risk prediction ability.