Evolution of the enhancer-rich regulatory region of the gene for the cell-type specific transcription factor POU1F1.

Precise spatio-temporal expression of genes in organogenesis is regulated by the coordinated interplay of DNA elements such as promoter and enhancers present in the regulatory region of a given locus. POU1F1 transcription factor plays a crucial role in the development of somatotrophs, lactotrophs and thyrotrophs in the anterior pituitary gland, and in maintaining high expression of growth hormone, prolactin and TSH. In mouse, expression of POU1F1 is controlled by a region fenced by two CTCF sites, containing 5 upstream enhancer elements, designated E-A (5' to 3'). Elements C, B and A correspond to elements shown previously to play a role in pituitary development and hormonal expression; functional roles for elements E and D have not been reported. We performed comparative sequence analysis of this regulatory region and discovered that three elements, B, C and E, are present in all vertebrate groups except Agnatha. One very long (>2 kb) element (A) is unique to mammals suggesting a specific change in regulation of the gene in this group. Using DNA accessibility assay (ATAC-seq) we showed that conserved elements in anterior pituitary of four non-mammals are open, suggesting functionality as regulatory elements. We showed that, in many non-mammalian vertebrates, an additional upstream exon closely follows element E, leading to alternatively spliced transcripts. Here, element E functions as an alternative promoter, but in mammals this feature is lost, suggesting conversion of alternative promoter to enhancer. Our work shows that regulation of POU1F1 changed markedly during the course of vertebrate evolution, use of a low number of enhancer elements combined with alternative promoters in non-mammalian vertebrates being replaced by use of a unique combination of regulatory units in mammals. Most importantly, our work suggests that evolutionary conversion of alternate promoter to enhancer could be one of the evolutionary mechanisms of enhancer birth.

Impact of Polyphenols on Inflammatory and Oxidative Stress Factors in Diabetes Mellitus: Nutritional Antioxidants and Their Application in Improving Antidiabetic Therapy.

Diabetes mellitus is a chronic metabolic disorder characterized by hyperglycaemia and oxidative stress. Oxidative stress plays a crucial role in the development and progression of diabetes and its complications. Nutritional antioxidants derived from dietary sources have gained significant attention due to their potential to improve antidiabetic therapy. This review will delve into the world of polyphenols, investigating their origins in plants, metabolism in the human body, and relevance to the antioxidant mechanism in the context of improving antidiabetic therapy by attenuating oxidative stress, improving insulin sensitivity, and preserving ß-cell function. The potential mechanisms of, clinical evidence for, and future perspectives on nutritional antioxidants as adjuvant therapy in diabetes management are discussed.

Spontaneous mutagenesis in human cells is controlled by REV1-Polymerase ζ and PRIMPOL.

Translesion DNA synthesis (TLS) facilitates replication over damaged or difficult-to-replicate templates by employing specialized DNA polymerases. We investigate the effect on spontaneous mutagenesis of three main TLS control mechanisms: REV1 and PCNA ubiquitylation that recruit TLS polymerases and PRIMPOL that creates post-replicative gaps. Using whole-genome sequencing of cultured human RPE-1 cell clones, we find that REV1 and Polymerase ζ are wholly responsible for one component of base substitution mutagenesis that resembles homologous recombination deficiency, whereas the remaining component that approximates oxidative mutagenesis is reduced in PRIMPOL-/- cells. Small deletions in short repeats appear in REV1-/-PCNAK164R/K164R double mutants, revealing an alternative TLS mechanism. Also, 500-5,000 bp deletions appear in REV1-/- and REV3L-/- mutants, and chromosomal instability is detectable in REV1-/-PRIMPOL-/- cells. Our results indicate that TLS protects the genome from deletions and large rearrangements at the expense of being responsible for the majority of spontaneous base substitutions.

A Real-World Multicenter Retrospective Observational Study on Polish Experience with Nintedanib Therapy in Patients with Idiopathic Pulmonary Fibrosis: The PolExNIB Study.

Nintedanib is a disease-modifying agent licensed for the treatment of IPF. Data on Polish experience with nintedanib in IPF are lacking. The present study aimed to describe the safety and efficacy profiles of nintedanib in a large real-world cohort of Polish patients with IPF. This was a multicenter, retrospective, observational study of IPF patients treated with nintedanib between March 2018 and October 2021. Data collection included baseline clinical characteristics, results of pulmonary function tests (PFTs), and a six-minute walk test (6MWT). Longitudinal data on PFTs, 6MWT, adverse drug reactions (ADRs), and treatment persistence were also retrieved. A total of 501 patients (70% male) with a median age of 70.9 years (IQR 65-75.7) were included in this study. Patients were followed on treatment for a median of 15 months (7-25.5). The majority of patients (66.7%) were treated with the full recommended dose of nintedanib and 33.3% of patients were treated with a reduced dose of a drug. Intermittent dose reductions or drug interruptions were needed in 20% of patients. Over up to 3 years of follow-up, pulmonary function remained largely stable with the minority experiencing disease progression. The most frequent ADRs included diarrhea (45.3%), decreased appetite (29.9%), abdominal discomfort (29.5%), weight loss (32.1%), nausea (20.8%), fatigue (19.2%), increased liver aminotransferases (15.4%), and vomiting (8.2%). A total of 203 patients (40.5%) discontinued nintedanib treatment due to diverse reasons including ADRs (10.2%), death (11.6%), disease progression (4.6%), patient's request (6.6%), and neoplastic disease (2.2%). This real-world study of a large cohort of Polish patients with IPF demonstrates that nintedanib therapy is safe, and is associated with acceptable tolerance and disease stabilization. These data support the findings of previously conducted clinical trials and observational studies on the safety and efficacy profiles of nintedanib in IPF.

A novel role for Mms2 in the control of spontaneous mutagenesis and Pol3 abundance.

Mms2 is a ubiquitin E2-variant protein with a very well-documented function in the tolerance pathway that protects both human and yeast cells from the lethal and mutagenic effects of DNA damage. Interestingly, a high expression level of human MMS2 is associated with poor survival prognosis in different cancer diseases. Here we have analyzed the physiological effects of Mms2 overproduction in yeast cells. We show that an increased level of this protein causes a spontaneous mutator effect independent of Ubc13, a cognate partner of Mms2 in the PCNA-polyubiquitinating complex responsible for the template switch. Instead, this new promutagenic role of Mms2 requires Ubc4 (E2) and two ubiquitin ligases of HECT and RING families, Rsp5 and Not4, respectively. We have established that the promutagenic activity of Mms2 is dependent on the activities of error-prone DNA polymerase ζ and Rev1. Additionally, it requires the ubiquitination of K164 in PCNA which facilitates recruitment of these translesion polymerases to the replication complex. Importantly, we have established also that the cellular abundance of Mms2 influences the cellular level of Pol3, the catalytic subunit of replicative DNA polymerase δ. Lack of Mms2 increases the Pol3 abundance, whereas in response to Mms2 overproduction the Pol3 level decreases. We hypothesize that increased levels of spontaneous mutagenesis may result from the Mms2-induced reduction in Pol3 accumulation leading to increased participation of error-prone polymerase ζ in the replication complex.

Evidence from a Systematic Review and Meta-Analysis Pointing to the Antidiabetic Effect of Polyphenol-Rich Plant Extracts from Gymnema montanum, Momordica charantia and Moringa oleifera.

In vitro and animal model studies are of great interest for selecting new phytochemicals, including polyphenols with antioxidative properties, as candidates for antidiabetic drugs. This review provides evidence from a critical literature data analysis on the effects of plant extract supplementation in diabetes mellitus management. We considered and meta-analyzed the efficacy of oral supplementation of plant extracts in animal model studies and examined physiological and oxidative stress parameters. Finally, 23 articles were included in the meta-analysis, revealing three plants with experimentally confirmed in vivo and in vitro antidiabetic properties: Gymnema montanum, Momordica charantia and Moringa oleifera. The following parameter changes resulted from an investigation of the supplementation: reduced oxidative stress, decreased insulin resistance, increased insulin release, reduced adiposity, and a modulatory effect on glycolysis and gluconeogenesis, as well as attenuation of diabetes-associated weight loss, reduced fasting blood glucose and lowered oxidative status. A comparison of Gymnema montanum versus Glybenclamide revealed the superiority of extracts over drug administration in some aspects. Although the analyzed extracts are promising candidates for antidiabetic treatment, there is much inconsistent data in the literature. Therefore, ultimate references for using these compounds in the prevention of diabetes are currently not applicable.

Anchors on prices of consumer goods only hold when decisions are hypothetical.

We elicit willingness to pay for different types of consumption goods, systematically manipulating irrelevant anchors (high vs. low) and incentives to provide true valuations (hypothetical questions vs. Becker-DeGroot-Marschak mechanism). On top of a strong hypothetical bias, we find that anchors only make a substantial, significant difference in the case of hypothetical data, the first experiments to directly document such an interaction. This finding suggests that hypothetical market research methods may deliver lower quality data. Moreover, it contributes to the discussion examining the mechanism underlying the anchoring effect, suggesting it could partly be caused by insufficient conscious effort to drift away from the anchor.

Persuasive Messages Will Not Increase COVID-19 Vaccine Acceptance: Evidence from a Nationwide Online Experiment.

Although mass vaccination is the best way out of the pandemic, the share of skeptics is substantial in most countries. Social campaigns can emphasize the many arguments that potentially increase acceptance for vaccines: e.g., that they have been developed, tested, and recommended by doctors and scientists; and that they are safe, effective, and in demand. We verified the effectiveness of such messages in an online experiment conducted in February and March 2021 with a sample of almost six thousand adult Poles, which was nationally representative in terms of key demographic variables. We presented respondents with different sets of information about vaccinating against COVID-19. After reading the information bundle, they indicated whether they would be willing to be vaccinated. We also asked them to justify their answers and indicate who or what might change their opinion. Finally, we elicited a number of individual characteristics and opinions. We found that nearly 45% of the respondents were unwilling to be vaccinated, and none of the popular messages we used was effective in reducing this hesitancy. We also observed a number of significant correlates of vaccination attitudes, with men, older, wealthier, and non-religious individuals, those with higher education, and those trusting science rather than COVID-19 conspiracy theories being more willing to be vaccinated. We discuss important consequences for campaigns aimed at reducing COVID-19 vaccine hesitancy.

Gender inequality and national gender gaps in overconfidence.

Using a large dataset of marathon runners, we estimate country- and gender-specific proxies for overconfidence. Subsequently, we correlate them with a number of indices, including various measures of gender equality. We find that in less gender-equal countries both males and females tend to be more self-confident than in more equal countries. While a substantial gender gap in overconfidence is observed, it only correlates with some sub-indices of gender equality. We conclude that there is likely a weak relationship between OC gender gap and gender inequality.

Primary CNS vasculitis: A systematic review on clinical characteristics associated with abnormal biopsy and angiography.

BACKGROUND: Primary Central Nervous System Vasculitis (PCNSV) remains a diagnostic challenge due to its variable and non-specific clinical manifestations. In part, the clinical heterogeneity of PCNSV may be a consequence of the modalities used for diagnosis; accordingly, there may be different subtypes of PCNSV based on whether the diagnosis was attained by biopsy or cerebral angiography. OBJECTIVE: To examine the frequency of symptoms, laboratory, and radiological features associated with PCNSV, and to identify distinct clinical features between biopsy and angiography defined PCNSV. METHODS: We conducted a systematic review of articles published in the English language from 1991 to 2019 that met all diagnostic criteria of PCNSV. RESULTS: We identified 55 studies, reporting on 907 PCNSV cases. Median age was 45 (IQR 50-36), and 53% were women. Biopsy compared to angiography defined PCNSV had a higher percentage of cognitive impairment, and seizures on initial presentation, and were more likely to have a subacute or progressive onset, abnormal CSF profile, small vessel involvement on angiography, and tumor-like lesions and gadolinium enhancement on MRI. Angiography defined PCNSV were more likely to have an acute onset, focal weakness and visual impairment on initial presentation, medium vessel involvement on angiography, and infarcts on MRI. Brain biopsy was diagnostic of PCNSV in 71% of cases, and demonstrated an alternative diagnosis in 37% of cases, the most common being infection (19%) and lymphoproliferative disease (18%). CONCLUSIONS: This study provides further evidence that there are distinct clinical features between biopsy and angiography defined PCNSV, which may aid in selecting patients for appropriate invasive tests.

Potential of Ocular Transmission of SARS-CoV-2: A Review.

PURPOSE OF REVIEW: to provide a prospective on the current mechanisms by which SARS-CoV-2 enters cells and replicates, and its implications for ocular transmission. The literature was analyzed to understand ocular transmission as well as molecular mechanisms by which SARS-CoV-2 enters cells and replicates. Analysis of gene expression profiles from available datasets, published immunohistochemistry, as well as current literature was reviewed, to assess the likelihood that ocular inoculation of SARS-CoV-2 results in systemic infection. RECENT FINDINGS: The ocular surface and retina have the necessary proteins, Transmembrane Serine Protease 2 (TMPRSS2), CD147, Angiotensin-Converting Enzyme 2 (ACE2) and Cathepsin L (CTSL) necessary to be infected with SARS-CoV-2. In addition to direct ocular infection, virus carried by tears through the nasolacrimal duct to nasal epithelium represent a means of ocular inoculation. SUMMARY: There is evidence that SARS-CoV-2 may either directly infect cells on the ocular surface, or virus can be carried by tears through the nasolacrimal duct to infect the nasal or gastrointestinal epithelium.

The lipid elongation enzyme ELOVL2 is a molecular regulator of aging in the retina.

Methylation of the regulatory region of the elongation of very-long-chain fatty acids-like 2 (ELOVL2) gene, an enzyme involved in elongation of long-chain polyunsaturated fatty acids, is one of the most robust biomarkers of human age, but the critical question of whether ELOVL2 plays a functional role in molecular aging has not been resolved. Here, we report that Elovl2 regulates age-associated functional and anatomical aging in vivo, focusing on mouse retina, with direct relevance to age-related eye diseases. We show that an age-related decrease in Elovl2 expression is associated with increased DNA methylation of its promoter. Reversal of Elovl2 promoter hypermethylation in vivo through intravitreal injection of 5-Aza-2'-deoxycytidine (5-Aza-dc) leads to increased Elovl2 expression and rescue of age-related decline in visual function. Mice carrying a point mutation C234W that disrupts Elovl2-specific enzymatic activity show electrophysiological characteristics of premature visual decline, as well as early appearance of autofluorescent deposits, well-established markers of aging in the mouse retina. Finally, we find deposits underneath the retinal pigment epithelium in Elovl2 mutant mice, containing components found in human drusen, a pathologic hallmark of age related macular degeneration. These findings indicate that ELOVL2 activity regulates aging in mouse retina, provide a molecular link between polyunsaturated fatty acids elongation and visual function, and suggest novel therapeutic strategies for the treatment of age-related eye diseases.

Early removal of senescent cells protects retinal ganglion cells loss in experimental ocular hypertension.

Experimental ocular hypertension induces senescence of retinal ganglion cells (RGCs) that mimics events occurring in human glaucoma. Senescence-related chromatin remodeling leads to profound transcriptional changes including the upregulation of a subset of genes that encode multiple proteins collectively referred to as the senescence-associated secretory phenotype (SASP). Emerging evidence suggests that the presence of these proinflammatory and matrix-degrading molecules has deleterious effects in a variety of tissues. In the current study, we demonstrated in a transgenic mouse model that early removal of senescent cells induced upon elevated intraocular pressure (IOP) protects unaffected RGCs from senescence and apoptosis. Visual evoked potential (VEP) analysis demonstrated that remaining RGCs are functional and that the treatment protected visual functions. Finally, removal of endogenous senescent retinal cells after IOP elevation by a treatment with senolytic drug dasatinib prevented loss of retinal functions and cellular structure. Senolytic drugs may have the potential to mitigate the deleterious impact of elevated IOP on RGC survival in glaucoma and other optic neuropathies.

Atrial fibrillation diagnosed after stroke and dementia risk: cohort study of first-ever ischaemic stroke patients aged 65 or older.

AIMS: Atrial fibrillation (AF) is a risk factor for dementia among ischaemic stroke patients in whom the AF was known before the stroke (KAF). Atrial fibrillation detected after stroke (AFDAS) has a different profile compared to KAF, including less frequent cardiovascular comorbidities and lower CHA2-DS2-VASC scores. Currently, it is unknown if AFDAS is also associated with increased dementia risk. We assessed the association between AFDAS and the incident risk of dementia. We also evaluated whether the use of oral anticoagulants (OAC) was associated with lower dementia risk among AFDAS patients. METHODS AND RESULTS: In this cohort study, we classified 9791 first-ever ischaemic stroke patients from the Ontario Stroke Registry into four groups: (i) No AF, (ii) KAF, (iii) Inpatient AFDAS (diagnosed during admission), and (iv) Outpatient AFDAS (diagnosed after discharge). We used multivariable Cox proportional models to estimate hazard ratios (HR) for the association between AFDAS and incident dementia risk. Dementia was determined through administrative datasets based on previously validated algorithms. In adjusted analyses, the dementia risk was higher for inpatient AFDAS [HR 1.78, 95% confidence interval (CI) 1.51-2.10] and outpatient AFDAS (HR 1.74, 95% CI 1.47-2.05) relative to no AF. Oral anticoagulants use was associated with lower dementia risk among patients with inpatient AFDAS (HR 0.58, 95% CI 0.43-0.79) and outpatient AFDAS (HR 0.60, 95% CI 0.43-0.83). CONCLUSION: Atrial fibrillation detected after stroke was independently associated with higher risk of dementia relative to no AF. Among patients with AFDAS, the use of OACs was associated with lower dementia risk.

Matching pennies games as asymmetric models of conflict.

De Dreu and Gross (D&G) seem to have disregarded some relevant experimental literature on games of conflict, most notably variations on "matching pennies" games. While in such games, "attacker" and "defender" are typically not explicitly labelled, players' differentiated roles yield naturally to such notions. These studies partly validate some of D&G's findings and interpretations.

Ischemic Stroke From Libman-Sacks Endocarditis Not Associated With Antiphospholipid Antibodies: Good Clinical Outcome Without Anticoagulation.

Libman-Sacks endocarditis (LSE), a cardiac complication of systemic lupus erythematosus, is commonly treated with anticoagulation for stroke prevention. We describe a patient with multifocal strokes secondary to LSE, treated with aspirin, without further recurrence. Our case highlights the importance of nuanced decision-making regarding antithrombotic choices for stroke prevention in LSE. (Level of Difficulty: Intermediate.).

Molecular Mechanisms Underlying Curcumin-Mediated Therapeutic Effects in Type 2 Diabetes and Cancer.

The growing prevalence of age-related diseases, especially type 2 diabetes mellitus (T2DM) and cancer, has become global health and economic problems. Due to multifactorial nature of both diseases, their pathophysiology is not completely understood so far. Compelling evidence indicates that increased oxidative stress, resulting from an imbalance between production of reactive oxygen species (ROS) and their clearance by antioxidant defense mechanisms, as well as the proinflammatory state contributes to the development and progression of the diseases. Curcumin (CUR; diferuloylmethane), a well-known polyphenol derived from the rhizomes of turmeric Curcuma longa, has attracted a great deal of attention as a natural compound with beneficial antidiabetic and anticancer properties, partly due to its antioxidative and anti-inflammatory actions. Although this polyphenolic compound is increasingly being recognized for its growing number of protective health effects, the precise molecular mechanisms through which it reduces diabetes- and cancer-related pathological events have not been fully unraveled. Hence, CUR is the subject of intensive research in the fields Diabetology and Oncology as a potential candidate in the treatment of both T2DM and cancer, particularly since current therapeutic options for their treatment are not satisfactory in clinics. In this review, we summarize the recent progress made on the molecular targets and pathways involved in antidiabetic and anticancer activities of CUR that are responsible for its beneficial health effects.

An assessment of health status and health behaviours in adolescents: main points and methods of the SOPKARD-Junior programme.

INTRODUCTION: The study involved preparing and implementation a model of complex screening programme for adolescents and comparison of anthropometric examinations between the population of the SOPKARD-Junior programme and representative sample of Polish children in the same age. MATERIAL AND METHODS: The screening programme in 14-15 year old pupils (n = 282) included: anthropometric, blood pressure, echocardiographic, electrocardiographic, carotid arteries, kidney and thyroid ultrasound examinations, as well as respiratory, dental and masticatory system, orthopaedic, psychological and psychiatric assessment. Blood and urine tests were also performed. The results of anthropometric examinations from the SOPKARD-Junior and OLAF programmes were used for comparative analysis. RESULTS: Statistically significant (p < 0.001) differences between young people from Sopot and their peers in the general Polish population were found in height (+3.61 cm for boys), body mass (+5.19 kg for boys and +3.99 kg for girls), body mass index (+0.99 kg/m2 for boys and +1.33 kg/m2 for girls), waist circumference (+4.52 cm for boys and +4.52 cm for girls) and hip circumference (+2.51 cm for boys). The highest attendance rate was achieved for examinations performed in school (e.g. anthropometric and blood pressure measurements - n = 268; 95%) and the lowest for the echocardiograpy performed in local hospital (n = 133; 47%). The mean score of the programme quality (scale 1-6) assessed by children was 4.63. CONCLUSIONS: The SOPKARD-Junior programme represents an attempt to develop a model of screening assessments for teenagers in Poland. Preliminary results of the SOPKARD-Junior programme indicate small differences in the biological development of Sopot youth in comparison with their peers from Polish population of the OLAF programme. The high attendance rate on research conducted at the school indicate that proposed health examinations in adolescents are acceptable and feasible.

Circulating tumour DNA methylation markers for diagnosis and prognosis of hepatocellular carcinoma.

An effective blood-based method for the diagnosis and prognosis of hepatocellular carcinoma (HCC) has not yet been developed. Circulating tumour DNA (ctDNA) carrying cancer-specific genetic and epigenetic aberrations may enable a noninvasive 'liquid biopsy' for diagnosis and monitoring of cancer. Here, we identified an HCC-specific methylation marker panel by comparing HCC tissue and normal blood leukocytes and showed that methylation profiles of HCC tumour DNA and matched plasma ctDNA are highly correlated. Using cfDNA samples from a large cohort of 1,098 HCC patients and 835 normal controls, we constructed a diagnostic prediction model that showed high diagnostic specificity and sensitivity (P < 0.001) and was highly correlated with tumour burden, treatment response, and stage. Additionally, we constructed a prognostic prediction model that effectively predicted prognosis and survival (P < 0.001). Together, these findings demonstrate in a large clinical cohort the utility of ctDNA methylation markers in the diagnosis, surveillance, and prognosis of HCC.