Search

Abstract ZBTB48 (also known as TZAP) is a transcription factor that has previously been reported to bind to telomeres and act as a negative regulator of telomere length in human cell lines. To explore whether transcription factor activity and telomere length regulation are conserved at the organismal level in vertebrates, we generate a zbtb48 −/− zebrafish line via CRISPR‒Cas genome editing. The zbtb48 −/− mutants display no obvious physical or behavioral abnormalities in the first two generations. We find no statistically significant changes in telomere length in first-generation adults. However, for the gene regulatory aspect of Zbtb48, similar to that in human cancer cell lines, we observe downregulation of mtfp1 at both the mRNA and protein levels in the zbtb48 −/− mutants. This suggests that mtfp1 is an evolutionarily conserved regulatory target of Zbtb48. Further investigation of the spatiotemporal expression of zbtb48 in previously published zebrafish data reveals low transcript expression in diverse tissues, except in germline stem cells and gametocytes of the gonads. Notably, Mtfp1 protein downregulation is detected in the ovaries of 40 dpf zbtb48 −/− mutants and in the testes of both 40 dpf and 10.5-month-old zbtb48 −/− mutants.

Abstract Colorectal cancer (CRC) is stratified into four consensus molecular subtypes (CMS1-4). CMS3 represents the metabolic subtype, but its wiring remains largely undefined. To identify the underlying tumorigenesis of CMS3, organoids derived from 16 genetically engineered mouse models are analyzed. Upon in vitro Cre-recombinase activation, transformation is established and transcriptional profiling reveals that distinct CMSs (CMS2-4) are modeled with different organoids. CMS3-like, metabolic signature-positive, organoids are induced by KRAS mutations. Interestingly, metabolic signatures are subsequently shown to result from enterocyte-like differentiation both in organoids and human cancers. Further analysis reveals carbamoyl-phosphate synthase 1 (CPS1) and sucrase-isomaltase (SI) as signature proteins. More importantly, CPS1 is crucial for de novo pyrimidine synthesis in CMS3 and its inhibition targets proliferation and stemness, facilitating enterocyte-like differentiation, while CMS2 and CMS4 models are not affected. Our data point to an enterocyte-like differentiation of CMS3 CRCs and reveal a selective vulnerability of this subtype through CPS1 inhibition.

BackgroundApart from the well-established skeletal effects, vitamin D has been explored as a secretagogue influencing various adipokines, including adiponectin and irisin. Recent evidence suggests that specific forms of 25-Hydroxyvitamin D (25(OHD), such as free and bioavailable 25(OH)D, may provide more accurate measurements of vitamin D status. The relationship between vitamin D status and serum irisin and adiponectin concentrations remains largely unexplored, particularly during pregnancy.MethodsWe analyzed data from 67 healthy maternal-neonatal pairs from Northern Greece at birth. Biochemical and hormonal tests were conducted on each maternal-neonatal pair. The vitamin D forms were estimated using validated mathematical models. Subsequently, regression analyses were conducted to determine the association between the vitamin D forms and adipokine levels.ResultsBioavailable maternal 25(OH)D was inversely associated with neonatal irisin concentrations [β=-73.46 (-140.573 to -6.341), p=0.034]. No other associations were observed between maternal vitamin D status and neonatal adipokine concentrations.ConclusionIn conclusion, maternal bioavailable vitamin D concentrations are inversely associated with neonatal serum irisin concentrations, warranting further studies to evaluate the underlying mechanisms for this finding.

Applications of learning analytics (LA) can raise concerns from students about their privacy in higher education contexts. Developing effective privacy-enhancing practices requires a systematic understanding of students’ privacy concerns and how they vary across national and cultural dimensions. We conducted a survey study with established instruments to measure privacy concerns and cultural values for university students in five countries (Germany, South Korea, Spain, Sweden, and the United States; N = 762). The results show that students generally trusted institutions with their data and disclosed information as they perceived the risks to be manageable even though they felt somewhat limited in their ability to control their privacy. Across the five countries, German and Swedish students stood out as the most trusting and least concerned, especially compared to US students who reported greater perceived risk and less control. Students in South Korea and Spain responded similarly on all five privacy dimensions (perceived privacy risk, perceived privacy control, privacy concerns, trusting beliefs, and non-self-disclosure behavior), despite their significant cultural differences. Culture measured at the individual level affected the antecedents and outcomes of privacy concerns. Perceived privacy risk and privacy control increase with power distance. Trusting beliefs increase with a desire for uncertainty avoidance and lower masculinity. Non-self-disclosure behaviors rise with power distance and masculinity and decrease with more uncertainty avoidance. Thus, cultural values related to trust in institutions, social equality and risk-taking should be considered when developing privacy-enhancing practices and policies in higher education.

Abstract Artificial intelligence (AI) is already widely used in daily communication, but despite concerns about AI’s negative effects on society the social consequences of using it to communicate remain largely unexplored. We investigate the social consequences of one of the most pervasive AI applications, algorithmic response suggestions (“smart replies”), which are used to send billions of messages each day. Two randomized experiments provide evidence that these types of algorithmic recommender systems change how people interact with and perceive one another in both pro-social and anti-social ways. We find that using algorithmic responses changes language and social relationships. More specifically, it increases communication speed, use of positive emotional language, and conversation partners evaluate each other as closer and more cooperative. However, consistent with common assumptions about the adverse effects of AI, people are evaluated more negatively if they are suspected to be using algorithmic responses. Thus, even though AI can increase the speed of communication and improve interpersonal perceptions, the prevailing anti-social connotations of AI undermine these potential benefits if used overtly.

Introduction Early-onset fetal growth restriction (FGR) requires timely, often preterm, delivery to prevent fetal hypoxia causing stillbirth or neurologic impairment. Antenatal corticosteroids (CCS) administration reduces neonatal morbidity and mortality following preterm birth, most effectively when administered within 1 week preceding delivery. Optimal timing of CCS administration is challenging in early-onset FGR, as the exact onset and course of fetal hypoxia are unpredictable. International guidelines do not provide a directive on this topic. In the Netherlands, two timing strategies are commonly practiced: administration of CCS when the umbilical artery shows (A) a pulsatility index above the 95thh centile and (B) absent or reversed end-diastolic velocity (a more progressed disease state). This study aims to (1) use practice variation to compare CCS timing strategies in early-onset FGR on fetal and neonatal outcomes and (2) develop a dynamic tool to predict the time interval in days until delivery, as a novel timing strategy for antenatal CCS in early-onset FGR.Methods and analysis A multicentre, retrospective cohort study will be performed including pregnancies complicated by early-onset FGR in six tertiary hospitals in the Netherlands in the period between 2012 and 2021 (estimated sample size n=1800). Main exclusion criteria are multiple pregnancies and fetal congenital or genetic abnormalities. Routinely collected data will be extracted from medical charts. Primary outcome for the comparison of the two CCS timing strategies is a composite of perinatal, neonatal and in-hospital mortality. Secondary outcomes include the COSGROVE core outcome set for FGR. A multivariable, mixed-effects model will be used to compare timing strategies on study outcomes. Primary outcome for the dynamic prediction tool is ‘days until birth’.Ethics and dissemination The need for ethical approval was waived by the Ethics Committee (University Medical Center Utrecht). Results will be published in open-access, peer-reviewed journals and disseminated by presentations at scientific conferences.Trial registration number ClinicalTrials.gov: NCT05606497

Extracellular vesicles (EV) are known to be released from the primary cilium, but the role ciliary proteins play in EV biogenesis remains unexplored. Here, the authors demonstrate increased secretion of small EVs with altered cargo composition from cells with known ciliarelated mutations. Wnt related molecules made up a majority of altered cargo

Cytochrome c oxidase is a membrane protein of the respiratory chain that consumes protons and molecular oxygen to produce water and uses the resulting energy to pump protons across the membrane. Our molecular dynamics simulations with an excess proton located at different positions in one of the proton-conducting channels, the K-channel, show a clear dependence of the number of water molecules inside the channel on the proton position. A higher hydration level facilitates the formation of hydrogen-bonded chains along which proton transfer can occur. However, a sufficiently high hydration level for such proton transport is observed only when the excess proton is located above S365, i.e., the lower third of the channel. From the channel entrance up to this point, proton transport is via water molecules as proton carriers. These hydronium ions move with their surrounding water molecules, up to K362, filling and widening the channel. The conformation of K362 depends on its own protonation state and on the hydration level, suggesting its role to be proton transport from a hydronium ion at the height of K362 to the upper part of the channel via a conformational change. The protonation-dependent conformational dynamics of E101 at the bottom of the channel renders proton transfer via E101 unlikely. Instead, its role is rather that of an amplifier of H96’s proton affinity, suggesting H96 as the initial proton acceptor.

Elective curriculums require undergraduates to choose from a large roster of courses for enrollment each term. It has proven difficult to characterize this fateful choice process because it remains largely unobserved. Using digital trace data to observe this process at scale at a private research university, together with qualitative student interviews, we provide a novel empirical study of course consideration as an important component of course selection. Clickstream logs from a course exploration platform used by most undergraduates at the case university reveal that students consider on average nine courses for enrollment for their first fall term (

Vitamin D has a long-established role in bone health. In the last two decades, there has been a dramatic resurgence in research interest in vitamin D due to studies that have shown its possible benefits for non-skeletal health. Underpinning the renewed interest in vitamin D was the identification of the vital role of intracrine or localized, tissue-specific, conversion of inactive pro-hormone 25-hydroxyvitamin D [25(OH)D] to active 1,25-dihydroxyvitamin D [1,25(OH)2D]. This intracrine mechanism is the likely driving force behind vitamin D action resulting in positive effects on human health. To fully capture the effect of this localized, tissue-specific conversion to 1,25(OH)2D, adequate 25(OH)D would be required. As such, low serum concentrations of 25(OH)D would compromise intracrine generation of 1,25(OH)2D within target tissues. Consistent with this is the observation that all adverse human health consequences of vitamin D deficiency are associated with a low serum 25(OH)D level and not with low 1,25(OH)2D concentrations. Thus, clinical investigators have sought to define what concentration of serum 25(OH)D constitutes adequate vitamin D status. However, since 25(OH)D is transported in serum bound primarily to vitamin D binding protein (DBP) and secondarily to albumin, is the total 25(OH)D (bound plus free) or the unbound free 25(OH)D the crucial determinant of the non-classical actions of vitamin D? While DBP-bound-25(OH)D is important for renal handling of 25(OH)D and endocrine synthesis of 1,25(OH)2D, how does DBP impact extra-renal synthesis of 1,25(OH)2D and subsequent 1,25(OH)2D actions? Are their pathophysiological contexts where total 25(OH)D and free 25(OH)D would diverge in value as a marker of vitamin D status? This review aims to introduce and discuss the concept of free 25(OH)D, the molecular biology and biochemistry of vitamin D and DBP that provides the context for free 25(OH)D, and surveys in vitro, animal, and human studies taking free 25(OH)D into consideration.

In this work we demonstrate efficient quality control of a variety of gasoline and ethanol (gasohol) blends using a multimode interference (MMI) fiber sensor. The operational principle relies on the fact that the addition of ethanol to the gasohol blend reduces the refractive index (RI) of the gasoline. Since MMI sensors are capable of detecting small RI changes, the ethanol content of the gasohol blend is easily determined by tracking the MMI peak wavelength response. Gasohol blends with ethanol contents ranging from 0% to 50% has been clearly identified using this device, which provides a linear response with a maximum sensitivity of 0.270 nm/% EtOH. The sensor can also distinguish when water incorporated in the blend has exceeded the maximum volume tolerated by the gasohol blend, which is responsible for phase separation of the ethanol and gasoline and could cause serious engine failures. Since the MMI sensor is straightforward to fabricate and does not require any special coating it is a cost effective solution for real time and in-situ monitoring of the quality of gasohol blends.

A universal pH indicator is used to fabricate a fiber optic ammonia sensor. The advantage of this pH indicator is that it exhibits sensitivity to ammonia over a broad wavelength range. This provides a differential response, with a valley around 500 nm and a peak around 650 nm, which allows us to perform ratiometric measurements. The ratiometric measurements provide not only an enhanced signal, but can also eliminate any external disturbance due to humidity or temperature fluctuations. In addition, the indicator is embedded in a hydrophobic and gas permeable polyurethane film named Tecoflex®. The film provides additional advantages to the sensor, such as operation in dry environments, efficient transport of the element to be measured to the sensitive area of the sensor, and prevent leakage or detachment of the indicator. The combination of the universal pH indicator and Tecoflex® film provides a reliable and robust fiber optic ammonia sensor.

La hipertensión arterial (HTA) dependiente de mineralocorticoides representa actualmente una de las formas secundarias de hipertensión de mayor prevalencia. Entre las causas más prevalentes está el hiperaldosteronismo primario (HAP) cuya prevalencia es cercana al 10% de la población de hipertensos. El HAP se detecta principalmente por una elevación de la razón aldosterona a actividad renina plasmática (ARR), ya que la hipokalemia es infrecuente de encontrar. La fisiopatología del HAP se presenta como un desequilibrio en el control electrolítico a nivel renal, por mayor actividad del receptor mineralocorticoides (MR), lo cual aumenta el volumen intravascular y la presión arterial. Recientemente se ha demostrado también que el exceso de aldosterona afecta también el endotelio vascular, el tejido cardiaco entre otros. Este exceso puede ser por una alteración a nivel de la glándula suprarrenal (generalmente hiperplasia o adenoma) o formas genéticas (familiares). Por otra parte, alteraciones parciales o totales de la enzima 11β-Hidroxiesteroide deshidrogenasa tipo 2 (11β-HSD2) resulta en una metabolización total o parcial de cortisol, imitando los efectos de aldosterona sobre MR. La actividad de esta enzima se evalúa midiendo la razón cortisol a cortisona en suero por HPLC-MS/MS. La prevalencia de alteraciones parciales de la actividad de la enzima 11β-HSD2 en estudios de cohorte alcanza en alrededor del 15% en población hipertensa. El diagnóstico del HAP o deficiencias de 11BHSD2, permitiría un tratamiento específico del cuadro hipertensivo mediantes el uso de bloqueadores del receptor mineralocorticoideo y/o uso de corticoides de acción prolongada sin actividad mineralocorticoidea como dexametasona o betametasona.

In virtual reality (VR) it is possible to embody avatars that are dissimilar to the physical self. We examined whether embodying a dissimilar self in VR would decrease anxiety in a public speaking situation. We report the results of an observational pilot study and two laboratory experiments. In the pilot study (N=252), participants chose an avatar to use in a public speaking task. Trait public speaking anxiety correlated with avatar preference, such that anxious individuals preferred dissimilar self-representations. In Study 1 (N=82), differences in anxiety during a speech in front of a virtual audience were compared among participants embodying an assigned avatar whose face was identical to their real self, an assigned avatar whose face was other than their real face, or embodied an avatar of their choice. Anxiety differences were not significant, but there was a trend for lower anxiety with the assigned dissimilar avatar compared to the avatar looking like the real self. Study 2 (N=105) was designed to explicate that trend, and further investigated anxiety differences with an assigned self or dissimilar avatar. The assigned dissimilar avatar reduced anxiety relative to the assigned self avatar for one measure of anxiety. We discuss implications for theories of self-representation as well as for applied uses of VR to treat social anxiety.

Immunomodulatory responses to the active form of vitamin D (1,25-dihydroxyvitamin D, 1,25D) have been recognized for many years, but it is only in the last five years that the potential role of this in normal human immune function has been recognized. Genome-wide analyses have played a pivotal role in redefining our perspective on vitamin D and immunity. The description of increased vitamin D receptor (VDR) and 1α-hydroxylase (CYP27B1) expression in macrophages following a pathogen challenge, has underlined the importance of intracrine vitamin D as key mediator of innate immune function. It is now clear that both macrophages and DCs are able to respond to 25-hydroxyvitamin D (25D), the major circulating vitamin D metabolite, thereby providing a link between the function of these cells and the variations in vitamin D status common to many humans. The identification of hundreds of primary 1,25D target genes in immune cells has also provided new insight into the role of vitamin D in the adaptive immune system, such as the modulation of antigen-presentation and T cells proliferation and phenotype, with the over-arching effects being to suppress inflammation and promote immune tolerance. In macrophages 1,25D promotes antimicrobial responses through the induction of antibacterial proteins, and stimulation of autophagy and autophagosome activity. In this way variations in 25D levels have the potential to influence both innate and adaptive immune responses. More recent genome-wide analyses have highlighted how cytokine signaling pathways can influence the intracrine vitamin D system and either enhance or abrogate responses to 25D. The current review will discuss the impact of intracrine vitamin D metabolism on both innate and adaptive immunity, whilst introducing the concept of disease-specific corruption of vitamin D metabolism and how this may alter the requirements for vitamin D in maintaining a healthy immune system in humans.

Patients with chronic kidney disease (CKD), who usually display low serum 25-hydroxyvitamin D (25D) and 1,25-dihydroxyvitamin D (1,25D), are at high risk of infection, notably those undergoing peritoneal dialysis (PD). We hypothesized that peritoneal macrophages from PD patients are an important target for vitamin D-induced antibacterial activity. Dialysate effluent fluid was obtained from 27 non-infected PD patients. Flow cytometry indicated that PD cells were mainly monocytic (37.9±17.7% cells CD14+/CD45+). Ex vivo analyses showed that PD cells treated with 25D (100 nM, 6 hrs) or 1,25D (5 nM, 6 hrs) induced mRNA for antibacterial cathelicidin (CAMP) but conversely suppressed mRNA for hepcidin (HAMP). PD cells from patients with peritonitis (n = 3) showed higher baseline expression of CAMP (18-fold±9, p

http://dx.doi.org/10.5028/jatm.v5i3.240 Aluminum that is incorporated in an energetic material such as a propellant plays a significant role in the combustion process by means of stabilization with regard to the burning and generation of additional energy. The use of simulation softwares to model the combustion mechanism and kinetic parameters of the elementary reactions that compose the oxidation were used as the pressure variation of the combustion chamber of a rocket motor conditions. The behavior of the molar fraction of the chemical species during the combustion and its posterior stabilization were observed. The systems submitted to higher pressures tend to stabilize more rapidly, according to the greater chemical speed of the elementary reactions.

Elective curriculums require undergraduates to choose from a large roster of courses for enrollment each term. It has proven difficult to characterize this fateful choice process because it remains largely unobserved. Using digital trace data to observe this process at scale at a private research university, together with qualitative student interviews, we provide a novel empirical study of course consideration as an important component of course selection. Clickstream logs from a course exploration platform used by most undergraduates at the case university reveal that students consider on average nine courses for enrollment for their first fall term (<2% of available courses) and these courses predict which academic major students declare two years later. Twenty-nine interviews confirm that students experience consideration as complex and reveal variation in consideration strategies that may influence how consideration unfolds. Consideration presents a promising site for intervention in problems of equity, career funneling, and college completion.

Online courses are increasingly used to scale up professional learning. However, engaging people throughout a course and encouraging them to take actions afterward is challenging, especially with culturally diverse participants whose response to encouragement may vary. Social norms can serve as a strong encouragement to participants, but they are mostly unobservable in online courses. We therefore tested how communicating three established kinds of social norms impacts behavioral outcomes and how the effects vary across different cultures. Findings from a randomized controlled field experiment in a Massive Open Online Course entitled Nature Education show that both the type of norm message (descriptive; dynamic; injunctive) and the cultural context (China; US) influence how the intervention improves course outcomes: US participants' completion rate rose 40% following an injunctive norm message stating that participants ought to conduct nature education, while other norm messages were ineffective for both US and Chinese participants. Regardless of the social norm message, nearly all participants engaged in nature education activities within three months after the course ended. Communicating social norms can impact participants' behavior in the course and beyond, which can offer a strategy for supporting online professional learning and tailoring messages to different cultural contexts.

Vitamin D binding protein (DBP) plays a key role in the bioavailability of active 1,25-dihydroxyvitamin D (1,25(OH)(2)D) and its precursor 25-hydroxyvitamin D (25OHD), but accurate analysis of DBP-bound and free 25OHD and 1,25(OH)(2)D is difficult. To address this, two new mathematical models were developed to estimate: 1) serum levels of free 25OHD/1,25(OH)(2)D based on DBP concentration and genotype; 2) the impact of DBP on the biological activity of 25OHD/1,25(OH)(2)D in vivo. The initial extracellular steady state (eSS) model predicted that 50 nM 25OHD and 100 pM 1,25(OH)(2)D),