Search Results (26)

2′-Deoxythymidine-5′-monophosphate, dTMP, is an essential precursor of thymine, one of the four canonical bases of DNA. In almost all living organisms, dTMP is synthesized de novo by a reductive methylation reaction of 2′-deoxyuridine-5′-monophosphate (dUMP) catalyzed by the thymidylate synthase, where the carbon used for the methylation is derived from methylenetetrahydrofolate (CH2THF). Many microbes, including human pathogens, utilize the flavin-dependent thymidylate synthase encoded by the thyX gene to generate dTMP. The mechanism of action relies on the reduced coenzyme FADH⁻, which acts both as a mediator, facilitating methylene transfer from CH2THF to dUMP, and as a reducing agent. Here, we present for the first-time crystallographic structures of ThyX from Thermotoga maritima in the reduced state alone and in complex with dUMP. ThyX flavin reduction appears to order the active site, favoring a flavin conformation that drastically deviates from that observed in the oxidized enzyme. The structures show that FADH⁻ potentially controls access to the folate site and the conformation of two active site loops, affecting the degree of accessibility of substrate pockets to the solvent. Our results provide the molecular basis for the sequential enzyme mechanism implemented by ThyX during dTMP biosynthesis. Full article

This paper aims to decode medieval theology from the vantage point of ancient Chinese poetry, employing a cross-textual methodology that encourages a fusion of horizons. It highlights Saint Bernard’s profound and influential theological exegesis of the “Song of Songs”, particularly his comparison of the divine–human relationship to the conjugal bond. The present study posits that readers from Chinese culture can gain access to Saint Bernard’s mystical theology through the sentiment of love, as portrayed in the Book of Odes (Shijing). Initially addressing love as a core human sentiment, this study progresses by juxtaposing the representations of love in the Book of Odes with those in the “Song of Songs”. This comparative analysis culminates in an exploration of Saint Bernard’s theological perspectives, illuminated through these analogous depictions of love. The results affirm that engaging with Saint Bernard’s discourse on love via the Book of Odes is not only feasible but also instrumental in dispelling widespread misconceptions. Full article

In the 11th–12th centuries, extreme ascetic practices reappeared in Western Europe, in particular, the wearing of hauberks and heavy iron chains, associated with penitence and eremitism. This article discusses the charisma of three ascetic saints of the 12th century: Bernard the Penitent (d. 1182), Wulfric of Haselbury (d. 1154/55), and Godric of Finchale (d. 1170). Their hagiographies were written shortly after their death. The authors emphasize that they were revered as holy men already in their lifetime. Their charismatic power was revealed by miracles of healing and prophecy, sometimes in visions. The manifestations of their charisma continued and even increased after their death and were transmitted and spread through their relics. Their mortifications and the signs of their holiness are comparable to those of the stylites and other hermits of Syria of late Antiquity. Full article

This study evaluates how the characteristics of daily rainfall and extreme events in Côte d’Ivoire changed during 1961–2015 using the rain gauge observation network of the National Meteorological Service (SODEXAM). The results indicate that the northern and southern parts of Cote d’Ivoire experienced a change from a wet to a dry period, with cut-offs in 1982 and 1983, respectively. In the northern part, this dry period was marked by a decrease in rainfall intensity, the length of wet spells, and the contribution of heavy and extreme rainfall, as well as an increase in the number of rainy days and a decrease in the length of dry spells. Over the southern part, this dry period was marked by an increase in the maximum length of dry spells associated with an increase in the maximum 1-day and 5-day precipitation events. The western part of Côte d’Ivoire experienced a late cut-off from the wet to dry period in 2000; the dry period was associated with a decrease in the number of rainy days, rainfall intensities, and maximum length of wet spells. Changes in the central part of Cote d’Ivoire presented high variability, and trends were less marked, even though a cut-off from a wet to dry period was detected in 1991. This study shows that Côte d’Ivoire, which is located in a subhumid and humid region and has an economy dependent on agriculture (especially cash crops, which comprise 60% of the GDP), is experiencing dry spells that are increasing in frequency and length. Combined with deforestation to increase production, this situation could lead to desertification and compromise the sustainable development goals of the country. The contribution of heavy rainfall was found to increase during the last 15 years, increasing the overall risk of floods, especially in urban areas where city authorities and populations are not prepared, thereby threatening infrastructure and human security. Full article

Facial nerve stimulation (FNS) is a potential complication which may affect the auditory performance of children with cochlear implants (CIs). We carried out an exploratory prospective observational study to investigate the effects of the electrical stimulation pattern on FNS reduction in young children with CI. Ten ears of seven prelingually deafened children with ages up to 6 years old who undergone a unilateral or bilateral CI surgery were included in this study. Electromyographic (EMG) action potentials from orbicularis oculi muscle were recorded using monopolar biphasic stimulation (ST1) and multi-mode monophasic stimulation with capacitive discharge (ST2). Presence of EMG responses, facial nerve stimulation thresholds (T-FNS) and EMG amplitudes were compared between ST1 and ST2. Intra-cochlear electrodes placement, cochlear-nerve and electrode-nerve distances were also estimated to investigate their effects on EMG responses. The use of ST2 significantly reduced the presence of intraoperative EMG responses compared to ST1. Higher stimulation levels were required to elicit FNS with ST2, with smaller amplitudes, compared to ST1. No and weak correlation was observed between cochlea-nerve and electrode-nerve distances and EMG responses, respectively. ST2 may reduce FNS in young children with CI. Differently from the electrical stimulation pattern, the cochlea-nerve and electrode-nerve distances seem to have limited effects on FNS in this population. Full article

Dihydrouridine (D) is an abundant modified base found in the tRNAs of most living organisms and was recently detected in eukaryotic mRNAs. This base confers significant conformational plasticity to RNA molecules. The dihydrouridine biosynthetic reaction is catalyzed by a large family of flavoenzymes, the dihydrouridine synthases (Dus). So far, only bacterial Dus enzymes and their complexes with tRNAs have been structurally characterized. Understanding the structure-function relationships of eukaryotic Dus proteins has been hampered by the paucity of structural data. Here, we combined extensive phylogenetic analysis with high-precision 3D molecular modeling of more than 30 Dus2 enzymes selected along the tree of life to determine the evolutionary molecular basis of D biosynthesis by these enzymes. Dus2 is the eukaryotic enzyme responsible for the synthesis of D20 in tRNAs and is involved in some human cancers and in the detoxification of β-amyloid peptides in Alzheimer’s disease. In addition to the domains forming the canonical structure of all Dus, i.e., the catalytic TIM-barrel domain and the helical domain, both participating in RNA recognition in the bacterial Dus, a majority of Dus2 proteins harbor extensions at both ends. While these are mainly unstructured extensions on the N-terminal side, the C-terminal side extensions can adopt well-defined structures such as helices and beta-sheets or even form additional domains such as zinc finger domains. 3D models of Dus2/tRNA complexes were also generated. This study suggests that eukaryotic Dus2 proteins may have an advantage in tRNA recognition over their bacterial counterparts due to their modularity. Full article

The role of minerals in the chemical evolution of RNA molecules is an important issue when considering the early stage of the Hadean Earth. In particular, the interaction between functional ribozymes and ancient minerals under simulated primitive conditions is a recent research focus. We are currently attempting to design a primitive RNA metabolic network which would function with minerals, and believe that the simulated chemical network of RNA molecules would be useful for evaluation of the chemical evolution from a simple RNA mixture to an RNA-based life-like system. First, we measured the binding interactions of oligonucleotides with four types of minerals; Aerosil silica, zirconium silicate, sepiolite, and montmorillonite. Oligonucleotides bound zirconium silicate and montmorillonite in the presence of MgCl₂, and bound sepiolite both in the presence and absence of MgCl₂, but they did not bind Aerosil. Based on the binding behavior, we attempted the self-cleavage reaction of the hammerhead ribozyme from an avocado viroid. This reaction was strongly inhibited by zirconium silicate, a compound regarded as mineral evidence for the existence of water. The present study suggests that the chemical evolution of functional RNA molecules requires specific conformational binding, resulting in efficient ribozyme function as well as zirconium silicate for the chemical evolution of biomolecules. Full article

Glucose homeostasis is a real challenge for extremely preterm infants (EPIs) who have both limited substrate availability and immature glucose metabolism regulation. In the first days of life, EPIs frequently develop transient glucose intolerance, which has a complex pathophysiology that associates unregulated gluconeogenesis, immature insulin secretion, and peripheral insulin resistance. In this population, glucocorticoid therapy is frequently administrated to prevent severe bronchopulmonary dysplasia. During this treatment, glucose intolerance classically increases and may lead to hyperglycemia. We report a case of neonatal hypoglycemia that was concomitant to a glucocorticoids administration, and that led to a congenital hyperinsulinism diagnosis in an EPI with a heterozygous ABCC8 variant. The variant was inherited from his mother, who had developed monogenic onset diabetes of the youth (MODY) at the age of 23. ABCC8 encodes a beta-cell potassium channel unit and causes congenital hyperinsulinism or MODY depending on the mutation location. Moreover, some mutations have been observed in the same patient to cause both hyperinsulinism in infancy and MODY in adulthood. In our case, the baby showed repeated and severe hypoglycemias, which were undoubtedly time-associated with the betamethasone intravenous administration. This hyperinsulinism was transient, and the infant has not yet developed diabetes at three years of age. We take the opportunity presented by this unusual clinical presentation to provide a review of the literature, suggesting new insights regarding the pathophysiology of the beta-pancreatic cells’ insulin secretion: glucocorticoids may potentiate basal insulin secretion in patients with ABCC8 mutation. Full article

The RNA world hypothesis suggests that chemical networks consisting of functional RNA molecules could have constructed a primitive life-like system leading a first living system. The chemical evolution scenario of RNA molecules should be consistent with the Hadean Earth environment. We have demonstrated the importance of the environment at both high temperature and high pressure, using different types of hydrothermal flow reactor systems and high-pressure equipment. In the present study, we have attempted to develop an alternative easy-to-implement method for high-pressure measurements and demonstrate that the system is applicable as an efficient research tool for high-pressure experiments at pressures up to 30 MPa. We demonstrate the usefulness of the system by detecting the high-pressure influence for the self-cleavage of avocado hammerhead ribozyme (ASBVd(−):HHR) at 45–65 °C. A kinetic analysis of the high-pressure behavior of ASBVd(−):HHR shows that the ribozyme is active at 30 MPa and its activity is sensitive to pressures between 0.1–30 MPa. The surprising finding that such a short ribozyme is effective for self-cleavage at a high pressure suggests the importance of pressure as a factor for selection of adaptable RNA molecules towards an RNA-based life-like system in the Hadean Earth environment deep in the ocean. Full article

Background: Immune checkpoint inhibitors (ICIs) have been a major advance in treating non-small-cell lung cancer (NSCLC). Programmed cell death protein-1/programmed death-ligand 1 blockade enhances immune function, mediating anti-tumor activity, yet causing immune-related adverse events (irAEs). We investigated the prognostic role of Grade 3–4 irAEs on overall survival (OS). Methods: This observational study recruited advanced NSCLC patients who received ICIs at Bichat-Claude Bernard University Hospital and in a community hospital, Saint-Joseph Foundation (Paris), between 1 January 2016 and 31 December 2019. Immunotherapy as a single-agent or double-drug combination was applied in the first and later lines. Univariable and multivariable analyses were instrumental in evaluating the prognostic impact of irAEs. Results: Overall, 201 consecutive ICI-treated patients were enrolled. High-grade irAEs (Grades 3–4) occurred in 36 patients (17.9%), including 11 (30.5%) cases of pneumonitis, 8 (22.2%) of colitis, 4 (11.1%) hepatic, 3 (8.3%) dermatological, 2 (5.5%) neurological events, and 2 cases (5.5%) of poly-arthralgia. The median OS was 10.4 ± 1.36 months (95% CI:7.7–13.1), being significantly higher in patients with high-grade irAEs than those without, 27.8 months vs. 8.1 months, respectively (HR = 2.5; p < 0.0001). Multivariable analysis revealed an independent association between high-grade irAEs and longer OS (HR = 0.29, 95% CI: 0.2–0.6, p < 0.0001). Conclusions: Our real-life study confirms that high-grade irAEs predict longer OS in advanced NSCLC. Full article

Cochlear implants provide hearing perception to people with severe to profound hearing loss. The electrode array (EA) inserted during the surgery directly stimulates the hearing nerve, bypassing the acoustic hearing system. The complications during the EA insertion in the inner ear may cause trauma leading to infection, residual hearing loss, and poor speech perception. This work aims to reduce the trauma induced during electrode array insertion process by carefully designing a sensing method, an actuation system, and data-driven control strategy to guide electrode array in scala tympani. Due to limited intra-operative feedback during the insertion process, complex bipolar electrical impedance is used as a sensing element to guide EA in real time. An automated actuation system with three degrees of freedom was used along with a complex impedance meter to record impedance of consecutive electrodes. Prediction of EA direction (medial, middle, and lateral) was carried out by an ensemble of random forest, shallow neural network, and k-nearest neighbour in an offline setting with an accuracy of 86.86%. The trained ensemble was then utilized in vitro for prediction and correction of EA direction in real time in the straight path with an accuracy of 80%. Such a real-time system also has application in other electrode implants and needle and catheter insertion guidance. Full article

Phthalates have been widely studied for their reprotoxic effects in male rodents and in particular on testosterone production, for which reference doses were established. The female rodent brain can also represent a target for exposure to these environmental endocrine disruptors. Indeed, a large range of behaviors including reproductive behaviors, mood-related behaviors, and learning and memory are regulated by sex steroid hormones. Here we review the experimental studies addressing the effects and mechanisms of phthalate exposure on these behaviors in female rodents, paying particular attention to the experimental conditions (period of exposure, doses, estrous stage of analyses etc.). The objective of this review is to provide a clear picture of the consistent effects that can occur in female rodents and the gaps that still need to be filled in terms of effects and mode(s) of action for a better risk assessment for human health. Full article

The Crucifixion and Last Judgment, or the so-called New York Diptych, is one of the most controversial paintings attributed to Jan van Eyck (ca. 1390–1441) and his workshop. For well over a century, art historians have vigorously discussed its attribution, composition, functional intent, and even its dating. In light of prior scholarship addressing these remarkable panels, this paper focuses on the skeleton represented in the Last Judgment to reveal its iconographical meanings. Specifically, I highlight the inscriptions written on the skeleton’s wings, suggesting that the texts were cited from an All Saints’ Day sermon delivered by the Burgundian abbot Bernard of Clairvaux (1090–1153) who discussed a temporal location for blessed or sinful souls. Full article

This study aimed to evaluate maternal left ventricular (LV) systo-diastolic function using conventional and TDI echocardiography and included 10 healthy Saint-Bernard pregnant bitches. M-mode, peak transmitral flow velocities during early diastole (E) and atrial contraction (A), aortic and pulmonic flow, myocardial performance index (MPI), TDI studies (peak myocardial velocities during early diastole (E’), atrial contraction (A’) and peak systole (S’)), and blood pressure were measured at 21 to 28 (T1), 40 (T2) and 60 (T3) days of gestation and four to eight weeks postpartum (T4). Cardiac output and heart rate were 20% and 9% higher at T3, respectively, compared to T4 (p < 0.01). Lateral S’ was 36% higher at T3 than at T1 (p < 0.05). Changes in diastolic function were demonstrated by 10% lower E wave and 15% A wave at T1, compared to T4 (p < 0.05). E’ and A’ were 23% and 42% higher at T3 compared to T4 (p < 0.01). Both lateral E/E’ and E’/A’ were 6% and 19% lower at T3 compared to T1 (p < 0.01 and p < 0.05, respectively). At T3, MPI was 51% and 34% lower when compared to T1 or T2 (p < 0.05). The echocardiographic evaluation of maternal cardiac function is important, as structural, and functional changes occur throughout pregnancy. Full article

Deep-sea species endemic to hydrothermal vents face the critical challenge of detecting active sites in a vast environment devoid of sunlight. This certainly requires specific sensory abilities, among which olfaction could be a relevant sensory modality, since chemical compounds in hydrothermal fluids or food odors could potentially serve as orientation cues. The temperature of the vent fluid might also be used for locating vent sites. The objective of this study is to observe the following key behaviors of olfaction in hydrothermal shrimp, which could provide an insight into their olfactory capacities: (1) grooming behavior; (2) attraction to environmental cues (food odors and fluid markers). We designed experiments at both deep-sea and atmospheric pressure to assess the behavior of the vent shrimp Rimicaris exoculata and Mirocaris fortunata, as well as of the coastal species Palaemon elegans and Palaemon serratus for comparison. Here, we show that hydrothermal shrimp groom their sensory appendages similarly to other crustaceans, but this does not clean the dense bacterial biofilm that covers the olfactory structures. These shrimp have previously been shown to possess functional sensory structures, and to detect the environmental olfactory signals tested, but we do not observe significant attraction behavior here. Only temperature, as a signature of vent fluids, clearly attracts vent shrimp and thus is confirmed to be a relevant signal for orientation in their environment. Full article