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Abstract Translation initiation is a highly regulated step needed for protein synthesis. Most cell-based mechanistic work on translation initiation has been done using non-stressed cells growing in medium with sufficient nutrients and oxygen. This has yielded our current understanding of ‘canonical’ translation initiation, involving recognition of the mRNA cap by eIF4E1 followed by successive recruitment of initiation factors and the ribosome. Many cells, however, such as tumor cells, are exposed to stresses such as hypoxia, low nutrients or proteotoxic stress. This leads to inactivation of mTORC1 and thereby inactivation of eIF4E1. Hence the question arises how cells translate mRNAs under such stress conditions. We study here how mRNAs are translated in an eIF4E1-independent manner by blocking eIF4E1 using a constitutively active version of eIF4E-binding protein (4E-BP). Via ribosome profiling we identify a subset of mRNAs that are still efficiently translated when eIF4E1 is inactive. We find that these mRNAs preferentially release eIF4E1 when eIF4E1 is inactive and bind instead to eIF3d via its cap-binding pocket. eIF3d then enables these mRNAs to be efficiently translated due to its cap-binding activity. In sum, our work identifies eIF3d-dependent translation as a major mechanism enabling mRNA translation in an eIF4E-independent manner.

IntroductionMost drugs fail during development and there is a clear and unmet need for approaches to better understand mechanistically how drugs exert both their intended and adverse effects. Gaining traction in this field is the use of disease data linking genes with pathological phenotypes and combining this with drugtarget interaction data.MethodsWe introduce methodology to associate drugs with effects, both intended and adverse, using a tripartite network approach that combines drug-target and target-phenotype data, in which targets can be represented as proteins and protein domains.ResultsWe were able to detect associations for over 140,000 ChEMBL drugs and 3,800 phenotypes, represented as Human Phenotype Ontology (HPO) terms. The overlap of these results with the SIDER databases of known drug side effects was up to 10 times higher than random, depending on the target type, disease database and score threshold used. In terms of overlap with drug-phenotype pairs extracted from the literature, the performance of our methodology was up to 17.47 times greater than random. The top results include phenotype-drug associations that represent intended effects, particularly for cancers such as chronic myelogenous leukemia, which was linked with nilotinib. They also include adverse side effects, such as blurred vision being linked with tetracaine.DiscussionThis work represents an important advance in our understanding of how drugs cause intended and adverse side effects through their action on disease causing genes and has potential applications for drug development and repositioning.

Después de haber presentado el marcaje de la plata en Castilla y en algunos centros europeos, estudiamos, en esta segunda parte, el peculiar marcaje de la plata del Reino de Aragón, que no tiene relación con el existente en Castilla, en Francia o Países Bajos. En Zaragoza el marcaje estuvo supervisado por jurados elegidos por el Ayuntamiento entre sus miembros, aunque contaron con la ayuda técnica de plateros. El resultado fue que se marcó la plata con un punzón alusivo a la ciudad. No fue necesario que los plateros marcaran la plata con su marca personal. El sistema de marcaje de la ciudad de Zaragoza se empleó también en otras importantes ciudades del reino como Tarazona, Calatayud o Daroca, aunque algunos plateros añadieron su marca personal por influjo del marcaje de Castilla. Sin embargo, a lo largo del siglo XVIII, y especialmente a partir del decreto real de 1752 sobre el marcaje de la plata, se fue generalizando el triple marcaje castellano por las ciudades de la Corona de Aragón.

The COVID-19 pandemic has significantly impacted communities worldwide, and effective management strategies are critical to reduce transmission rates and minimize the impact of the disease. In this study, we modeled and analyzed the COVID-19 transmission dynamics and derived relevant epidemiological values for three regions of the Philippines, namely, the National Capital Region (NCR), Davao City, and Baguio City, under different community quarantine implementations. The unique features and differences of these regions-of-interest were accounted for in simulating the disease spread and in estimating key epidemiological parameters fitted to the reported COVID-19 cases. Results support the robustness of the model formulated and provides insights into the effect of the government's implemented intervention protocols. With a forecasting feature, this modeling framework is beneficial for science-based decision support, policy making, and assessment for recent and future pandemics wherever regions-of-interest.

Se repasa el complejo proceso de contratación que afectó al retablo mayor de Zúñiga. Se aporta nueva documentación que permite proponer que en este retablo se pudo utilizar una traza de Arnao Spierinck o de Bruselas. Se revisa y aquilata el estilo y la evolución de los escultores de la familia Ayala y de Pedro de Gabiria. Pero, sobre todo, se indaga en las obras de Juan Ruiz de Heredia, autor del retablo de Mues –junto con Martín Gumet– y al que también se adjudica la imagen de Nuestra Señora de Beatasis en Zúñiga, y la imaginería de los retablos de Agoncillo (La Rioja), El Busto, Armañanzas y Piedramillera en Navarra. También trabajó la piedra y se le adjudican las imágenes de la portada de Santa María de Los Arcos, sobre todo la figura de María con el Niño.

Abstract Neurofibromatosis Type II (NFII) is a genetic condition caused by loss of the NF2 gene, resulting in activation of the YAP/TAZ pathway and recurrent Schwann cell tumors, as well as meningiomas and ependymomas. Unfortunately, few pharmacological options are available for NFII. Here, we undertake a genome-wide CRISPR/Cas9 screen to search for synthetic-lethal genes that, when inhibited, cause death of NF2 mutant Schwann cells but not NF2 wildtype cells. We identify ACSL3 and G6PD as two synthetic-lethal partners for NF2, both involved in lipid biogenesis and cellular redox. We find that NF2 mutant Schwann cells are more oxidized than control cells, in part due to reduced expression of genes involved in NADPH generation such as ME1. Since G6PD and ME1 redundantly generate cytosolic NADPH, lack of either one is compatible with cell viability, but not down-regulation of both. Since genetic deficiency for G6PD is tolerated in the human population, G6PD could be a good pharmacological target for NFII.

Bortezomib and oncolytic virotherapy are two emerging targeted cancer therapies. Bortezomib, a proteasome inhibitor, disrupts protein degradation in cells, leading to the accumulation of unfolded proteins that induce apoptosis. On the other hand, virotherapy uses genetically modified oncolytic viruses (OVs) to infect cancer cells, trigger cell lysis, and activate anti-tumor response. Despite progress in cancer treatment, identifying administration protocols for therapeutic agents remains a significant concern, aiming to strike a balance between efficacy, minimizing toxicity, and administrative costs. In this work, optimal control theory was employed to design a cost-effective and efficient co-administration protocols for bortezomib and OVs that could significantly diminish the population of cancer cells via the cell death program with the NFKB-BAX-RIP1 signaling network. Both linear and quadratic control strategies were explored to obtain practical treatment approaches by adapting necroptosis protocols to efficient cell death programs. Our findings demonstrated that a combination therapy commencing with the administration of OVs followed by bortezomib infusions yields an effective tumor-killing outcome. These results could provide valuable guidance for the development of clinical administration protocols in cancer treatment.

Summary: Background: Sleep and circadian rhythm disruptions are common in patients with mood disorders. The intricate relationship between these disruptions and mood has been investigated, but their causal dynamics remain unknown. Methods: We analysed data from 139 patients (76 female, mean age = 23.5 ± 3.64 years) with mood disorders who participated in a prospective observational study in South Korea. The patients wore wearable devices to monitor sleep and engaged in smartphone-delivered ecological momentary assessment of mood symptoms. Using a mathematical model, we estimated their daily circadian phase based on sleep data. Subsequently, we obtained daily time series for sleep/circadian phase estimates and mood symptoms spanning >40,000 days. We analysed the causal relationship between the time series using transfer entropy, a non-linear causal inference method. Findings: The transfer entropy analysis suggested causality from circadian phase disturbance to mood symptoms in both patients with MDD (n = 45) and BD type I (n = 35), as 66.7% and 85.7% of the patients with a large dataset (>600 days) showed causality, but not in patients with BD type II (n = 59). Surprisingly, no causal relationship was suggested between sleep phase disturbances and mood symptoms. Interpretation: Our findings suggest that in patients with mood disorders, circadian phase disturbances directly precede mood symptoms. This underscores the potential of targeting circadian rhythms in digital medicine, such as sleep or light exposure interventions, to restore circadian phase and thereby manage mood disorders effectively. Funding: Institute for Basic Science, the Human Frontiers Science Program Organization, the National Research Foundation of Korea, and the Ministry of Health & Welfare of South Korea.

Abstract - Using fallacious argumentative means, such as the antistréphon, causes dilemmas and leads the judge to not decide and therefore to postpone the trial, thus avoiding an injustice verdict. Noctes Atticae by Gellius contains an example (5.10.1-16). In another passage (12.7.1-7) the dilemma and the deferment of the trial are determined by the same facts advanced in the judgment. By both Gellian passages, postponing the judgement is a substantial non liquet but with the function of preventing an injustice.

Estudiamos el marcaje de la plata en Castilla y lo comparamos con el que adoptaron las autoridades civiles de París y Brujas, ciudad esta última con la que Burgos estuvo relacionada tanto en lo mercantil como en lo artístico. Precisamos los cargos municipales que vigilaron la producción con metales preciosos y señalamos las diferentes funciones que tuvieron, afinadores, contrastes y marcadores. Estudiamos el triple sistema de marcar la plata que se adoptó en Burgos y Valladolid que fueron ciudades de referencia para el resto del territorio castellano. Sin embargo, las ciudades de la Corona de Aragón, que trabajaron plata de once dineros, adoptaron un sistema de marcaje de vigilancia por parte de las autoridades de la ciudad, pero sin apenas participación de los platero.

En este trabajo se presentan los resultados obten¡dos del análisis de algunos casos de interacción entre dos especies en un sistema ecológico. Se trataron en particular la depredación y la competición entre dos espec¡es, y a partir de los modelos matemáticos que rigen estos tipos de interacc¡ones, procedimos con el análisis cualitativo de las ecuac¡ones planteadas.

Precisamos algunos datos y aportamos noticias sobre la actividad patrimonial de los Velasco en Burgos y en La Rioja occidental. Identificamos a los enterrados en el panteón familiar de Medina de Pomar y precisamos las reformas que se hicieron en el monasterio de Santa Clara. Se revisa la acción de los Condestables en la capilla de la catedral de Burgos y se aportan noticias sobre el monasterio de Briviesca, que pasó de Juan Gil de Hontañón a Juan de Rasines en 1523. Comentamos los datos sobre la estancia de Simón de Colonia en Haro y sobre la construcción de un nuevo monasterio en Ajubarte.

Abstract Stem cells show intrinsic interferon signalling, which protects them from viral infections at all ages. In the ageing brain, interferon signalling also reduces the ability of stem cells to activate. Whether these functions are linked and at what time interferons start taking on a role in stem cell functioning is unknown. Additionally, the molecular link between interferons and activation in neural stem cells and how this relates to progenitor production is not well understood. Here we combine single‐cell transcriptomics, RiboSeq and mathematical models of interferon to show that this pathway is important for proper stem cell function at all ages in mice. Interferon orchestrates cell cycle and mTOR activity to post‐transcriptionally repress Sox2 and induces quiescence. The interferon response then decreases in the subsequent maturation states. Mathematical simulations indicate that this regulation is beneficial for the young and harmful for the old brain. Our study establishes molecular mechanisms of interferon in stem cells and interferons as genuine regulators of stem cell homeostasis and a potential therapeutic target to repair the ageing brain.

Abstract HIV-infected individuals could be at a greater risk for developing lung cancer than the general population due to the higher prevalence in the former of human papillomavirus (HPV) in the oral cavity and higher smoking rates. Our aim was to assess HPV prevalence and E6 viral oncogene transcription in lung cancer samples from HIV-infected individuals. This was a single-center, retrospective study of a cohort of HIV-1-infected patients diagnosed with and treated for lung cancer. Pathological lung samples archived as smears or formalin-fixed paraffin-embedded blocks were subjected to HPV genotyping, detection of human p16 protein and assessment for HPV E6 mRNA expression. Lung cancer samples from 41 patients were studied, including squamous cell carcinoma (32%), adenocarcinoma (34%), non-small cell cancer (27%), and small cell cancer (7%). HPV DNA was detected in 23 out of 41 (56%, 95% CI 41–70%) of samples and high-risk (HR)-HPV types were detected in 16 out of 41 (39%, 95% CI 26–54%), HPV-16 being the most prevalent [13/16 (81.3%, 95% CI 57.0–93%]. In samples with sufficient material left: expression of p16 was detected in 3 out of 10 (30%) of HR-HPV DNA-positive tumors and in 3 out of 7 (43%) of the negative ones; and E6 mRNA was detected in 2 out of 10 (20%) of HPV-16-positive samples (squamous lung cancers). These two patients had a background of a previous HPV-related neoplasia and smoking. HR-HPV DNA detection was prevalent in lung cancers in HIV-infected patients. However, viral oncogene expression was limited to patients with previous HPV-related cancers.

Exercise and increased physical activity are vital components of the standard treatment guidelines for many chronic diseases such as diabetes, obesity and cardiovascular disease. Although strenuous exercise cannot be recommended to people with numerous chronic conditions, walking is something most people can perform. In comparison to high-intensity training, the metabolic consequences of low-intensity walking have been less well studied. We present here a feasibility study of a subject who performed an exercise intervention of low-intensity, non-fatiguing walking on a deskmill/treadmill for 200 min daily, approximately the average time a German spends watching television per day. This low-impact physical activity has the advantages that it can be done while performing other tasks such as reading or watching TV, and it can be recommended to obese patients or patients with heart disease. We find that this intervention led to substantial weight loss, comparable to that of bariatric surgery. To study the metabolic changes caused by this intervention, we performed an in-depth metabolomic profiling of the blood both directly after walking to assess the acute changes, as well as 1.5 days after physical activity to identify the long-term effects that persist. We find changes in acylcarnitine levels suggesting that walking activates fatty acid beta oxidation, and that this mitochondrial reprogramming is still visible 1.5 days post-walking. We also find that walking mildly increases gut permeability, leading to increased exposure of the blood to metabolites from the gut microbiome. Overall, these data provide a starting point for designing future intervention studies with larger cohorts.

Como resultado del desarrollo de instrumentos científicos de bajo costo y buen desempeño, se han realizado algunos arreglos experimentales, aplicación de métodos de medición y herramientas (tanto gráficas como formales) para obtener resultados confiables. Muchos de los ensayos fueron pruebas de concepto que, a pesar de no ser cuantitativos, han sido rescatados por su valor en el entendimiento de algunos fenómenos físicos y químicos, útiles en la enseñanza de ciencias e ingeniería. Se analizan algunos métodos usando dos de los recursos disponibles normalmente en una computadora personal: el micrófono y la cámara web; el primero para pruebas basadas en sonido y la segunda para espectrometría tanto de radiación visible como de fotones Raman. Las técnicas descritas han sido examinadas como apoyo al desarrollo de instrumentos científicos alternativos (ICA).

The cell cycle regulates translation during mitosis by controlling DENR stability. Here, the authors show the non-canonical translation initiation complex DENR·MCTS1 is phosphorylated during mitosis by CDK1 and 2, enabling the translation of genes needed for proper mitotic progression.

Anovulation refers to a menstrual cycle characterized by the absence of ovulation. Exogenous hormones such as synthetic progesterone and estrogen have been used to attain this state to achieve contraception. However, large doses are associated with adverse effects such as increased risk for thrombosis and myocardial infarction. This study utilizes optimal control theory on a modified menstrual cycle model to determine the minimum total exogenous estrogen/progesterone dose, and timing of administration to induce anovulation. The mathematical model correctly predicts the mean daily levels of pituitary hormones LH and FSH, and ovarian hormones E2, P4, and Inh throughout a normal menstrual cycle and reflects the reduction in these hormone levels caused by exogenous estrogen and/or progesterone. Results show that it is possible to reduce the total dose by 92% in estrogen monotherapy, 43% in progesterone monotherapy, and that it is most effective to deliver the estrogen contraceptive in the mid follicular phase. Finally, we show that by combining estrogen and progesterone the dose can be lowered even more. These results may give clinicians insights into optimal formulations and schedule of therapy that can suppress ovulation. Author summary Hormonal contraceptives composed of exogenous estrogen and/or progesterone are commonly administered artificial means of birth control. Despite many benefits, adverse side effects associated with high doses such as thrombosis and myocardial infarction, cause hesitation to usage. Our study presents an improved mathematical model for hormonal control of the menstrual cycle and applies optimal control theory to minimize total exogenous estrogen and/or progesterone dose, and determine timing of administration that lead to contraception. We observe a reduction in dosage of about 92% in estrogen monotherapy and 43% in progesterone monotherapy. Our simulations show that it is most effective to deliver the estrogen contraceptive in the mid follicular phase. In addition, we illustrate that combination therapy significantly lower doses further. Our findings may give clinicians insights into optimal dosing scheme for contraception.

Reset control is a kind of hybrid control which is capable of overcoming fundamental limitations on the performance intrinsic to linear time invariant (LTI) systems. In this work, we develop a novel control strategy for first order LTI plants with time delay, based on the proportional-integral plus Clegg integrator (PI+CI) controller, a hybrid extension of the proportional-integral (PI) controller, augmented with a new mechanism for keeping its state constant during a given interval of time (reset-and-hold strategy). This strategy is capable of producing an approximation of a flat response which greatly improves the performance in comparison with non-hybrid linear strategies, extending previous results developed for first order systems without delay. Well-posedness and closed-loop stability of the resulting control system are analyzed under the Hybrid Inclusions (HI) framework, and a set of sufficient stability conditions are provided. Furthermore, a case study is developed that showcases the possibilities of this new approach.

During development, organs grow to achieve a size necessary for their function; how final organ size is sensed to trigger growth arrest, however, remains unclear. Here the authors show that Drosophila wing disc size is determined by the hormone ecdysone through a TORC1-dependent mechanism.

The Coronavirus disease 2019 (COVID-19) has exposed many systemic vulnerabilities in many countries' health system, disaster preparedness, and adequate response capabilities. With the early lack of data and information about the virus and the many differing local-specific factors contributing to its transmission, managing its spread had been challenging. The current work presents a modified Susceptible-Exposed-Infectious-Recovered compartmental model incorporating intervention protocols during different community quarantine periods. The COVID-19 reported cases before the vaccine rollout in Davao City, Philippines, are utilized to obtain baseline values for key epidemiologic model parameters. The probable secondary infections (i.e., time-varying reproduction number) among other epidemiological indicators were computed. Results show that the cases in Davao City were driven by the transmission rates, positivity proportion, latency period, and the number of severely symptomatic patients. This paper provides qualitative insights into the transmission dynamics of COVID-19 along with the government's implemented intervention protocols. Furthermore, this modeling framework could be used for decision support, policy making, and system development for the current and future pandemics.

Se presentan dos cruces góticas casi inéditas que se habían considerado del final de la Edad Media. A partir del estudio comparado y de la lectura de la inscripción de una de ellas, se propone al autor, Augerius, y al comitente, fray Martín de Maluenda, abad del monasterio de Piedra, abad con intervalos de 1284 a 1313. Recubiertas de filigrana, fueron originalmente cruces anicónicas vinculadas a la tradición hispana. De virtuosísima elaboración, estas cruces, casi desconocidas, tienen una importancia trascendental para el estudio de la platería española y europea.

S-acylation is the post-translational covalent attachment of fatty acids (FA) onto cysteines. Nuskova et al. find that exposure of cells to different FAs affects which FA is used to S-acylate GNAI proteins, thereby altering GNAI function and EGFR pathway activation, linking metabolism to signaling.

Abstract This study aimed to ascertain, for the first time, whether serum magnesium (Mg) concentration is affected by the presence of hepatocellular carcinoma (HCC). We retrospectively enrolled consecutive cirrhotic patients with a diagnosis of HCC (n = 130) or without subsequent evidence of HCC during surveillance (n = 161). Serum levels of Mg were significantly (P

Liver cirrhosis development is a multifactorial process resulting from a combination of environmental and genetic factors. The aim of the study was to develop accurate non-invasive diagnostic and prognostic models for alcoholic cirrhosis. Consecutive subjects with at-risk alcohol intake were retrospectively enrolled (110 cirrhotic patients and 411 non-cirrhotics). At enrollment, the data about lifetime drinking history were collected and all patients were tested for Patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409, Transmembrane 6 Superfamily 2 (TM6SF2) rs58542926, and hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) rs72613567 variants. In cross-sectional analyses, models for the diagnosis of cirrhosis were developed using multivariate logistic regression. A predictive score for cirrhosis development over 24 years was built by evaluating time-dependent AUC curves. The best diagnostic accuracy was demonstrated by the model, which also includes daily alcohol consumption, duration of hazardous alcohol use, and genetic variants, with AUCs of 0.951 (95% CI 0.925–0.977) and 0.887 (95% CI 0.925–0.977) for cirrhosis and compensated cirrhosis, respectively. The predictive model for future cirrhosis development (AUC of 0.836 95% CI: 0.769–0.904) accounted for age at onset of at-risk alcohol consumption and the number of PNPLA3 and HSD17B13 variant alleles. We have developed accurate genetic and alcohol consumption models for the diagnosis of alcoholic cirrhosis and the prediction of its future risk.

Abstract Background To compare oncological results and safety profile of balloon micro-catheter trans-arterial chemoembolization (b-TACE) and drug-eluting-microsphere (DEM-TACE) in patients with hepatocellular-carcinoma (HCC). Methods This is a case–control, retrospective, single-center study. Between January-2015/March-2019, 149 patients (131 males [87.9%]) with 226 HCC were treated, 22 patients (35 HCC; 19 [86.4%] males) with b-TACE and 127 with DEM-TACE (191 HCC, 112 [88.2%] males). Embolization protocol was standardized (sequential 100 ± 25 and 200 ± 25 μm microspheres). Results were evaluated by modified-response-evaluation-criteria-in-solid-tumor [mRECIST] at 1, 3–6 and 9–12 months and time to recurrence after complete response [TTR] at 1 years. Cox’s regression weighted with tumor dimensions was performed. Adverse events (AEs) were recorded. Results mRECIST oncological response at all time points (1, 3–6 and 9–12 months) for both treatments were similar, with the exception of Objective response rate at 9-12 months. Objective response at 1 and 3–6 months between b-TACE vs DEM-TACE [23/35 (65.7%) vs 119/191 (62.3%), 21/29 (72.4%) vs 78/136 (57.4%) (p > 0.05), respectively]. On the contrary, at 9–12 months, it was significantly higher in b-TACE subgroup than DEM-TACE (15/19 [78.9%] vs 48/89 [53.9%], p = 0.05). TTR for complete response at 1 year had a better trend for b-TACE vs DEM-TACE (278.0 days [196.0–342.0] vs 219.0 days [161.0–238.0], OR 0.68 [0.4–1.0], p = 0.10). The use of balloon micro-catheter reduced the relative risk of the event of recurrence by 0.63 [CI95% 0.38–1.04]; p = 0.07). No significant differences were found in AEs rate. Conclusion b-TACE showed a trend of better oncological response over DEM-TACE with and longer TTR with a similar adverse events rate, in patients presenting with larger tumors.

PURPOSE: Upper airway (UA) surgery is commonly employed in the treatment of patients with obstructive sleep apnea (OSA). The intricate pathophysiology of OSA, variability in sites and patterns of UA collapse, and the interaction between anatomical and non-anatomical factors in individual patients may contribute to possible surgical failures. This clinical consensus statement aims to identify areas of agreement among a development group comprising international experts in OSA surgery, regarding the appropriate definition, predictive factors in patients, and management of surgical failure in OSA treatment. METHODS: A clinical consensus statement (CCS) was developed using the Delphi method by a panel of 35 contributors from various countries. A systematic literature review adhering to PRISMA guidelines was conducted. A survey consisting of 60 statements was then formulated and presented to the experts. RESULTS: Following two rounds of the Delphi process, consensus or strong consensus was achieved on 36 items, while 24 items remained without consensus. Specifically, 5 out of 10 statements reached consensus regarding on the Definition of Surgical Success/Failure after OSA Surgery. Regarding the Predictive Factors of Surgical Failure in OSA Surgery, consensus was reached on 10 out of 13 statements. In the context of the Diagnostic Workup in OSA Surgery, consensus was achieved on 9 out of 13 statements. Lastly, in Treatment in Surgical Failure Cases, consensus was reached on 12 out of 24 statements. CONCLUSION: The management of OSA after surgical failure presents a significant clinical challenge for sleep specialists. This CCS provides valuable guidance for defining, preventing, and addressing surgical failures in the treatment of OSA syndrome.