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Network monitoring systems can struggle to detect the full sequence of actions in a multi-step cyber attack, frequently resulting in multiple alerts (some of which are false positive (FP)) and missed actions. The challenge of easing the job of security analysts by triggering a single and accurate alert per attack requires developing and evaluating advanced event correlation techniques and models that have the potential to devise relationships between the different observed events/alerts.This work introduces a flexible architecture designed for hierarchical and iterative correlation of alerts and events. Its key feature is the sequential correlation of operations targeting specific attack episodes or aspects. This architecture utilizes IDS alerts or similar cybersecurity sensors, storing events and alerts in a non-relational database. Modules designed for knowledge creation then query these stored items to generate meta-alerts, also stored in the database. This approach facilitates creating a more refined knowledge that can be built on top of existing one by creating specialized modules. For illustrative purposes, we make a case study where we use this architectural approach to explore the feasibility of monitoring the progress of attacks of increased complexity by increasing the levels of the hyperalerts defined, including a case of a multi-step attack that adheres to the ATT&CK model. Although the mapping between the observations and the model components (i.e., techniques and tactics) is challenging, we could fully monitor the progress of two attacks and up to 5 out of 6 steps of the most complex attack by building up to three specialized modules. Despite some limitations due to the sensors and attack scenarios tested, the results indicate the architecture’s potential for enhancing the detection of complex cyber attacks, offering a promising direction for future cybersecurity research.

Abstract Follicular lymphoma (FL) is an indolent, germinal center B cell–derived lymphoid neoplasm, for which recent advances in treatment have substantially improved patient survival. However, FL remains an incurable and heterogeneous disease, with groups of patients experiencing early disease progression, histologic transformation, or a high risk of treatment-related toxicity. Additionally, FL is a continually relapsing disease, and response rates and disease-control intervals decrease with each subsequent line of therapy. In this review, we explore the current treatment landscape for relapsed or refractory FL and promising therapies in development, highlighting the efficacy and potential risks of each treatment. We provide a real-world perspective on the unmet needs of patients with FL. Novel therapeutic approaches in development offer a wide array of options for clinicians when treating relapsed or refractory FL. A nuanced approach is required to address the needs of individual patients, taking into consideration both the risks and benefits of each treatment option, as well as patient preferences.

Abstract Despite the development of novel therapies for acute myeloid leukemia, outcomes remain poor for most patients, and therapeutic improvements are an urgent unmet need. Although treatment regimens promoting differentiation have succeeded in the treatment of acute promyelocytic leukemia, their role in other acute myeloid leukemia subtypes needs to be explored. Here we identify and characterize two lysine deacetylase inhibitors, CM-444 and CM-1758, exhibiting the capacity to promote myeloid differentiation in all acute myeloid leukemia subtypes at low non-cytotoxic doses, unlike other commercial histone deacetylase inhibitors. Analyzing the acetylome after CM-444 and CM-1758 treatment reveals modulation of non-histone proteins involved in the enhancer–promoter chromatin regulatory complex, including bromodomain proteins. This acetylation is essential for enhancing the expression of key transcription factors directly involved in the differentiation therapy induced by CM-444/CM-1758 in acute myeloid leukemia. In summary, these compounds may represent effective differentiation-based therapeutic agents across acute myeloid leukemia subtypes with a potential mechanism for the treatment of acute myeloid leukemia.

Abstract Adaptation of avian pathogenic E. coli (APEC) to changing host environments including virulence factors expression is vital for disease progression. FdeC is an autotransporter adhesin that plays a role in uropathogenic Escherichia coli (UPEC) adhesion to epithelial cells. Expression of fdeC is known to be regulated by environmental conditions in UPEC and Shiga toxin-producing E. coli (STEC). The observation in a previous study that an APEC strain IMT5155 in which the fdeC gene was disrupted by a transposon insertion resulted in elevated adhesion to chicken intestinal cells prompted us to further explore the role of fdeC in infection. We found that the fdeC gene prevalence and FdeC variant prevalence differed between APEC and nonpathogenic E. coli genomes. Expression of the fdeC gene was induced at host body temperature, an infection relevant condition. Disruption of fdeC resulted in greater adhesion to CHIC-8E11 cells and increased motility at 42 °C compared to wild type (WT) and higher expression of multiple transporter proteins that increased inorganic ion export. Increased motility may be related to increased inorganic ion export since this resulted in downregulation of YbjN, a protein known to supress motility. Inactivation of fdeC in APEC strain IMT5155 resulted in a weaker immune response in chickens compared to WT in experimental infections. Our findings suggest that FdeC is upregulated in the host and contributes to interactions with the host by down-modulating motility during colonization. A thorough understanding of the regulation and function of FdeC could provide novel insights into E. coli pathogenesis.

Abstract Introduction Blinding is a methodologically important aspect in randomised controlled trials yet frequently overlooked in trials of spinal manual therapy interventions for back pain. To help inform the blinding methods of a future, double-placebo-controlled trial comparing spinal manual therapy and nerve root injection for lumbosacral radicular pain, we set four objectives: (1) to assess the feasibility of blinding participants, randomly allocated to an active or placebo-control spinal manual therapy intervention protocol, (2) to assess the feasibility of blinding outcome assessors within the trial, (3) to explore the influence of spinal manual therapy experience and low back pain on blinding, and (4) to explore factors contributing to perceptions about intervention assignment among participants and outcome assessors. Methods and analysis Two-parallel-group, single-centre, placebo-controlled, methodological blinding feasibility randomised trial. We will recruit between 60 and 100 adults with or without back pain and with or without experience of spinal manual therapy from Zurich, Switzerland. Participants will be randomised to either an active spinal manual therapy or a placebo-control spinal manual therapy protocol—both interventions delivered over two study visits, up to two weeks apart. The primary outcome is participant blinding using the Bang blinding index within each intervention arm immediately after each of the two study visits. Secondary outcomes are participant blinding using the James blinding index, outcome assessor blinding (Bang and James blinding indices), self-reported factors influencing perceived intervention assignment among participants and outcome assessors, and participant-reported credibility and expectancy of study interventions. Other outcomes—included to blind the study objective from participants—are lumbar spine range of motion, self-rated general health, satisfaction with care, pain intensity, and function. Intervention provider outcomes include intervention component fidelity and quality of intervention delivery. Ethics and dissemination The independent ethics commission of Canton Zurich granted ethical approval for this study (KEK 2023–00381). Written informed consent will be obtained from all participants. Findings will be disseminated in scientific conferences and a peer-reviewed publication and inform the blinding methods of a future double-placebo controlled trial comparing spinal manual therapy and nerve root injection for lumbosacral radicular pain—the SALuBRITY trial. Trial registration NCT05778396.

Abstract The metabolic functions of the liver are spatially organized in a phenomenon called zonation, linked to the differential exposure of portal and central hepatocytes to nutrient-rich blood. The mTORC1 signaling pathway controls cellular metabolism in response to nutrients and insulin fluctuations. Here we show that simultaneous genetic activation of nutrient and hormone signaling to mTORC1 in hepatocytes results in impaired establishment of postnatal metabolic and zonal identity of hepatocytes. Mutant hepatocytes fail to upregulate postnatally the expression of Frizzled receptors 1 and 8, and show reduced Wnt/β-catenin activation. This defect, alongside diminished paracrine Wnt2 ligand expression by endothelial cells, underlies impaired postnatal maturation. Impaired zonation is recapitulated in a model of constant supply of nutrients by parenteral nutrition to piglets. Our work shows the role of hepatocyte sensing of fluctuations in nutrients and hormones for triggering a latent metabolic zonation program.

El presente estudio analizó algunas de las ideas que rigen el pensamiento de las personas en su comunicación incesante dentro del área económica del sistema social y que están en la base de la narrativa que los impulsa a actuar. El propósito fue encontrar los elementos de una nueva narrativa para la época actual. Las ideas y propuestas analizadas en las obras de cinco autores en el campo de las ciencias sociales, sirvieron de guía a la investigación. Se observaron las indicaciones de la Teoría Fundamentada (Glaser y Strauss, 1967/2006) y del método cualitativo empleado por Herzberg (1959), con la finalidad de encontrar el metadiscurso, que es la esencia del pensamiento en el contenido subyacente de las ideas expresadas (Hyland, 1998). Se encontró que las relaciones de empatía y compasión, como base de las relaciones éticas entre personas y grupos, marcan ahora el rumbo de la actuación en sociedad.

Abstract Study design Single-centre, two-parallel group, methodological randomised controlled trial to assess blinding feasibility. Background Trials of manual therapy interventions of the back face methodological challenges regarding blinding feasibility and success. We assessed the feasibility of blinding an active manual soft tissue mobilisation and control intervention of the back. We also assessed whether blinding is feasible among outcome assessors and explored factors influencing perceptions about intervention assignment. Methods On 7–8 November 2022, 24 participants were randomly allocated (1:1 ratio) to active or control manual interventions of the back. The active group (n = 11) received soft tissue mobilisation of the lumbar spine. The control group (n = 13) received light touch over the thoracic region with deep breathing exercises. The primary outcome was blinding of participants immediately after a one-time intervention session, as measured by the Bang blinding index (Bang BI). Bang BI ranges from –1 (complete opposite perceptions of intervention received) to 1 (complete correct perceptions), with 0 indicating ‘random guessing’—balanced ‘active’ and ‘control’ perceptions within an intervention arm. Secondary outcomes included blinding of outcome assessors and factors influencing perceptions about intervention assignment among both participants and outcome assessors, explored via thematic analysis. Results 24 participants were analysed following an intention-to-treat approach. 55% of participants in the active manual soft tissue mobilisation group correctly perceived their group assignment beyond chance immediately after intervention (Bang BI: 0.55 [95% confidence interval (CI), 0.25 to 0.84]), and 8% did so in the control group (0.08 [95% CI, −0.37 to 0.53]). Bang BIs in outcome assessors were 0.09 (−0.12 to 0.30) and −0.10 (−0.29 to 0.08) for active and control participants, respectively. Participants and outcome assessors reported varying factors related to their perceptions about intervention assignment. Conclusions Blinding of participants allocated to an active soft tissue mobilisation of the back was not feasible in this methodological trial, whereas blinding of participants allocated to the control intervention and outcome assessors was adequate. Findings are limited due to imprecision and suboptimal generalisability to clinical settings. Careful thinking and consideration of blinding in manual therapy trials is warranted and needed. Trial registration ClinicalTrials.gov: NCT05822947 (retrospectively registered)

The objective of this work is to analyze and compare AC microgrid (ACMG) solutions to introduce the topic to new researchers. The methodology used to achieve this goal is a systematic literature review using five questions: (1) How have ACMGs evolved in five years? (2) What are the standards for ACMGs? (3) What are the different schemes for connecting MGs to the utility grid? (4) What are the different control schemes in ACMGs? (5) What is an appropriate way to compare results when working with ACMGs? The articles were published in Q1/Q2 journals as based on either the Scimago Journal Rank (SJR) and/or the Journal Citation Report (JCR) between 2018 and 2022 and were from three databases: (1) Web of Science (WoS), (2) Scopus, and (3) IEEE Xplore. Publications not describing pure ACMGs, review papers, publications not related to the questions, and papers describing work that did not meet a quality assessment were excluded, resulting in 34 articles being included in this review. Results show: (1) the energy sources and AC bus nature of microgrids over five years, (2) the identification and quantification of cited standards for microgrids, (3) the pros and cons of different schemes for connecting an AC microgrid to the main grid, (4) the control schemes, classified in a hierarchical control structure, and (5) the simulation tools and experimental benches used in microgrids. Most studies considered a generic energy source and a low-voltage three-phase AC bus, 16 standards were found, and the most cited standard was IEEE Standard 1547. The most common connection scheme to the utility grid was a direct connection, most of the works proposed a modification to a hierarchical control system scheme, and the most common simulation tool was MATLAB. The preferred experimental setup consisted of parallel inverters for testing a control scheme, a prototype when proposing a power electronic system, and a laboratory microgrid for testing fault detection methods.

Summary: Mouse embryonic stem cells (mESCs) in the primed pluripotency state, which resembles the post-implantation epiblast, can be de-differentiated in culture to a naive state that resembles the pre-implantation inner cell mass. We report that primed-to-naive mESC transition entails a significant slowdown of DNA replication forks and the compensatory activation of dormant origins. Using isolation of proteins on nascent DNA coupled to mass spectrometry, we identify key changes in replisome composition that are responsible for these effects. Naive mESC forks are enriched in MRE11 nuclease and other DNA repair proteins. MRE11 is recruited to newly synthesized DNA in response to transcription-replication conflicts, and its inhibition or genetic downregulation in naive mESCs is sufficient to restore the fork rate of primed cells. Transcriptomic analyses indicate that MRE11 exonuclease activity is required for the complete primed-to-naive mESC transition, demonstrating a direct link between DNA replication dynamics and the mESC de-differentiation process.

Summary: The co-culture of two adult human colorectal cancer cell lines, Caco-2 and HT29, on Transwell is commonly used as an in vitro gut mimic, yet the translatability of insights from such a system to adult human physiological contexts is not fully characterized. Here, we used single-cell RNA sequencing on the co-culture to obtain a detailed survey of cell type heterogeneity in the system and conducted a holistic comparison with human physiology. We identified the intestinal stem cell-, transit amplifying-, enterocyte-, goblet cell-, and enteroendocrine-like cells in the system. In general, the co-culture was fetal intestine-like, with less variety of gene expression compared to the adult human gut. Transporters for major types of nutrients were found in the majority of the enterocytes-like cells in the system. TLR 4 was not expressed in the sample, indicating that the co-culture model is incapable of mimicking the innate immune aspect of the human epithelium.

Abstract Autophosphorylation controls the transition between discrete functional and conformational states in protein kinases, yet the structural and molecular determinants underlying this fundamental process remain unclear. Here we show that c-terminal Tyr 530 is a de facto c-Src autophosphorylation site with slow time-resolution kinetics and a strong intermolecular component. On the contrary, activation-loop Tyr 419 undergoes faster kinetics and a cis-to-trans phosphorylation switch that controls c-terminal Tyr 530 autophosphorylation, enzyme specificity, and strikingly, c-Src non-catalytic function as a substrate. In line with this, we visualize by X-ray crystallography a snapshot of Tyr 530 intermolecular autophosphorylation. In an asymmetric arrangement of both catalytic domains, a c-terminal palindromic phospho-motif flanking Tyr 530 on the substrate molecule engages the G-loop of the active kinase adopting a position ready for entry into the catalytic cleft. Perturbation of the phospho-motif accounts for c-Src dysfunction as indicated by viral and colorectal cancer (CRC)-associated c-terminal deleted variants. We show that c-terminal residues 531 to 536 are required for c-Src Tyr 530 autophosphorylation, and such a detrimental effect is caused by the substrate molecule inhibiting allosterically the active kinase. Our work reveals a crosstalk between the activation and c-terminal segments that control the allosteric interplay between substrate- and enzyme-acting kinases during autophosphorylation.

Los juicios finales, el último y más ambicioso libro de crítica de Peter Elmore, es una contribución fundamental al estudio del campo cultural e intelectual peruano en la segunda mitad del siglo XX. Sustentado en una minuciosa reconstrucción bibliográfica, el libro establece que el hallazgo del ciclo mítico de Inkarri entre 1955 y 1956 fue el origen de la visión letrada más difundida e influyente de las mentalidades andinas. A partir de este descubrimiento, la intelligentsia peruana postula que el campesinado indígena tiene una mentalidad de raíz mítica y de proyección mesiánica. En Los juicios finales, Elmore analiza el impacto de esta visión en las ciencias sociales, la literatura y las artes plásticas. En esta nota de comentario bibliográfico, además de examinar cada sección y capítulo, identifico la centralidad de dos figuras para los objetivos y la organización del libro: José María Arguedas (quien fue el difusor más creativo de la nueva perspectiva sobre las mentalidades andinas) y Alberto Flores Galindo (cuya tesis sobre la “utopía andina” tiene diferencias sustanciales con la del “mesianismo andino”). Finalmente, esta nota comenta algunos límites de Los juicios finales, particularmente la ausencia de una perspectiva interseccional de género, raza y clase que relativice la escena (invocada en la introducción) del “encuentro entre el intelectual y el hombre andino”.

Abstract Pancreatic acinar cells rely on PTF1 and other transcription factors to deploy their transcriptional program. We identify NFIC as a NR5A2 interactor and regulator of acinar differentiation. NFIC binding sites are enriched in NR5A2 ChIP-Sequencing peaks. Nfic knockout mice have a smaller, histologically normal, pancreas with reduced acinar gene expression. NFIC binds and regulates the promoters of acinar genes and those involved in RNA/protein metabolism, and Nfic knockout pancreata show defective ribosomal RNA maturation. NFIC dampens the endoplasmic reticulum stress program through binding to gene promoters and is required for resolution of Tunicamycin-mediated stress. NFIC is down-regulated during caerulein pancreatitis and is required for recovery after damage. Normal human pancreata with low levels of NFIC transcripts display reduced expression of genes down-regulated in Nfic knockout mice. NFIC expression is down-regulated in mouse and human pancreatic ductal adenocarcinoma. Consistently, Nfic knockout mice develop a higher number of mutant Kras-driven pre-neoplastic lesions.

This study analyses the effect of solar field size, biomass boiler and thermal storage capacity for a time dependant demand. The main results to obtain from the simulation will be solar share, biomass consumption and annual coverage with the proposed systems and a selection of the optimum size of these variables for the study case design. Results gathered show that, while there is an increment in solar energy obtained while selecting bigger solar panel areas, tank relations for these big systems show improvement in smaller sizes, visible in the increment of biomass energy used when bigger storage sizes to solar collector areas used.

Biological processes are intrinsically noisy, and yet, the result of development-like the species-specific size and shape of organs-is usually remarkably precise. This precision suggests the existence of mechanisms of feedback control that ensure that deviations from a target size are minimized. Still, we have very limited understanding of how these mechanisms operate. Here, we investigate the problem of organ size precision using the Drosophila eye. The size of the adult eye depends on the rates at which eye progenitor cells grow and differentiate. We first find that the progenitor net growth rate results from the balance between their proliferation and apoptosis, with this latter contributing to determining both final eye size and its variability. In turn, apoptosis of progenitor cells is hampered by Dpp, a BMP2/4 signaling molecule transiently produced by early differentiating retinal cells. Our genetic and computational experiments show how the status of retinal differentiation is communicated to progenitors through the differentiation-dependent production of Dpp, which, by adjusting the rate of apoptosis, exerts a feedback control over the net growth of progenitors to reduce final eye size variability.

En el presente estudio desarrollamos un análisis en torno al uso y la utilidad de herramientas estadísticas para el análisis de la lingüística histórica. En concreto, nos centramos en PAUP* y las múltiples posibilidades de análisis que nos permite. De este modo, analizamos los archivos proporcionados por el proyecto IELEX siguiendo los criterios de Máxima Parsimonia y Máxima Verosimilitud, desarrollando una interpretación de los datos proporcionados y proporcionando también una guía de los comandos y procesos seguidos que puede servir de ayuda y guía al investigador. Del mismo modo, pretendemos abogar por el uso de la estadística y de las múltiples herramientas que proporciona para los análisis de tipo cuantitativo en el ámbito de las Humanidades Digitales.

Introduction: The mechanisms involved in cancer initiation, progression, drug resistance, and disease recurrence are traditionally investigated through in vitro adherent monolayer (2D) cell models. However, solid malignant tumor growth is characterized by progression in three dimensions (3D), and an increasing amount of evidence suggests that 3D culture models, such as spheroids, are suitable for mimicking cancer development. The aim of this report was to reaffirm the relevance of simpler 3D culture methods to produce highly reproducible spheroids, especially in the context of drug cytotoxicity measurements.Methods: Human A549 lung adenocarcinoma, LnCaP prostate adenocarcinoma, MNNG/HOS osteosarcoma and U251 glioblastoma cell lines were grown into spheroids for 20 days using either Liquid Overlay Technique (LOT) or Hanging Drop (HD) in various culture plates. Their morphology was examined by microscopy. Sensitivity to doxorubicin was compared between MNNG/HOS cells grown in 2D and 3D.Results: For all cell lines studied, the morphology of spheroids generated in round-bottom multiwell plates was more repeatable than that of those generated in flat-bottom multiwell plates. HD had no significant advantage over LOT when the spheroids were cultured in round-bottom plates. Finally, the IC50 of doxorubicin on MNNG/HOS cultured in 3D was 18.8 times higher than in 2D cultures (3D IC50 = 15.07 ± 0.3 µM; 2D IC50 = 0.8 ± 0.4 µM; *p < 0.05).Discussion: In conclusion, we propose that the LOT method, despite and because of its simplicity, is a relevant 3D model for drug response measurements that could be scaled up for high throughput screening.

Abstract Acute intermittent porphyria (AIP) is a rare disease caused by a deficiency of hydroxymethylbilane synthase (HMBS), the third enzyme of the heme‐synthesis pathway. Decreased enzymatic activity in the liver induces an overproduction of heme‐precursors and acute neurological attacks. We report a 36‐years‐old female with AIP with a long‐term history of severe, disabling, recurrent attacks, who underwent curative liver transplantation. Tissue samples from the explant were obtained for transcriptome analysis. Whole RNA was extracted and 16 gene‐transcripts were selected and investigated by quantitative polymerase chain reaction. These included nine genes encoding enzymes that consecutively catalyze heme‐synthesis and catabolism in the liver (ALAS1; ALAD; HMBS; UROS; UROD; CPOX; PPOX; FECH; HMOX1). Additionally, we studied genes related to inflammation (IL6; TNF) insulin signaling (PGC‐1α; IGF‐1; FOXO‐1) and tryptophan metabolism (TDO2; IDO). Transcripts of eight house‐keeping genes were co‐measured for normalization. All transcripts were also measured in five control samples from healthy living liver donors. The transcriptome of the controls showed important differences between the various genes, with the first two genes of the heme‐synthesis pathway, ALAS1 and ALAD showing strikingly high mRNA levels compared to the consecutive HMBS gene. Transcripts of several genes significantly differed in the AIP liver compared to controls. Transcripts of HMOX1 and UROS were increased in the AIP liver whereas transcripts of UROD; CPOX, PPOX, and TDO2 were decreased. ALAS1 expression was not increased, possibly due to hemin administered to the patient before transplantation. These results highlight several transcriptomic changes related to heme homeostasis in AIP.

Small proteins encoded by previously assumed non-coding RNAs can have cell regulatory functions. Here the authors report that TINCR lncRNA encodes pTINCR, a ubiquitin-like protein (UBL) that promotes epithelial differentiation through the SUMOylation and activation of CDC42, and it has tumour suppressor activity in epithelial cancers.

Abstract Cancer is a multifactorial disease that is responsible for 10 million deaths per year. The intra- and inter-heterogeneity of malignant tumors make it difficult to develop single targeted approaches. Similarly, their diversity requires various models to investigate the mechanisms involved in cancer initiation, progression, drug resistance and recurrence. Of the in vitro cell-based models, monolayer adherent (also known as 2D culture) cell cultures have been used for the longest time. However, it appears that they are often less appropriate than the three-dimensional (3D) cell culture approach for mimicking the biological behavior of tumor cells, in particular the mechanisms leading to therapeutic escape and drug resistance. Multicellular tumor spheroids are widely used to study cancers in 3D, and can be generated by a multiplicity of techniques, such as liquid-based and scaffold-based 3D cultures, microfluidics and bioprinting. Organoids are more complex 3D models than multicellular tumor spheroids because they are generated from stem cells isolated from patients and are considered as powerful tools to reproduce the disease development in vitro. The present review provides an overview of the various 3D culture models that have been set up to study cancer development and drug response. The advantages of 3D models compared to 2D cell cultures, the limitations, and the fields of application of these models and their techniques of production are also discussed.

La caracterización de un paisaje cultural permite la identificación de valores singulares y específicos que sirvan como base para su reactivación y recuperación, lo que es especialmente beneficioso al hablar de territorios en riesgo de despoblación. Se toma como caso de estudio a caracterizar el valle del río Beas (Beas de Segura, Jaén), que reúne recursos patrimoniales históricamente influenciados por la presencia del agua, tales como regadíos, producción molinera, industria textil, sistemas anti-inundaciones o infraestructuras de abastecimiento que, no obstante, ven comprometida su permanencia en la actualidad. El objeto de la investigación es establecer la relación directa entre la caracterización del paisaje y su recuperación sostenible: frente a una tendencia habitual en el mundo rural de sustitución de características locales por aquellas extraídas de modelos urbanos estandarizados, se propone la divulgación y re-significación de estos valores mediante una metodología de registro multiescalar y con soporte cartográfico. De esta manera, se pretende favorecer no solo la lucha contra la despoblación de Beas de Segura, sino también la definición de herramientas transferibles a otros municipios con problemáticas semejantes.

Different sizing criteria for thermal energy storage (TES) has been developed through the years, regarding specific situations for thermal solar panels, which tend not to be representative for new, more complex systems, in which heating and cooling are provided through using also solar thermal collectors. This article aims to provide a simplified and elegant solution for future tank selection in a more variable combination of technologies, through the use of parametric simulation and an inhouse developed methodolgy.

Objectives: To describe and assess the risk of bias of the primary input studies that underpinned the Global Burden of Disease Study (GBD) 2019 modelled prevalence estimates of low back pain (LBP), neck pain (NP), and knee osteoarthritis (OA), from Australia, Brazil, Canada, Spain, and Switzerland. To evaluate the certainty of the GBD modelled prevalence evidence.Methods: Primary studies were identified using the GBD Data Input Sources Tool and their risk of bias was assessed using a validated tool. We rated the certainty of modelled prevalence estimates based on the GRADE Guidelines 30―the GRADE approach for modelled evidence.Results: Seventy-two primary studies (LBP: 67, NP: 2, knee OA: 3) underpinned the GBD estimates. Most studies had limited representativeness of their study populations, used suboptimal case definitions and applied assessment instruments with unknown psychometric properties. The certainty of modelled prevalence estimates was low, mainly due to risk of bias and indirectness.Conclusion: Beyond the risk of bias of primary input studies for LBP, NP, and knee OA in GBD 2019, the certainty of country-specific modelled prevalence estimates still have room for improvement.

Summary: Ubiquitination controls numerous cellular processes, and its deregulation is associated with many pathologies. The Nse1 subunit in the Smc5/6 complex contains a RING domain with ubiquitin E3 ligase activity and essential functions in genome integrity. However, Nse1-dependent ubiquitin targets remain elusive. Here, we use label-free quantitative proteomics to analyze the nuclear ubiquitinome of nse1-C274A RING mutant cells. Our results show that Nse1 impacts the ubiquitination of several proteins involved in ribosome biogenesis and metabolism that, importantly, extend beyond canonical functions of Smc5/6. In addition, our analysis suggests a connection between Nse1 and RNA polymerase I (RNA Pol I) ubiquitination. Specifically, Nse1 and the Smc5/6 complex promote ubiquitination of K408 and K410 in the clamp domain of Rpa190, a modification that induces its degradation in response to blocks in transcriptional elongation. We propose that this mechanism contributes to Smc5/6-dependent segregation of the rDNA array, the locus transcribed by RNA Pol I.

There is a general agreement among researchers that supercritical carbon dioxide (sCO2) cycles will be part of the next generation of thermal power plants, especially in concentrating solar power (CSP) plants. While certain studies focus on maximizing the efficiency of these cycles in the hope of achieving a reduction in electricity costs, it is important to note that this assumption does not always hold true. This work provides a comprehensive analysis of the differences between minimizing the cost and maximizing the efficiency for the most remarkable sCO2 cycles. The analysis considers the most important physical uncertainties surrounding CSP and sCO2 cycles, such as turbine inlet temperature, ambient temperature, pressure drop and turbomachinery efficiency. Moreover, the uncertainties related to cost are also analyzed, being divided into uncertainties of sCO2 component costs and uncertainties of heating costs. The CSP system with partial cooling (sometimes with reheating and sometimes without it) is the cheapest configuration in the analyzed cases. However, the differences in cost are generally below 5% (and sometimes neglectable), while the differences in efficiency are significantly larger and below 15%. Besides the much lower efficiency of systems with simple cycle, if the heating cost is low enough, their cost could be even lower than the cost of the system with partial cooling. Systems with recompression cycles could also achieve costs below systems with partial cooling if the design’s ambient temperature and the pressure drop are low.

This work proposes a new Pumped Thermal Energy Storage (PTES) configuration that works with supercritical CO2 as the working fluid and molten salts as the thermal storage fluid. The net work generated by this novel proposal is 12.46 MW in the load and 10 MW in the discharge, reaching an efficiency of 80.26%. In addition, a techno-economic optimization is carried out to quantify the discounted cost per unit of energy discharged from this storage technology with a value of 0.116 €/kWh. This technology places this technology as a strong candidate for the future energy solution due to its low wear per duty cycle and easy power scalability. It presents a lower initial cost than other technologies with low LCOS.

review of book

Exercise generates a site-specific increase in Reactive Oxygen Species (ROS) within muscle that promotes changes in gene transcription and mitochondrial biogenesis, required for the beneficial adaptive response. We demonstrate that Peroxiredoxin 2 (Prdx2), an abundant cytoplasmic 2-Cys peroxiredoxin, is required for the adaptive hormesis response to physiological levels of H2O2 in myoblasts and following exercise in C. elegans. A short bolus addition of H2O2 increases mitochondrial capacity and improves myogenesis of cultured myoblasts, this beneficial adaptive response was suppressed in myoblasts with decreased expression of cytoplasmic Prdxs. Moreover, a swimming exercise protocol in C. elegans increased mitochondrial content, fitness, survival and longevity in wild type (N2) worms. In contrast, prdx-2 mutant worms had decreased fitness, disrupted mitochondria, reduced survival and lifespan following exercise. Global proteomics following exercise identified distinct changes in the proteome of N2 and prdx-2 mutants. Furthermore, a redox proteomic approach to quantify reversible oxidation of specific Cysteine residues revealed a more reduced redox state in the non-exercised prdx-2 mutant strain that become oxidized following exercise. In contrast, specific Cys residues from regulatory proteins become more reduced in the N2 strain following exercise, establishing the key regulatory role of PRDX-2 in a redox signalling cascade following endogenous ROS generation. Our results demonstrate that conserved cytoplasmic 2-Cys Peroxiredoxins are required for the beneficial adaptive response to a physiological redox stress.

En la España del XVIII existía la necesidad, entre los propios españoles, de crear una autoimagen de España que sirviera como respuesta a las heteroimágenes tan negativas proyectadas desde Francia. La narración El sol de Sevilla (1800), de Pablo de Olavide, fue uno de los intentos más destacados por construir esta clase de discurso nacionalista. Aunque no es aún una novela histórica o romántica, se ambienta en la época de los Reyes Católicos y mitifica la idea de España como potencia civilizadora de otras a partir de una religión presentada siempre como sinónimo de paz y fraternidad entre humanos. Una religión que, de hecho, en Francia cada vez se estaba cuestionando más, lo cual el propio Olavide había señalado como causa de toda la barbarie acontecida durante la Revolución Francesa, de la que él mismo había sido víctima.

Solar Heat for Industrial Processes (SHIP) is one of the most promising alternatives to decarbonize the industry. The present work aims to analyze the influence of thermal pipelines inertia on a small-scale solar concentrator of 20 kW with a phase-change material thermal storage. Two dynamic simulations for this SHIP system integrated into a tube steel factory in Romania were developed with Dymola software: one of them considered the thermal inertia of the pipelines and the other did not. By comparing the simulation results, we have found that the pipeline inertia conveyed delays in the start-up sequence of the system and decreased the temperatures of heat transfer fluids until the steady state is reached. Furthermore, the thermal inertia decreased the total energy produced. Other researchers have also found delays due to the inertia of the pipelines, but the delays were lower than ours. The difference in the delays may be due to the small scale of the SHIP system analyzed in the present work. Finally, we can conclude that dynamic simulation became important in SHIP systems because of the difference found with the non-inertia simulation.

Abstract Gastric cancer ranks the fifth most common and third leading cause of cancer‐related deaths worldwide. Alterations in the RTK/MAPK, WNT, cell adhesion, TP53, TGFβ, NOTCH, and NFκB signaling pathways could be identified as main oncogenic drivers. A combination of altered pathways can be associated with molecular subtypes of gastric cancer. In order to generate model systems to study the impact of different pathway alterations in a defined genetic background, we generated three murine organoid models: a RAS‐activated (KrasG12D, Tp53R172H), a WNT‐activated (Apcfl/fl, Tp53R172H), and a diffuse (Cdh1fl/fl, Apcfl/fl) model. These organoid models were morphologically and phenotypically diverse, differed in proteome expression signatures and possessed individual drug sensitivities. A differential vulnerability to RTK/MAPK pathway interference based on the different mitogenic drivers and according to the level of dependence on the pathway could be uncovered. Furthermore, an association between RTK/MAPK pathway activity and susceptibility to HDAC inhibition was observed. This finding was further validated in patient‐derived organoids from gastric adenocarcinoma, thus identifying a novel treatment approach for RTK/MAPK pathway altered gastric cancer patients.

Osteosarcoma (OS) is a rare malignant primary bone tumours characterized by a high genetic and cell composition heterogeneity. Unfortunately, despite the use of drug combinations and the recent development of immunotherapies, the overall survival has not improved in the last four decades. Due to the key role of the tumour microenvironment in the pathogenesis of OS, a better understanding of its microenvironment is mandatory to develop new therapeutic approaches. From retrospective biological cohorts of OS, we analysed by immunohistochemistry the presence of lipopolysaccharide (LPS)-binding protein (LBP) in diagnostic biopsies with local disease and compared their level of infiltration to patients suffering from metastatic status. LBP is considered as a marker of LPS exposure and can indirectly reflect the presence of Gram-negative microbiota. LBP were detected in the cytoplasm of OS cells as well as in tumour-associated macrophage. Tumour samples of patients with local disease were significantly enriched in LBP compared to tumour tissues of patients with metastatic status. Lung metastatic tissues showed similar level of LBP compared to paired primary tumours. Overall, this study strongly suggests the presence of Gram-negative bacteria in OS tissues and demonstrated their significant differential level according the metastatic status. This tumour-associated microbiome may help in the conceptualisation of new therapeutic approach to trigger efficient therapeutic responses against cancer.

The Anabaena genus is a model organism of filamentous cyanobacteria whose vegetative cells can differentiate under nitrogen-limited conditions into a type of cell called a heterocyst. These heterocysts lose the possibility to divide and are necessary for the filament because they can fix and share environmental nitrogen. In order to distribute the nitrogen efficiently, heterocysts are arranged to form a quasi-regular pattern whose features are maintained as the filament grows. Recent efforts have allowed advances in the understanding of the interactions and genetic mechanisms underlying this dynamic pattern. Here, we present a systematic review of the existing theoretical models of nitrogen-fixing cell differentiation in filamentous cyanobacteria. These filaments constitute one of the simplest forms of multicellular organization, and this allows for several modeling scales of this emergent pattern. The system has been approached at three different levels. From bigger to smaller scale, the system has been considered as follows: at the population level, by defining a mean-field simplified system to study the ratio of heterocysts and vegetative cells; at the filament level, with a continuous simplification as a reaction-diffusion system; and at the cellular level, by studying the genetic regulation that produces the patterning for each cell. In this review, we compare these different approaches noting both the virtues and shortcomings of each one of them.

Purpose: To describe the clinical and multimodal imaging findings, including optical coherence tomography (OCT), and OCT angiography (OCTA) in a case presenting with acute fovealitis after COVID-19 infection, and its differential diagnosis. Observations: A 39-year-old man presenting with acute central metamorphopsia in his right eye (OD) right after positive test for COVID-19 underwent comprehensive ophthalmic examination, including best corrected visual acuity (BCVA), color fundus (CF) examination, optical coherence tomography (OCT), OCT angiography (OCTA), fundus autofluorescence (FAF) and fluorescein angiography (FA). Baseline BCVA was 20/40 in his OD and fundus examination showed small inferior juxtafoveal hemorrhages with no other vascular abnormalities or peripheral changes. The OCT B-scans revealed a central focal defect of the ellipsoid and interdigitation zones associated with foveal and perifoveal columnar hyperreflectivities involving the photoreceptor layers, the external limiting membrane and outer nuclear layer up to the outer plexiform layer with preservation of the retinal pigment epithelium-Bruch's membrane complex. Both FAF and FA images were unremarkable. Over three months follow-up, the findings progressively resolved, and BCVA improved to 20/20. Conclusions and importance: The presence of hyperreflective material at the fovea in association with adjacent hemorrhages, the absence of alterations of the retinal pigment epithelium in OCT, OCTA, FAF and FA suggested the diagnosis of acute fovealitis in COVID-19 context. The presence of these findings highlights the importance of detailed ophthalmic evaluation in symptomatic patients with COVID-19 positive test.

The Anabaena genus is a model organism of filamentous cyanobacteria whose vegetative cells can differentiate under nitrogen-limited conditions into a type of cell called heterocyst. These heterocysts lose the possibility to divide and are necessary for the colony because they can fix and share environmental nitrogen. In order to distribute the nitrogen efficiently, heterocysts are arranged to form a quasi-regular pattern whose features are maintained as the filament grows. Recent efforts have allowed advances in the understanding of the interactions and genetic mechanisms underlying this dynamic pattern. However, the main role of the patA and hetF genes are yet to be clarified; in particular, the patA mutant forms heterocysts almost exclusively in the terminal cells of the filament. In this work, we investigate the function of these genes and provide a theoretical model that explains how they interact within the broader genetic network, reproducing their knock-out phenotypes in several genetic backgrounds, including a nearly uniform concentration of HetR along the filament for the patA mutant. Our results suggest a role of hetF and patA in a post-transcriptional modification of HetR which is essential for its regulatory function. In addition, the existence of molecular leakage out of the filament in its boundary cells is enough to explain the preferential appearance of terminal heterocysts, without any need for a distinct regulatory pathway.

Microgrids represent a promising energy technology, because of the inclusion in them of clean and smart energy technologies. They also represent research challenges, including controllability, stability, and implementation. This article presents a dSPACE-control-platform-based implementation of a fixed-switching-frequency modulated model predictive control (M2PC) strategy, as an inner controller of a two-level, three-phase voltage source inverter (VSI) working in an islanded AC microgrid. The developed controller is hierarchical, as it includes a primary controller to share the load equally with the other power converter with its own local modulated predictive-based controller. All details of the implementation are given for establishing the dSPACE-based implementation of the control on a dSPACE ds1103 control platform, using MATLAB/Simulink for the controller design, I/O implementation and configuration with the embedded dSPACE’s real-time interface in Simulink, and then using the ControlDesk software for monitoring and testing of the real plant. The latter consists of the VSI operating with LCL filters, and sharing an RL load with a paralleled VSI with exactly the same controller. Finally, the obtained experimental waveforms are shown, with our respective conclusions representing this work, which is a very valuable tool for helping microgrid researchers implement dSPACE-based real-time simulations.

The mechanistic target of rapamycin complex 1 (mTORC1) integrates nutrient and hormonal signals to control metabolism. Here the authors investigate the effects of constitutive nutrient signaling through genetic activation of RagA in adult mice and show that constitutive nutrient signaling regulates the response to feeding-fasting cycles and does not drive liver cancer.

Abstract Background One hundred fifty million contagions, more than 3 million deaths and little more than 1 year of COVID-19 have changed our lives and our health management systems forever. Ageing is known to be one of the significant determinants for COVID-19 severity. Two main reasons underlie this: immunosenescence and age correlation with main COVID-19 comorbidities such as hypertension or dyslipidaemia. This study has two aims. The first is to obtain cut-off points for laboratory parameters that can help us in clinical decision-making. The second one is to analyse the effect of pandemic lockdown on epidemiological, clinical, and laboratory parameters concerning the severity of the COVID-19. For these purposes, 257 of SARSCoV2 inpatients during pandemic confinement were included in this study. Moreover, 584 case records from a previously analysed series, were compared with the present study data. Results Concerning the characteristics of lockdown series, mild cases accounted for 14.4, 54.1% were moderate and 31.5%, severe. There were 32.5% of home contagions, 26.3% community transmissions, 22.5% nursing home contagions, and 8.8% corresponding to frontline worker contagions regarding epidemiological features. Age > 60 and male sex are hereby confirmed as severity determinants. Equally, higher severity was significantly associated with higher IL6, CRP, ferritin, LDH, and leukocyte counts, and a lower percentage of lymphocyte, CD4 and CD8 count. Comparing this cohort with a previous 584-cases series, mild cases were less than those analysed in the first moment of the pandemic and dyslipidaemia became more frequent than before. IL-6, CRP and LDH values above 69 pg/mL, 97 mg/L and 328 U/L respectively, as well as a CD4 T-cell count below 535 cells/μL, were the best cut-offs predicting severity since these parameters offered reliable areas under the curve. Conclusion Age and sex together with selected laboratory parameters on admission can help us predict COVID-19 severity and, therefore, make clinical and resource management decisions. Demographic features associated with lockdown might affect the homogeneity of the data and the robustness of the results.

The availability of Bruton tyrosine kinase (BTK) inhibitors has brought about a paradigm shift in the treatment of patients with B-cell lymphomas and chronic lymphocytic leukemia. BTK was clinically validated as a target by the efficacy of the first-in-class inhibitor ibrutinib. The extended survival conferred by BTK inhibitors has brought long-term tolerability to the foreground. To minimize toxicities thought to be attributable to off-target kinase inhibition, a next generation of BTK inhibitors with greater selectivity was developed. In the United States, zanubrutinib, a next-generation BTK inhibitor, has been approved for treating adults with mantle cell lymphoma who have received at least one prior therapy, for adults with Waldenström macroglobulinemia, and for adults with relapsed or refractory marginal zone lymphoma who have received at least one anti-CD20–based therapy. Because few head-to-head comparative trials of BTK inhibitors have so far been reported, no BTK ‘inhibitor of choice’ can be identified. Zanubrutinib has promising efficacy in its approved indications and appears to have reduced cardiac toxicities, particularly atrial fibrillation, which may influence the choice of BTK inhibitor treatment by prescribers. Further studies are needed to inform on optimal treatment sequencing of zanubrutinib and its combination with other agents. Here, we summarize existing clinical evidence for its efficacy and safety in mantle cell lymphoma, Waldenström macroglobulinemia, marginal zone lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, and other B-lymphoproliferative indications. Plain Language Summary Zanubrutinib is a drug that was shown to effectively treat cancer of B cells without causing excessive serious side effects Patients with certain B-cell malignancies (cancers of white blood cells) benefit from treatment with Bruton tyrosine kinase (BTK) inhibitors, drugs that block the BTK protein and keep cancer from growing and spreading. Patients experience extended survival with ibrutinib, the first-generation BTK inhibitor approved by US Food and Drug Administration (FDA); however, one in five patients quit treatment because of harmful side effects. Ibrutinib-related side effects such as increased risk of bleeding, atrial fibrillation (abnormal heart rhythm), and high blood pressure are thought to be caused by ibrutinib blocking other proteins besides the intended target protein BTK. To reduce these side effects, zanubrutinib, a next-generation BTK inhibitor, was designed to block BTK more specifically than ibrutinib. Results of clinical studies on zanubrutinib treatment appear promising in patients with several types of B-cell malignancies, including mantle cell lymphoma (MCL), Waldenström macroglobulinemia (WM), marginal zone lymphoma (MZL), chronic lymphocytic leukemia, and small lymphocytic lymphoma. There are not yet enough clinical data to determine which BTK inhibitor is most effective in treating B-cell malignancies without causing harmful side effects. Early data from the phase 3 ALPINE clinical study suggest that zanubrutinib works better than ibrutinib, and fewer patients experience side effects and quit treatment. Zanubrutinib is currently approved for use for treatment of adult patients with MCL who have received at least one prior therapy, for adults with WM, and for adults with MZL who have received at least one anti-CD20–based therapy.

The effects of partial shading or dust accumulation on the panels of photovoltaic systems connected to the grid can generate a considerable reduction in energy performance, being necessary to provide the appropriate voltage to the grid regardless of the irradiance level. This paper addresses this problem and presents a comprehensive control strategy and its implementation for a grid-connected microinverter composed of a push–pull converter followed by an H-bridge inverter. In the push–pull converter, a hybrid MPPT algorithm and a PI control enable work in the MPP of the PV panel. In the H-bridge inverter, a cascade control consisting of a PI control and a predictive control allows the connection to the grid. A proof-of-concept prototype is implemented in order to validate the proposal. Experimental tests were performed by connecting the microinverter to a PV panel and a programmable photovoltaic panel emulator to check the MPPT performance. Furthermore, partial shading conditions were simulated on the dc source to check if the global maximum power point is reached. Experimental results demonstrate the feasibility of the topology and the control approach, obtaining MPPT performance in the topology above 99% at different power and voltage levels on the MPPT, even in the presence of partial shading conditions.

Re-education of the tumor microenvironment with immune checkpoint inhibitors (ICI) has provided the most significant advancement in cancer management, with impressive efficacy and durable response reported. However, low response rates and a high frequency of immune-related adverse events (irAEs) remain associated with ICI therapies. The latter can be linked to their high affinity and avidity for their target that fosters on-target/off-tumor binding and subsequent breaking of immune self-tolerance in normal tissues. Many multispecific protein formats have been proposed to increase the tumor cell’s selectivity of ICI therapies. In this study, we explored the engineering of a bispecific Nanofitin by the fusion of an anti-epidermal growth factor receptor (EGFR) and anti-programmed cell death ligand 1 (PDL1) Nanofitin modules. While lowering the affinity of the Nanofitin modules for their respective target, the fusion enables the simultaneous engagement of EGFR and PDL1, which translates into a selective binding to tumor cells co-expressing EGFR and PDL1 only. We demonstrated that affinity-attenuated bispecific Nanofitin could elicit PDL1 blockade exclusively in an EGFR-directed manner. Overall, the data collected highlight the potential of this approach to enhance the selectivity and safety of PDL1 checkpoint inhibition.