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Summary: Since the nineties, the incidence of sporadic early-onset (EO) cancers has been rising worldwide. The underlying reasons are still unknown. However, identifying them is vital for advancing both prevention and intervention. Here, we exploit available knowledge derived from clinical observations to formulate testable hypotheses aimed at defining the causal factors of this epidemic and discuss how to experimentally test them. We explore the potential impact of exposome changes from the millennials to contemporary young generations, considering both environmental exposures and enhanced susceptibilities to EO-cancer development. We emphasize how establishing the time required for an EO cancer to develop is relevant to defining future screening strategies. Finally, we discuss the importance of integrating multi-dimensional data from international collaborations to generate comprehensive knowledge and translate these findings back into clinical practice.

Summary: Replication origin assembly is a pivotal step in chromosomal DNA replication. In this process, the ORC complex binds DNA and, together with the CDC6 and CDT1, promotes the loading of the MCM helicase. Chemicals targeting origin assembly might be useful to sensitize highly proliferative cancer cells. However, identifying such compounds is challenging due to the multistage nature of this process. Here, using Xenopus laevis egg extract we set up a high-throughput screening to isolate MCM chromatin loading inhibitors, which led to the identification of NSC-95397 as a powerful inhibitor of replication origin assembly that targets CDC6 protein and promotes its degradation. Using systems developed to test selective drug-induced lethality we show that NSC-95397 triggers cell death both in human cells and Xenopus embryos that have higher proliferative ability. These findings demonstrate the effectiveness of molecules disrupting DNA replication processes in targeting hyperproliferating cells, highlighting their potential as anti-cancer molecules.

This study investigates the impact of vertical greenery systems (VGSs) applied to several typical wall configurations on indoor thermal conditions in a building module situated in the Mediterranean climate of Catania, Italy. By means of dynamic simulations in TRNSYS vers.18, the research compares the thermal behavior of walls made of either hollow clay blocks (Poroton) or lava stone blocks against a lightweight wall setup already in place at the University of Catania. The primary focus is on evaluating the VGSs’ capability of reducing peak inner surface temperatures and moderating heat flux fluctuations entering the building. The findings indicate that adding an outer vertical greenery layer to heavyweight walls can decrease the peak inner surface temperature by up to 1.0 °C compared to the same bare wall. However, the greenery’s positive impact is less pronounced than in the case of the lightweight wall. This research underscores the potential of green facades in enhancing the indoor thermal environment in buildings in regions with climates like the Mediterranean one, providing valuable insights for sustainable building design and urban planning.

Different soil and water pollution sources around an undisclosed First Nation (The FN) in Northern Ontario (Canada) are linked by community health documents and oral histories to a cluster of blood cancer. The site's environmental hydrogeochemical records available are difficult to follow, whereas geophysical data reveals possible pathways of contaminants displayed as 3D maps of subsoil contrasting geoelectrical properties. Through an Indigenous Integrated Knowledge Translation (IIKT) strategy, we have co-constructed with The FN an interdisciplinary framework of non-hierarchical syncretic exchange between geoscience-based environmental engineering praxes and Indigenous Knowledge. The IIKT is articulated through Talking Circles of flexible multidirectional exchanges between The FN and the research team, to address community-identified needs and maintain qualitative and contextual value in the investigative agenda. The Talking Circles have guided our efforts to collect, handle, integrate, and understand hydrogeochemical and geophysical data. Thus, we build a culturally-appropriate knowledge base for self-sufficient environmental monitoring capacities with the community to ensure informed decisions about the land. The sustainability of the proposed framework relies on the non-invasiveness and low cost of the environmental/engineering tools used, the transparency of the community-driven results obtained, and its scalability to other Indigenous communities.

Abstract Multiciliated cells (MCCs) project dozens to hundreds of motile cilia from their apical surface to promote the movement of fluids or gametes in the mammalian brain, airway or reproductive organs. Differentiation of MCCs requires the sequential action of the Geminin family transcriptional activators, GEMC1 and MCIDAS, that both interact with E2F4/5-DP1. How these factors activate transcription and the extent to which they play redundant functions remains poorly understood. Here, we demonstrate that the transcriptional targets and proximal proteomes of GEMC1 and MCIDAS are highly similar. However, we identified distinct interactions with SWI/SNF subcomplexes; GEMC1 interacts primarily with the ARID1A containing BAF complex while MCIDAS interacts primarily with BRD9 containing ncBAF complexes. Treatment with a BRD9 inhibitor impaired MCIDAS-mediated activation of several target genes and compromised the MCC differentiation program in multiple cell based models. Our data suggest that the differential engagement of distinct SWI/SNF subcomplexes by GEMC1 and MCIDAS is required for MCC-specific transcriptional regulation and mediated by their distinct C-terminal domains.

The COVID-19 pandemic has sparked a surge in research on microbiology and virology, shedding light on overlooked aspects such as the infection of bacteria by RNA virions in the animal microbiome. Studies reveal a decrease in beneficial gut bacteria during COVID-19, indicating a significant interaction between SARS-CoV-2 and the human microbiome. However, determining the origins of the virus remains complex, with observed phenomena such as species jumps adding layers to the narrative. Prokaryotic cells play a crucial role in the disease’s pathogenesis and transmission. Analyzing previous studies highlights intricate interactions from clinical manifestations to the use of the nitrogen isotope test. Drawing parallels with the history of the Poliovirus underscores the need to prioritize investigations into prokaryotic cells hosting RNA viruses.

This paper investigates the microclimate in a conference room with thermal stratification, taking as a case study the chapel of Villa San Saverio, now the seat of the “Scuola Superiore” of the University of Catania (Italy). Surveys of the former chapel were conducted to monitor air temperature and relative humidity. Subsequently, the investigation relied on numerical simulations of a simplified computational fluid dynamics (CFD) model built with the DesignBuilder v7.0 software and validated by comparison with measured values. Simulations were then carried out considering three different scenarios: the current state without any HVAC system and two possible HVAC system configurations providing both air conditioning and ventilation. The results show that, from a comfort perspective, a lightweight radiant floor heating system, assisted by an appropriate ventilation system for air renewal placed at the floor level near the occupants, is preferable to floor-level fan coils and high ventilation channels. Furthermore, this was also confirmed by a preliminary energy analysis of the two HVAC options, where the ventilation effectiveness of the winter period, the temperature of the water the emitters are fed, the consequent COP value of the heat pump, and the electricity consumption were taken into consideration.

Nucleolar and Spindle-Associated Protein 1 (NuSAP1) is an important mitotic regulator, implicated in control of mitotic microtubule stability and chromosome segregation. NuSAP1 regulates these processes by interacting with several protein partners. Its abundance, activity and interactions are therefore tightly regulated during mitosis. Protein conjugation with SUMO (Small Ubiquitin-like MOdifier peptide) is a reversible post-translational modification that modulates rapid changes in the structure, interaction(s) and localization of proteins. NuSAP1 was previously found to interact with RANBP2, a nucleoporin with SUMO ligase and SUMO-stabilizing activity, but how this interaction affects NuSAP1 activity has remained elusive. Here, we show that NuSAP1 interacts with RANBP2 and forms proximity ligation products with SUMO2/3 peptides in a RANBP2-dependent manner at key mitotic sites. A bioinformatic search identified two putative SUMO consensus sites in NuSAP1, within the DNA-binding and the microtubule-binding domains, respectively. Site-specific mutagenesis, and mitotic phenotyping in cell lines expressing each NuSAP1 mutant version, revealed selective roles of each individual site in control of NuSAP1 localization and in generation of specific mitotic defects and distinct fates in daughter cells. These results identify therefore two new regulatory sites for NuSAP1 functions and implicate RANBP2 in control of NuSAP1 activity.

The footprints of petroleum microseepage can be associated with chemical and microbial processes in initially homogeneous strata and/or with the fluid transport properties of the rocks through which oil and gas migrate. This work examines the role of such driving factors in two contrasting geological settings by comparing numerical modeling predictions for upward methane microseepage with some field evidence for hydrocarbons transport and accumulation. The two case studies are a monitoring borehole (BH8) from a landfill in southern Ontario, Canada, and an oil well (Saltarin 1A) from the Eastern Llanos Basin in Colombia. Profiles of relative methane concentrations versus depth were generated using a time-dependent, one-dimensional, simulation of the advection-diffusion equation applied to multiple strata of soils, and sediments. The model employs the layered sequences of these two geological settings. The results obtained hinge on the standard permeability values for the rock types involved and their corresponding flow velocities and diffusion coefficients. Resistivity logs were utilized as direct proxies of hydrocarbon concentrations. As additional evidence for petroleum microseepage, experiments of electron paramagnetic resonance (EPR) were carried out in drilling cuts of Saltarin 1A to measure traces of organic matter free radicals concentrations (OMFRC). Extractable organic matter (EOM) and magnetic susceptibility data were also considered in interpreting the EPR results. Qualitative comparisons between modeled methane profiles and their corresponding resistivity logs suggest that microseepage and hydrocarbon accumulations are conditioned by the fluid transport properties of the rocks contained by BH8 and Saltarin 1A. Moreover, in most of the Saltarin 1A sequence, the OMFRC profiles follow the trends displayed by the resistivity and modeled methane logs. Thus, the EPR data also indicates that hydrocarbon microseepage and accumulation are largely controlled by lithology. Conversely, EOM and magnetic susceptibility appear to be evidence for hydrocarbon-mediated near-surface chemical processes.

Tpr nucleoporin is known to be essential for nuclear transport and mitosis processes. Here the authors explore the link between Tpr and genome instability providing insights into the role of Tpr in safeguarding cells from RNA-mediated replication stress.

During embryonic development, it is vital to maintain rapid genome duplication. Here, the authors shed light on the mechanism by revealing that SSRP1 stimulates replication origin assembly on somatic nuclei in Xenopus laevis egg extract by promoting histone H1 eviction from somatic chromatin.

Thermal comfort during the summer in the Passivhaus concept relies mainly on natural ventilation to provide indoor cooling. Do airflow modeling tools accurately predict overheating in summer and for anticipated warmer climates? What effect do simplifications of airflow modeling techniques have on the overheating assessment of Passivhaus dwellings? Measured data and a calibrated thermal model are employed in the present study to address this question. The calibrated model is then used to create a standalone building energy model (BEM), a BEM coupled with an airflow network model (AFN), and a BEM coupled with an AFN supported by the wind pressure coefficients obtained from computational fluid dynamics (CFD) simulation. The outcome of each modeling approach was then compared against each other within three different European climates. Results showed that the overheating frequency prediction found with the default design infiltration and natural ventilation inputs commonly used in the literature agreed fairly with those obtained from the AFN + CFD in temperate or colder climates (< 2% difference), but were significantly underestimating overheating in Passivhaus buildings located at warmer climates (9.4% difference). For Passivhaus dwellings in warmer climates, the airflow modeling approach is unlikely to provide for an accurate estimation of the overheating incidence. 'Practice relevance' With overheating becoming a major issue in Europe, the prediction of the indoor thermal performance by using dynamic building simulations became common practice by researchers and practitioners. This study scrutinized the three most common methods of modeling airflow phenomena (BEM, AFN and CFD) when performing building energy simulations. For Passivhaus buildings located in warmer climates, the choice of airflow modeling approach is important to obtain an accurate prediction of overheating. The study found that BEM is unlikely to be suitable for predicting the extent and frequency of overheating in home and warm climates. The AFN + CFD approach provides a more reliable approach for predicting overheating in hot and warm summer climates. For Passivhaus homes in locations with cooler summers, the difference between modeling approaches became mostly insignificant, so the simpler BEM models may be sufficient when performing an overheating analysis in that context.

Accumulation of uremic toxins may lead to the life-threatening condition “uremic syndrome” in patients with advanced chronic kidney disease (CKD) requiring renal replacement therapy. Clinical evaluation of proximal tubular secretion of organic cations (OC), of which some are uremic toxins, is desired, but difficult. The biomedical knowledge on OC secretion and cellular transport partly relies on studies using the fluorescent tracer 4-dimethylaminostyryl)-N-methylpyridinium (ASP+), which has been used in many studies of renal excretion mechanisms of organic ions and which could be a candidate as a PET tracer. This study is aimed at expanding the knowledge of the tracer characteristics of ASP+ by recording the distribution and intensity of ASP+ signals in vivo both by fluorescence and by positron emission tomography (PET) imaging and at investigating if the fluorescence signal of ASP+ is influenced by the presence of albumin. Two-photon in vivo microscopy of male Münich Wistar Frömter rats showed that a bolus injection of ASP+ conferred a fluorescence signal to the blood plasma lasting for about 30 minutes. In the renal proximal tubule, the bolus resulted in a complex pattern of fluorescence including a rapid and strong transient signal at the brush border, a very low signal in the luminal fluid, and a slow transient intracellular signal. PET imaging using 11C-labelled ASP+ showed accumulation in the liver, heart, and kidney. Fluorescence emission spectra recorded in vitro of ASP+ alone and in the presence of albumin using both 1-photon excitation and two-photon excitation showed that albumin strongly enhance the emission from ASP+ and induce a shift of the emission maximum from 600 to 570 nm. Conclusion. The renal pattern of fluorescence observed from ASP+ in vivo is likely affected by the local concentration of albumin, and quantification of ASP+ fluorescent signals in vivo cannot be directly translated to ASP+ concentrations.

Acute myeloid leukemia (AML) is a type of blood cancer that affects both adults and children. Benzene exposure has been reported to increase the risk of developing AML in children. The assessment of the potential relationship between environmental benzene exposure and childhood has been documented in the literature using odds ratios and/or risk ratios, with data fitted to unconditional logistic regression. A common feature of the studies involving relationships between environmental risk factors and health outcomes is the lack of proper analysis to evidence causation. Although statistical causal analysis is commonly used to determine causation by evaluating a distribution’s parameters, it is challenging to infer causation in complex systems from single correlation coefficients. Machine learning (ML) approaches, based on causal pattern recognition, can provide an accurate alternative to model counterfactual scenarios. In this work, we propose a framework using average treatment effect (ATE) and Uplift modeling to evidence causation when relating exposure to benzene indoors and outdoors to childhood AML, effectively predicting causation when exposed indoors to this contaminant. An analysis of the assumptions, cross-validation, sample size, and interaction between predictors are also provided, guiding future works looking at the universalization of this approach in predicting health outcomes.

In the modern era, the consumption of antibiotics represents a revolutionary weapon against several infectious diseases, contributing to the saving of millions of lives worldwide. However, the misuse of antibiotics for human and animal purposes has fueled the process of antimicrobial resistance (AMR), considered now a global emergency by the World Health Organization (WHO), which significantly increases the mortality risk and related medical costs linked to the management of bacterial diseases. The current research aiming at developing novel efficient antibiotics is very challenging, and just a few candidates have been identified so far due to the difficulties connected with AMR. Therefore, novel therapeutic or prophylactic strategies to fight AMR are urgently needed. In this scenario, vaccines constitute a promising approach that proves to be crucial in preventing pathogen spreading in primary infections and in minimizing the usage of antibiotics following secondary bacterial infections. Unfortunately, most of the vaccines developed against the main resistant pathogens are still under preclinical and clinical evaluation due to the complexity of pathogens and technical difficulties. In this review, we describe not only the main causes of AMR and the role of vaccines in reducing the burden of infectious diseases, but we also report on specific prophylactic advancements against some of the main pathogens, focusing on new strategies that aim at improving vaccine efficiency.

Physical activity (PA) and nutrition are the essential components of a healthy lifestyle, as they can influence energy balance, promote functional ability of various systems and improve immunity. Infections and their associated symptoms are the common and frequent challenges to human health that are causing severe economic and social consequences around the world. During aging, human immune system undergoes dramatic aging-related changes/dysfunctions known as immunosenescence. Clinically, immunosenescence refers to the gradual deterioration of immune system that increases exposure to infections, and reduces vaccine efficacy. Such phenomenon is linked to impaired immune responses that lead to dysfunction of multiple organs, while lack of physical activity, progressive loss of muscle mass, and concomitant decline in muscle strength facilitate immunosenescence and inflammation. In the present review, we have discussed the role of nutrition and PA, which can boost the immune system alone and synergistically. Evidence suggests that long-term PA is beneficial in improving immune system and preventing various infections. We have further discussed several nutritional strategies for improving the immune system. Unfortunately, the available evidence shows conflicting results. In terms of interaction with food intake, PA does not tend to increase energy intake during a short time course. However, overcoming nutritional deficiencies appears to be the most practical recommendation. Through the balanced nutritious diet intake one can fulfill the bodily requirement of optimal nutrition that significantly impacts the immune system. Supplementation of a single nutrient as food is generally not advisable. Rather incorporating various fruits and vegetables, whole grains, proteins and probiotics may ensure adequate nutrient intake. Therefore, multi-nutrient supplements may benefit people having deficiency in spite of sufficient diet. Along with PA, supplementation of probiotics, bovine colostrum, plant-derived products and functional foods may provide additional benefits in improving the immune system.

A Positive Energy District (PED) is a portion of urban area with defined boundaries that can produce energy in excess of its own consumption. The aim of this study is to analyse design variations among the six projects (12 case studies) of PED belonging to the European Smart Cities and Communities programme. Thus, it will be possible to identify the reasons behind the energy choices related to generation, storage and distribution that appear in the different geographical areas. To achieve this, different data were collected by consulting official documents and creating questionnaires that were communicated with the project representatives. Thus, the result of this study is a catalogue of the energy system solutions adopted in the studied PEDs with a critical analysis of the different motivations behind them in order to outline general trends in the geographical areas with similar characteristics. In conclusion, this study defined which technological choices are the most common in territories with similar profiles and how divergent those with different profiles are. Furthermore, applied to a large catalogue of PED, the methodology identified would make it possible to create different operating models for different territorial types and urban settlements.

In the original publication [...]

Fluorescence microscopy has represented a crucial technique to explore the cellular and molecular mechanisms in the field of biomedicine. However, the conventional one-photon microscopy exhibits many limitations when living samples are imaged. The new technologies, including two-photon microscopy (2PM), have considerably improved the in vivo study of pathophysiological processes, allowing the investigators to overcome the limits displayed by previous techniques. 2PM enables the real-time intravital imaging of the biological functions in different organs at cellular and subcellular resolution thanks to its improved laser penetration and less phototoxicity. The development of more sensitive detectors and long-wavelength fluorescent dyes as well as the implementation of semi-automatic software for data analysis allowed to gain insights in essential physiological functions, expanding the frontiers of cellular and molecular imaging. The future applications of 2PM are promising to push the intravital microscopy beyond the existing limits. In this review, we provide an overview of the current state-of-the-art methods of intravital microscopy, focusing on the most recent applications of 2PM in kidney physiology.

Unrepaired DNA damage during embryonic development can be potentially inherited by a large population of cells. However, the quality control mechanisms that minimize the contribution of damaged cells to developing embryos remain poorly understood. Here, we uncovered an ATR- and CHK1-mediated transcriptional response to replication stress (RS) in mouse embryonic stem cells (ESCs) that induces genes expressed in totipotent two-cell (2C) stage embryos and 2C-like cells. This response is mediated by Dux, a multicopy retrogene defining the cleavage-specific transcriptional program in placental mammals. In response to RS, DUX triggers the transcription of 2C-like markers such as murine endogenous retrovirus-like elements (MERVL) and Zscan4. This response can also be elicited by ETAA1-mediated ATR activation in the absence of RS. ATR-mediated activation of DUX requires GRSF1-dependent post-transcriptional regulation of Dux mRNA. Strikingly, activation of ATR expands ESCs fate potential by extending their contribution to both embryonic and extra-embryonic tissues. These findings define a novel ATR dependent pathway involved in maintaining genome stability in developing embryos by controlling ESCs fate in response to RS.

Summary: It has been long assumed that normally leading strand synthesis must proceed coordinated with the lagging strand to prevent strand uncoupling and the pathological accumulation of single-stranded DNA (ssDNA) in the cell, a dogma recently challenged by in vitro studies in prokaryotes. Here, we report that human DNA polymerases can function independently at each strand in vivo and that the resulting strand uncoupling is supported physiologically by a cellular tolerance to ssDNA. Active forks rapidly accumulate ssDNA at the lagging strand when POLA1 is inhibited without triggering a stress response, despite ssDNA formation being considered a hallmark of replication stress. Acute POLA1 inhibition causes a lethal RPA exhaustion, but cells can duplicate their DNA with limited POLA1 activity and exacerbated strand uncoupling as long as RPA molecules suffice to protect the elevated ssDNA. Although robust, this uncoupled mode of DNA replication is also an in-built weakness that can be targeted for cancer treatment. : Using specific POLA1 inhibitors, Ercilla et al. show that DNA synthesis works independently at leading and lagging strands and can be “uncoupled” in vivo. The authors show that cells can naturally tolerate ssDNA formation during DNA replication as long as it is protected by the surplus of RPA molecules. Keywords: DNA replication, polymerase alpha, POLA1, CD437, lagging strand, strand uncoupling, RPA, ssDNA, replication catastrophe, ATR

Among the several methods investigated over the past few years for the thermal mitigation of buildings in urban areas, green roof systems seem to be one of the most suitable solutions for several reasons, and researchers encourage the further study and implementation of these roofing techniques because of the potential benefits that they offer. So far, intensive, extensive and semi-intensive green roofs are considered to be a better option in terms of both energy efficiency and green area increase. However, there are some aspects that cause green roofs not to be suitable to every application, preventing their use from spreading, such as high maintenance and costs required by these sophisticated systems. Few studies aimed at overcoming the limits of green roofs have hinted at the possibility of implementing hydroponic cultures in green roof systems. This soil-less technology might overcome some issues, such as identifying the suitable substrate to support the growth of the vegetation. This paper aims to provide a systematic review of hydroponic green roof systems (HGRS), based on the rigorous analysis of the evidence gathered from the thorough evaluation of the available literature on the subject, in order to assess their potential use as an alternative to traditional green roofs. The review was carried out by analyzing studies that have assessed the performance of hydroponic green roofs as well as those of comparable systems, such as pond roofs and green roofs. The results of these studies show that HGRS provide similar performances to the above-mentioned systems in terms of the passive conditioning effect, lowering the cooling/heating load of buildings, with slight changes depending on the climatic conditions. However, they offer other significant properties such as higher efficiency in water runoff management, alongside others discussed in this paper, while also requiring minor maintenance. Significant results have been provided; however, gaps in the knowledge have also emerged, and further studies need to be conducted to provide exhaustive information.

In order to reach the ambitious decarbonizing goals set by the European Union for 2030, deep renovation of the existing European building stock is a key issue. Within this context, the recently funded H2020 project “e-SAFE” is investigating market-ready wooden envelope renovation solutions for non-historic buildings, which encompass both energy and seismic improvement. The research carried out in the project aims at developing, testing and demonstrating these solutions on a real pilot. More specifically, this paper presents preliminary analyses to verify that the solutions satisfy the requisites set by the national regulations in force in most European countries, in terms of hygrothermal and acoustic performance. The analysis, carried out following relevant technical European Standards and based on calculations, considers different climate conditions and existing wall structures, selected amongst those most commonly adopted in Europe. The results show that the addition of a Cross Laminated Timber (CLT) layer with some wooden-based insulation on the outer side allows reaching very good thermal and acoustic performance. However, interstitial condensation may occur in cold climates under high indoor humidity values. This aspect deserves further investigation accounting for the transient behavior of the walls and all vapor transport mechanisms.

Summary: Fanconi anemia (FA) is a genetic disorder characterized by a defect in DNA interstrand crosslink (ICL) repair, chromosomal instability, and a predisposition to cancer. Recently, two RAD51 mutations were reported to cause an FA-like phenotype. Despite the tight association of FA/HR proteins with replication fork (RF) stabilization during normal replication, it remains unknown how FA-associated RAD51 mutations affect replication beyond ICL lesions. Here, we report that these mutations fail to protect nascent DNA from MRE11-mediated degradation during RF stalling in Xenopus laevis egg extracts. Reconstitution of DNA protection in vitro revealed that the defect arises directly due to altered RAD51 properties. Both mutations induce pronounced structural changes and RAD51 filament destabilization that is not rescued by prevention of ATP hydrolysis due to aberrant ATP binding. Our results further interconnect the FA pathway with DNA replication and provide mechanistic insight into the role of RAD51 in recombination-independent mechanisms of genome maintenance. : Zadorozhny et al. find that RAD51 mutations associated with Fanconi anemia not only impair DNA crosslink repair but also affect DNA replication during fork stalling. The mutant proteins cause RAD51 filament destabilization and induce pronounced structural changes resulting from aberrant ATP binding and hydrolysis. Keywords: Fanconi anemia, RAD51, replication, recombination

The cell cycle division protein Cdc45 is required for genome duplication in eukaryotes. Here, the authors determine the crystal structure of human Cdc45 and combine it with functional data to improve our understanding of its role in DNA replication.

Building energy simulations are normally run through Typical Weather Years (TWYs) that reflect the average trend of local long-term weather data. This paper presents a research aimed at generating updated typical weather files for the city of Catania (Italy), based on 18 years of records (2002–2019) from a local weather station. The paper reports on the statistical analysis of the main recorded variables, and discusses the difference with the data included in a weather file currently available for the same location based on measurements taken before the 1970s but still used in dynamic energy simulation tools. The discussion also includes a further weather file, made available by the Italian Thermotechnical Committee (CTI) in 2015 and built upon the data registered by the same weather station but covering a much shorter period. Three new TWYs are then developed starting from the recent data, according to well-established procedures reported by ASHRAE and ISO standards. The paper discusses the influence of the updated TWYs on the results of building energy simulations for a typical residential building, showing that the cooling and heating demand can differ by 50% or even 65% from the simulations based on the outdated weather file.

The development of metastatic cancer is a multistage process, which often requires decades to complete. Impairments in DNA damage control and DNA repair in cancer cell precursors generate genetically heterogeneous cell populations. However, despite heterogeneity most solid cancers have stereotypical behaviours, including invasiveness and suppression of immune responses that can be unleashed with immunotherapy targeting lymphocyte checkpoints. The mechanisms leading to the acquisition of stereotypical properties remain poorly understood. Reactivation of embryonic development processes in cells with unstable genomes might contribute to tumour expansion and metastasis formation. However, it is unclear whether these events are linked to immune response modulation. Tumours and embryos have non-self-components and need to avoid immune responses in their microenvironment. In mammalian embryos, neo-antigens are of paternal origin, while in tumour cells DNA mismatch repair and replication defects generate them. Inactivation of the maternal immune response towards the embryo, which occurs at the placental–maternal interface, is key to ensuring embryonic development. This regulation is accomplished by the trophoblast, which mimics several malignant cell features, including the ability to invade normal tissues and to avoid host immune responses, often adopting the same cancer immunoediting strategies. A better understanding as to whether and how genotoxic stress promotes cancer development through reactivation of programmes occurring during early stages of mammalian placentation could help to clarify resistance to drugs targeting immune checkpoint and DNA damage responses and to develop new therapeutic strategies to eradicate cancer.

The performance of space heating and cooling systems in buildings is usually measured by applying the first law of thermodynamics, which makes it possible to quantify the energy losses of the single components and to measure their energy conversion efficiency. However, this common approach does not properly consider that different forms of energy have different potentials to produce useful work, the latter being a function of the temperature at which energy is made available. As a result, it is not possible to properly address how the “quality„ of energy is exploited or conserved in the different processes. On the contrary, the second law of thermodynamics is able to do that by introducing the concept of exergy: This is the maximum amount of work that can be produced through an ideal reversible process evolving until a full condition of equilibrium with the environment is attained. Exergy is; thus, a possible way to measure the “quality„ of an energy flow or an energy source. This perspective is particularly relevant when dealing with buildings and their energy conversion systems, which usually deliver thermal energy at a temperature level that is close to the environmental temperature. This means that the users require “low-quality„ energy; notwithstanding, this energy comes from the depletion of “high-quality„ energy sources, such as fossil fuels and electricity. The exergy analysis helps with identifying such irrational use of the energy sources, which cannot come to light from the energy analysis. In this paper, a literature review identifies methods and metrics commonly used to carry out the exergy analysis of buildings and their energy technologies, while also underlining discrepancies and open methodological issues. Then, the review discusses the main lessons learned from selected works, providing significant advice about the rational use of energy in buildings as well as the most effective technological solutions.

A combined gravimetric and geochronological interpretation of the Parguaza intrusion in the Guayana shield, southwestern Venezuela, indicates that there is a pattern of inverse cooling within this pluton. Based on a positive correlation between Rb/Sr whole rock apparent ages and residual Bouguer anomaly, density contrasts over the Parguaza intrusion are linked to temperature and crystallization of mineral phases. This hypothesis is supported by density measurements on hand samples and by independent geochemical evidence. A simple 2D gravity model is constrained by surface geology, Rb/Sr apparent ages (whole rock) and residual Bouguer anomalies. Gravimetric modeling implies a model of horsts and grabens that accounts for inverse zoning of the intrusion as a result of geological and age contrasts across the faults.

Centrosomes consist of two centrioles embedded in pericentriolar material and function as the main microtubule organising centres in dividing animal cells. They ensure proper formation and orientation of the mitotic spindle and are therefore essential for the maintenance of genome stability. Centrosome function is crucial during embryonic development, highlighted by the discovery of mutations in genes encoding centrosome or spindle pole proteins that cause autosomal recessive primary microcephaly, including Cep63 and Cep152. In this study we show that Cep63 functions to ensure that centriole duplication occurs reliably in dividing mammalian cells. We show that the interaction between Cep63 and Cep152 can occur independently of centrosome localisation and that the two proteins are dependent on one another for centrosomal localisation. Further, both mouse and human Cep63 and Cep152 cooperate to ensure efficient centriole duplication by promoting the accumulation of essential centriole duplication factors upstream of SAS-6 recruitment and procentriole formation. These observations describe the requirement for Cep63 in maintaining centriole number in dividing mammalian cells and further establish the order of events in centriole formation.

M-phase Promoting Factor (MPF; the cyclin B-cdk 1 complex) is activated at M-phase onset by removal of inhibitory phosphorylation of cdk1 at thr-14 and tyr-15. At M-phase exit, MPF is destroyed by ubiquitin-dependent cyclin proteolysis. Thus, control of MPF activity via inhibitory phosphorylation is believed to be particularly crucial in regulating transition into, rather than out of, M-phase. Using the in vitro cell cycle system derived form Xenopus eggs, here we show, however, that inhibitory phosphorylation of cdk1 contributes to control MPF activity during M-phase exit. By sampling extracts at very short intervals during both meiotic and mitotic exit, we found that cyclin B1-associated cdk1 underwent transient inhibitory phosphorylation at tyr-15 and that cyclin B1-cdk1 activity fell more rapidly than the cyclin B1 content. Inhibitory phosphorylation of MPF correlated with phosphorylation changes of cdc25C, the MPF phosphatase, and physical interaction of cdk1 with wee1, the MPF kinase, during M-phase exit. MPF down-regulation required Ca(++)/calmodulin-dependent kinase II (CaMKII) and cAMP-dependent protein kinase (PKA) activities at meiosis and mitosis exit, respectively. Treatment of M-phase extracts with a mutant cyclin B1-cdk1AF complex, refractory to inhibition by phosphorylation, impaired binding of the Anaphase Promoting Complex/Cyclosome (APC/C) to its co-activator Cdc20 and altered M-phase exit. Thus, timely M-phase exit requires a tight coupling of proteolysis-dependent and proteolysis-independent mechanisms of MPF inactivation.

Mre11/Rad50/Nbs1 complex (MRN) is essential to suppress the generation of double-strand breaks (DSBs) during DNA replication. MRN also plays a role in the response to DSBs created by DNA damage. Hypomorphic mutations in Mre11 (which causes an ataxia-telangiectasia-like disease [ATLD]) and mutations in the ataxia-telangiectasia-mutated (ATM) gene lead to defects in handling damaged DNA and to similar clinical and cellular phenotypes. Using Xenopus egg extracts, we have designed a simple assay to define the biochemistry of Mre11. MRN is required for efficient activation of the DNA damage response induced by DSBs. We isolated a high molecular weight DNA damage signaling complex that includes MRN, damaged DNA molecules, and activated ATM. Complex formation is partially dependent upon Zn(2+) and requires an intact Mre11 C-terminal domain that is deleted in some ATLD patients. The ATLD truncation can still perform the role of Mre11 during replication. Our work demonstrates the role of Mre11 in assembling DNA damage signaling centers that are reminiscent of irradiation-induced foci. It also provides a molecular explanation for the similarities between ataxia-telangiectasia (A-T) and ATLD.