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The pathological assembly of intrinsically disordered proteins/peptides (IDPs) into amyloid fibrils is associated with a range of human pathologies, including neurodegeneration, metabolic diseases and systemic amyloidosis. These debilitating disorders affect hundreds of millions of people worldwide, and the number of people affected is increasing sharply. However, the discovery of therapeutic agents has been immensely challenging largely because of (i) the diverse number of aggregation pathways and the multi-conformational and transient nature of the related proteins or peptides and (ii) the under-development of experimental pipelines for the identification of disease-modifying molecules and their mode-of-action. Here, we describe current approaches used in the search for small-molecule modulators able to control or arrest amyloid formation commencing from IDPs and review recently reported accelerators and inhibitors of amyloid formation for this class of proteins. We compare their targets, mode-of-action and effects on amyloid-associated cytotoxicity. Recent successes in the control of IDP-associated amyloid formation using small molecules highlight exciting possibilities for future intervention in protein-misfolding diseases, despite the challenges of targeting these highly dynamic precursors of amyloid assembly.

A data-driven model is used to predict one-hour ahead heat loads based on present and recent history of weather and heat loads. A computationally inexpensive method is built to deliver load forecasting based on existing data quality and resolution from smart meters. Optimal model formulation is discussed and optimized at 4-hour historical values. The model is trained and tested against synthetic data from a building energy simulation, resulting in absolute error <4% and R2values in the range of 0.92 to 0.94.

There is an ongoing trend towards temperature reduction in District Heating Networks, allowing for the reduction of distribution heat loss and enabling the integration of low exergy heat production systems. There is a clear scientific consensus on the improved sustainability of such systems. However, there is not sufficient knowledge on how to deliver a successful transition to a low temperature District Heating system, while ensuring the operational levels of the existing system. This paper presents the experience on the progressive temperature reduction of a district heating subnetwork over the 2018–2021 period in Tartu, Estonia. Data from heat meters is extensively used to assess the capacity of substations and network branches to deliver the required heat and quality levels. Faulty substations are identified for targeted assessment and improvement works. Several substations have been identified as missing some of the performance criteria. This has led to further analysis, closer supervision and interventions in the operational conditions of the network. This is an ongoing process, expected to remain in the established procedures of the DH network operator. At the end of the process, a temperature reduction of 7 ºC has shown an improvement of 4.8% in network heat loss.

ABSTRACTThe present investigation refers to the improvement of tensile properties, hardness, and creep resistance obtained from a high-chromium novel steel grade formulated by the combination of innovative steel composition and heat treatment. The novel steel grade has evolved from the P92 steel grade, and shows a better behaviour than that offered by the P92 steel grade, thus representing a promising metallurgical strategy for increasing the efficiency of power plants, and subsequently reducing the CO2emissions.

This work presents a review, using bibliometric methods, of the state of research on natural language processing in Mexico, understanding this as the methods to process human language, including semantic techniques, statistical techniques or a combination of both. It includes an identification of the most productive groups in the country, the main actors involved in research, their collaboration links, as well as the main topics that are investigated. This last aspect is compared with the subjects reported in the international literature to identify differences and similarities on research interests between researchers working in Mexico and those reported in mainstream literature. We conclude with a characterization of research carried out in Mexico about language technologies and we found that the research subjects investigated are somewhat similar to those that are reported in the international literature when time is not considered in the analysis. Nevertheless, when this variable is included, there are practically no similarities in the subjects researched in México and those researched in the world.

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The Tepary bean (Phaseolus acutifolius) lectin fraction (TBLF) exhibits differential cytotoxicity on colon cancer cells and inhibition of early tumorigenesis in the colon (50 mg/kg, three times per week, for 6 weeks). TBLF showed low toxicity with the ability to activate the immune system; however, some adverse effects are the loss in body weight gain, intestinal atrophy, and pancreatic hyperplasia. After a recovery period of 2 weeks after treatment, reversion of pancreatic hyperplasia but no recovery of intestinal atrophy was observed. As TBLF has shown anticancer effects on the colon, it is important to characterize the adverse effects and how they can be reversed. Sprague Dawley rats were administered with TBLF (50 mg/kg) for 6 weeks, three times per week, and then allowed to recover for 6 weeks post-treatment. After TBLF administration, small intestine atrophy, villus atrophy, and cryptic hyperplasia were confirmed, as well as increased intestinal mucus production, increased permeability and a decrease in the apparent ileal digestibility of crude proteins. The colon showed damage in the simple prismatic tissue and decreased crypt depth, and changes in microbiota and a decrease in the apparent fecal digestibility of crude protein were determined. Our results show that the adverse effects provoked by TBLF were partially reversed after 6 weeks of recovery post-treatment, suggesting that increasing the recovery period it could be possible to reverse all adverse effects observed.

Aggregation of human α-synuclein (αSyn) is linked to Parkinson’s disease (PD) pathology. The central region of the αSyn sequence contains the non-amyloid β-component (NAC) crucial for aggregation. However, how NAC flanking regions modulate αSyn aggregation remains unclear. Using bioinformatics, mutation and NMR, we identify a 7-residue sequence, named P1 (residues 36–42), that controls αSyn aggregation. Deletion or substitution of this ‘master controller’ prevents aggregation at pH 7.5 in vitro. At lower pH, P1 synergises with a sequence containing the preNAC region (P2, residues 45–57) to prevent aggregation. Deleting P1 (ΔP1) or both P1 and P2 (ΔΔ) also prevents age-dependent αSyn aggregation and toxicity in C. elegansmodels and prevents αSyn-mediated vesicle fusion by altering the conformational properties of the protein when lipid bound. The results highlight the importance of a master-controller sequence motif that controls both αSyn aggregation and function—a region that could be targeted to prevent aggregation in disease.

A new method, simple and fast, for fluconazole (FLU) quantification in cerebrospinal fluid (CSF) samples using dispersive liquid–liquid microextraction (DLLME) and an eco-friendly mobile phase for HPLC-PDA was developed. The study of DLLME extraction condition covered the investigation of 12 combinations of extraction and disperser solvents followed by a fractional factorial design 2(7−3)to determine the influence of seven factors. After this stage, a central composite design was performed for three factors and a response surface was obtained. Aiming a compromise between a good recovery and a low organic solvent use it was established an extraction condition that consists of: 100 μL of chloroform, 100 μL of isopropyl alcohol, 200 μL of CSF, 200 μL of 50 mM phosphate buffer pH 7.3 and centrifugation for 5 min at 2200gand 4 °C. The HPLC analysis used an Ascentis® Express C18 column (100 mm × 4.6 mm, 2.7 μm) and an Ascentis® Express C18 guard column (3 mm × 4.6 mm, 2.7 μm), ethanol : water (15 : 85, v/v) as mobile phase, temperature of 45 °C, flow rate of 0.8 mL min−1and phenacetin as internal standard. The method validation was performed according to European Agency's Guideline on Bioanalytical Validation Methodology and a linear range was obtained from 0.25 to 62.5 μg mL−1, with precision and accuracy within the recommended limits and recovery of 70% for FLU and 81% for phenacetin. Samples were stable in the studies performed and the method showed to be selective and with no carryover effect. The feasibility of the obtained method was confirmed by FLU determination at a CSF from a patient who was treated for neuromycosis. Therefore, here is described a method that meets many principles of green analytical chemistry and is useful for FLU therapeutic monitoring.

Understanding the mechanical failure modes of lithium-ion battery [Li-ion batteries (LIBs)] electrodes is exceptionally important for enabling high specific energy and flexible LIB technologies. In this work, the failure modes of lithium cobalt oxide (LCO) cathodes under repeated bending and the role of the polymer binder in improving the mechanical durability of the LCO electrodes for use in flexible LIBs are investigated. Mechanical and electrochemical evaluations of LCO electrodes (areal capacity of ≥2.5 mA h cm–2) employing poly(vinylidene fluoride) (PVDF) binder were carried out, followed by extensive optical and electron microscopies. We find that the molecular weight (MW) of the PVDF significantly influenced the surface and bulk microstructure of the LCO electrodes, particularly the distribution of carbon additive and binder, which plays a crucial role in affecting the mechanical and electrochemical properties of the electrodes. Multiple mechanical failure modes (e.g., surface scratches and microcracks) observed in the LCO electrodes subjected to repeated bending originated from the use of low MW PVDF; these failure modes were successfully mitigated by using a high MW PVDF. Remarkably, the optimized flexible LCO electrode incorporating high MW PVDF showed comparable discharge capacity retention during galvanostatic cycling after repeated bending (7000 cycles at 50 mm bending diameter) to electrodes not subjected to the repeated bending. This study highlights the importance of carrying out a comprehensive investigation of the failure mechanisms in flexible electrodes, which identified the pivotal role of the PVDF MW in the electrode microstructure and its effects on the electrode resilience to failure during repeated bending.

To evaluate the effectiveness of dental treatment in improving oral health in critical patients. This randomised clinical trial was conducted in a general intensive care unit (ICU) at a tertiary care public facility from 1 January 2011 to 8 August 2013. Data from 254 adult patients staying in the ICUfor 48 hours or more were analysed. The experimental group (n= 127) had access to dental treatment provided by a dentist four to five times a week, in addition to routine oral hygiene, whereas the control group (n= 127) had access only to routine oral hygiene, including topical application of chlorhexidine, provided by the ICUnursing staff. The baseline oral health status of the enrolled patients was poor and included edentulism, caries, gingivitis, periodontitis and residual roots. Dental treatment consisted of toothbrushing, tongue scraping, removal of calculus, scaling and root planing, caries restoration and tooth extraction. The Oral Hygiene Index Simplified (OHI‐S) and Gingival Index (GI) scores decreased in the experimental group but did not change significantly in the control group during the ICUstay. Dental treatment prevented most of the episodes of respiratory tract infections, as previously reported. No severe adverse events from the dental treatment were observed. From an interprofessional perspective, our results support the idea of including dentists in the ICUteam to improve oral health in critical patients and effectively prevent respiratory tract infections, in addition to the improvement achievable by applying chlorhexidine alone.

The goal in this work is to build a multivariate linear model to predict tensile strength since is one of the most significant mechanical properties of carbon-black reinforced rubber blends. This model is based in the relationship between the final mechanical properties and the material composition, with the advantage of using this model to improve the design of the composition of the blend. In order to predict this relevant physical attribute of rubber blends a linear regression is performed, but previously a multivariate analysis of the data is done to get a better accuracy in the validation of the model. The number of used instances and the values are determined by a Taguchi design of experiments, and the output values are obtained from the tensile strength test following the corresponding standard. After the performance of the multivariate analysis where the input variables are under a detail study, a selection of the best features help to improve the accuracy of the model, passing from a 24.80% to a 20.60% of error.

Squamous-cell features in bladder cancer, which have been linked to chronic inflammation, represent a challenge to providers and patients because these tumors tend to be chemorefractory. We provide evidence that neutrophil inflammation, measured with peripheral blood levels of neutrophil-to-lymphocyte ratio as a surrogate, is linked to prognosis with patients displaying low NLR showing a 4-fold survival outcome and being highly responsive to neoadjuvant chemotherapy.

Light chain amyloidosis is the most common form of systemic amyloidosis. This disease is caused by the formation and deposition of amyloid fibers made from immunoglobulin light chains. Environmental conditions such as pH and temperature can affect protein structure and induce the development of these fibers. Several studies have shed light on the native state, stability, dynamics, and final amyloid state of these proteins; however, the initiation process and the fibril formation pathway remain poorly understood structurally and kinetically. To study this, we analyzed the unfolding and aggregation process of the 6aJL2 protein under acidic conditions, with temperature changes, and upon mutation, using biophysical and computational techniques. Our results suggest that the differences in amyloidogenicity displayed by 6aJL2 under these conditions are caused by traversing different aggregation pathways, including unfolded intermediates and the formation of oligomers.

The focus of this paper is to show a novel electromagnetic servo brake with ABS function. This electro-mechanical device is designed to be installed in mid-range commercial vehicles, and its operation is performed by the battery of the vehicle itself. A control system based on a linear controller was designed to regulate the electric current used by the servo brake. The device designed was constructed and experimentally validated using a test bench. The good agreement obtained from the experiments suggests that the servo brake with ABS function designed could be used in mid-range commercial vehicles in order to reduce the speed of the wheels while simultaneously preventing the wheels from locking safely.

The purpose of this study was to analyze the behavior of a lumbar spine disc prosthesis with different materials. The study was performed at L4-L5 lumbar motion segment using the finite element method (FEM). A healthy Finite Element (FE) model was used as a reference with which to compare the results of the FE simulations of the artificial discs. The healthy and the artificial FE models were subjected to a combination of 0.5 MPa Compression pre-load and 10Nm of Flexion moment. The artificial FE models were based on Maverick artificial disc, and the three materials proposed for study the artificial disk were Titanium, Ceramic and CrCoMo alloy. The most suitable material for developed the artificial disc was the CoCrMo alloy due to: The von Mises stresses on the bone with which this artificial disc was in contact were reduced as much as possible and also, were very similar to the von Mises stresses obtained in the bones from the healthy disc.

Solar walls can be used to increase the overall energy efficiency of a building. Phase Change Materials (PCM) are capable of increasing the effective thermal mass of building elements, thus decreasing the overall energy consumption. Recently, the incorporation of PCM in a solar wall has been proposed, aiming to increase the total energy efficiency of the system. The main scope of this work is to investigate the thermal behaviour of a PCM-enhanced solar wall (PCMESW), using experimental and numerical simulation techniques. A prototype PCMESW is installed in a large-scale test facility and is exposed to dynamically changing climate conditions. A broad range of sensors, used to monitor the time-evolution of several important physical parameters, is employed to assess the dynamic response of the PCMESW. In addition, a Computational Fluid Dynamics tool is used to numerically investigate the thermal behaviour of the PCMESW prototype. Predictions of the developing flow- and thermal-field in the PCMESW’s air cavity are validated by means of comparison with the obtained measurements; in general, good levels of agreement are observed. Results of the numerical simulations may support the design optimization process of innovative PCMESW systems.

ABSTRACTAcinetobacter baumannii, a Gram-negative multidrug-resistant (MDR) bacterium, is now recognized as one of the more common nosocomial pathogens. Because most clinical isolates are found to be multidrug resistant, alternative therapies need to be developed to control this pathogen. We constructed a bacteriophage genomic library based on prophages induced from 13 A. baumanniistrains and screened it for genes encoding bacteriolytic activity. Using this approach, we identified 21 distinct lysins with different activities and sequence diversity that were capable of killing A. baumannii. The lysin (PlyF307) displaying the greatest activity was further characterized and was shown to efficiently kill (>5-log-unit decrease) all tested A. baumanniiclinical isolates. Treatment with PlyF307 was able to significantly reduce planktonic and biofilm A. baumanniiboth in vitroand in vivo. Finally, PlyF307 rescued mice from lethal A. baumanniibacteremia and as such represents the first highly active therapeutic lysin specific for Gram-negative organisms in an array of native lysins found in Acinetobacterphage.