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Many high-yielding reactions for forming peptide bonds have been developed but these are complex, requiring activated amino-acid precursors and heterogeneous supports. Herein we demonstrate the programmable one-pot dehydration–hydration condensation of amino acids forming oligopeptide chains in around 50% yield. A digital recursive reactor system was developed to investigate this process, performing these reactions with control over parameters such as temperature, number of cycles, cycle duration, initial monomer concentration and initial pH. Glycine oligopeptides up to 20 amino acids long were formed with very high monomer-to-oligomer conversion, and the majority of these products comprised three amino acid residues or more. Having established the formation of glycine homo-oligopeptides, we then demonstrated the co-condensation of glycine with eight other amino acids (Ala, Asp, Glu, His, Lys, Pro, Thr and Val), incorporating a range of side-chain functionality. Typically, in order to form large peptides, complex procedures or activating agents are required. Here, the authors show that simple aqueous conditions with dehydration-hydration cycles are sufficient for the oligomerization of amino acids into peptides (up to 20 amino acids long) in yields of up to 50%.

Research on prebiotic chemistry and the origins of nucleic acids and proteins has traditionally been focussed on only one or the other. However, if nucleotides and amino acids co-existed on the early Earth, their mutual interactions and reactivity should be considered explicitly. Here we set out to investigate nucleotide/nucleoside formation by simple dehydration reactions of constituent building blocks (sugar, phosphate, and nucleobase) in the presence of different amino acids. We demonstrate the simultaneous formation of glycosidic bonds between ribose, purines, and pyrimidines under mild conditions without catalysts or activated reagents, as well as nucleobase exchange, in addition to the simultaneous formation of nucleotide and nucleoside isomers from several nucleobases. Clear differences in the distribution of glycosylation products are observed when glycine is present. This work demonstrates that reaction networks of nucleotides and amino acids should be considered when exploring the emergence of catalytic networks in the context of molecular evolution. The direct glycosylation of ribose by nucleobases offers an intuitive route to nucleosides, but is known to be challenging under prebiotically plausible reaction conditions. Here, the addition of amino acids is shown to influence the product distribution, and a dynamic exchange of nucleobases between nucleosides and nucleotides is observed.

The previously published version of this Article contained errors in Fig. 1. In Fig. 1a, an oxygen atom was omitted from one structure. In Fig. 1b, one structure was drawn as the incorrect enantiomer. These errors have been corrected in both the PDF and HTML versions of the Article.

In this paper, we describe denaturing and non-denaturing ion-pair reversed-phase liquid chromatography (RPLC) methods for analyzing small interfering ribonucleic acid (siRNA). Drug formulations consisting of one or two siRNA duplexes were analyzed in non-denaturing conditions at a low column temperature to separate intact duplexes from single-stranded oligonucleotide contaminants and quantify them. In a denaturing method, we used an elevated column temperature to ensure the denaturation of siRNA duplexes into their single-stranded oligonucleotide counterparts. The goal of the denaturing LC method was to investigate the impurities in daughter oligonucleotides in siRNA. A column with chemically modified C18 column hardware showed improvements in analytical performance for nucleic acids compared to a conventional C18 stainless-steel column with the same pore size.

Low tidal volume (VT) during anesthesia minimizes lung injury but may be associated to a decrease in functional lung volume impairing lung mechanics and efficiency. Lung recruitment (RM) can restore lung volume but this may critically depend on the post-RM selected PEEP. This study was a randomized, two parallel arm, open study whose primary outcome was to compare the effects on driving pressure of adding a RM to low-VT ventilation, with or without an individualized post-RM PEEP in patients without known previous lung disease during anesthesia. Consecutive patients scheduled for major abdominal surgery were submitted to low-VT ventilation (6 ml·kg-1) and standard PEEP of 5 cmH2O (pre-RM, n = 36). After 30 min estabilization all patients received a RM and were randomly allocated to either continue with the same PEEP (RM-5 group, n = 18) or to an individualized open-lung PEEP (OL-PEEP) (Open Lung Approach, OLA group, n = 18) defined as the level resulting in maximal Cdyn during a decremental PEEP trial. We compared the effects on driving pressure and lung efficiency measured by volumetric capnography. OL-PEEP was found at 8±2 cmH2O. 36 patients were included in the final analysis. When compared with pre-RM, OLA resulted in a 22% increase in compliance and a 28% decrease in driving pressure when compared to pre-RM. These parameters did not improve in the RM-5. The trend of the DP was significantly different between the OLA and RM-5 groups (p = 0.002). VDalv/VTalv was significantly lower in the OLA group after the RM (p = 0.035). Lung recruitment applied during low-VT ventilation improves driving pressure and lung efficiency only when applied as an open-lung strategy with an individualized PEEP in patients without lung diseases undergoing major abdominal surgery. ClinicalTrials.gov NCT02798133.

During apoptosis, cells undergo characteristic morphological changes in which the cytoskeleton plays an active role. The cytoskeleton rearrangements have been mainly attributed to actinomyosin ring contraction, while microtubule and intermediate filaments are depolymerized at early stages of apoptosis. However, recent results have shown that microtubules are reorganized during the execution phase of apoptosis forming an apoptotic microtubule network (AMN). Evidence suggests that AMN is required to maintain plasma membrane integrity and cell morphology during the execution phase of apoptosis. The new “two coffins” hypothesis proposes that both AMN and apoptotic cells can adopt two morphological patterns, round or irregular, which result from different cytoskeleton kinetic reorganization during the execution phase of apoptosis induced by genotoxic agents. In addition, round and irregular-shaped apoptosis showed different biological properties with respect to AMN maintenance, plasma membrane integrity and phagocyte responses. These findings suggest that knowing the type of apoptosis may be important to predict how fast apoptotic cells undergo secondary necrosis and the subsequent immune response. From a pathological point of view, round-shaped apoptosis can be seen as a physiological and controlled type of apoptosis, while irregular-shaped apoptosis can be considered as a pathological type of cell death closer to necrosis.

Brain-age can be inferred from structural neuroimaging and compared to chronological age (brain-age delta) as a marker of biological brain aging. Accelerated aging has been found in neurodegenerative disorders like Alzheimer’s disease (AD), but its validation against markers of neurodegeneration and AD is lacking. Here, imaging-derived measures from the UK Biobank dataset (N=22,661) were used to predict brain-age in 2,314 cognitively unimpaired (CU) individuals at higher risk of AD and mild cognitive impaired (MCI) patients from four independent cohorts with available biomarker data: ALFA+, ADNI, EPAD, and OASIS. Brain-age delta was associated with abnormal amyloid-β, more advanced stages (AT) of AD pathology and APOE -ε4 status. Brain-age delta was positively associated with plasma neurofilament light, a marker of neurodegeneration, and sex differences in the brain effects of this marker were found. These results validate brain-age delta as a non-invasive marker of biological brain aging in non-demented individuals with abnormal levels of biomarkers of AD and axonal injury.

Introduction/objectivesThe use of non-occupational post-exposure prophylaxis (nPEP) emerges as a strategic intervention to reduce HIV infection risk following sexual encounters in our setting. Notwithstanding, there is a scarcity of contemporary data regarding adherence to this treatment, its effectiveness and tolerance. Our study aims to delve into these factors among individuals who have resorted to nPEP after high-risk sexual encounters.MethodsWe conducted a retrospective observational study of cases administered nPEP for HIV from 1 January 2018 to 31 December 2021 at a tertiary hospital in Madrid. The study included all adults over 18 years who sought care at the emergency department of the Fundación Jiménez Díaz Hospital following a risky sexual encounter and were subsequently recommended HIV nPEP treatment.Results878 individuals received nPEP for HIV and underwent initial serological tests. Of these, 621 had comprehensive follow-ups. The prescribed regimen for all was raltegravir (RAL) 1200 mg combined with tenofovir/emtricitabine (TDF/FTC) 245/200 mg daily for 28 days. The study revealed a 1.1% rate (n=10) of previously undetected infection and a 0.16% (n=1) failure rate of nPEP. Regarding regimen tolerability, 5.6% (n=35) experienced symptoms linked to the treatment, yet none necessitated discontinuation of the regimen. On the contrary, six per cent (n=53) reported symptoms consistent with an STI during one of the medical visits; specifically, 4.4% had urethritis, and 1.6% had proctitis.ConclusionnPEP with RAL/TDF/FTC demonstrates high efficacy and safety, contingent on proper adherence. There is an observed increase in STI prevalence in this cohort, with nearly half of the participants not engaging in appropriate follow-up after initiating nPEP.

Atherosclerosis is the most common cause of cardiac deaths worldwide. Classically, atherosclerosis has been explained as a simple arterial lipid deposition with concomitant loss of vascular elasticity. Eventually, this condition can lead to consequent blood flow reduction through the affected vessel. However, numerous studies have demonstrated that more factors than lipid accumulation are involved in arterial damage at the cellular level, such as inflammation, autophagy impairment, mitochondrial dysfunction, and/or free-radical overproduction. In order to consider the correction of all of these pathological changes, new approaches in atherosclerosis treatment are necessary. Ubiquinone or coenzyme Q10 is a multifunctional molecule that could theoretically revert most of the cellular alterations found in atherosclerosis, such as cholesterol biosynthesis dysregulation, impaired autophagy flux and mitochondrial dysfunction thanks to its redox and signaling properties. In this review, we will show the latest advances in the knowledge of the relationships between coenzyme Q10 and atherosclerosis. In addition, as atherosclerosis phenotype is closely related to aging, it is reasonable to believe that coenzyme Q10 supplementation could be beneficial for both conditions.

Patients with diabetes and chronic kidney disease (CKD-DM) often have residual albuminuria despite pharmacological treatment. Finerenone targets mineralocorticoid overactivation, but real-world evidence remains limited. This study evaluated the impact of finerenone in a cohort of patients with CKD-DM. This was a real-life study including patients with CKD-DM and an estimated glomerular filtration rate (eGFR) ≥ 20 mL/min/1.73 m , treated with finerenone, aged ≥ 18 years, and followed at the Nephrology Department of Vall d'Hebron Hospital. Clinical and laboratory data were collected at baseline and at 1, 3, and 6 months of treatment. Changes in albuminuria and eGFR were analyzed in patients who completed 6 months of follow-up. A total of 60 patients were included in the analysis; 39 (65%) were male, with a median age of 79 ± 10.12 years. Finerenone was initiated at 10 mg daily in 57 patients (95%), with 38.3% escalating to 20 mg after 1 month. After 6 months, the urinary albumin-to-creatinine ratio (UACR) decreased by 37.1% ( = 0.012, n = 34). Patients with an initial eGFR drop > 20% showed a greater UACR decrease of around 43% at 3 ( = 0.012) and 6 months ( = 0.013). A significant 9.5% decline in eGFR was observed at 1 month, followed by stabilization at 3 and 6 months. Finerenone was discontinued in 10% of the patients due to adverse events. Hyperkalemia occurred in 18.3% of the patients, but no hospitalizations for adverse events or heart failure were reported. In summary, finerenone induced a significant 37.1% reduction in albuminuria after 6 months of treatment. This reduction was more pronounced in patients who experienced an initial eGFR dip ≥ 20%. Finerenone was generally well tolerated and appears to be a promising therapeutic strategy for reducing albuminuria in this population.