Magnetite mineralization inside cross-linked protein crystals

Crystallization in confined spaces is a widespread process in nature that also has important implications for the stability and durability of many man-made materials. It has been reported that confinement can alter essential crystallization events, such as nucleation and growth and, thus, have an impact on crystal size, polymorphism, morphology, and stability. Therefore, the study of nucleation in confined spaces can help us understand similar events that occur in nature, such as biomineralization, design new methods to control crystallization, and expand our knowledge in the field of crystallography. Although the fundamental interest is clear, basic models at the laboratory scale are scarce mainly due to the difficulty in obtaining well-defined confined spaces allowing a simultaneous study of the mineralization process outside and inside the cavities. Herein, we have studied magnetite precipitation in the channels of cross-linked protein crystals (CLPCs) with different channel pore sizes, as a model of crystallization in confined spaces. Our results show that nucleation of an Fe-rich phase occurs inside the protein channels in all cases, but, by a combination of chemical and physical effects, the channel diameter of CLPCs exerted a precise control on the size and stability of those Fe-rich nanoparticles. The small diameters of protein channels restrain the growth of metastable intermediates to around 2 nm and stabilize them over time. At larger pore diameters, recrystallization of the Fe-rich precursors into more stable phases was observed. This study highlights the impact that crystallization in confined spaces can have on the physicochemical properties of the resulting crystals and shows that CLPCs can be interesting substrates to study this process

Advances of hyaluronic acid in stem cell therapy and tissue engineering, including current clinical trials

yaluronic acid (HA), as one of the main components of the extracellular matrix (ECM), plays a significant role in a multitude of biological processes involving cell migration, proliferation, differentiation, wound healing and inflammation. Thanks to its excellent biocompatibility, biodegradability and hygroscopic properties, HA has been used in its natural form for joint lubrication and ocular treatment. The chemical structure of HA can be easily modified by direct reaction with its carboxyl and hydroxyl groups. Recently, HA derivatives have been synthesised with the aim of developing HA-based materials with increased mechanical strength, improved cell interactions and reduced biodegradation and studied for regenerative medicine purposes, including cell therapy and tissue engineering. In this context, the present manuscript reviews HA applications from a basic point of view – including chemical modifications and cellular biology aspects related to clinical translation – and future perspectives of using biofabrication technologies for regenerative medicine. A detailed description of current clinical trials, testing advanced therapies based on combination of stem cells and HA formulations, is included. The final goal was to offer an integral portrait and a deeper comprehension of the current applications of HA from bench to bedside

Time-related efficacy of liver cell isografts in fulminant hepatic failure

We and others have reported that dispersed liver cells transplanted into the spleen parenchyma of syngeneic rats remained functional and viable for a long time. This report describes our results with hepatocellular transplantation as a therapeutic method in a model of fulminant hepatic failure (FHF) in the rat. 60 male Sprague-Dawley rats weighing 200-250 g were used. The FHF was reached through an Eck's fistula with 2/3 hepatectomy at the same time. This model produced lethal hepatic failure in a highly reproducible manner. Liver cells were isolated by the collagenase method. 40 X 10(6) hepatocytes suspended in Hanks' balanced salt solution were transplanted into the spleen parenchyma 24 hr before (group 1), at the same time as (group 2), and 24 hr after (group 3) FHF was achieved. Additional sham-operated animals (groups 4 and 5) and a control group (group 6) were used. The hepatocellular transplantation markedly increased the survival of the animals with induced FHF to 80% (group 1) and 60% (group 2)--but not in group 3 (20%),--compared with 10% in the control group. This study shows that dispersed liver cells transplanted into the spleen can provide sufficient support to allow animals with lethal hepatic failure to survive and recover. Nevertheless the efficacy of transplantation is a time-related phenomenon with the FHF induction

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Análisis de la resistencia inmune en un modelo murino experimental alimentado con dietas lipídicas e infectado con Listeria monocytogenes

Algunas dietas lipídicas están implicadas en la reducción de ciertas funciones inmunes. Sin embargo, la acción inmunosupresora de estas dietas puede tener efectos adversos sobre la resistencia inmune del individuo frente a enfermedades de naturaleza infecciosa. En el presente estudio tratamos de valorar el estado inmune de ratones alimentados con dietas lipídicas e infectados experimentalmente con una cepa virulenta de Listeria monocytogenes. Ratones de la raza Balb/c fueron divididos en cuatro grupos alimentados cada uno de ellos con su respectiva dieta: dieta baja en lípidos (control, 2,5%), dieta rica en aceite de oliva (AO, 20%), dieta rica en aceite de pescado (AP, 20%) y dieta rica aceite de coco (AC, 20%). Los animales fueron alimentados durante un mes y posteriormente infectados con L. monocytogenes por vía endovenosa. Los resultados han mostrado una reducción de la supervivencia en animales alimentados con AP, así como un incremento significativo en el número de bacterias viables aisladas a partir de bazo. Además hemos podido observar un aumento de la capacidad bactericida de células peritoneales procedentes de ratones alimentados con AO, aunque la invasividad de L. monocytogenes en este grupo fue mayor que en el resto. Finalmente, una reducción significativa de la linfoproliferación fue observada en el grupo alimentado con AP, mientras que la actividad de células natural killer (NK) no se ha visto modificada. Estos resultados indican que dietas lipídicas constituidas por ácidos grasos poliinsaturados de la serie n-3 reducen la resistencia inmune de los ratones, mientras que una dieta constituida por AO no produce un efecto inmusupresor tan relevante y por consiguiente no reduce drásticamente la resistencia inmune siendo más eficiente en la eliminación de L. monocytogenes

Increased aquaporin-7 expression is associated with changes in rat brown adipose tissue whitening in obesity: impact of cold exposure and bariatric surgery

Glycerol is a key metabolite for lipid accumulation in insulin-sensitive tissues. We examined the role of aquaporin-7 (AQP7), the main glycerol channel in adipocytes, in the improvement of brown adipose tissue (BAT) whitening, a process whereby brown adipocytes differentiate into white like unilocular cells, after cold exposure or bariatric surgery in male Wistar rats with diet-induced obesity (DIO) (n = 229). DIO promoted BAT whitening, evidenced by increased BAT hypertrophy, steatosis and upregulation of the lipogenic factors Pparg2 , Mogat2 and Dgat1. AQP7 was detected in BAT capillary endothelial cells and brown adipocytes, and its expression was upregulated by DIO. Interestingly, AQP7 gene and protein expressions were downregulated after cold exposure (4( ?)C) for 1 week or one month after sleeve gastrectomy in parallel to the improvement of BAT whitening. Moreover, Aqp7 mRNA expression was positively associated with transcripts of the lipogenic factors Pparg2 , Mogat2 and Dgat1 and regulated by lipogenic (ghrelin) and lipolytic (isoproterenol and leptin) signals. Together, the upregulation of AQP7 in DIO might contribute to glycerol influx used for triacylglycerol synthesis in brown adipocytes, and hence, BAT whitening. This process is reversible by cold exposure and bariatric surgery, thereby suggesting the potential of targeting BAT AQP7 as an anti-obesity therapy

Bifunctional polymeric inhibitors of human influenza A viruses

Purpose. New antiviral agents were prepared by attaching derivatives of sialic acid (1) and of the drug zanamivir (2) to poly(isobutylene-alt-maleic anhydride) (poly-(1 + 2)) or by mixing poly-1 and poly-2, followed by assaying them against wild-type and drug-resistant influenza A Wuhan viruses. Methods. Individually or together 1 and 2 were covalently bonded to the polymer. The antiviral potencies of the resultant poly-1, poly-2, poly-(1 + 2), and poly-1 + poly-2, as well as 1 and 2, were assessed using plaque reduction assay. Results. Attaching 1 to the polymer improved at best millimolar IC[subscript 50] values over three orders of magnitude. While 2 exhibited micromolar IC[subscript 50] values, poly-2 was >100-fold even more potent. The IC50 of poly-(1 + 2) against the wild-type strain was >300-fold and ~17-fold better than of poly-1 and poly-2, respectively. In contrast, the potency of poly-(1 + 2) vs. poly-2 against the mutant strain merely doubled. The mixture of poly-1 + poly-2 inhibited both viral strains similarly to poly-2. Conclusions. The bifunctional poly-(1 + 2) acts synergistically against the wild-type influenza virus, but not against its drug-resistant mutant, as compared to a physical mixture of the monofunctional poly-1 and poly-2.National Institutes of Healt