LIM protein Ajuba promotes liver cell proliferation through its involvement in DNA replication and DNA damage control.

The LIM-domain protein Ajuba is associated with cell proliferation, a fundamental process of tissue regeneration and cancer. We report that in the liver, Ajuba expression is increased during regeneration and in tumor cells and tissues. Knockout of Ajuba using CRISPR/Cas9 is embryonic lethal in mice. shRNA targeting of Ajuba reduces cell proliferation, delays cell entry into S-phase, reduces cell survival and tumor growth in vivo, and increases expression of the DNA damage marker γH2AX. Ajuba binding partners include proteins involved in DNA replication and damage, such as SKP2, MCM2, MCM7 and RPA70. Taken together, our data support that Ajuba promotes liver cell proliferation associated with development, regeneration, and tumor growth and is involved in DNA replication and damage repair

Impaired liver regeneration in aged mice can be rescued by silencing Hippo core kinases MST1 and MST2.

The liver has an intrinsic capacity to regenerate in response to injury or surgical resection. Nevertheless, circumstances in which hepatocytes are unresponsive to proliferative signals result in impaired regeneration and hepatic failure. As the Hippo pathway has a canonical role in the maintenance of liver size, we investigated whether it could serve as a therapeutic target to support regeneration. Using a standard two-thirds partial hepatectomy (PH) model in young and aged mice, we demonstrate that the Hippo pathway is modulated across the phases of liver regeneration. The activity of the core kinases MST1 and LATS1 increased during the early hypertrophic phase and returned to steady state levels in the proliferative phase, coinciding with activation of YAP1 target genes and hepatocyte proliferation. Moreover, following PH in aged mice, we demonstrate that Hippo signaling is anomalous in non-regenerating livers. We provide pre-clinical evidence that silencing the Hippo core kinases MST1 and MST2 with siRNA provokes hepatocyte proliferation in quiescent livers and rescues liver regeneration in aged mice following PH. Our data suggest that targeting the Hippo core kinases MST1/2 has therapeutic potential to improve regeneration in non-regenerative disorders

The Sassi di Matera as the oldest bioclimatic architecture model.

The Sassi of Matera are the oldest example of bioclimatic architecture in the world, thanks to its materials, its typological and functional characteristics, but above all thanks to techniques and technologies. The calcareous rock or tuff characterizes the whole architecture of the Sassi, caved into this soft rock or made of tuff blocks. This material has been used since ancient times, for its characteristics of breathability, insulation and porosity, combined with wise technique of building according to functional types and elements improved over time, allowed to make inhabitable caves and cisterns and wisely exploit the most valuable natural resource, water. The typical evolution of housing models of the Sassi is the different way of exploiting the natural features and the materials, unchanging over time. The tuff has always been the basic element of this type of architecture, which from the cave becomes constructed, structural layouts reinterpreted by the forms and the natural examples, since the Palaeolithic period. The research wants to investigate the structural examples of the past to confirm the importance of form, technique and the different types of construction on bioclimatic definition of the building , a “natural governor” of the thermal and hygrometrical comfort for an high quality performances

Verso un nuovo Manuale per il Recupero dei Sassi di Matera

The research has its origins in the cultural and architectural juncture, which always took place in the reality of the Sassi of Matera, without any precise and decisive regulatory reference or exchange of professional knowledge that can transmit the necessary sensitivity to restore the heritage. Main objective is to define a new approach to the discipline of restoration, intended as protection, preservation, planning and reuse of the antique (areas), so that they can meet the contemporary needs, reinterpreting the broader concept and a sense of sustainability. The research wants to create an application method, a system of coded examples, to determine a method for upgrading the existing architectural and landscape heritage. The restoration is therefore the same as project of the modern architecture in the ancient which, without the pioneering and indelible mark of architects, with his creativity, his maximalist and his minimalism. The Research stems from the recovery manual of the Sassi of Amerigo Restucci (1998), passing by the Code of Practice of Antonino Giuffrè to bring about a recognition of "transformative" approaches adopted in recent decades, towards a more informed critical evaluation and resulting in a "rule" for "conscious recovery" and, at the same time, respectful of the historical balance, architectural and cultural characteristics of the Sassi of Matera.Il progetto di ricerca ha origine nella contingenza culturale e architettonica, cui i Sassi di Matera sono sottoposti quotidianamente, senza alcun preciso e deciso riferimento normativo o scambio di conoscenze professionali in grado di trasmettere la sensibilità necessaria al recupero dei luoghi. L'obiettivo principale è la definizione di un nuovo approccio verso la disciplina del restauro, inteso come tutela, salvaguardia, progettazione e riuso dell'antico, così da poter ottemperare alle esigenze contemporanee, reinterpretando il più ampio concetto e senso di sostenibilità. La ricerca vuole creare un indirizzo applicativo, un sistema fatto di esempi codificati, in grado di determinare un metodo per la rivalorizzazione del patrimonio architettonico e paesaggistico esistente. L'intervento di restauro è quindi il progetto stesso di architettura del moderno nell'antico, sapiente gioco di storia tecnica, che rifulge i pioneristici e indelebili segni dell'architetto, l'estro creativo, i massimalismi e i minimalismi. La ricerca muove i passi dal Manuale di Recupero di Amerigo Restucci del 1998, passando per il Codice di Pratica di Antonino Giuffrè per giungere ad una ricognizione sul campo degli approcci “trasformativi” adottati negli ultimi decenni, verso una più consapevole capacità critica di valutazione e conseguente “regola” modificativa per un “recupero consapevole” e rispettoso degli equilibri storico, architettonici e culturali dei Sassi di Matera

Evaluating the Acceptability, Swallowability, and Palatability of Film-Coated Mini-Tablet Formulation in Young Children: Results from an Open-Label, Single-Dose, Cross-Over Study

Mini-tablets are advantageous over liquid formulations in overcoming challenges related to stability, taste, and dosage. This open-label, single-dose, cross-over study investigated the acceptability and safety of drug-free, film-coated mini-tablets in children aged 1 month–6 years (stratified: 4–6 years, 2–<4 years, 1–<2 years, 6–<12 months, and 1–<6 months), and their preference for swallowing either a high quantity of 2.0 mm or a low quantity of 2.5 mm diameter mini-tablets. The primary endpoint was acceptability derived from swallowability. The secondary endpoints were investigator-observed palatability, acceptability as a composite endpoint derived from both swallowability and palatability, and safety. Of 320 children randomized, 319 completed the study. Across all tablet sizes, quantities and age groups, acceptability rates based on swallowability were high (at least 87%). Palatability was rated as “pleasant/neutral” in 96.6% of children. The acceptability rates as per the composite endpoint were at least 77% and 86% for the 2.0 mm and 2.5 mm film-coated mini-tablets, respectively. No adverse events or deaths were reported. Recruitment in the 1–<6-months group was stopped early due to coughing—evaluated as “choked on” in three children. Both 2.0 mm and 2.5 mm film-coated mini-tablets are suitable formulations for young children

BOK promotes chemical-induced hepatocarcinogenesis in mice.

BCL-2-related ovarian killer (BOK) is a conserved and widely expressed BCL-2 family member with sequence homology to pro-apoptotic BAX and BAK, but with poorly understood pathophysiological function. Since several members of the BCL-2 family are critically involved in the regulation of hepatocellular apoptosis and carcinogenesis we aimed to establish whether loss of BOK affects diethylnitrosamine (DEN)-induced hepatocarcinogenesis in mice. Short-term exposure to DEN lead to upregulation of BOK mRNA and protein in the liver. Of note, induction of CHOP and the pro-apoptotic BH3-only proteins PUMA and BIM by DEN was strongly reduced in the absence of BOK. Accordingly, Bok -/- mice were significantly protected from DEN-induced acute hepatocellular apoptosis and associated inflammation. As a consequence, Bok -/- animals were partially protected against chemical-induced hepatocarcinogenesis showing fewer and, surprisingly, also smaller tumors than WT controls. Gene expression profiling revealed that downregulation of BOK results in upregulation of genes involved in cell cycle arrest. Bok -/- hepatocellular carcinoma (HCC) displayed higher expression levels of the cyclin kinase inhibitors p19INK4d and p21cip1. Accordingly, hepatocellular carcinoma in Bok -/- animals, BOK-deficient human HCC cell lines, as well as non-transformed cells, showed significantly less proliferation than BOK-proficient controls. We conclude that BOK is induced by DEN, contributes to DEN-induced hepatocellular apoptosis and resulting hepatocarcinogenesis. In line with its previously reported predominant localization at the endoplasmic reticulum, our findings support a role of BOK that links the cell cycle and cell death machineries upstream of mitochondrial damage