Core charge distribution and self assembly of columnar phases: the case of triphenylenes and azatriphenylenes

<p>Abstract</p> <p>Background</p> <p>The relation betweeen the structure of discotic molecules and columnar properties, a crucial point for the realization of new advanced materials, is still largely unknown. A paradigmatic case is that hexa-alkyl-thio substituted triphenylenes present mesogenic behavior while the corresponding azatriphenylenes, similar in shape and chemical structure, but with a different core charge distribution, do not form any liquid crystalline mesophase. This study is aimed at investigating, with the help of computer simulations techniques, the effects on phase behaviour of changes of the charge distribution in the discotic core.</p> <p>Results</p> <p>We described the shape and the pair, dispersive and electrostatic, interactions of hexa alkyl triphenylenes by uniaxial Gay-Berne discs with embedded point charges. Gay-Berne parameters were deduced by fitting the dispersive energies obtained from an atomistic molecular dynamics simulation of a small sample of hexa-octyl-thio triphenylene molecules in columnar phase, while a genetic algorithm was used to get a minimal set of point charges that properly reproduces the ab anitio electrostatic potential. We performed Monte Carlo simulations of three molecular models: the pure Gay-Berne disc, used as a reference, the Gay-Berne disc with hexa-thio triphenylene point charges, the Gay-Berne disc with hexa-thio azatriphenylene point charges. The phase diagram of the pure model evidences a rich polymorphism, with isotropic, columnar and crystalline phases at low pressure, and the appearance of nematic phase at higher pressure.</p> <p>Conclusion</p> <p>We found that the intermolecular electrostatic potential among the cores is fundamental in sta-bilizing/destabilizing columnar phases; in particular the triphenylene charge distribution stabilizes the columnar structure, while the azatriphenylene distribution suppresses its formation in favor of the nematic phase. We believe the present model could be successfully employed as the basis for coarse-grained level simulations of a wider class of triphenylene derivatives.</p

Acetylcholine regulates ghrelin secretion in humans

Ghrelin secretion has been reportedly increased by fasting and energy restriction but decreased by food intake, glucose, insulin, and somatostatin. However, its regulation is still far from clarified. The cholinergic system mediates some ghrelin actions, e.g. stimulation of gastric contractility and acid secretion and its orexigenic activity. To clarify whether ghrelin secretion undergoes cholinergic control in humans, we studied the effects of pirenzepine [PZ, 100 mg per os (by mouth)], a muscarinic antagonist, or pyridostigmine (PD, 120 mg per os), an indirect cholinergic agonist, on ghrelin, GH, insulin, and glucose levels in six normal subjects. PD increased (P < 0.05) GH (change in area under curves, mean +/- SEM, 790.9 +/- 229.3 microg(*)min/liter) but did not modify insulin and glucose levels. PZ did not significantly modify GH, insulin, and glucose levels. Circulating ghrelin levels were increased by PD (11290.5 +/- 6688.7 pg(*)min/ml; P < 0.05) and reduced by PZ (-23205.0 +/- 8959.5 pg(*)min/ml; P < 0.01). The PD-induced ghrelin peak did not precede that of GH. In conclusion, circulating ghrelin levels in humans are increased and reduced by cholinergic agonists and antagonists, respectively. Thus, ghrelin secretion is under cholinergic, namely muscarinic, control in humans. The variations in circulating ghrelin levels induced by PD and PZ are unlikely to mediate the cholinergic influence on GH secretion

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

DEFINIZIONE DEL RUOLO DELLA TRANSGLUTAMINASI DI TIPO 2 (TG2) IN CANCRO E SEGNALAZIONE CELLULARE

La Transglutaminasi di Tipo 2 (TG2) è un enzima ubiquitario multifunzionale implicato nella regolazione di numerose vie di segnalazione cellulari che supportano la sopravvivenza, la morte e l’omeostasi delle cellule eucariotiche. Considerando le sue multiple localizzazioni sia all’interno che all’esterno della cellula, la TG2 prende parte nella regolazione di numerosi cascate di segnale intracellulari in maniera tessuto- e cellula-specifica, rendendo questo enzima un fattore importante nello sviluppo e nella progressione di diverse patologie. Nei tumori, il ruolo di TG2 è altamente dibattuto. Inizialmente associato a funzioni pro-apoptotiche, la TG2 è stata anche descritta come un oncogene. Per far luce su queste controversie, la mia ricerca si è focalizzata sulla comprensione dei ruoli svolti da questo enzima nel contesto tumorale. Di recente abbiamo dimostrato che l’espressione di TG2 regola la via di segnale del Wnt, un importante fattore per lo sviluppo e la morfogenesi dei vertebrati. Considerando la funzione critica del Wnt nella regolazione degli hallmark tumorali, abbiamo voluto chiarire il ruolo di TG2 nella tumorigenesi e verificare se questo dipendeva dall’asse TG2-Wnt. A tale scopo, abbiamo condotto studi di meta-analisi su database pubblici i quali hanno rivelato che TG2 esercita un ruolo prognostico positivo solamente in un tipo di cancro su 32 considerati, ovvero il melanoma cutaneo. Ad oggi, pochi e contrastanti dati descrivono la funzione dell’espressione di TG2 nel melanoma cutaneo, ma nessuno di essi permette di comprendere il ruolo prognostico di questa proteina in questo tipo di tumore. Combinando dati di bionformatica e analisi multi-omiche con validazioni in vitro ed in vivo abbiamo scoperto la presenza di un asse TG2-MITF che regola l’eterogeneità intratumorale del melanoma, modulando il “phenotypic switch” e spingendo verso il differenziamento delle cellule di melanoma. Ulteriori analisi bioinformatiche hanno rivelato un’associazione fortemente positiva tra l’espressione di TG2 e la risposta immunitaria anti-tumorale, suggerendo che la TG2 potrebbe essere considerata un nuovo promettente biomarcatore di prognosi in melanoma, contribuendo ad identificare i pazienti che trarrebbero maggior beneficio dall’utilizzo dell’immunoterapia. Da queste nuove scoperte, l’identificazione di questo intricato reticolo di interazioni rappresenta un fondamentale elemento predittivo che potrebbe aprire la strada per comprendere nuove vulnerabilità del melanoma e definire meglio il ruolo che questo enigmatico enzima gioca nel contesto tumorale.Transglutaminase type 2 (TG2) is an ubiquitous multifunctional enzyme implicated in the regulation of several cellular pathways that support survival, death, and general homeostasis of eukaryotic cells. Due to its multiple localizations both inside and outside the cell, TG2 participates in the regulation of many crucial intracellular signaling cascades in a tissue- and cell-specific manner, making this enzyme an important player in disease development and progression. In malignancies, TG2 role is currently highly debated. Initially associated with pro-apoptotic functions, TG2 has also been described as an oncogene. To shed light on such controversies, my research focused on understanding the role of this enzyme in the tumour context. Recently, we demonstrated that TG2 expression regulates the Wnt signaling pathway, which is important for vertebrate development and morphogenesis. Considering the critical function of Wnt in regulating cancer hallmarks, we wished to better elucidate the role TG2 plays on tumorigenesis and check if it depended on the TG2-Wnt axis. To this aim, we conducted meta-analysis studies on publicly available datasets, which revealed that TG2 exerts a positive prognostic value in only one out of 32 cancer-types, namely Skin Cutaneous Melanoma (SKCM). To date, very few and contrasting results depicted the function of TG2 expression in SKCM, but none of them allows to comprehend the prognostic value of the protein in this type of tumour. By combining bioinformatic analyses and multi-omics profiling with in vitro and in vivo validations, we discovered the presence of a TG2-MITF axis that regulates melanoma intra-tumor heterogeneity by modulating the “phenotypic switch” and driving melanoma cells differentiation. Further bioinformatic analyses revealed a strong positive association between TG2 expression and anti-tumoral immune response, suggesting that TG2 may be presented as a new promising immune biomarker of prognosis in SKCM, which may contribute to identifying patients who would benefit the most from adjuvant immunotherapy. According to the novel findings summarized above, discovering this intricate reticulum of interactions represents an invaluable predictive element which could pave the way for unraveling melanoma vulnerabilities and better understanding the role that this enigmatic enzyme plays in a tumor context

From rod-like to disc-like Gay–Berne biaxial nematics and back

By means of Monte Carlo simulations at constant pressure and temperature, the phase behaviour of pure systems of soft biaxial Gay–Berne ellipsoids, prototypical models for thermotropic mesogens, was determined as a function of temperature and three different pressures. To reduce the number of free shape and energy parameters to only one, the medium ellipsoid axis σx, particles possessing identical total volume and length σz were studied, with interactions parameterised in terms of products of axes lengths. The resulting phase diagrams present a variety of crystalline and liquid crystalline phases characterised by different biaxiality and preferential axis alignment, with GB particles behaving like rods for more elongated shapes, and like discs for more squashed ones. In agreement with previous simulation and theoretical studies using simpler models, the transition between rod to disc behaviour (and back) occurs approximately when the so-called dual-shape condition is reached, i.e. when σx = √σyσz. This shape ideally identifies also the position of a Landau point, in which at a specific temperature, isotropic, calamitic nematic, discotic nematic, and biaxial nematic may coexist, and hence a direct isotropic to biaxial nematic transition could in principle occur. We did not observe such event in our simulations

Promising prognostic value of Transglutaminase type 2 and its correlation with tumor-infiltrating immune cells in skin cutaneous melanoma

Tissue Transglutaminases (TGs) are crosslinking enzymes with pleiotropic functions that have been linked to the development and progression of numerous cancers, with a recent focus on their ability to remodel the tumor microenvironment. Although several pieces of evidence demonstrated their importance in the regulation of the major signaling pathways that control oncogenesis, the correlation between TGs with clinical and pathological features remains controversial and to be further explored. Moreover, an assessment of the TGs alterations together with a functional analysis associated with clinical features and prognostic values are still lacking and would help to understand these intricacies, particularly in human cancers. In the present study, we processed data from numerous public datasets to investigate TGs distribution and prognostic signature in cancer patients. Here, we found that skin cutaneous melanoma (SKCM) shows the highest abundance of TGs mutations among the other human cancers. Interestingly, among all the TGs, TG2 is the only member whose expression is associated with a better overall survival in SKCM, although its expression increases with the worsening of the tumor phenotype. Our analysis revealed a strong positive association between TG2 expression and anti-tumoral immune response, which would explain the relationship between high mRNA levels and better overall survival. Our data suggest that TG2 may be presented as a new promising immune biomarker of prognosis in SKCM, which may contribute to identifying patients who would benefit the most from adjuvant immunotherapy

A Meta-Analysis Study to Infer Voltage-Gated K+ Channels Prognostic Value in Different Cancer Types

: Potassium channels are often highly expressed in cancer cells with respect to healthy ones, as they provide proliferative advantages through modulating membrane potential, calcium homeostasis, and various signaling pathways. Among potassium channels, Shaker type voltage-gated Kv channels are emerging as promising pharmacological targets in oncology. Here, we queried publicly available cancer patient databases to highlight if a correlation exists between Kv channel expression and survival rate in five different cancer types. By multiple gene comparison analysis, we found a predominant expression of KCNA2, KCNA3, and KCNA5 with respect to the other KCNA genes in skin cutaneous melanoma (SKCM), uterine corpus endometrial carcinoma (UCEC), stomach adenocarcinoma (STAD), lung adenocarcinoma (LUAD), and lung squamous cell carcinoma (LUSC). This analysis highlighted a prognostic role of KCNA3 and KCNA5 in SKCM, LUAD, LUSC, and STAD, respectively. Interestingly, KCNA3 was associated with a positive prognosis in SKCM and LUAD but not in LUSC. Results obtained by the analysis of KCNA3-related differentially expressed genes (DEGs); tumor immune cell infiltration highlighted differences that may account for such differential prognosis. A meta-analysis study was conducted to investigate the role of KCNA channels in cancer using cancer patients' datasets. Our study underlines a promising correlation between Kv channel expression in tumor cells, in infiltrating immune cells, and survival rate

Mimicking electrostatic interactions with a set of effective charges. A genetic algorithm

We present a genetic algorithm apt to determine a set of effective charges that approximate the electrostatic field around a molecule. We show that these charges provide a reasonably good approximation to the pair electrostatic interaction and argue that the method should provide a valuable tool in computer simulations of condensed phases, particularly liquid crystals