Pathophysiological Mechanisms In Gaseous Therapies For Severe Malaria

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Over 200 million people worldwide suffer from malaria every year, a disease that causes 584,000 deaths annually. In recent years, significant improvements have been achieved on the treatment of severe malaria, with intravenous artesunate proving superior to quinine. However, mortality remains high, at 8% in children and 15% in adults in clinical trials, and even worse in the case of cerebral malaria (18% and 30%, respectively). Moreover, some individuals who do not succumb to severe malaria present long-term cognitive deficits. These observations indicate that strategies focused only on parasite killing fail to prevent neurological complications and deaths associated with severe malaria, possibly because clinical complications are associated in part with a cerebrovascular dysfunction. Consequently, different adjunctive therapies aimed at modulating malaria pathophysiological processes are currently being tested. However, none of these therapies has shown unequivocal evidence in improving patient clinical status. Recently, key studies have shown that gaseous therapies based mainly on nitric oxide (NO), carbon monoxide (CO), and hyperbaric (pressurized) oxygen (HBO) alter vascular endothelium dysfunction and modulate the host immune response to infection. Considering gaseous administration as a promising adjunctive treatment against severe malaria cases, we review here the pathophysiological mechanisms and the immunological aspects of such therapies.844874882HHS \ National Institutes of Health (NIH) [AI118302-02]MCTI \ Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Fabio Trindade Maranhao Costa [2012/16525-2]Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ)Carvalho through a Cientista do Nosso Estado fellowshipConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

Pathophysiological Mechanisms In Gaseous Therapies For Severe Malaria.

Over 200 million people worldwide suffer from malaria every year, a disease that causes 584,000 deaths annually. In recent years, significant improvements have been achieved on the treatment of severe malaria, with intravenous artesunate proving superior to quinine. However, mortality remains high at 8% in children and 15% in adults in clinical trials, and even worse in the case of cerebral malaria (18% and 30%, respectively). Moreover, some individuals who do not succumb to severe malaria present long-term cognitive deficits. These observations indicate that strategies focused only on parasite killing fail to prevent neurological complications and deaths associated with severe malaria, possibly because clinical complications are associated in part with a cerebrovascular dysfunction. Consequently, different adjunctive therapies aimed at modulating malaria pathophysiological processes are currently being tested. However, none of these therapies has shown unequivocal evidence in improving patients' clinical status. Recently, key studies have shown that gaseous therapies based mainly on nitric oxide (NO), carbon monoxide (CO) and hyperbaric (pressurized) oxygen (HBO) alter vascular endothelium dysfunction and modulate host immune response to infection. Considering gaseous administration as a promising adjunctive treatment against severe malaria cases, we review here the pathophysiological mechanisms and the immunological aspects of such therapies.8

Search for dinucleon decay into pions at Super-Kamiokande

A search for dinucleon decay into pions with the Super-Kamiokande detector has been performed with an exposure of 282.1 kiloton-years. Dinucleon decay is a process that violates baryon number by two units. We present the first search for dinucleon decay to pions in a large water Cherenkov detector. The modes $^{16}$O$(pp) \rightarrow$ $^{14}$C$\pi^{+}\pi^{+}$, $^{16}$O$(pn) \rightarrow$ $^{14}$N$\pi^{+}\pi^{0}$, and $^{16}$O$(nn) \rightarrow$ $^{14}$O$\pi^{0}\pi^{0}$ are investigated. No significant excess in the Super-Kamiokande data has been found, so a lower limit on the lifetime of the process per oxygen nucleus is determined. These limits are: $\tau_{pp\rightarrow\pi^{+}\pi^{+}} > 7.22 \times 10^{31}$ years, $\tau_{pn\rightarrow\pi^{+}\pi^{0}} > 1.70 \times 10^{32}$ years, and $\tau_{nn\rightarrow\pi^{0}\pi^{0}} > 4.04 \times 10^{32}$ years. The lower limits on each mode are about two orders of magnitude better than previous limits from searches for dinucleon decay in iron.Comment: 20 pages, 17 figures. Accepted for publication in Physical Review D on March 30, 201

Multiscale Interactions of climate variability and rainfall in the Sogamoso River Basin: Implications for the 1998–2000 and 2010–2012 multiyear La Niña events

In this research, we explored rainfall variability in the Sogamoso River Basin (SRB), its relationship with multiple scales of variability associated with El Niño–Southern Oscillation (ENSO), and the implications for rainfall prolongation during multiyear La Niña events. First, we examined time-frequency rainfall variations in the SRB based on the standardized precipitation index (SPI) from 1982 to 2019, using wavelet transform and principal component analysis (PCA). In addition, we applied wavelet analysis to investigate the links at different time scales between ENSO and the main mode of rainfall variability in the SRB. Finally, we explored the role that each scale of variability played in the prolongation and intensity of rainfall in the SRB during the 1998–2000 and 2010–2012 multiyear La Niña events. The results of the wavelet analyses revealed significant ENSO relationships affecting SRB rainfall at three different scales: quasi-biennial (2–3-years) between 1994 and 2002, as well as from 2008 to 2015; interannual (5–7 years) from 1995 to 2011; and quasidecadal (9–12 years) from 1994 to 2012. This indicates that multiyear events are a consequence of the interaction of several scales of variability rather than a unique scale. During the 1998–2000 event, El Niño conditions were observed during the first half of 1998; subsequently, a cooling of the central and eastern tropical Pacific (western tropical Pacific) on the quasi-biennial (interannual) scale was observed during 1999; in 2000, only La Niña conditions were observed on the interannual scale. Therefore, during this event, the quasi-biennial (interannual) scale promoted wet conditions in the Caribbean, the Andes, and the Colombian Pacific from June–August (JJA) 1998 to JJA 1999 (during 1999–2000). During the 2010–2012 La Niña event, the interbasin sea surface temperature gradient between the tropical Pacific and tropical North Atlantic contributed to strengthening (weakening) of the Choco jet (Caribbean low-level jet) on the quasi-biennial scale during 2010, and the interannual scale prolonged its intensification (weakening) during 2011–2012, acting to extend the rainy periods over most of the Colombian territory. Variations on quasi-decadal scales were modulated by the Pacific decadal oscillation (PDO), resulting in a further intensification of the 2010–2012 La Niña event, which developed under conditions of the cold PDO (CPDO) phase, whereas the 1998–2000 La Niña occurred during the transition from warm (WPDO, 1977–1998) to cold (CPDO, 2001–2015) conditions. These results indicate that the interaction of quasi-biennial to quasi-decadal scales of variability could play a differential role in the configuration and prolongation of rainfall events in the SRB

The uronic acid content of coccolith-associated polysaccharides provides insight into coccolithogenesis and past climate

Unicellular phytoplanktonic algae (coccolithophores) are among the most prolific producers of calcium carbonate on the planet, with a production of ∼1026 coccoliths per year. During their lith formation, coccolithophores mainly employ coccolith-associated polysaccharides (CAPs) for the regulation of crystal nucleation and growth. These macromolecules interact with the intracellular calcifying compartment (coccolith vesicle) through the charged carboxyl groups of their uronic acid residues. Here we report the isolation of CAPs from modern day coccolithophores and their prehistoric predecessors and we demonstrate that their uronic acid content (UAC) offers a species-specific signature. We also show that there is a correlation between the UAC of CAPs and the internal saturation state of the coccolith vesicle that, for most geologically abundant species, is inextricably linked to carbon availability. These findings suggest that the UAC of CAPs reports on the adaptation of coccolithogenesis to environmental changes and can be used for the estimation of past CO2 concentrations

A General Model for Multilocus Epistatic Interactions in Case-Control Studies

Background: Epistasis, i.e., the interaction of alleles at different loci, is thought to play a central role in the formation and progression of complex diseases. The complexity of disease expression should arise from a complex network of epistatic interactions involving multiple genes. Methodology: We develop a general model for testing high-order epistatic interactions for a complex disease in a casecontrol study. We incorporate the quantitative genetic theory of high-order epistasis into the setting of cases and controls sampled from a natural population. The new model allows the identification and testing of epistasis and its various genetic components. Conclusions: Simulation studies were used to examine the power and false positive rates of the model under different sampling strategies. The model was used to detect epistasis in a case-control study of inflammatory bowel disease, in which five SNPs at a candidate gene were typed, leading to the identification of a significant three-locus epistasis