The air that we breathe contains nearly 21% oxygen, most of which is utilized by mitochondria during respiration. While we cannot live without it, it was perceived as a bane to aerobic organisms due ...to the generation of reactive oxygen and nitrogen metabolites by mitochondria and other cellular compartments. However, this dogma was challenged when these species were demonstrated to modulate cellular responses through altering signaling pathways. In fact, since this discovery of a dichotomous role of reactive species in immune function and signal transduction, research in this field grew at an exponential pace and the pursuit for mechanisms involved began. Due to a significant number of review articles present on the reactive species mediated cell death, we have focused on emerging novel pathways such as autophagy, signaling and maintenance of the mitochondrial network. Despite its role in several processes, increased reactive species generation has been associated with the origin and pathogenesis of a plethora of diseases. While it is tempting to speculate that anti-oxidant therapy would protect against these disorders, growing evidence suggests that this may not be true. This further supports our belief that these reactive species play a fundamental role in maintenance of cellular and tissue homeostasis.
The 2019 novel coronavirus (2019-nCoV/SARS-CoV-2) originally arose as part of a major outbreak of respiratory disease centered on Hubei province, China. It is now a global pandemic and is a major ...public health concern. Taxonomically, SARS-CoV-2 was shown to be a Betacoronavirus (lineage B) closely related to SARS-CoV and SARS-related bat coronaviruses, and it has been reported to share a common receptor with SARS-CoV (ACE-2). Subsequently, betacoronaviruses from pangolins were identified as close relatives to SARS-CoV-2. Here, we perform structural modeling of the SARS-CoV-2 spike glycoprotein. Our data provide support for the similar receptor utilization between SARS-CoV-2 and SARS-CoV, despite a relatively low amino acid similarity in the receptor binding module. Compared to SARS-CoV and all other coronaviruses in Betacoronavirus lineage B, we identify an extended structural loop containing basic amino acids at the interface of the receptor binding (S1) and fusion (S2) domains. We suggest this loop confers fusion activation and entry properties more in line with betacoronaviruses in lineages A and C, and be a key component in the evolution of SARS-CoV-2 with this structural loop affecting virus stability and transmission.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 19 (COVID-19) has rapidly spread to the entire world within a few months. The origin of ...SARS-CoV-2 has been related to the lineage B Betacoronavirus SARS-CoV and SARS-related coronaviruses found in bats. Early characterizations of the SARS-CoV-2 genome revealed the existence of a distinct four amino acid insert within the spike (S) protein (underlined, SPRRAR↓S), at the S1/S2 site located at the interface between the S1 receptor binding subunit and the S2 fusion subunit. Notably, this insert appears to be a distinguishing feature among SARS-related sequences and introduces a potential cleavage site for the protease furin. Here, we investigate the potential role of this novel S1/S2 cleavage site and present direct biochemical evidence for proteolytic processing by a variety of proteases. We discuss these findings in the context of the origin of SARS-CoV-2, viral stability, and transmission.
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•SARS-CoV-2 spike protein harbors a distinct four amino acid insertion at the S1/S2 site•The S1/S2 site can be cleaved by furin-like, trypsin-like, and cathepsin proteases•The S1/S2 insert likely enhances spike protein cleavage by several proteases in vivo
Biochemistry; Virology
•Coronaviruses are wide-ranging diseases in humans and animals.•SARS-CoV-2 is a bat-origin zoonotic coronavirus causing the COViD-19 pandemic.•SARS-CoV-2 can also infect cats and ferrets and has been ...detected in dogs.•The SARS-CoV-2 receptor ACE2 is highly similar between cats and humans.
Coronaviruses (CoVs) cause disease in a range of agricultural and companion animal species, and can be important causes of zoonotic infections. In humans, several coronaviruses circulate seasonally. Recently, a novel zoonotic CoV named SARS-CoV-2 emerged from a bat reservoir, resulting in the COVID-19 pandemic. With a focus on felines, we review here the evidence for SARS-CoV-2 infection in cats, ferrets and dogs, describe the relationship between SARS-CoV-2 and the natural coronaviruses known to infect these species, and provide a rationale for the relative susceptibility of these species to SARS-CoV-2 through comparative analysis of the ACE-2 receptor.
Long-Term Renal Outcomes after Cisplatin Treatment Latcha, Sheron; Jaimes, Edgar A; Patil, Sujata ...
Clinical journal of the American Society of Nephrology,
07/2016, Letnik:
11, Številka:
7
Journal Article
Recenzirano
Odprti dostop
Nephrotoxicity remains the dose-limiting side effect of cisplatin, an effective chemotherapeutic agent with applications across diverse tumor types. This study presents data on renal outcomes across ...multiple tumor types in 821 adults. We report on incidence of AKI, initial and long-term changes in eGFR after cisplatin, and relationships between cumulative dose, initial eGFR, age, sex, and long-term renal function.
This was a retrospective study of adult patients treated with cisplatin from January 1, 2000 to September 21, 2011 who had survived ≥5 years after initial dose. The Modification of Diet in Renal Disease equation was used to calculate eGFR. AKI was defined as an increase from the baseline creatinine of >25% within 30 days after the first cycle of cisplatin. Chi-squared tests were done to evaluate the relationships between categorical or ordinal variables; ANOVAs or t tests were used to evaluate continuous or categorical variables. Changes in eGFR over time were evaluated in a growth curve model.
Mean follow-up was 6 years (25th and 75th percentiles, 4 and 9 years). AKI occurred in 31.5% of patients, with a median initial decline in eGFR of 10 ml/min per 1.73 m(2) (25th and 75th percentiles, -41.5 and -23.3 ml/min per 1.73 m(2)). At any time point after the first cycle of cisplatin, <3% of patients progressed to eGFR<29 ml/min per 1.73 m(2), and none were known to be on dialysis. Age was associated with a higher risk for AKI after cisplatin. Compared with age <25 years old, the odds ratios for AKI versus no AKI are 1.22 for >26-44 years old (95% confidence interval 95% CI, 0.60 to 2.4), 1.54 for >45-65 years old (95% CI, 0.78 to 3), and 2.96 for >66 years old (95% CI, 1.4 to 6.1). The lowest dose categories of cisplatin (≤100 and 101-250 mg/m(2)) are associated with increases in eGFR (P=0.06 and P=0.02, respectively) compared with the highest dose category (>701 mg/m(2)).
This is the largest study of adult patients with cancer who received cisplatin for treatment across multiple tumor types. Most patients experience small but permanent declines in eGFR, but none progressed to ESRD requiring hemodialysis.
Abstract
The human lens plays a crucial role in the vision process, since it is responsible for the accommodation mechanism and for the reduction of optical aberrations. Its modeling is important for ...the comprehension of the relationship between its physiological and optical properties, and ultimately for ophthalmic purposes. In this work we propose a modified version of the Poisson-Gauss function to construct a lens model that permits the fine-tuning of optical properties of the corresponding schematic eye. Particularly, we analyze how the refractive power of a schematic eye varies as the modification of the Poisson-Gauss function is induced. This can be useful in the modeling of personalized eyes with ophthalmic relevance.
Feline coronavirus (FCoV) is a complex viral agent that causes a variety of clinical manifestations in cats, commonly known as feline infectious peritonitis (FIP). It is recognized that FCoV can ...occur in two different serotypes. However, differences in the S protein are much more than serological or antigenic variants, resulting in the effective presence of two distinct viruses. Here, we review the distinct differences in the S proteins of these viruses, which are likely to translate into distinct biological outcomes. We introduce a new concept related to the non-taxonomical classification and differentiation among FCoVs by analyzing and comparing the genetic, structural, and functional characteristics of FCoV and the FCoV S protein among the two serotypes and FCoV biotypes. Based on our analysis, we suggest that our understanding of FIP needs to consider whether the presence of these two distinct viruses has implications in clinical settings.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the agent causing the COVID-19 pandemic. SARS-CoV-2 B.1.1.7 (Alpha), a WHO variant of concern first identified in the United Kingdom in ...late 2020, contains several mutations including P681H in the spike S1/S2 cleavage site, which is predicted to increase cleavage by furin, potentially impacting the viral cell entry. Here, we studied the role of the P681H mutation in B.1.1.7 cell entry. We performed assays using fluorogenic peptides mimicking the Wuhan-Hu-1 and B.1.1.7 S1/S2 sequence and observed no significant difference in furin cleavage. Functional assays using pseudoparticles harboring SARS-CoV-2 spikes and cell-to-cell fusion assays demonstrated no differences between Wuhan-Hu-1, B.1.1.7, or a P681H point mutant. Likewise, we observed no differences in viral growth between USA-WA1/2020 and a B.1.1.7 isolate in cell culture. Our findings suggest that, although the B.1.1.7 P681H mutation may slightly increase S1/S2 cleavage, this does not significantly impact viral entry or cell-cell spread.
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•SARS-CoV-2 B.1.1.7 P681H mutation in the spike is predicted to enhance viral infection•P681H does not significantly impact furin cleavage, viral entry, or cell-cell spread•Other mutations in the SARS-CoV-2 B.1.1.7 VOC may account for increased infection rates
Virology
This study tests the geometrical parameterization method for Electrical Bio-Impedance Spectroscopy (EBIS) readings previously proposed by one of the authors. This method uses the data of just three ...frequencies (therefore called 3P method). The test was carried out by the analysis of parameterization from 26 spectra (selected from 13 data sets) by the non-linear square (NLS) method, the 3P method and a combination of the two (3P-NLS). Additionally, the behaviour of the 3P method for 4 levels of noise and 3 different ways of segmenting the spectra were also explored with a MATLAB simulation of 400 spectra. Finally, a system for the classification of EBIS readings is presented, based on deviations of the raw data from the semi-circle obtained by the parameterization methods. Overall, the results suggest a very good performance of the 3P method when compared with the other two. The 3P method performs very well with levels of noise of 1 and 2%, but performs poorly with levels of noise of 5% and 10%. The results support the idea that the 3P method could be used with confidence for the parameterization of EBIS spectra, after the selection of three adequate frequencies according to specific applications.
Microalbuminuria is an important clinical marker of several cardiovascular, metabolic, and other diseases such as diabetes, hypertension, atherosclerosis, and cancer. The accurate detection of ...microalbuminuria relies on albumin quantification in the urine, usually via an immunoturbidity assay; however, like many antibody-based assessments, this method may not be robust enough to function in global health applications, point-of-care assays, or wearable devices. Here, we develop an antibody-free approach using synthetic molecular recognition by constructing a polymer to mimic fatty acid binding to the albumin, informed by the albumin crystal structure. A single-walled carbon nanotube, encapsulated by the polymer, as the transduction element produces a hypsochromic (blue) shift in photoluminescence upon the binding of albumin in clinical urine samples. This complex, incorporated into an acrylic material, results in a nanosensor paint that enables the detection of microalbuminuria in patient samples and comprises a rapid point-of-care sensor robust enough to be deployed in resource-limited settings.
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