Diametrically opposed effects of hypoxia and oxidative stress on two viral transactivators

<p>Abstract</p> <p>Background</p> <p>Many pathogens exist in multiple physiological niches within the host. Differences between aerobic and anaerobic conditions are known to alter the expression of bacterial virulence factors, typically through the conditional activity of transactivators that modulate their expression. More recently, changes in physiological niches have been shown to affect the expression of viral genes. For many viruses, differences in oxygen tension between hypoxia and normoxia alter gene expression or function. Oxygen tension also affects many mammalian transactivators including AP-1, NFkB, and p53 by affecting the reduced state of critical cysteines in these proteins. We have recently determined that an essential cys-x-x-cys motif in the EBNA1 transactivator of Epstein-Barr virus is redox-regulated, such that transactivation is favoured under reducing conditions. The crucial Tat transactivator of human immunodeficiency virus (HIV) has an essential cysteine-rich region, and is also regulated by redox. Contrary to EBNA1, it is reported that Tat's activity is increased by oxidative stress. Here we have compared the effects of hypoxia, oxidative stress, and cellular redox modulators on EBNA1 and Tat.</p> <p>Results</p> <p>Our results indicate that unlike EBNA1, Tat is less active during hypoxia. Agents that generate hydroxyl and superoxide radicals reduce EBNA1's activity but increase transactivation by Tat. The cellular redox modulator, APE1/Ref-1, increases EBNA1's activity, without any effect on Tat. Conversely, thioredoxin reductase 1 (TRR1) reduces Tat's function without any effect on EBNA1.</p> <p>Conclusions</p> <p>We conclude that oxygen partial pressure and oxidative stress affects the functions of EBNA1 and Tat in a dramatically opposed fashion. Tat is more active during oxidative stress, whereas EBNA1's activity is compromised under these conditions. The two proteins respond to differing cellular redox modulators, suggesting that the oxidized cysteine adduct is a disulfide bond(s) in Tat, but sulfenic acid in EBNA1. The effect of oxygen partial pressure on transactivator function suggests that changes in redox may underlie differences in virus-infected cells dependent upon the physiological niches they traffic to.</p

Pilus distribution among lineages of group b <i>streptococcus</i>: an evolutionary and clinical perspective

&lt;b&gt;Background&lt;/b&gt;&lt;p&gt;&lt;/p&gt; Group B Streptococcus (GBS) is an opportunistic pathogen in both humans and bovines. Epidemiological and phylogenetic analyses have found strains belonging to certain phylogenetic lineages to be more frequently associated with invasive newborn disease, asymptomatic maternal colonization, and subclinical bovine mastitis. Pilus structures in GBS facilitate colonization and invasion of host tissues and play a role in biofilm formation, though few large-scale studies have estimated the frequency and diversity of the three pilus islands (PIs) across diverse genotypes. Here, we examined the distribution of pilus islands (PI) 1, 2a and 2b among 295 GBS strains representing 73 multilocus sequence types (STs) belonging to eight clonal complexes. PCR-based RFLP was also used to evaluate variation in the genes encoding pilus backbone proteins of PI-2a and PI-2b.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Results&lt;/b&gt;&lt;p&gt;&lt;/p&gt; All 295 strains harbored one of the PI-2 variants and most human-derived strains contained PI-1. Bovine-derived strains lacked PI-1 and possessed a unique PI-2b backbone protein allele. Neonatal strains more frequently had PI-1 and a PI-2 variant than maternal colonizing strains, and most CC-17 strains had PI-1 and PI-2b with a distinct backbone protein allele. Furthermore, we present evidence for the frequent gain and loss of genes encoding certain pilus types.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Conclusions&lt;/b&gt;&lt;p&gt;&lt;/p&gt; These data suggest that pilus combinations impact host specificity and disease presentation and that diversification often involves the loss or acquisition of PIs. Such findings have implications for the development of GBS vaccines that target the three pilus islands

性、勞動與新工會主義 : 荷安柏與辛尼帕爾一席談

這場對話是 1999 年 4 月 30 日在辛尼帕爾於紐約大學的辦公室中進行

Correction: Printable and flexible electronics: from TFTs to bioelectronic devices

Correction for 'Printable and flexible electronics: from TFTs to bioelectronic devices' by M. Magliulo et al., J. Mater. Chem. C, 2015, 3, 12347–12363

Semicircular canal size constrains vestibular function in miniaturized frogs

Miniaturization has evolved repeatedly in frogs in the moist leaf litter environments of rainforests worldwide. Miniaturized frogs are among the world’s smallest vertebrates and exhibit an array of enigmatic features. One area where miniaturization has predictable consequences is the vestibular system, which acts as a gyroscope, providing sensory information about movement and orientation. We investigated the vestibular system of pumpkin toadlets, Brachycephalus (Anura: Brachycephalidae), a clade of miniaturized frogs from Brazil. The semicircular canals of miniaturized frogs are the smallest recorded for adult vertebrates, resulting in low sensitivity to angular acceleration due to insufficient displacement of endolymph. This translates into a lack of postural control during jumping in Brachycephalus and represents a physical constraint resulting from Poiseuille’s law, which governs movement of fluids within tubes

A Decade of Change: An Institutional Experience with Breast Surgery in 1995 and 2005

Introduction: With the adoption of routine screening mammography, breast cancers are being diagnosed at earlier stages, with DCIS now accouting for 22.5% of all newly diagnosed breast cancers. This has been attributed to both increased breast cancer awareness and improvements in breast imaging techniques. How have these changes, including the increased use of image-guided sampling techniques, influenced the clinical practice of breast surgery?Methods: The institutional pathology database was queried for all breast surgeries, including breast reconstruction, performed in 1995 and 2005. Cosmetic procedures were excluded. The results were analysed utilizing the Chi-square test.Results: Surgical indications changed during 10-year study period, with an increase in preoperatively diagnosed cancers undergoing definitive surgical management. ADH, and to a lesser extent, ALH, became indications for surgical excision. Fewer surgical biopsies were performed for indeterminate abnormalities on breast imaging, due to the introduction of stereotactic large core biopsy. While the rate of benign breast biopsies remained constant, there was a higher percentage of precancerous and DCIS cases in 2005. The overall rate of mastectomy decreased from 36.8% in 1995 to 14.5% in 2005. With the increase in sentinel node procedures, the rate of ALND dropped from 18.3% to 13.7%. Accompanying the increased recognition of early-stage cancers, the rate of positive ALND also decreased, from 43.3% to 25.0%.Conclusions: While the rate of benign breast biopsies has remained constant over a recent 10-year period, fewer diagnostic surgical image-guided biopsies were performed in 2005. A greater percentage of patients with breast cancer or preinvasive disease have these diagnoses determined before surgery. More preinvasive and Stage 0 cancers are undergoing surgical management. Earlier stage invasive cancers are being detected, reflected by the lower incidence of axillary nodal metastases

Persistent organic pollutants (POPs) increase rage signaling to promote downstream cardiovascular remodeling

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. Background: Antimicrobial resistance (AMR) is a global threat and the antimicrobial stewardship program (ASP) is a globally used tool to combat AMR. There is little information on the views among Pakistani physicians regarding AMR and the benefits of hospital antimicrobial stewardship implementation. This study was designed to explore the physicians’ views about ASP. Methods: Qualitative face-to-face and telephonic interviews were conducted by using purposive sampling method with 22 physicians working in seven tertiary care public hospitals of Punjab, Pakistan. All interviews were audio recorded and transcribed verbatim. Qualitative software was used, and a thematic analysis was conducted. Results: Three broad themes were identified: (1) the growing concern of antimicrobial resistance in Pakistan, (2) the role(s) of healthcare professionals in antibiotic prescribing, and (3) managing antibiotic resistance in hospitals. Inadequate resources, poor healthcare facilities, and insufficiently trained medical staff were the major hurdles in ASP implementation in Pakistan. Conclusions: Our study found a poor familiarity of hospital ASP among physicians working in public sector tertiary care teaching hospitals, and a number of distinct themes emerged during this study that could be helpful in establishing the concept of hospital ASP in Pakistan. Overall, physicians showed a positive attitude towards the enforcement of ASP in all healthcare settings, including teaching hospitals

Mixed invasive fungal infections among COVID-19 patients

Background and Purpose: The healthcare system in India collapsed during the secondwave of the COVID-19 pandemic. A fungal epidemic was announced amid the pandemic with several cases of COVID-associated mucormycosis and pulmonary aspergillosis being reported. However, there is limited data regarding mixed fungal infections in COVID-19 patients. Therefore, we present a series of ten consecutive COVID-19 patients with mixed invasive fungal infections (MIFIs).Materials and Methods: Among COVID-19 patients hospitalized in May 2021 at atertiary care center in North India, 10 cases of microbiologically confirmed COVID-19-associated mucormycosis-aspergillosis (CAMA) were evaluated.Results: All patients had diabetes and the majority of them were infected with severeCOVID-19 pneumonia (6/10, 60%) either on admission or in the past month while twowere each of moderate (20%) and mild (20%) categories of COVID-19; and were treatedwith steroid and cocktail therapy. The patients were managed with amphotericin-B along with surgical intervention. In total, 70% of all CAMA patients (Rhizopus arrhizus with Aspergillus flavus in seven and Aspergillus fumigatus complex in three patients)survived.Conclusion: The study findings reflected the critical importance of a high index ofclinical suspicion and accurate microbiological diagnosis in managing invasive dualmolds and better understanding of the risk and progression of MIFIs among COVID-19patients. Careful scrutiny and identification of MIFIs play a key role in theimplementation of effective management strategies