Title: AHA News: If You Think Before You Snack, It's Not So Bad
Category: Health News
Created: 3/26/2020 12:00:00 AM
Last Editorial Review: 3/27/2020 12:00:00 AM

Title: On Some Farms, Washing Machines Give Leafy Greens a Spin -- But Is That Safe?
Category: Health News
Created: 4/24/2020 12:00:00 AM
Last Editorial Review: 4/24/2020 12:00:00 AM

Title: The Sooner Young Smokers Start, The Less Likely They Are to Quit
Category: Health News
Created: 4/13/2020 12:00:00 AM
Last Editorial Review: 4/14/2020 12:00:00 AM

Title: All That Social Media Hasn't Hurt Kids' Social Skills, Study Finds
Category: Health News
Created: 4/17/2020 12:00:00 AM
Last Editorial Review: 4/17/2020 12:00:00 AM

Title: Is Coronavirus Also Sexually Transmitted?
Category: Health News
Created: 5/7/2020 12:00:00 AM
Last Editorial Review: 5/8/2020 12:00:00 AM

Title: Thousands of COVID-19 Cases Among Inmates and Staff at U.S. Prisons and Jails: CDC
Category: Health News
Created: 5/7/2020 12:00:00 AM
Last Editorial Review: 5/8/2020 12:00:00 AM

A new consensus document provides guidance on the safe reintroduction of cardiovascular procedures and testing derailed by the COVID-19 pandemic.

COVID-19 has led the ESC to transition its annual congress to a virtual format; ESC 2020 Congress 'Challenging Times, Infinite Possibilities' will run online from August 29 to September 1.

The most recent meeting of the PMC Advisory Committee was held at the National Library of Medicine on June 15, 2009. The committee meets at least once a year and its members are appointed by the NIH Director from the biomedical information communities and the general public. Dr. Gary Ward, of the Department of Microbiology & Molecular Genetics at the University of Vermont, has been appointed to serve as Chair of the Committee through January 2011.

Four new members have been appointed to serve on the PMC National Advisory Committee: Mike Rossner of Rockefeller University Press, Jan Fassler of the University of Iowa, Ivy Anderson of the California Digital Library, and Delores Meglio from the Knovel Corporation. Each member will serve a 4-year term. The next meeting of the committee is scheduled for June 4, 2010. For more information on the committee, see PMC National Advisory Committee.

Four new members have been appointed to serve on the PMC National Advisory Committee: Philip Bourne, of the University of California, San Diego; Sophia Colamarino, an independent consultant in San Francisco; Paul Courant, of the University of Michigan; and Patricia Thibodeau, of Duke University. Each member will serve a 4-year term. The next meeting of the committee is scheduled for Friday, June 17, 2011. For more information on the committee, see PMC National Advisory Committee.

The PMC Advisory Committee will hold its annual meeting at the National Library of Medicine on Friday, June 17, 2011 from 9:30 am to 3 pm. Four new committee members will be joining the group, see New Members Appointed to PMC Advisory Committee. Presentations will include discussions relating to the NIH Public Access policy and a viewing of the PMC 10th Anniversary video. For more information, see PMC National Advisory Committee.

The following new members have been appointed to serve on the PMC National Advisory Committee: Martha Bedard, Dean of Libraries at the University of New Mexico; and Lorraine Haricombe, Dean of Libraries at the University of Kansas and a member of SPARC's board. The next meeting of the committee is scheduled for June 19, 2012. For more information, see PMC National Advisory Committee.

The Journal Archiving Tag Suite(JATS), known formerly as the NLM DTD, has now been officially adopted as an American National Standards Institute (ANSI)/ National Information Standards Organization (NISO) standard. According to the press release from NISO, "JATS provides a common XML format in which publishers and archives can exchange journal content by preserving the intellectual content of journals independent of the form in which that content was originally delivered." For more information, see NISO Publishes Journal Article Tag Suite (JATS) Standard.

As of February 1, 2013, the following new members have been appointed to serve on the PMC National Advisory Committee: Ms. Sharon Terry of the Genetic Alliance; Dr. C. Victor Jongneel of the University of Illinois at Urbana-Champaign; Dr. Bevin Engelward of the Massachusetts Institute of Technology; Dr. Randall Morse of the Wadsworth Center; and Dr. Adelita Cantu of the University of Texas. For more information, see PMC National Advisory Committee.

This year's PMC Advisory Committee meeting will be held on Tuesday, June 10. The meeting will take place in the NLM Board room starting at 9:30 am. Stay tuned for further details.

In the NLM Strategic Plan released earlier this year, we noted that “[c]reating efficient ways to link the literature with associated datasets enables knowledge generation and discovery.” To that end, PMC is now aggregating data citations, data availability statements and supplementary materials, as available, in an Associated Data box. This box will only display on articles that have one or more of these features in the article.

To limit your search to records with an Associated Data box, you can use the new "Associated Data" facet on the search results page:

We hope that exposing this content in a consistent format and in an easy to find and easy to access manner, you will more readily find the datasets you need to further accelerate discovery and advance health. As part of our ongoing commitment to making data findable, accessible, interoperable, and re-usable (FAIR), we encourage you to contact us with your feedback on these updates and with any other suggestions you may have for improving discovery of related data in PMC.

Title: Heart Drug Combos Might Also Lower Your Dementia Risk: Study
Category: Health News
Created: 3/13/2020 12:00:00 AM
Last Editorial Review: 3/16/2020 12:00:00 AM

Title: Prescription-Strength Steroid Creams Sold Over-the-Counter Can Be Dangerous
Category: Health News
Created: 1/23/2020 12:00:00 AM
Last Editorial Review: 1/24/2020 12:00:00 AM

Title: U.S. Deaths From High Blood Pressure Soar, Especially in the South: Study
Category: Health News
Created: 3/23/2020 12:00:00 AM
Last Editorial Review: 3/24/2020 12:00:00 AM

Title: Solosec (secnidazole)
Category: Medications
Created: 4/17/2020 12:00:00 AM
Last Editorial Review: 4/17/2020 12:00:00 AM

Title: Menopause May Someday Disappear as Women Postpone Pregnancy: Study
Category: Health News
Created: 4/24/2020 12:00:00 AM
Last Editorial Review: 4/27/2020 12:00:00 AM

Title: Seniors, Getting Off the Sofa Brings Big Health Benefits
Category: Health News
Created: 3/5/2020 12:00:00 AM
Last Editorial Review: 3/6/2020 12:00:00 AM

Title: Therapy by Phone Helps Parkinson's Patients Manage Depression
Category: Health News
Created: 4/10/2020 12:00:00 AM
Last Editorial Review: 4/13/2020 12:00:00 AM

Title: Some NFL Players May Be Misdiagnosed With Brain Disease: Study
Category: Health News
Created: 4/27/2020 12:00:00 AM
Last Editorial Review: 4/28/2020 12:00:00 AM

Title: What Is Nasogastric Intubation Used For?
Category: Procedures and Tests
Created: 5/4/2020 12:00:00 AM
Last Editorial Review: 5/4/2020 12:00:00 AM

Title: Flu Season That's Sickened 26 Million May Be at Its Peak
Category: Health News
Created: 2/21/2020 12:00:00 AM
Last Editorial Review: 2/21/2020 12:00:00 AM

Title: Could the Weather Swings of Climate Change Make Flu Seasons Worse?
Category: Health News
Created: 2/20/2020 12:00:00 AM
Last Editorial Review: 2/21/2020 12:00:00 AM

Title: Flu Vaccine Making a Strong Showing This Season
Category: Health News
Created: 2/20/2020 12:00:00 AM
Last Editorial Review: 2/21/2020 12:00:00 AM

Title: Unplugging From Social Media on Vacation? It's Tough at First
Category: Health News
Created: 8/14/2019 12:00:00 AM
Last Editorial Review: 8/14/2019 12:00:00 AM

Title: Some Cities' Smog Can Ruin Your Vacation
Category: Health News
Created: 12/3/2019 12:00:00 AM
Last Editorial Review: 12/3/2019 12:00:00 AM

This first-in-human phase I study evaluated the pharmacokinetics, safety, and preliminary efficacy of telisotuzumab, formerly called ABT-700, an antagonistic antibody directed against c-Met. For dose escalation (3+3 design), 3 to 6 patients with advanced solid tumors were enrolled into four dose cohorts (5–25 mg/kg). In the dose-expansion phase, a subset of patients was prospectively selected for MET amplification (FISH screening). Patients received telisotuzumab intravenously on day 1 every 21 days. For dose expansion, 15 mg/kg was chosen as the dose on the basis of safety, pharmacokinetics, and other data from the escalation cohorts. Forty-five patients were enrolled and received at least one dose of telisotuzumab (dose escalation, n = 15; dose expansion, n = 30). Telisotuzumab showed a linear pharmacokinetics profile; peak plasma concentration was proportional to dose level. There were no acute infusion reactions and no dose-limiting toxicities were observed. The most common treatment-related adverse events included hypoalbuminemia (n = 9, 20.0%) and fatigue (n = 5, 11.1%). By Response Evaluation Criteria In Solid Tumors (RECIST), 4 of 10 (40.0%) patients with MET-amplified tumors had confirmed partial response in target lesions (one ovarian, two gastric, and one esophageal), two (20.0%) had stable disease, three (30.0%) had progressive disease; one patient was unable to be evaluated. Among patients with nonamplified tumors (n = 35), no objective responses were observed; however, 11 patients had stable disease per RECIST criteria. In conclusion, telisotuzumab has an acceptable safety profile with clinical activity observed in patients with MET-amplified advanced solid tumors.

Long noncoding RNAs (lncRNA) have been found to play critical roles in tumorigenesis and the development of various cancers, including hepatocellular carcinoma (HCC). Metastasis associated with lung adenocarcinoma transcript-1 (MALAT1) has been identified as an oncogene and prognostic biomarker in HCC. Here, we demonstrated that MALAT1 expression was obviously high in sorafenib-resistant HCC cells. Furthermore, knockdown of MALAT1 increased sorafenib sensitivity in nonresponsive HCC cells, whereas forced expression of MALAT1 conferred sorafenib resistance to responsive HCC cells in vitro. In addition, loss/gain-of-function assays revealed that MALAT1 promoted cell proliferation, migration, and epithelial–mesenchymal transition in HCC cells. Mechanistically, MALAT1 regulated Aurora-A expression by sponging miR-140-5p, thus promoting sorafenib resistance in HCC cells. Moreover, MALAT1 inhibition enhanced the antitumor efficacy of sorafenib in vivo. Clinically, we found that MALAT1 expression was negatively correlated with miR-140-5p expression but positively correlated with Aurora-A expression in patients with HCC and that upregulated MALAT1 was closely correlated with poor survival outcomes in patients with HCC. These findings indicated that MALAT1 may be a novel target for prognosis prediction and therapeutic strategies in patients with HCC treated with sorafenib.

Overexpression of transcription factor 3 in alveolar soft part sarcoma(ASPS) results in upregulation of cell proliferation pathways. No standard treatment algorithm exists for ASPS; multikinase inhibitors[tyrosine kinase inhibitor (TKI)] and immune checkpoint inhibitors (ICI) have shown clinical benefit. To date, no studies have reported on management strategies or sequencing of therapy. We evaluated ASPS treatment patterns and responses in an experimental therapeutics clinic. Genomic and morphoproteomic analysis was performed to further elucidate novel targets. We retrospectively reviewed patients with ASPS treated on clinical trials. Demographic and clinical next-generation sequencing (NGS) profiles were collected. AACR GENIE database was queried to further evaluate aberrations in ASPS. Morphoproteomic analysis was carried out to better define the biology of ASPS with integration of genomic and proteomic findings. Eleven patients with ASPS were identified; 7 received NGS testing and mutations in CDKN2A (n = 1) and hepatocyte growth factor (n = 1) were present. Ten patients were treated with TKIs with stable disease as best response and 4 patients with ICI (three partial responses). Within GENIE, 20 patients were identified harboring 3 called pathogenic mutations. Tumor mutation burden was low in all samples. Morphoproteomic analysis confirmed the expression of phosphorylated c-Met. In addition, fatty acid synthase and phosphorylated-STAT3 were detected in tumor cell cytoplasm and nuclei. Patients with ASPS have a quiescent genome and derive clinical benefit from VEGF-targeting TKIs. Morphoproteomic analysis has provided both additional correlative pathways and angiogenic mechanisms that are targetable for patients with ASPS. Our study suggests that sequential therapy with TKIs and immune checkpoint inhibitors is a reasonable management strategy.

Purpose: The purpose of this study was to analyze associations between the oral health literacy of refugees and two oral health outcomes: dental care utilization and oral health self-efficacy.Methods: A convenience sample of refugees in the greater Los Angeles area attending English as a second language (ESL) classes sponsored by two refugee assistance organizations was used for this cross-sectional, correlational study. Participants responded to a questionnaire using items from the Health Literacy in Dentistry (HeLD) scale, in addition to items concerning dental care utilization and oral health self-efficacy. Descriptive statistics, chi-square and Fisher's Exact tests were used to analyze results.Results: Sixty-two refugees volunteered to participate (n=62). A majority of the respondents were female from Iraq or Syria, and selected the item “with little difficulty” for all oral health literacy tasks. In regards to dental care utilization, more than half of the respondents were considered high utilizers (63%, n=34) meaning they had visited a dental office within the last year; while a little more than one-third (37%, n=20), were low utilizers, indicating they had either never been to a dental office or it had been more than one year since they had dental treatment. Statistical analysis showed associations between oral health literacy and dental care utilization. However, few associations between oral health literacy and oral health self-efficacy were identified (p=0.0045).Conclusions: Results support the provision of easily obtainable and understandable oral health information to increase oral health literacy and dental care utilization among refugee populations. Future research is needed to examine the oral health literacy among refugees resettling in the United States.

Membrane-bound proteins have been proposed to mediate the transport of long-chain FA (LCFA) transport through the plasma membrane (PM). These proposals are based largely on reports that PM transport of LCFAs can be blocked by a number of enzymes and purported inhibitors of LCFA transport. Here, using the ratiometric pH indicator (2',7'-bis-(2-carboxyethyl)-5-(and-6-)-carboxyfluorescein and acrylodated intestinal FA-binding protein-based dual fluorescence assays, we investigated the effects of nine inhibitors of the putative FA transporter protein CD36 on the binding and transmembrane movement of LCFAs. We particularly focused on sulfosuccinimidyl oleate (SSO), reported to be a competitive inhibitor of CD36-mediated LCFA transport. Using these assays in adipocytes and inhibitor-treated protein-free lipid vesicles, we demonstrate that rapid LCFA transport across model and biological membranes remains unchanged in the presence of these purported inhibitors. We have previously shown in live cells that CD36 does not accelerate the transport of unesterified LCFAs across the PM. Our present experiments indicated disruption of LCFA metabolism inside the cell within minutes upon treatment with many of the "inhibitors" previously assumed to inhibit LCFA transport across the PM. Furthermore, using confocal microscopy and a specific anti-SSO antibody, we found that numerous intracellular and PM-bound proteins are SSO-modified in addition to CD36. Our results support the hypothesis that LCFAs diffuse rapidly across biological membranes and do not require an active protein transporter for their transmembrane movement.

The autosomal dominant disorder Schnyder corneal dystrophy (SCD) is caused by mutations in UbiA prenyltransferase domain-containing protein-1 (UBIAD1), which uses geranylgeranyl pyrophosphate (GGpp) to synthesize the vitamin K₂ subtype menaquinone-4 (MK-4). SCD is characterized by opacification of the cornea, owing to aberrant build-up of cholesterol in the tissue. We previously discovered that sterols stimulate association of UBIAD1 with ER-localized HMG-CoA reductase, which catalyzes a rate-limiting step in the synthesis of cholesterol and nonsterol isoprenoids, including GGpp. Binding to UBIAD1 inhibits sterol-accelerated ER-associated degradation (ERAD) of reductase and permits continued synthesis of GGpp in cholesterol-replete cells. GGpp disrupts UBIAD1-reductase binding and thereby allows for maximal ERAD of reductase as well as ER-to-Golgi translocation of UBIAD1. SCD-associated UBIAD1 is refractory to GGpp-mediated dissociation from reductase and remains sequestered in the ER to inhibit ERAD. Here, we report development of a biochemical assay for UBIAD1-mediated synthesis of MK-4 in isolated membranes and intact cells. Using this assay, we compared enzymatic activity of WT UBIAD1 with that of SCD-associated variants. Our studies revealed that SCD-associated UBIAD1 exhibited reduced MK-4 synthetic activity, which may result from its reduced affinity for GGpp. Sequestration in the ER protects SCD-associated UBIAD1 from autophagy and allows intracellular accumulation of the mutant protein, which amplifies the inhibitory effect on reductase ERAD. These findings have important implications not only for the understanding of SCD etiology but also for the efficacy of cholesterol-lowering statin therapy, which becomes limited, in part, because of UBIAD1-mediated inhibition of reductase ERAD.

ABSTRACT

Human immunodeficiency virus type 1 (HIV-1) establishes lifelong infections in humans, a process that relies on its ability to thwart innate and adaptive immune defenses of the host. Recently, we reported that HIV-1 infection results in a dramatic reduction of the cellular peroxisome pool. Peroxisomes are metabolic organelles that also function as signaling platforms in the innate immune response. Here, we show that the HIV-1 accessory protein Vpu is necessary and sufficient for the depletion of cellular peroxisomes during infection. Vpu induces the expression of four microRNAs that target mRNAs encoding proteins required for peroxisome formation and metabolic function. The ability of Vpu to downregulate peroxisomes was found to be dependent upon the Wnt/β-catenin signaling pathway. Given the importance of peroxisomes in innate immune signaling and central nervous system function, the roles of Vpu in dampening antiviral signaling appear to be more diverse than previously realized. Finally, our findings highlight a potential role for Wnt/β-catenin signaling in peroxisome homeostasis through modulating the production of biogenesis factors.

IMPORTANCE People living with HIV can experience accelerated aging and the development of neurological disorders. Recently, we reported that HIV-1 infection results in a dramatic loss of peroxisomes in macrophages and brain tissue. This is significant because (i) peroxisomes are important for the innate immune response and (ii) loss of peroxisome function is associated with cellular aging and neurodegeneration. Accordingly, understanding how HIV-1 infection causes peroxisome depletion may provide clues regarding how the virus establishes persistent infections and, potentially, the development of neurological disorders. Here, we show that the accessory protein Vpu is necessary and sufficient for the induction of microRNAs that target peroxisome biogenesis factors. The ability of Vpu to downregulate peroxisome formation depends on the Wnt/β-catenin pathway. Thus, in addition to revealing a novel mechanism by which HIV-1 uses intracellular signaling pathways to target antiviral signaling platforms (peroxisomes), we have uncovered a previously unknown link between the Wnt/β-catenin pathway and peroxisome homeostasis.

ABSTRACT

The synergy between Mycobacterium tuberculosis and human immunodeficiency virus-1 (HIV-1) interferes with therapy and facilitates the pathogenesis of both human pathogens. Fundamental mechanisms by which M. tuberculosis exacerbates HIV-1 infection are not clear. Here, we show that exosomes secreted by macrophages infected with M. tuberculosis, including drug-resistant clinical strains, reactivated HIV-1 by inducing oxidative stress. Mechanistically, M. tuberculosis-specific exosomes realigned mitochondrial and nonmitochondrial oxygen consumption rates (OCR) and modulated the expression of host genes mediating oxidative stress response, inflammation, and HIV-1 transactivation. Proteomics analyses revealed the enrichment of several host factors (e.g., HIF-1α, galectins, and Hsp90) known to promote HIV-1 reactivation in M. tuberculosis-specific exosomes. Treatment with a known antioxidant—N-acetyl cysteine (NAC)—or with inhibitors of host factors—galectins and Hsp90—attenuated HIV-1 reactivation by M. tuberculosis-specific exosomes. Our findings uncover new paradigms for understanding the redox and bioenergetics bases of HIV-M. tuberculosis coinfection, which will enable the design of effective therapeutic strategies.

IMPORTANCE Globally, individuals coinfected with the AIDS virus (HIV-1) and with M. tuberculosis (causative agent of tuberculosis [TB]) pose major obstacles in the clinical management of both diseases. At the heart of this issue is the apparent synergy between the two human pathogens. On the one hand, mechanisms induced by HIV-1 for reactivation of TB in AIDS patients are well characterized. On the other hand, while clinical findings clearly identified TB as a risk factor for HIV-1 reactivation and associated mortality, basic mechanisms by which M. tuberculosis exacerbates HIV-1 replication and infection remain poorly characterized. The significance of our research is in identifying the role of fundamental mechanisms such as redox and energy metabolism in catalyzing HIV-M. tuberculosis synergy. The quantification of redox and respiratory parameters affected by M. tuberculosis in stimulating HIV-1 will greatly enhance our understanding of HIV-M. tuberculosis coinfection, leading to a wider impact on the biomedical research community and creating new translational opportunities.

ABSTRACT

Over the last decade, innate immune priming has been evidenced in many invertebrate phyla. If mechanistic models have been proposed, molecular studies aiming to substantiate these models have remained scarce. We reveal here the transcriptional signature associated with immune priming in the oyster Crassostrea gigas. Oysters were fully protected against Ostreid herpesvirus 1 (OsHV-1), a major oyster pathogen, after priming with poly(I·C), which mimics viral double-stranded RNA. Global analysis through RNA sequencing of oyster and viral genes after immune priming and viral infection revealed that poly(I·C) induces a strong antiviral response that impairs OsHV-1 replication. Protection is based on a sustained upregulation of immune genes, notably genes involved in the interferon pathway and apoptosis, which control subsequent viral infection. This persistent antiviral alert state remains active over 4 months and supports antiviral protection in the long term. This acquired resistance mechanism reinforces the molecular foundations of the sustained response model of immune priming. It further opens the way to applications (pseudovaccination) to cope with a recurrent disease that causes dramatic economic losses in the shellfish farming industry worldwide.

IMPORTANCE In the last decade, important discoveries have shown that resistance to reinfection can be achieved without a functional adaptive immune system, introducing the concept of innate immune memory in invertebrates. However, this field has been constrained by the limited number of molecular mechanisms evidenced to support these phenomena. Taking advantage of an invertebrate species, the Pacific oyster (Crassostrea gigas), in which we evidenced one of the longest and most effective periods of protection against viral infection observed in an invertebrate, we provide the first comprehensive transcriptomic analysis of antiviral innate immune priming. We show that priming with poly(I·C) induced a massive upregulation of immune-related genes, which control subsequent viral infection, and it was maintained for over 4 months after priming. This acquired resistant mechanism reinforces the molecular foundations of the sustained response model of immune priming. It opens the way to pseudovaccination to prevent the recurrent diseases that currently afflict economically or ecologically important invertebrates.

ABSTRACT

Recent global advocacy efforts have highlighted the importance of development of a vaccine against group A Streptococcus (GAS). Combo5 is a non-M protein-based vaccine that provides protection against GAS skin infection in mice and reduces the severity of pharyngitis in nonhuman primates. However, Combo5 with the addition of aluminum hydroxide (alum) as an adjuvant failed to protect against invasive GAS infection of mice. Here, we show that formulation of Combo5 with adjuvants containing saponin QS21 significantly improves protective efficacy, even though all 7 adjuvants tested generated high antigen-specific IgG antibody titers, including alum. Detailed characterization of Combo5 formulated with SMQ adjuvant, a squalene-in-water emulsion containing a TLR4 agonist and QS21, showed significant differences from the results obtained with alum in IgG subclasses generated following immunization, with an absence of GAS opsonizing antibodies. SMQ, but not alum, generated strong interleukin-6 (IL-6), gamma interferon (IFN-), and tumor necrosis alpha (TNF-α) responses. This work highlights the importance of adjuvant selection for non-M protein-based GAS vaccines to optimize immune responses and protective efficacy.

IMPORTANCE Availability of a group A Streptococcus vaccine remains an unmet public health need. Here, we tested different adjuvant formulations to improve the protective efficacy of non-M protein vaccine Combo5 in an invasive disease model. We show that novel adjuvants can dramatically shape the type of immune response developed following immunization with Combo5 and significantly improve protection. In addition, protection afforded by Combo5 is not mediated by opsonizing antibodies, believed to be the main correlate of protection against GAS infections. Overall, this report highlights the importance of adjuvant selection in raising protective immune responses against GAS invasive infection. Adjuvants that can provide a more balanced Th1/Th2-type response may be required to optimize protection of GAS vaccines, particularly those based on non-M protein antigens.

ABSTRACT

Bacteria harbor viruses called bacteriophages that, like all viruses, co-opt the host cellular machinery to replicate. Although this relationship is at first glance parasitic, there are social interactions among and between bacteriophages and their bacterial hosts. These social interactions can take on many forms, including cooperation, altruism, and cheating. Such behaviors among individuals in groups of bacteria have been well described. However, the social nature of some interactions between phages or phages and bacteria is only now becoming clear. We are just beginning to understand how bacteriophages affect the sociobiology of bacteria, and we know even less about social interactions within bacteriophage populations. In this review, we discuss recent developments in our understanding of bacteriophage sociobiology, including how selective pressures influence the outcomes of social interactions between populations of bacteria and bacteriophages. We also explore how tripartite social interactions between bacteria, bacteriophages, and an animal host affect host-microbe interactions. Finally, we argue that understanding the sociobiology of bacteriophages will have implications for the therapeutic use of bacteriophages to treat bacterial infections.

ABSTRACT

The initiation of Escherichia coli chromosomal DNA replication starts with the oligomerization of the DnaA protein at repeat sequences within the origin (ori) region. The amount of ori DNA per cell directly correlates with the growth rate. During fast growth, the cell generation time is shorter than the time required for complete DNA replication; therefore, overlapping rounds of chromosome replication are required. Under these circumstances, the ori region DNA abundance exceeds the DNA abundance in the termination (ter) region. Here, high ori/ter ratios are found to persist in (p)ppGpp-deficient [(p)ppGpp⁰] cells over a wide range of balanced exponential growth rates determined by medium composition. Evidently, (p)ppGpp is necessary to maintain the usual correlation of slow DNA replication initiation with a low growth rate. Conversely, ori/ter ratios are lowered when cell growth is slowed by incrementally increasing even low constitutive basal levels of (p)ppGpp without stress, as if (p)ppGpp alone is sufficient for this response. There are several previous reports of (p)ppGpp inhibition of chromosomal DNA synthesis initiation that occurs with very high levels of (p)ppGpp that stop growth, as during the stringent starvation response or during serine hydroxamate treatment. This work suggests that low physiological levels of (p)ppGpp have significant functions in growing cells without stress through a mechanism involving negative supercoiling, which is likely mediated by (p)ppGpp regulation of DNA gyrase.

IMPORTANCE Bacterial cells regulate their own chromosomal DNA synthesis and cell division depending on the growth conditions, producing more DNA when growing in nutritionally rich media than in poor media (i.e., human gut versus water reservoir). The accumulation of the nucleotide analog (p)ppGpp is usually viewed as serving to warn cells of impending peril due to otherwise lethal sources of stress, which stops growth and inhibits DNA, RNA, and protein synthesis. This work importantly finds that small physiological changes in (p)ppGpp basal levels associated with slow balanced exponential growth incrementally inhibit the intricate process of initiation of chromosomal DNA synthesis. Without (p)ppGpp, initiations mimic the high rates present during fast growth. Here, we report that the effect of (p)ppGpp may be due to the regulation of the expression of gyrase, an important enzyme for the replication of DNA that is a current target of several antibiotics.

ABSTRACT

Mitochondrial Ca²⁺ transport mediated by the uniporter complex (MCUC) plays a key role in the regulation of cell bioenergetics in both trypanosomes and mammals. Here we report that Trypanosoma brucei MCU (TbMCU) subunits interact with subunit c of the mitochondrial ATP synthase (ATPc), as determined by coimmunoprecipitation and split-ubiquitin membrane-based yeast two-hybrid (MYTH) assays. Mutagenesis analysis in combination with MYTH assays suggested that transmembrane helices (TMHs) are determinants of this specific interaction. In situ tagging, followed by immunoprecipitation and immunofluorescence microscopy, revealed that T. brucei ATPc (TbATPc) coimmunoprecipitates with TbMCUC subunits and colocalizes with them to the mitochondria. Blue native PAGE and immunodetection analyses indicated that the TbMCUC is present together with the ATP synthase in a large protein complex with a molecular weight of approximately 900 kDa. Ablation of the TbMCUC subunits by RNA interference (RNAi) significantly increased the AMP/ATP ratio, revealing the downregulation of ATP production in the cells. Interestingly, the direct physical MCU-ATPc interaction is conserved in Trypanosoma cruzi and human cells. Specific interaction between human MCU (HsMCU) and human ATPc (HsATPc) was confirmed in vitro by mutagenesis and MYTH assays and in vivo by coimmunoprecipitation. In summary, our study has identified that MCU complex physically interacts with mitochondrial ATP synthase, possibly forming an MCUC-ATP megacomplex that couples ADP and P_i transport with ATP synthesis, a process that is stimulated by Ca²⁺ in trypanosomes and human cells.

IMPORTANCE The mitochondrial calcium uniporter (MCU) is essential for the regulation of oxidative phosphorylation in mammalian cells, and we have shown that in Trypanosoma brucei, the etiologic agent of sleeping sickness, this channel is essential for its survival and infectivity. Here we reveal that that Trypanosoma brucei MCU subunits interact with subunit c of the mitochondrial ATP synthase (ATPc). Interestingly, the direct physical MCU-ATPc interaction is conserved in T. cruzi and human cells.

ABSTRACT

Adjuvants can be used to potentiate the function of antibiotics whose efficacy has been reduced by acquired or intrinsic resistance. In the present study, we discovered that human milk oligosaccharides (HMOs) sensitize strains of group B Streptococcus (GBS) to trimethoprim (TMP), an antibiotic to which GBS is intrinsically resistant. Reductions in the MIC of TMP reached as high as 512-fold across a diverse panel of isolates. To better understand HMOs’ mechanism of action, we characterized the metabolic response of GBS to HMO treatment using ultrahigh-performance liquid chromatography–high-resolution tandem mass spectrometry (UPLC-HRMS/MS) analysis. These data showed that when challenged by HMOs, GBS undergoes significant perturbations in metabolic pathways related to the biosynthesis and incorporation of macromolecules involved in membrane construction. This study represents reports the metabolic characterization of a cell that is perturbed by HMOs.

IMPORTANCE Group B Streptococcus is an important human pathogen that causes serious infections during pregnancy which can lead to chorioamnionitis, funisitis, premature rupture of gestational membranes, preterm birth, neonatal sepsis, and death. GBS is evolving antimicrobial resistance mechanisms, and the work presented in this paper provides evidence that prebiotics such as human milk oligosaccharides can act as adjuvants to restore the utility of antibiotics.

ABSTRACT

A bioinformatics approach was employed to identify transcriptome alterations in the peripheral blood mononuclear cells of well-characterized human subjects who were diagnosed with early disseminated Lyme disease (LD) based on stringent microbiological and clinical criteria. Transcriptomes were assessed at the time of presentation and also at approximately 1 month (early convalescence) and 6 months (late convalescence) after initiation of an appropriate antibiotic regimen. Comparative transcriptomics identified 335 transcripts, representing 233 unique genes, with significant alterations of at least 2-fold expression in acute- or convalescent-phase blood samples from LD subjects relative to healthy donors. Acute-phase blood samples from LD subjects had the largest number of differentially expressed transcripts (187 induced, 54 repressed). This transcriptional profile, which was dominated by interferon-regulated genes, was sustained during early convalescence. 6 months after antibiotic treatment the transcriptome of LD subjects was indistinguishable from that of healthy controls based on two separate methods of analysis. Return of the LD expression profile to levels found in control subjects was concordant with disease outcome; 82% of subjects with LD experienced at least one symptom at the baseline visit compared to 43% at the early convalescence time point and only a single patient (9%) at the 6-month convalescence time point. Using the random forest machine learning algorithm, we developed an efficient computational framework to identify sets of 20 classifier genes that discriminated LD from other bacterial and viral infections. These novel LD biomarkers not only differentiated subjects with acute disseminated LD from healthy controls with 96% accuracy but also distinguished between subjects with acute and resolved (late convalescent) disease with 97% accuracy.

IMPORTANCE Lyme disease (LD), caused by Borrelia burgdorferi, is the most common tick-borne infectious disease in the United States. We examined gene expression patterns in the blood of individuals with early disseminated LD at the time of diagnosis (acute) and also at approximately 1 month and 6 months following antibiotic treatment. A distinct acute LD profile was observed that was sustained during early convalescence (1 month) but returned to control levels 6 months after treatment. Using a computer learning algorithm, we identified sets of 20 classifier genes that discriminate LD from other bacterial and viral infections. In addition, these novel LD biomarkers are highly accurate in distinguishing patients with acute LD from healthy subjects and in discriminating between individuals with active and resolved infection. This computational approach offers the potential for more accurate diagnosis of early disseminated Lyme disease. It may also allow improved monitoring of treatment efficacy and disease resolution.