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'Ringing in the Ears' May Drive Some to the Brink of Suicide

Title: 'Ringing in the Ears' May Drive Some to the Brink of Suicide
Category: Health News
Created: 5/2/2019 12:00:00 AM
Last Editorial Review: 5/3/2019 12:00:00 AM




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New Saliva-Based COVID-19 Test an Easier Alternative

Title: New Saliva-Based COVID-19 Test an Easier Alternative
Category: Health News
Created: 4/27/2020 12:00:00 AM
Last Editorial Review: 4/28/2020 12:00:00 AM




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New Initiative to Study Coronavirus Genome

Title: New Initiative to Study Coronavirus Genome
Category: Health News
Created: 5/1/2020 12:00:00 AM
Last Editorial Review: 5/1/2020 12:00:00 AM




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How One Very Ill Infant Survived COVID-19

Title: How One Very Ill Infant Survived COVID-19
Category: Health News
Created: 5/1/2020 12:00:00 AM
Last Editorial Review: 5/1/2020 12:00:00 AM




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How Do You Give a Mental Nerve Block?

Title: How Do You Give a Mental Nerve Block?
Category: Procedures and Tests
Created: 4/21/2020 12:00:00 AM
Last Editorial Review: 4/21/2020 12:00:00 AM




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Gentle Yoga May Deliver Migraine Relief

Title: Gentle Yoga May Deliver Migraine Relief
Category: Health News
Created: 5/6/2020 12:00:00 AM
Last Editorial Review: 5/7/2020 12:00:00 AM




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Will a Jolt of Java Get Your Creative Juices Flowing?

Title: Will a Jolt of Java Get Your Creative Juices Flowing?
Category: Health News
Created: 3/9/2020 12:00:00 AM
Last Editorial Review: 3/9/2020 12:00:00 AM




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On Some Farms, Washing Machines Give Leafy Greens a Spin -- But Is That Safe?

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




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Study Confirms Safety, Effectiveness of Children's Vaccines

Title: Study Confirms Safety, Effectiveness of Children's Vaccines
Category: Health News
Created: 4/23/2020 12:00:00 AM
Last Editorial Review: 4/24/2020 12:00:00 AM




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COVID-19 Data Dives: Good Serosurveys Are Needed. Not All Are Good

Bill Hanage describes the many uncertainties surrounding current data examining the prevalence of SARS-CoV-2.




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New Angiotensin Studies in COVID-19 Give More Reassurance

A deluge of new data does not suggest harm with ACE inhibitors and angiotensin blockers in COVID-19 rates or outcomes but suggests possible differential effects of the two drug classes.




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Multisociety Roadmap for Restarting Elective Cardiac Cases

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




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Diagnosing Mild Cognitive Impairment in Women

One problem with memory tests is that cut-off scores for mild cognitive impairment don’t reflect that women tend to have stronger verbal memory than men.




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Gentle Yoga May Deliver Migraine Relief

People suffering from regular migraines despite medication might consider investing in a yoga mat.




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Alcohol Abuse Agitated by COVID-19 Stirring Liver Concerns

Hospitals are seeing an increase in admissions related to alcohol abuse as recovery centers are shutting down and people are drinking more during the pandemic.




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PMC Canada's Manuscript Submission System Goes Live!

The PMC Canada manuscript submission system was released on April 28, 2010. The system will enable researchers funded by the Canadian Institutes of Health Research to deposit their peer-reviewed research publications, in compliance with CIHR's Policy on Access to Research Outputs.




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The PMC 10th Anniversary Video is now on YouTube!

A video celebrating PMC's first decade is now available for viewing on the NCBI YouTube Channel. The PMC 10th Anniversary Video can also be found on the regular YouTube site.




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New responsive PubMed site replaces PubMed Mobile

Our new, responsive PubMed site replaces PubMed Mobile. You now have the full PubMed experience on any size screen, including the ability to save and email citations, use the Clipboard, and send citations to My NCBI Collections on your mobile device.




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Heading to Work on a Bike? You Might Live Longer

Title: Heading to Work on a Bike? You Might Live Longer
Category: Health News
Created: 2/25/2020 12:00:00 AM
Last Editorial Review: 2/26/2020 12:00:00 AM




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Doctors Describe First Drone Delivery of Diabetes Meds to Patient

Title: Doctors Describe First Drone Delivery of Diabetes Meds to Patient
Category: Health News
Created: 3/30/2020 12:00:00 AM
Last Editorial Review: 3/31/2020 12:00:00 AM




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Patch Pump Device Could Offer Cheaper Insulin Delivery

Title: Patch Pump Device Could Offer Cheaper Insulin Delivery
Category: Health News
Created: 4/1/2020 12:00:00 AM
Last Editorial Review: 4/2/2020 12:00:00 AM




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Trump Signs Massive Relief Package Into Law as U.S. Coronavirus Cases Reach 9,000

Title: Trump Signs Massive Relief Package Into Law as U.S. Coronavirus Cases Reach 9,000
Category: Health News
Created: 3/19/2020 12:00:00 AM
Last Editorial Review: 3/19/2020 12:00:00 AM




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Modern Livestock Farming Can Pose Public Health Risk

Title: Modern Livestock Farming Can Pose Public Health Risk
Category: Health News
Created: 5/7/2020 12:00:00 AM
Last Editorial Review: 5/8/2020 12:00:00 AM




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After 2nd Patient Cured of HIV, Hope Revives for an End to AIDS

Title: After 2nd Patient Cured of HIV, Hope Revives for an End to AIDS
Category: Health News
Created: 3/10/2020 12:00:00 AM
Last Editorial Review: 3/11/2020 12:00:00 AM




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Active Older Vets More Likely to Fall, But Less Likely to Get Hurt: Study

Title: Active Older Vets More Likely to Fall, But Less Likely to Get Hurt: Study
Category: Health News
Created: 4/20/2020 12:00:00 AM
Last Editorial Review: 4/21/2020 12:00:00 AM




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How Does Cognitive Behavioral Therapy Treat Depression?

Title: How Does Cognitive Behavioral Therapy Treat Depression?
Category: Procedures and Tests
Created: 4/29/2020 12:00:00 AM
Last Editorial Review: 4/29/2020 12:00:00 AM




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Male Fertility Supplements Fail to Deliver

Title: Male Fertility Supplements Fail to Deliver
Category: Health News
Created: 1/7/2020 12:00:00 AM
Last Editorial Review: 1/8/2020 12:00:00 AM




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Birth Control Pills (List of Oral Contraceptives and Side Effects)

Title: Birth Control Pills (List of Oral Contraceptives and Side Effects)
Category: Medications
Created: 12/31/1997 12:00:00 AM
Last Editorial Review: 1/30/2020 12:00:00 AM




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FDA Warns of Defective EpiPen Dangers

Title: FDA Warns of Defective EpiPen Dangers
Category: Health News
Created: 3/25/2020 12:00:00 AM
Last Editorial Review: 3/26/2020 12:00:00 AM




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How Is a Transjugular Liver Biopsy Done?

Title: How Is a Transjugular Liver Biopsy Done?
Category: Procedures and Tests
Created: 5/6/2020 12:00:00 AM
Last Editorial Review: 5/6/2020 12:00:00 AM




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Is a 'Universal' Flu Vaccine on the Horizon?

Title: Is a 'Universal' Flu Vaccine on the Horizon?
Category: Health News
Created: 3/9/2020 12:00:00 AM
Last Editorial Review: 3/10/2020 12:00:00 AM




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Women Are Much Safer Drivers Than Men, British Study Finds

Title: Women Are Much Safer Drivers Than Men, British Study Finds
Category: Health News
Created: 4/7/2020 12:00:00 AM
Last Editorial Review: 4/7/2020 12:00:00 AM




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More Trees, Parks May Mean Longer Lives for City Dwellers

Title: More Trees, Parks May Mean Longer Lives for City Dwellers
Category: Health News
Created: 4/28/2020 12:00:00 AM
Last Editorial Review: 4/29/2020 12:00:00 AM




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AI May Help Guide Patients to Most Effective Antidepressant

Title: AI May Help Guide Patients to Most Effective Antidepressant
Category: Health News
Created: 2/10/2020 12:00:00 AM
Last Editorial Review: 2/11/2020 12:00:00 AM




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Is Electroconvulsive (ECT) Therapy Safe?

Title: Is Electroconvulsive (ECT) Therapy Safe?
Category: Procedures and Tests
Created: 3/6/2020 12:00:00 AM
Last Editorial Review: 3/6/2020 12:00:00 AM




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Tukysa Approved for Unresectable, Metastatic HER2-Positive Breast Cancer

Title: Tukysa Approved for Unresectable, Metastatic HER2-Positive Breast Cancer
Category: Health News
Created: 4/20/2020 12:00:00 AM
Last Editorial Review: 4/21/2020 12:00:00 AM




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FDA Approves Trodelvy for Metastatic Triple-Negative Breast Cancer

Title: FDA Approves Trodelvy for Metastatic Triple-Negative Breast Cancer
Category: Health News
Created: 4/24/2020 12:00:00 AM
Last Editorial Review: 4/24/2020 12:00:00 AM




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Residents Perspectives on and Application of Dental Public Health Competencies Using Case-Based Methods

The aims of this study were to qualitatively assess dental public health (DPH) residents’ perspectives on teaching methods for DPH competencies and to develop and implement a case-based simulation to address those competencies, constructed on the basis of the qualitative assessment. Focus group discussions were conducted with 18 DPH residents enrolled in two university-based DPH programs. Topic areas discussed in the two focus groups were perceived value of DPH competencies, ways to acquire new DPH skills/abilities, and additional skills/abilities needed by DPH residents. The focus groups’ responses showed that the residents felt competent in the analytical thinking competencies such as research methodology and critiquing literature. They emphasized the importance of learning leadership skills and reported feeling somewhat uncertain about their mastery of the policy and advocacy and system evaluation competencies. Of the two distinct categories of DPH skills and competencies— analytical/critical thinking and practical competencies—these residents reported that a greater proportion of time needed to be devoted to integrating the practical competencies into their education. Based on the residents’ feedback, the authors developed a structured seminar series taking a case-based approach to simulate real-world DPH problems, using real and semi-hypothetical planning projects to meet the residents’ perceived needs and covering gaps between didactic learning and practice.




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Impact of Collaborative Leadership in Dental School Team Clinics

Dental students’ ability to critique team performance in dental school team clinics is a key component of dental education. The aim of this study was to determine if students’ perceptions of their team leaders’ openness of communication, cooperative decision making, and well-defined goals were positively related to the students’ improvement-oriented voice behavior and willingness to raise concerns in the clinical environment. This study used a voluntary 12-question survey, distributed via email to all 311 students at the University of Nevada, Las Vegas School of Dental Medicine after completion of the spring 2017 semester. Eighty-seven students responded, for a response rate of 28%. Responses were stratified by team, class year, and gender, and the quantitative distribution of answers to each question was correlated with each other. Team leader collaborative qualities, which included openness for communication, cooperative decision making, and well-defined goals, were found to have a significant positive relationship with students’ willingness to both raise concerns and make suggestions. Additionally, when measured by class year and gender, team differences in voice behavior assessment by students across the teams were found to be independent of class year, and no significant differences were found by gender. These results suggested that, to maintain high levels of communication, proper reporting of concerns, and a high standard of care, dental schools should encourage team leaders to enhance their capacity to present active collaborative behaviors in the school’s clinic. The study also highlighted potential opportunities for further study of faculty traits and development in the dental school team model.




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The Additive Effects of Cell Phone Use and Dental Hygiene Practice on Finger Muscle Strength: A Pilot Study

Purpose: The purpose of this study was to determine strength of muscles involved with instrumentation (scaling) by dental hygienists and the additive effects of cellular (mobile) phone usage, as indicated by measurements of muscular force generation.Methods: A convenience sample of licensed dental hygienists currently in clinical practice (n=16) and an equal number of individuals not currently using devices/tools repetitively for work (n=16), agreed to participate in this pilot study. All participants completed a modified cell phone usage questionnaire to determine their use pattern and frequency. Upon completion of the questionnaire, participants' force production in six muscle groups was measured using a hand-held dynamometer. Descriptive statistics were used to analyze the data.Results: A total of 16 licensed dental hygienists (n=16) and 16 participants with no history of using tools/devices repetitively for work (n=16), comprised the experimental and control groups, repectively. The control group generated greater muscle force than the experimental group for the abductor pollicis longus (p=0.045). Significant differences were identified when comparing the low mobile phone users in the experimental group to the control group for the flexor pollicis brevis (p=0.031), abductor pollicis longus (p=0.031), and flexor digitorum (p=0.006), with the control group demonstrating higher muscle force. Years in clinical practice and mobile phone use was shown to have a significant effect on muscular force generation for the flexor pollicis brevis (F=3.645, df=3, p=0.020) and flexor digitorum (F=3.560, df=3, p=0.022); subjects who practiced dental hygiene the longest produced the least amount of muscle force.Conclusion: Results from this pilot study indicate there are no significant additive effects of cell phone use and dental hygiene practice on finger muscles used for instrumentation. However, results indicate that dental hygiene practice demonstrated significant effects on muscular strength as compared to individuals who do not use tools/devices repetitively for work. The small sample size may have impacted results and the study should be repeated with a larger sample.




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Oral Health-Related Quality of Life of Children: An Assessment of the Relationship between Child and Caregiver Reporting

Purpose: Oral and craniofacial conditions or diseases can impact an individual's health and quality of life. The purpose of this study was to assess the perceived oral health related quality of life (OHRQoL) of children, and evaluate the reported level of agreement between caregivers and their children.Methods: Purposive sampling was used to recruit children ages 8-15, and their caregivers from a dental clinic in a pediatric hospital for this descriptive, cross-sectional study. A modified version of a validated measure, Child Oral Health Impact Profile-Short Form (COHIP-SF), was used for a 22-item questionnaire encompassing three subscales: oral health, functional well-being, and social emotional well-being. Two additional items were included to assess child/caregiver's level of agreement. A dental chart review was also conducted to assess the child's overbite, overjet, and decayed surfaces. Data were analyzed through descriptive statistics and examined for assumptions of normality and linearity.Results: Sixty child/caregiver pairs (n=120) participated in this study. Overbite, overjet and decayed surfaces were not found to be related to any OHRQoL variable, including child/caregiver ratings and overall agreement (p>.05). Average OHRQoL scores for caregivers found to be more positive those of their children (p=.02). Agreement between caregivers and the child's gender was shown to be significant (p=.01). Female child scores differed significantly from males with respect to their caregiver responses (p=.02). Caregivers rated a higher OHRQoL for female children, thus overestimating their female child's reported OHRQoL.Conclusions: The moderate level of agreement found between children and caregivers reinforces the importance of including the child, as well as the caregiver, when assessing OHRQoL.




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SSO and other putative inhibitors of FA transport across membranes by CD36 disrupt intracellular metabolism, but do not affect FA translocation [Research Articles]

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.




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Hepatic monoamine oxidase B is involved in endogenous geranylgeranoic acid synthesis in mammalian liver cells [Research Articles]

Geranylgeranoic acid (GGA) originally was identified in some animals and has been developed as an agent for preventing second primary hepatoma. We previously have also identified GGA as an acyclic diterpenoid in some medicinal herbs. Recently, we reported that in human hepatoma-derived HuH-7 cells, GGA is metabolically labeled from 13C-mevalonate. Several cell-free experiments have demonstrated that GGA is synthesized through geranylgeranial by oxygen-dependent oxidation of geranylgeraniol (GGOH), but the exact biochemical events giving rise to GGA in hepatoma cells remain unclear. Monoamine oxidase B (MOAB) has been suggested to be involved in GGOH oxidation. Here, using two human hepatoma cell lines, we investigated whether MAOB contributes to GGA biosynthesis. Using either HuH-7 cell lysates or recombinant human MAOB, we found that: 1) the MAO inhibitor tranylcypromine dose-dependently downregulates endogenous GGA levels in HuH-7 cells; and 2) siRNA-mediated MAOB silencing reduces intracellular GGA levels in HuH-7 and Hep3B cells. Unexpectedly, however, CRISPR/Cas9-generated MAOB-KO human hepatoma Hep3B cells had GGA levels similar to those in MAOB-WT cells. A sensitivity of GGA levels to siRNA-mediated MAOB downregulation was recovered when the MAOB-KO cells were transfected with a MAOB-expression plasmid, suggesting that MAOB is the enzyme primarily responsible for GGOH oxidation and that some other latent metabolic pathways may maintain endogenous GGA levels in the MAOB-KO hepatoma cells. Along with the previous findings, these results provide critical insights into the biological roles of human MAOB and provide evidence that hepatic MAOB is involved in endogenous GGA biosynthesis via GGOH oxidation.




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Schnyder corneal dystrophy-associated UBIAD1 is defective in MK-4 synthesis and resists autophagy-mediated degradation [Research Articles]

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.




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Lipid rafts and neurodegeneration: structural and functional roles in physiologic aging and neurodegenerative diseases [Thematic Reviews]

Lipid rafts are small, dynamic membrane areas characterized by the clustering of selected membrane lipids as the result of the spontaneous separation of glycolipids, sphingolipids, and cholesterol in a liquid-ordered phase. The exact dynamics underlying phase separation of membrane lipids in the complex biological membranes are still not fully understood. Nevertheless, alterations in the membrane lipid composition affect the lateral organization of molecules belonging to lipid rafts. Neural lipid rafts are found in brain cells, including neurons, astrocytes, and microglia, and are characterized by a high enrichment of specific lipids depending on the cell type. These lipid rafts seem to organize and determine the function of multiprotein complexes involved in several aspects of signal transduction, thus regulating the homeostasis of the brain. The progressive decline of brain performance along with physiological aging is at least in part associated with alterations in the composition and structure of neural lipid rafts. In addition, neurodegenerative conditions, such as lysosomal storage disorders, multiple sclerosis, and Parkinson’s, Huntington’s, and Alzheimer’s diseases, are frequently characterized by dysregulated lipid metabolism, which in turn affects the structure of lipid rafts. Several events underlying the pathogenesis of these diseases appear to depend on the altered composition of lipid rafts. Thus, the structure and function of lipid rafts play a central role in the pathogenesis of many common neurodegenerative diseases.




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Commentary on SSO and other putative inhibitors of FA transport across membranes by CD36 disrupt intracellular metabolism, but do not affect fatty acid translocation [Commentaries]




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Using Colonization Assays and Comparative Genomics To Discover Symbiosis Behaviors and Factors in Vibrio fischeri

ABSTRACT

The luminous marine Gram-negative bacterium Vibrio (Aliivibrio) fischeri is the natural light organ symbiont of several squid species, including the Hawaiian bobtail squid, Euprymna scolopes, and the Japanese bobtail squid, Euprymna morsei. Work with E. scolopes has shown how the bacteria establish their niche in the light organ of the newly hatched host. Two types of V. fischeri strains have been distinguished based upon their behavior in cocolonization competition assays in juvenile E. scolopes, i.e., (i) niche-sharing or (ii) niche-dominant behavior. This study aimed to determine whether these behaviors are observed with other V. fischeri strains or whether they are specific to those isolated from E. scolopes light organs. Cocolonization competition assays between V. fischeri strains isolated from the congeneric squid E. morsei or from other marine animals revealed the same sharing or dominant behaviors. In addition, whole-genome sequencing of these strains showed that the dominant behavior is polyphyletic and not associated with the presence or absence of a single gene or genes. Comparative genomics of 44 squid light organ isolates from around the globe led to the identification of symbiosis-specific candidates in the genomes of these strains. Colonization assays using genetic derivatives with deletions of these candidates established the importance of two such genes in colonization. This study has allowed us to expand the concept of distinct colonization behaviors to strains isolated from a number of squid and fish hosts.

IMPORTANCE There is an increasing recognition of the importance of strain differences in the ecology of a symbiotic bacterial species and, in particular, how these differences underlie crucial interactions with their host. Nevertheless, little is known about the genetic bases for these differences, how they manifest themselves in specific behaviors, and their distribution among symbionts of different host species. In this study, we sequenced the genomes of Vibrio fischeri isolated from the tissues of squids and fishes and applied comparative genomics approaches to look for patterns between symbiont lineages and host colonization behavior. In addition, we identified the only two genes that were exclusively present in all V. fischeri strains isolated from the light organs of sepiolid squid species. Mutational studies of these genes indicated that they both played a role in colonization of the squid light organ, emphasizing the value of applying a comparative genomics approach in the study of symbioses.




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Modulation of Monocyte-Driven Myositis in Alphavirus Infection Reveals a Role for CX3CR1+ Macrophages in Tissue Repair

ABSTRACT

Arthritogenic alphaviruses such as Ross River and Chikungunya viruses cause debilitating muscle and joint pain and pose significant challenges in the light of recent outbreaks. How host immune responses are orchestrated after alphaviral infections and lead to musculoskeletal inflammation remains poorly understood. Here, we show that myositis induced by Ross River virus (RRV) infection is driven by CD11bhi Ly6Chi inflammatory monocytes and followed by the establishment of a CD11bhi Ly6Clo CX3CR1+ macrophage population in the muscle upon recovery. Selective modulation of CD11bhi Ly6Chi monocyte migration to infected muscle using immune-modifying microparticles (IMP) reduced disease score, tissue damage, and inflammation and promoted the accumulation of CX3CR1+ macrophages, enhancing recovery and resolution. Here, we detail the role of immune pathology, describing a poorly characterized muscle macrophage subset as part of the dynamics of alphavirus-induced myositis and tissue recovery and identify IMP as an effective immunomodulatory approach. Given the lack of specific treatments available for alphavirus-induced pathologies, this study highlights a therapeutic potential for simple immune modulation by IMP in infected individuals in the event of large alphavirus outbreaks.

IMPORTANCE Arthritogenic alphaviruses cause debilitating inflammatory disease, and current therapies are restricted to palliative approaches. Here, we show that following monocyte-driven muscle inflammation, tissue recovery is associated with the accumulation of CX3CR1+ macrophages in the muscle. Modulating inflammatory monocyte infiltration using immune-modifying microparticles (IMP) reduced tissue damage and inflammation and enhanced the formation of tissue repair-associated CX3CR1+ macrophages in the muscle. This shows that modulating key effectors of viral inflammation using microparticles can alter the outcome of disease by facilitating the accumulation of macrophage subsets associated with tissue repair.




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A Polar Flagellar Transcriptional Program Mediated by Diverse Two-Component Signal Transduction Systems and Basal Flagellar Proteins Is Broadly Conserved in Polar Flagellates

ABSTRACT

Bacterial flagella are rotating nanomachines required for motility. Flagellar gene expression and protein secretion are coordinated for efficient flagellar biogenesis. Polar flagellates, unlike peritrichous bacteria, commonly order flagellar rod and hook gene transcription as a separate step after production of the MS ring, C ring, and flagellar type III secretion system (fT3SS) core proteins that form a competent fT3SS. Conserved regulatory mechanisms in diverse polar flagellates to create this polar flagellar transcriptional program have not been thoroughly assimilated. Using in silico and genetic analyses and our previous findings in Campylobacter jejuni as a foundation, we observed a large subset of Gram-negative bacteria with the FlhF/FlhG regulatory system for polar flagellation to possess flagellum-associated two-component signal transduction systems (TCSs). We present data supporting a general theme in polar flagellates whereby MS ring, rotor, and fT3SS proteins contribute to a regulatory checkpoint during polar flagellar biogenesis. We demonstrate that Vibrio cholerae and Pseudomonas aeruginosa require the formation of this regulatory checkpoint for the TCSs to directly activate subsequent rod and hook gene transcription, which are hallmarks of the polar flagellar transcriptional program. By reprogramming transcription in V. cholerae to more closely follow the peritrichous flagellar transcriptional program, we discovered a link between the polar flagellar transcription program and the activity of FlhF/FlhG flagellar biogenesis regulators in which the transcriptional program allows polar flagellates to continue to produce flagella for motility when FlhF or FlhG activity may be altered. Our findings integrate flagellar transcriptional and biogenesis regulatory processes involved in polar flagellation in many species.

IMPORTANCE Relative to peritrichous bacteria, polar flagellates possess regulatory systems that order flagellar gene transcription differently and produce flagella in specific numbers only at poles. How transcriptional and flagellar biogenesis regulatory systems are interlinked to promote the correct synthesis of polar flagella in diverse species has largely been unexplored. We found evidence for many Gram-negative polar flagellates encoding two-component signal transduction systems with activity linked to the formation of flagellar type III secretion systems to enable production of flagellar rod and hook proteins at a discrete, subsequent stage during flagellar assembly. This polar flagellar transcriptional program assists, in some manner, the FlhF/FlhG flagellar biogenesis regulatory system, which forms specific flagellation patterns in polar flagellates in maintaining flagellation and motility when activity of FlhF or FlhG might be altered. Our work provides insight into the multiple regulatory processes required for polar flagellation.




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Robustness in an Ultrasensitive Motor

ABSTRACT

In Escherichia coli, the chemotaxis response regulator CheY-P binds to FliM, a component of the switch complex at the base of the bacterial flagellar motor, to modulate the direction of motor rotation. The bacterial flagellar motor is ultrasensitive to the concentration of unbound CheY-P in the cytoplasm. CheY-P binds to FliM molecules both in the cytoplasm and on the motor. As the concentration of FliM unavoidably varies from cell to cell, leading to a variation of unbound CheY-P concentration in the cytoplasm, this raises the question whether the flagellar motor is robust against this variation, that is, whether the rotational bias of the motor is more or less constant as the concentration of FliM varies. Here, we showed that the motor is robust against variations of the concentration of FliM. We identified adaptive remodeling of the motor as the mechanism for this robustness. As the level of FliM molecules changes, resulting in different amounts of the unbound CheY-P molecules, the motor adaptively changes the composition of its switch complex to compensate for this effect.

IMPORTANCE The bacterial flagellar motor is an ultrasensitive motor. Its output, the probability of the motor turning clockwise, depends sensitively on the occupancy of the protein FliM (a component on the switch complex of the motor) by the input CheY-P molecules. With a limited cellular pool of CheY-P molecules, cell-to-cell variation of the FliM level would lead to large unwanted variation of the motor output if not compensated. Here, we showed that the motor output is robust against the variation of FliM level and identified the adaptive remodeling of the motor switch complex as the mechanism for this robustness.