A Transducing Bacteriophage Infecting Staphylococcus epidermidis Contributes to the Expansion of a Novel Siphovirus Genus and Implies the Genus Is Inappropriate for Phage Therapy.

The effort to discover novel phages infecting Staphylococcus epidermidis contributes to both the development of phage therapy and the expansion of genome-based phage phylogeny. Here, we report the genome of an S. epidermidis-infecting phage, Lacachita, and compare its genome with those of five other phages with high sequence identity. These phages represent a novel siphovirus genus, which was recently reported in the literature. The published member of this group was favorably evaluated as a phage therapeutic agent, but Lacachita is capable of transducing antibiotic resistance and conferring phage resistance to transduced cells. Members of this genus may be maintained within their host as extrachromosomal plasmid prophages, through stable lysogeny or pseudolysogeny. Therefore, we conclude that Lacachita may be temperate and members of this novel genus are not suitable for phage therapy. IMPORTANCE This project describes the discovery of a culturable bacteriophage infecting Staphylococcus epidermidis that is a member of a rapidly growing novel siphovirus genus. A member of this genus was recently characterized and proposed for phage therapy, as there are few phages currently available to treat S. epidermidis infections. Our data contradict this, as we show Lacachita is capable of moving DNA from one bacterium to another, and it may be capable of maintaining itself in a plasmid-like state in infected cells. These phages' putative plasmid-like extrachromosomal state appears to be due to a simplified maintenance mechanism found in true plasmids of Staphylococcus and related hosts. We suggest Lacachita and other identified members of this novel genus are not suitable for phage therapy.

Structural and Biochemical Characterization of Staphylococcus aureus Cysteine Desulfurase Complex SufSU.

In this work, we provide the first in vitro characterization of two essential proteins from Staphylococcus aureus (S. aureus) involved in iron-sulfur (Fe-S) cluster biogenesis: the cysteine desulfurase SufS and the sulfurtransferase SufU. Together, these proteins form the transient SufSU complex and execute the first stage of Fe-S cluster biogenesis in the SUF-like pathway in Gram-positive bacteria. The proteins involved in the SUF-like pathway, such as SufS and SufU, are essential in Gram-positive bacteria since these bacteria tend to lack redundant Fe-S cluster biogenesis pathways. Most previous work characterizing the SUF-like pathway has focused on Bacillus subtilis (B. subtilis). We focus on the SUF-like pathway in S. aureus because of its potential to serve as a therapeutic target to treat S. aureus infections. Herein, we characterize S. aureus SufS (SaSufS) by X-ray crystallography and UV-vis spectroscopy, and we characterize S. aureus SufU (SaSufU) by a zinc binding fluorescence assay and small-angle X-ray scattering. We show that SaSufS is a type II cysteine desulfurase and that SaSufU is a Zn2+-containing sulfurtransferase. Additionally, we evaluated the cysteine desulfurase activity of the SaSufSU complex and compared its activity to that of B. subtilis SufSU. Subsequent cross-species activity analysis reveals a surprising result: SaSufS is significantly less stimulated by SufU than BsSufS. Our results set a basis for further characterization of SaSufSU as well as the development of new therapeutic strategies for treating infections caused by S. aureus by inhibiting the SUF-like pathway.

Complete Genome Sequences of Five Phietaviruses Infecting Staphylococcus aureus.

The annotated whole-genome sequences of five cultured phietaviruses infecting Staphylococcus aureus are presented. They are closely related to prophages that were previously sequenced as part of S. aureus genomes.

Impact of trace mineral source on beef replacement heifer growth, reproductive development, and biomarkers of maternal recognition of pregnancy and embryo survival.

Trace minerals are known to play important roles in early embryo development. The study objective was to determine effects of trace mineral source on heifer reproductive performance. Beef heifers (n = 129) were randomly assigned to one of two treatments. From weaning through breeding, all heifers were individually fed a basal diet supplemented with cobalt (Co), copper (Cu), manganese (Mn), and zinc (Zn) either from organic sources (COMP; Cu, Mn, and Zn amino acid complexes and Co glucoheptonate; Availa-4, Zinpro Corporation, Eden Prairie, MN) or inorganic sources (INORG; Cu, Mn, and Zn hydroxychlorides; Intellibond C, M, and Z, Micronutrients, Indianapolis, IN) and Co as CoSO4. Blood samples and a reproductive tract score (RTS) were collected to determine pubertal status. All animals were synchronized and artificially inseminated. Pregnancy status was determined by lymphocyte gene expression, circulating concentrations of pregnancy-associated glycoproteins (PAGs), and by transrectal ultrasonography after artificial insemination. Embryonic loss was defined as when a previously pregnant animal was subsequently diagnosed not pregnant. Data were analyzed using the MIXED procedure in SAS. Puberty (P = 0.44), pelvic area (P = 0.74), RTS (P = 0.49), and estrus expression (P = 0.82) were not influenced by treatment. There was no effect of treatment (P = 0.37) or treatment by time (P = 0.19) on pregnancy, but there was a tendency (P = 0.13) for decreased embryonic loss among COMP heifers (27 ± 6%) compared to INORG heifers (38 ± 6%). There was a treatment by pregnancy status by time interaction (P < 0.01) on circulating PAG concentrations with PAG concentrations tending (P = 0.08) to be greater on day 25 among heifers in the COMP treatment compared to heifers in the INORG group. In summary, source of trace mineral did not affect puberty, RTS, pelvic area, or overall pregnancy success, but feeding complexed trace minerals tended to increase circulating PAG concentrations and embryo survival.

Mitochondrial dysfunction as a critical event in the pathophysiology of bipolar disorder.

The understanding of the pathophysiology of bipolar disorder (BD) remains modest, despite recent advances in neurobiological research. The mitochondrial dysfunction hypothesis of bipolar disorder has been corroborated by several studies involving postmortem brain analysis, neuroimaging, and specific biomarkers in both rodent models and humans. Evidence suggests that BD might be related to abnormal mitochondrial morphology and dynamics, neuroimmune dysfunction, and atypical mitochondrial metabolism and oxidative stress pathways. Mitochondrial dysfunction in mood disorders is also associated with abnormal Ca2+ levels, glutamate excitotoxicity, an imbalance between pro- and antiapoptotic proteins towards apoptosis, abnormal gene expression of electron transport chain complexes, and decreased ATP synthesis. This paper aims to review and discuss the implications of mitochondrial dysfunction in BD etiology and to explore mitochondria as a potential target for novel therapeutic agents.

Beliefs About the Influence of Rest During Concussion Recovery May Predict Activity and Symptom Progression Within an Active Duty Military Population.

OBJECTIVES: To evaluate relationships between beliefs about the impact of rest and the level of activities and symptoms over time among active duty Service members sustaining concussion, and whether these relationships vary by provision of concussion education. DESIGN: Longitudinal study using multilevel modeling to assess the relationship between beliefs about rest within 72 hours of concussion and change in activity and symptom level over time, as well as interaction by concussion education at the initial clinic visit. SETTING: Three military treatment facilities. PARTICIPANTS: Study participants included active duty Service members diagnosed with a concussion (N=111; median age, 24 y). Individuals with previous history of concussion within 12 months of study enrollment were excluded. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Activity questionnaire and the Neurobehavioral Symptom Inventory assessed within 72 hours of concussion; at 1 week; and at 1, 3, and 6 month(s) postinjury. RESULTS: Receipt of concussion education from providers was significantly associated with greater belief that rest influences concussion recovery. Greater belief that rest influences symptom recovery at the acute stage of concussion was associated with a greater increase in activities over time, but only among those who received education from their provider. Additionally, greater belief about the influence of rest was related to a more rapid decrease in symptoms over time. CONCLUSIONS: Concussed Service members who underestimate the influence of rest during acute recovery may be at risk for poorer recovery. Treatment of Service members with postconcussive symptoms should consider patient knowledge and/or beliefs about rest and recovery, which may influence prognosis. Our results support the provider's use of concussion education to correct potential misconceptions that may negatively impact symptom recovery.

Accelerated aging in bipolar disorder: A comprehensive review of molecular findings and their clinical implications.

Bipolar disorder (BD) has been associated with clinical signs of accelerated aging, which potentially underlies its association with several age-related medical conditions, such as hypertension, metabolic imbalances, dementia, and cancer. This paper aims to comprehensively review evidence of biological aging in BD and explore findings and controversies related to common biological clocks in patients, including telomere length, DNA methylation, mitochondrial DNA copy number, inflammation, and oxidative stress. Our results suggest a complex interplay between biological markers and a potential key role of environmental factors, such as childhood trauma and psychological stress, in determining premature aging in patients. Moreover, given its multifactorial nature, our summary evidences the need for further studies incorporating clinical evidence with biomarkers of accelerated aging in BD. Results of this review strongly suggest BD as an accelerated aging disease seen in both clinical and molecular aspects. Understanding the pathophysiology of aging in BD may ultimately lead to identification of pathways that can be targeted for prevention of premature aging in patients and early onset of aging-related conditions.

Activity Level During Acute Concussion May Predict Symptom Recovery Within an Active Duty Military Population.

OBJECTIVE: To evaluate the impact on symptom resolution of activity acutely following a concussion and the role of acute-phase symptoms on this relationship among active duty service members (SMs). SETTING: Three military installations. PARTICIPANTS: Sixty-two SMs aged 18 to 44 years who sustained a concussion within 72 hours of enrollment. DESIGN: Longitudinal design with data collected within 72 hours of injury (baseline, n = 62) and at 1 week (n = 57), 1 month (n = 50), 3 months (n = 41), and 6 months (n = 40) postinjury. MAIN MEASURES: Baseline activity level using a 60-item Activity Questionnaire. Symptom level at baseline and during follow-up using Neurobehavioral Symptoms Inventory. RESULTS: Significant interaction (Pi < .05) was found, with significant main effects (P < .05) limited to SMs with elevated baseline symptomatology. Among these participants, greater baseline total activity was significantly related to greater vestibular symptoms at 1, 3, and 6 months (ß = .61, .63, and .59, respectively). Significant associations were also found for particular types of baseline activity (eg, physical; vestibular/balance; military-specific) and symptoms at 1, 3, and/or 6 months postinjury. CONCLUSION: These results provide support for clinical guidance that symptomatic SMs, particularly those with high levels of acute symptoms, may need to avoid excessive activity acutely following concussion.

Activity Level and Type During Post-acute Stages of Concussion May Play an Important Role in Improving Symptoms Among an Active Duty Military Population.

Background: Previous research demonstrates that early rest and gradual increases in activity after concussion can improve symptoms; however, little is known about the intensity and type of activity during post-acute time periods-specifically months post-injury-that may promote optimal recovery in an active duty service member (SM) population. Objective: The objectives of this study were to investigate how activity level and type at the post-acute stages of concussion (at 1 and 3 month[s] post-injury) impact subsequent symptoms among SMs, and how this relationship might differ by the level of symptoms at the time of injury. Methods: Participants included 39 SMs ages 19-44 years from 3 military installations who were enrolled within 72 h after sustaining a concussion. Linear regression was used to evaluate whether the association between activity level at 1 or 3 month(s) post-injury (as measured by a multi-domain Activity Questionnaire) and subsequent symptoms at 3 and/or 6 months (as measured by the Neurobehavioral Symptom Inventory) varied by the level of symptoms at acute stages of concussion. Partial correlation was used to evaluate relationships that did not differ by acute symptom level. Symptoms at the time of activity assessment (1 or 3 month[s]) were accounted for in all models, as well as activity level at acute stages of concussion. Results: Greater physical and vestibular/balance activity at 1 month were significantly correlated with lower symptoms at 3 months, but not at 6 months post-injury. There were no significant associations found between activity (total or by type) at 3 months and symptoms at 6 months. The association between activity level at either 1 or 3 months and subsequent symptoms at 3 and/or 6 months did not differ by the level of acute symptoms. Conclusion: The intensity and type of activities in which SMs engage at post-acute stages of concussion may impact symptom recovery. Although low levels of activity have been previously shown to be beneficial during the acute stage of injury, higher levels of activity may provide benefit at later stages. These findings provide support for the importance of monitoring and managing activity level beyond the acute stage of concussion.

TSPO upregulation in bipolar disorder and concomitant downregulation of mitophagic proteins and NLRP3 inflammasome activation.

Bipolar disorder (BD) is a chronic, debilitating illness with a global prevalence of up to 4.8%. The importance of understanding how dysfunctional mitochondria and mitophagy contribute to cell survival and death in BD is becoming increasingly apparent. Therefore, the purpose of this study was to evaluate the mitophagic pathway and NLRP3 inflammasome activation in peripheral blood mononuclear cells (PBMCs) of patients with BD and healthy individuals. Since 18-kDa translocator protein (TSPO) plays an important role in regulating mitochondrial function and since TSPO itself impairs cellular mitophagy, we also investigated the changes in the TSPO-related pathway. Our results showed that patients with BD had lower levels of Parkin, p62/SQSTM1 and LC3A and an upregulation of TSPO pathway proteins (TSPO and VDAC), both in terms of mRNA and protein levels. Additionally, we found a negative correlation between mitophagy-related proteins and TSPO levels, while VDAC correlated negatively with p62/SQSTM1 and LC3 protein levels. Moreover, we found that the gene expression levels of the NLRP3-related proteins NLRP3, ASC, and pro-casp1 were upregulated in BD patients, followed by an increase in caspase-1 activity as well as IL-1ß and IL-18 levels. As expected, there was a strong positive correlation between NLRP3-related inflammasome activation and TSPO-related proteins. The data reported here suggest that TSPO-VDAC complex upregulation in BD patients, the simultaneous downregulation of mitophagic proteins and NLRP3 inflammasome activation could lead to an accumulation of dysfunctional mitochondria, resulting in inflammation and apoptosis. In summary, the findings of this study provide novel evidence that mitochondrial dysfunction measured in peripheral blood is associated with BD.

Efficacy of the Mantram Repetition Program for Insomnia in Veterans With Posttraumatic Stress Disorder: A Naturalistic Study.

Statistics show that more than 80% of Veterans mention posttraumatic stress disorder (PTSD)-related symptoms when seeking treatment. Sleep disturbances and nightmares are among the top 3 presenting problems. Current PTSD trauma-focused therapies generally do not improve sleep disturbances. The mantram repetition program (MRP), a mind-body-spiritual intervention, teaches a portable set of cognitive-spiritual skills for symptom management. The aim of this study was to evaluate the efficacy of the MRP on insomnia in Veterans with PTSD in a naturalistic, clinical setting. Results show that participation in the MRP significantly reduced insomnia, as well as decreased self-reported and clinician-assessed PTSD symptom burden.

Multi-site evaluation of a complementary, spiritually-based intervention for Veterans: The Mantram Repetition Program.

BACKGROUND: Mental and physical symptoms affect Veterans' quality of life. Despite available conventional treatments, an increasing number of Veterans are seeking complementary approaches to symptom management. Research on the Mantram Repetition Program (MRP), a spiritually-based intervention, has shown significant improvements in psychological distress and spiritual well-being in randomized trials. However, these findings have not been replicated in real-world settings. METHODS: In this naturalistic study, we analyzed outcomes from 273 Veterans who participated in MRP at six sites and explored outcomes based on facilitator training methods. Measures included satisfaction and symptoms of anxiety, depression, and somatization using the Brief Symptom Inventory-18; Functional Assessment of Chronic Illness Therapy-Spiritual Well-being questionnaire; and the Mindfulness Attention Awareness Scale. RESULTS: There were significant improvements in all outcomes (p's < .001) regardless of how facilitators were trained. Patient satisfaction was high. CONCLUSION: The MRP was disseminated successfully yielding improvements in psychological distress, spiritual well-being, and mindfulness.