Institutional Betrayal Related to Sexual Trauma in Military Service Members and Veterans: An Examination of Posttraumatic Sequelae

Military sexual harassment and/or assault (MSH/A) is pervasive and destructive. MSH/A survivors who believe the institution played a role in the traumatic experience by failing to respond in a supportive manner or for failing to keep them safe may feel betrayed by the military itself, a concept referred to as institutional betrayal. Previous research suggests it is more harmful to be abused by trusted others or institutions due to the violation of trust. This two-study dissertation explored experiences of MSH/A-related institutional betrayal to identify survivors at-risk for worse posttraumatic outcomes. Study #1 evaluated whether PTSD explained the relationship between MSH/A type and somatic symptom severity, and whether this relationship depended on experiences of institutional betrayal. Study #2 examined whether exposure to killing and/or death during combat strengthened the link between institutional betrayal and risk for suicidal behaviors. Findings revealed MSH/A perpetrators were typically male, a fellow servicemember, unit member, battle buddy, or first-line leader. The most common experiences of MSH/A-related institutional betrayal included responding inadequately once MSH/A was reported, creating an environment in which MSH/A seemed normal or common, making it difficult to report MSH/A, not taking proactive steps to prevent MSH/A, and mishandling the case once reported. PTSD explained the link between MSH and somatic symptom severity, but contrary to hypotheses in Study #1 and #2, institutional betrayal was unrelated to somatic symptom severity and suicide risk. Alternatively, MSH was an independent risk factor for severe posttraumatic distress, including suicide risk, somatic symptom severity, PTSD, depression, and alcohol abuse when compared to MSA. MSH is often the precursor to MSA, but the experience goes unreported or is not taken seriously by leadership, which likely contributes to the cycle of violence and maintains the abuse. This dissertation illustrates that any type of sexual violence is demeaning and has the potential to cause harm. Prevention strategies are needed to thwart MSH, thereby decreasing risk for MSA, suicidal behavior, somatic symptom severity, PTSD, depression, and alcohol abuse. It is imperative that the Department of Defense increases accountability for perpetrators and ensures leadership does not tolerate sexual violence or retaliate upon disclosure

Acceptance and Commitment Therapy (ACT) Among U.S. Veterans: A Systematic Review

Veterans of the United States military represent a large sample of the population and a distinctive culture. Veterans have a high prevalence rate of a variety of psychological disorders and disabilities. Research on treatments that meet the needs of this culturally unique group is essential. Acceptance and Commitment Therapy (ACT) may meet this need with its unified treatment approach and its focus on functioning rather than diagnosis. In this study we examine the current state of the literature of ACT for U.S. Veterans. A systematic review of 249 papers found 34 unique relevant studies involving 21 single arm studies, eight randomized clinical trials, two non-randomized controlled trials, and three case studies that met inclusion criteria. Overall, results suggest ACT is a promising intervention for Veterans across multiple conditions (e.g., anxiety disorders, depression, chronic pain) as well as intervention delivery (in-person and telehealth) and type (group and individual therapy). Limitations highlighted include recruitment methods of studies included, lack of active control conditions, and the limited number of randomized trials. Future researchers should continue to examine which presentations respond to ACT and seek to understand what types of adaptations may be necessary to increase the effectiveness of ACT for U.S. Veterans

Proteasome β5i Subunit Deficiency Affects Opsonin Synthesis and Aggravates Pneumococcal Pneumonia.

Immunoproteasomes, harboring the active site subunits β5i/LMP7, β1i/LMP2, and β2i/MECL1 exert protective, regulatory or modulating functions during infection-induced immune responses. Immunoproteasomes are constitutively expressed in hematopoietic derived cells, constituting the first line of defense against invading pathogens. To clarify the impact of immunoproteasomes on the innate immune response against Streptococcus pneumoniae, we characterized the progression of disease and analyzed the systemic immune response in β5i/LMP7-/- mice. Our data show that β5i/LMP7 deficiency, which affected the subunit composition of proteasomes in murine macrophages and liver, was accompanied by reduced transcription of genes encoding immune modulating molecules such as pentraxins, ficolins, and collectins. The diminished opsonin expression suggested an impaired humoral immune response against invading pneumococci resulting in an aggravated systemic dissemination of S. pneumoniae in β5i/LMP7-/- mice. The impaired bacterial elimination in β5i/LMP7-/- mice was accompanied by an aggravated course of pneumonia with early mortality as a consequence of critical illness during the late phase of disease. In summary our results highlight an unsuspected role for immuno-subunits in modulating the innate immune response to extracellular bacterial infections

<em>N</em>-glycosylation of asparagine 8 regulates surface expression of major histocompatibility complex class I chain-related protein A (MICA) alleles dependent on threonine 24

NKG2D is an activating receptor expressed on several types of human lymphocytes. NKG2D ligands can be induced upon cell stress and are frequently targeted post-translationally in infected or transformed cells to avoid immune recognition. Virus infection and inflammation alter protein N-glycosylation, and we have previously shown that changes in cellular N-glycosylation are involved in regulation of NKG2D ligand surface expression. The specific mode of regulation through N-glycosylation is, however, unknown. Here we investigated whether direct N-glycosylation of the NKG2D ligand MICA itself is critical for cell surface expression and sought to identify the essential residues. We found that a single N-glycosylation site (Asn(8)) was important for MICA018 surface expression. The frequently expressed MICA allele 008, with an altered transmembrane and intracellular domain, was not affected by mutation of this N-glycosylation site. Mutational analysis revealed that a single amino acid (Thr(24)) in the extracellular domain of MICA018 was essential for the N-glycosylation dependence, whereas the intracellular domain was not involved. The HHV7 immunoevasin, U21, was found to inhibit MICA018 surface expression by affecting N-glycosylation, and the retention was rescued by T24A substitution. Our study reveals N-glycosylation as an allele-specific regulatory mechanism important for regulation of surface expression of MICA018, and we pinpoint the residues essential for this N-glycosylation dependence. In addition, we show that this regulatory mechanism of MICA surface expression is likely targeted during different pathological conditions

Head-to-head comparison of the penetration efficiency of lipid-based nanoparticles in a 3D tumor spheroid model

Most tumor-targeted drug delivery systems must overcome a large variety of physiological barriers before reaching the tumor site and diffuse through the tight network of tumor cells. Many studies focus on optimizing the first part, the accumulation of drug carriers at the tumor site, ignoring the penetration efficiency, i.e., a measure of the ability of a drug delivery system to overcome tumor surface adherence and uptake. We used 3D tumor spheroids in combination with light-sheet fluorescence microscopy in a head-to-head comparison of a variety of commonly used lipid-based nanoparticles, including liposomes, PEGylated liposomes, lipoplexes and reconstituted high-density lipoproteins (rHDL). Whilst PEGylation of liposomes only had minor effects on the penetration efficiency, we show that lipoplexes mainly associated to the periphery of tumor spheroids, possibly due to their positive surface charge leading to fusion with the cells at the spheroid surface or aggregation. Surprisingly, the rHDL showed significantly higher penetration efficiency and high accumulation inside the spheroid. While these findings indeed could be relevant when designing novel drug delivery systems based on lipid-based nanoparticles, we stress that the used platform and detailed image analysis is a versatile tool for in vitro studies of the penetration efficiency of nanoparticles in tumors.</div

β5i/LMP7^-/- mice exhibit a diminished expression of opsonizing molecules in lung, liver and macrophages.

<p>(A) Gene expression analysis of lungs, 48 h after transnasal application of 5×10⁶ CFU PN36/mouse, performed by RT and Real Time PCR (each group with n = 5–6; statistical analysis by Mann Whitney U Test. *p<0.05). (B) Gene expression analysis of BMM co-cultivated with D39Δcps (MOI 10) for 4 h, performed by RT and Real Time PCR (each group with n = 4, illustrated experiment is representative for 4 individual replicates; showing mean± SD; statistical analysis by student’s t-test **p<0.01). (C) Gene expression analysis of liver 48 h after transnasal application of 5×10⁶ CFU PN36/mouse, performed by RT and Real Time PCR (each group with n = 12–14; statistical analysis by Mann Whitney U Test. *p<0.05; **p<0.01).</p