The frequency and function of nucleoprotein-specific CD8+ T cells are critical for heterosubtypic immunity against influenza virus infection.

Cytotoxic T lymphocytes (CTLs) mediate host defense against viral and intracellular bacterial infections and tumors. However, the magnitude of CTL response and their function needed to confer heterosubtypic immunity against influenza virus infection are unknown. We addressed the role of CD8+ T cells in the absence of any cross-reactive antibody responses to influenza viral proteins using an adenoviral vector expressing a 9mer amino acid sequence recognized by CD8+ T cells. Our results indicate that both CD8+ T cell frequency and function are crucial for heterosubtypic immunity. Low morbidity, lower viral lung titers, low to minimal lung pathology, and better survival upon heterosubtypic virus challenge correlated with the increased frequency of NP-specific CTLs. NP-CD8+ T cells induced by differential infection doses displayed distinct RNA transcriptome profiles and functional properties. CD8+ T cells induced by a high dose of influenza virus secreted significantly higher levels of IFN-γ and exhibited higher levels of cytotoxic function. The mice that received NP-CD8+ T cells from the high-dose virus recipients through adoptive transfer had lower viral titers following viral challenge than those induced by the low dose of virus, suggesting differential cellular programming by antigen dose. Enhanced NP-CD8+ T-cell functions induced by a higher dose of influenza virus strongly correlated with the increased expression of cellular and metabolic genes, indicating a shift to a more glycolytic metabolic phenotype. These findings have implications for developing effective T cell vaccines against infectious diseases and cancer. IMPORTANCE: Cytotoxic T lymphocytes (CTLs) are an important component of the adaptive immune system that clears virus-infected cells or tumor cells. Hence, developing next-generation vaccines that induce or recall CTL responses against cancer and infectious diseases is crucial. However, it is not clear if the frequency, function, or both are essential in conferring protection, as in the case of influenza. In this study, we demonstrate that both CTL frequency and function are crucial for providing heterosubtypic immunity to influenza by utilizing an Ad-viral vector expressing a CD8 epitope only to rule out the role of antibodies, single-cell RNA-seq analysis, as well as adoptive transfer experiments. Our findings have implications for developing T cell vaccines against infectious diseases and cancer.

mRNA-encoded Cas13 treatment of Influenza via site-specific degradation of genomic RNA.

The CRISPR-Cas13 system has been proposed as an alternative treatment of viral infections. However, for this approach to be adopted as an antiviral, it must be optimized until levels of efficacy rival or exceed the performance of conventional approaches. To take steps toward this goal, we evaluated the influenza viral RNA degradation patterns resulting from the binding and enzymatic activity of mRNA-encoded LbuCas13a and two crRNAs from a prior study, targeting PB2 genomic and messenger RNA. We found that the genome targeting guide has the potential for significantly higher potency than originally detected, because degradation of the genomic RNA is not uniform across the PB2 segment, but it is augmented in proximity to the Cas13 binding site. The PB2 genome targeting guide exhibited high levels (>1 log) of RNA degradation when delivered 24 hours post-infection in vitro and maintained that level of degradation over time, with increasing multiplicity of infection (MOI), and across modern influenza H1N1 and H3N2 strains. Chemical modifications to guides with potent LbuCas13a function, resulted in nebulizer delivered efficacy (>1-2 log reduction in viral titer) in a hamster model of influenza (Influenza A/H1N1/California/04/09) infection given prophylactically or as a treatment (post-infection). Maximum efficacy was achieved with two doses, when administered both pre- and post-infection. This work provides evidence that mRNA-encoded Cas13a can effectively mitigate Influenza A infections opening the door to the development of a programmable approach to treating multiple respiratory infections.

mRNA-encoded Cas13 can be used to treat dengue infections in mice.

Dengue is a major global health threat, and there are no approved antiviral agents. Prior research using Cas13 only demonstrated dengue mitigation in vitro. Here we demonstrate that systemic delivery of mRNA-encoded Cas13a and guide RNAs formulated in lipid nanoparticles can be used to treat dengue virus (DENV) 2 and 3 in mice. First, we identified guides against DENV 2 and 3 that demonstrated in vitro efficacy. Next, we confirmed that Cas13 enzymatic activity is necessary for DENV 2 or DENV 3 mitigation in vitro. Last, we show that a single dose of lipid-nanoparticle-formulated mRNA-encoded Cas13a and guide RNA, administered 1 day post-infection, promotes survival of all infected animals and serum viral titre decreases on days 2 and 3 post-infection after lethal challenge in mice. Off-target analysis in mice using RNA sequencing showed no collateral cleavage. Overall, these data demonstrate the potential of mRNA-encoded Cas13 as a pan-DENV drug.

Subpopulation commensalism promotes Rac1-dependent invasion of single cells via laminin-332.

Phenotypic heterogeneity poses a significant hurdle for cancer treatment but is under-characterized in the context of tumor invasion. Amidst the range of phenotypic heterogeneity across solid tumor types, collectively invading cells and single cells have been extensively characterized as independent modes of invasion, but their intercellular interactions have rarely been explored. Here, we isolated collectively invading cells and single cells from the heterogeneous 4T1 cell line and observed extensive transcriptional and epigenetic diversity across these subpopulations. By integrating these datasets, we identified laminin-332 as a protein complex exclusively secreted by collectively invading cells. Live-cell imaging revealed that laminin-332 derived from collectively invading cells increased the velocity and directionality of single cells. Despite collectively invading and single cells having similar expression of the integrin α6ß4 dimer, single cells demonstrated higher Rac1 activation upon laminin-332 binding to integrin α6ß4. This mechanism suggests a novel commensal relationship between collectively invading and single cells, wherein collectively invading cells promote the invasive potential of single cells through a laminin-332/Rac1 axis.

Viral and host factors associated with SARS-CoV-2 disease severity in Georgia, USA.

While SARS-CoV-2 vaccines have shown strong efficacy, their suboptimal uptake combined with the continued emergence of new viral variants raises concerns about the ongoing and future public health impact of COVID-19. We investigated viral and host factors, including vaccination status, that were associated with SARS-CoV-2 disease severity in a setting with low vaccination rates. We analyzed clinical and demographic data from 1,957 individuals in the state of Georgia, USA, coupled with viral genome sequencing from 1,185 samples. We found no difference in disease severity between individuals infected with Delta and Omicron variants among the participants in this study, after controlling for other factors, and we found no specific mutations associated with disease severity. Compared to those who were unvaccinated, vaccinated individuals experienced less severe SARS-CoV-2 disease, and the effect was similar for both variants. Vaccination within 270 days before infection was associated with decreased odds of moderate and severe outcomes, with the strongest association observed at 91-270 days post-vaccination. Older age and underlying health conditions, especially immunosuppression and renal disease, were associated with increased disease severity. Overall, this study provides insights into the impact of vaccination status, variants/mutations, and clinical factors on disease severity in SARS-CoV-2 infection when vaccination rates are low. Understanding these associations will help refine and reinforce messaging around the crucial importance of vaccination in mitigating the severity of SARS-CoV-2 disease.

Examining the effects of soil entrainment during nuclear cloud rise on fallout predictions using a multiscale atmospheric modeling framework.

Current operational models for nuclear cloud rise over land were developed and validated using observations from shallow-buried or surface detonations, where lofted soil quickly mixed with fission products from the detonation. These models poorly predict fallout from elevated detonations near the fallout-free height of burst (FFHOB), where interactions with the ground are limited and the mixing of fission products and lofted soil is incomplete. Fallout-free is a misnomer at this HOB, as fallout was observed in these cases, but was below the levels of concern, especially off-grounds of the nuclear test site. To correctly characterize and model fallout from detonations near the FFHOB, models must be developed which can capture the stratified nature of the particle and activity-size distributions within the cloud. Previously, it was shown that the Weather Research and Forecasting (WRF) model can accurately simulate nuclear cloud rise for airbursts with little to no ground interactions (Arthur et al., 2021). That work is expanded here by (1) using a radiation-hydrodynamics code to improve the fireball initialization in WRF, (2) further developing an aerosol package from WRF-Chem to simulate lofted soil, and (3) combining the WRF cloud rise simulations with the operational models used at the National Atmospheric Release Advisory Center (NARAC) for fallout modeling. Using this combination of codes, the Upshot-Knothole Grable detonation, which was just below the FFHOB, is simulated from seconds after detonation through cloud rise and fallout, and results are compared to historical test data. The results show improved prediction of dose rate and highlight the need to correctly characterize the entrainment of material into the cloud and the subsequent mixing of fission products with entrained material.

Live-cell invasive phenotyping uncovers the ALK2/BMP6 iron homeostasis pathway as a therapeutic vulnerability in LKB1-mutant lung cancer.

The acquisition of invasive properties is a prerequisite for tumor progression and metastasis. Molecular subtypes of KRAS-driven lung cancer exhibit distinct modes of invasion that likely contribute to unique growth properties and therapeutic susceptibilities. Despite this, pre-clinical discovery strategies designed to exploit invasive phenotypes are lacking. To address this, we designed an experimental system to screen for targetable signaling pathways linked to active early invasion phenotypes in the two most prominent molecular subtypes, TP53 and LKB1, of KRAS-driven lung adenocarcinoma (LUAD). By combining live-cell imaging of human bronchial epithelial cells in a 3D invasion matrix with RNA transcriptome profiling, we identified the LKB1-specific upregulation of bone morphogenetic protein 6 (BMP6). Examination of early-stage lung cancer patients confirmed upregulation of BMP6 in LKB1-mutant lung tumors. At the molecular level, we find that the canonical iron regulatory hormone Hepcidin is induced via BMP6 signaling upon LKB1 loss, where intact LKB1 kinase activity is necessary to maintain signaling homeostasis. Furthermore, pre-clinical studies in a novel Kras/Lkb1-mutant syngeneic mouse model show that potent growth suppression was achieved by inhibiting the ALK2/BMP6 signaling axis with single agents that are currently in clinical trials. We show that alterations in the iron homeostasis pathway are accompanied by simultaneous upregulation of ferroptosis protection proteins. Thus, LKB1 is sufficient to regulate both the 'gas' and 'breaks' to finely tune iron-regulated tumor progression.

HIV, asymptomatic STI, and the rectal mucosal immune environment among young men who have sex with men.

Young men who have sex with men (YMSM) are disproportionately affected by HIV and bacterial sexually transmitted infections (STI) including gonorrhea, chlamydia, and syphilis; yet research into the immunologic effects of these infections is typically pursued in siloes. Here, we employed a syndemic approach to understand potential interactions of these infections on the rectal mucosal immune environment among YMSM. We enrolled YMSM aged 18-29 years with and without HIV and/or asymptomatic bacterial STI and collected blood, rectal secretions, and rectal tissue biopsies. YMSM with HIV were on suppressive antiretroviral therapy (ART) with preserved blood CD4 cell counts. We defined 7 innate and 19 adaptive immune cell subsets by flow cytometry, the rectal mucosal transcriptome by RNAseq, and the rectal mucosal microbiome by 16S rRNA sequencing and examined the effects of HIV and STI and their interactions. We measured tissue HIV RNA viral loads among YMSM with HIV and HIV replication in rectal explant challenge experiments among YMSM without HIV. HIV, but not asymptomatic STI, was associated with profound alterations in the cellular composition of the rectal mucosa. We did not detect a difference in the microbiome composition associated with HIV, but asymptomatic bacterial STI was associated with a higher probability of presence of potentially pathogenic taxa. When examining the rectal mucosal transcriptome, there was evidence of statistical interaction; asymptomatic bacterial STI was associated with upregulation of numerous inflammatory genes and enrichment for immune response pathways among YMSM with HIV, but not YMSM without HIV. Asymptomatic bacterial STI was not associated with differences in tissue HIV RNA viral loads or in HIV replication in explant challenge experiments. Our results suggest that asymptomatic bacterial STI may contribute to inflammation particularly among YMSM with HIV, and that future research should examine potential harms and interventions to reduce the health impact of these syndemic infections.

Outbreak of severe acute respiratory coronavirus virus 2 (SARS-CoV-2) in hospitalized hemodialysis patients: An epidemiologic and genomic investigation.

We performed an epidemiological investigation and genome sequencing of severe acute respiratory coronavirus virus 2 (SARS-CoV-2) to define the source and scope of an outbreak in a cluster of hospitalized patients. Lack of appropriate respiratory hygiene led to SARS-CoV-2 transmission to patients and healthcare workers during a single hemodialysis session, highlighting the importance of infection prevention precautions.

The rectal mucosal immune environment and HIV susceptibility among young men who have sex with men.

Young men who have sex with men (YMSM) represent a particularly high-risk group for HIV acquisition in the US, despite similarly reported rates of sexual activity as older, adult MSM (AMSM). Increased rates of HIV infection among YMSM compared to AMSM could be partially attributable to differences within the rectal mucosal (RM) immune environment associated with earlier sexual debut and less lifetime exposure to receptive anal intercourse. Using an ex vivo explant HIV challenge model, we found that rectal tissues from YMSM supported higher levels of p24 at peak viral replication timepoints compared to AMSM. Among YMSM, the RM was characterized by increased CD4+ T cell proliferation, as well as lower frequencies of tissue resident CD8+ T cells and pro-inflammatory cytokine producing CD4+ and CD8+ T cells. In addition, the microbiome composition of YMSM was enriched for anaerobic taxa that have previously been associated with HIV acquisition risk, including Prevotella, Peptostreptococcus, and Peptoniphilus. These distinct immunologic and microbiome characteristics were found to be associated with higher HIV replication following ex vivo challenge of rectal explants, suggesting the RM microenvironment of YMSM may be uniquely conducive to HIV infection.

Esophageal lichen planus: Current knowledge, challenges and future perspectives.

Lichen planus (LP) is a frequent, chronic inflammatory disease involving the skin, mucous membranes and/or skin appendages. Esophageal involvement in lichen planus (ELP) is a clinically important albeit underdiagnosed inflammatory condition. This narrative review aims to give an overview of the current knowledge on ELP, its prevalence, pathogenesis, clinical manifestation, diagnostic criteria, and therapeutic options in order to provide support in clinical management. Studies on ELP were collected using PubMed/Medline. Relevant clinical and therapeutical characteristics from published patient cohorts including our own cohort were extracted and summarized. ELP mainly affects middle-aged women. The principal symptom is dysphagia. However, asymptomatic cases despite progressed macroscopic esophageal lesions may occur. The pathogenesis is unknown, however an immune-mediated mechanism is probable. Endoscopically, ELP is characterized by mucosal denudation and tearing, trachealization, and hyperkeratosis. Scarring esophageal stenosis may occur in chronic courses. Histologic findings include mucosal detachment, T-lymphocytic infiltrations, epithelial apoptosis (Civatte bodies), dyskeratosis, and hyperkeratosis. Direct immuno-fluorescence shows fibrinogen deposits along the basement membrane zone. To date, there is no established therapy. However, treatment with topical steroids induces symptomatic and histologic improvement in two thirds of ELP patients in general. More severe cases may require therapy with immunosuppressors. In symptomatic esophageal stenosis, endoscopic dilation may be necessary. ELP may be regarded as a precancerous condition as transition to squamous cell carcinoma has been documented in literature. ELP is an underdiagnosed yet clinically important differential diagnosis for patients with unclear dysphagia or esophagitis. Timely diagnosis and therapy might prevent potential sequelae such as esophageal stenosis or development of invasive squamous cell carcinoma. Further studies are needed to gain more knowledge about the pathogenesis and treatment options.

Postoperative Intracranial Hypotension-Associated Venous Congestion after Spinal Surgery Managed with Multiple Blood Patches: Case Report.

BACKGROUND: Postoperative intracranial hypotension-associated venous congestion (PIHV) is a rare event. The authors report the case of a patient presenting with PIHV after spinal surgery following the sudden loss of cerebrospinal fluid (CSF) induced by suction drainage. METHODS: A 69-year-old patient underwent uneventful revision surgery for wound dehiscence after lumbar surgery with placement of a subfascial suction drain. RESULTS: Postoperatively, the patient presented with fluctuating consciousness and a generalized tonic-clonic seizure. Computed tomography (CT) and serial magnetic resonance imaging (MRI) were performed showing convexity subarachnoid hemorrhages (SAHs), diffuse swelling of the brain and thalami and striatum bilaterally without diffusion restriction, and signs of intracranial hypertension resulting in pseudohypoxic brain swelling in PIHV. A dural leak at L3-L4 was treated with several CT-guided patches combining autologous blood and fibrin glue injections. The patient recovered without neurologic deficit and follow-up MRI revealed progressive complete reversal of brain swelling, and re-expansion of CSF spaces. CONCLUSION: PIHV is a rare but potentially fatal entity. Awareness of PIHV after cranial or spinal surgery leads to early treatment of CSF hypovolemia and possibly better clinical outcome. Following acute CSF volume loss, an acute elevation of cerebral blood volume overcoming autoregulatory mechanisms seems a likely explanation for diffuse cerebral vasogenic edema and SAH in PIHV.

Subgingival Microbiome in Pregnancy and a Potential Relationship to Early Term Birth.

Background: Periodontal disease in pregnancy is considered a risk factor for adverse birth outcomes. Periodontal disease has a microbial etiology, however, the current state of knowledge about the subgingival microbiome in pregnancy is not well understood. Objective: To characterize the structure and diversity of the subgingival microbiome in early and late pregnancy and explore relationships between the subgingival microbiome and preterm birth among pregnant Black women. Methods: This longitudinal descriptive study used 16S rRNA sequencing to profile the subgingival microbiome of 59 Black women and describe microbial ecology using alpha and beta diversity metrics. We also compared microbiome features across early (8-14 weeks) and late (24-30 weeks) gestation overall and according to gestational age at birth outcomes (spontaneous preterm, spontaneous early term, full term). Results: In this sample of Black pregnant women, the top twenty bacterial taxa represented in the subgingival microbiome included a spectrum representative of various stages of biofilm progression leading to periodontal disease, including known periopathogens Porphyromonas gingivalis and Tannerella forsythia. Other organisms associated with periodontal disease reflected in the subgingival microbiome included several Prevotella spp., and Campylobacter spp. Measures of alpha or beta diversity did not distinguish the subgingival microbiome of women according to early/late gestation or full term/spontaneous preterm birth; however, alpha diversity differences in late pregnancy between women who spontaneously delivered early term and women who delivered full term were identified. Several taxa were also identified as being differentially abundant according to early/late gestation, and full term/spontaneous early term births. Conclusions: Although the composition of the subgingival microbiome is shifted toward complexes associated with periodontal disease, the diversity of the microbiome remains stable throughout pregnancy. Several taxa were identified as being associated with spontaneous early term birth. Two, in particular, are promising targets of further investigation. Depletion of the oral commensal Lautropia mirabilis in early pregnancy and elevated levels of Prevotella melaninogenica in late pregnancy were both associated with spontaneous early term birth.

Rapid Detection and Characterization of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Omicron Variant in a Returning Traveler.

We describe rapid detection of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant using targeted spike single-nucleotide polymorphism polymerase chain reaction and viral genome sequencing. This case occurred in a fully vaccinated and boosted returning traveler with mild symptoms who was identified through community surveillance rather than clinical care.

Direct Immunodetection of Global A-to-I RNA Editing Activity with a Chemiluminescent Bioassay.

Adenosine-to-inosine (A-to-I) editing is a conserved eukaryotic RNA modification that contributes to development, immune response, and overall cellular function. Here, we utilize Endonuclease V (EndoV), which binds specifically to inosine in RNA, to develop an EndoV-linked immunosorbency assay (EndoVLISA) as a rapid, plate-based chemiluminescent method for measuring global A-to-I editing signatures in cellular RNA. We first optimize and validate our assay with chemically synthesized oligonucleotides. We then demonstrate rapid detection of inosine content in treated cell lines, demonstrating equivalent performance against current standard RNA-seq approaches. Lastly, we deploy our EndoVLISA for profiling differential A-to-I RNA editing signatures in normal and diseased human tissue, illustrating the utility of our platform as a diagnostic bioassay. Together, the EndoVLISA method is cost-effective, straightforward, and utilizes common laboratory equipment, offering a highly accessible new approach for studying A-to-I editing. Moreover, the multi-well plate format makes this the first assay amenable for direct high-throughput quantification of A-to-I editing for applications in disease detection and drug development.

Responses of Chlamydomonas reinhardtii during the transition from P-deficient to P-sufficient growth (the P-overplus response): The roles of the vacuolar transport chaperones and polyphosphate synthesis.

Phosphorus (P) assimilation and polyphosphate (polyP) synthesis were investigated in Chlamydomonas reinhardtii by supplying phosphate (PO43- ; 10 mg P·L-1 ) to P-depleted cultures of wildtypes, mutants with defects in genes involved in the vacuolar transporter chaperone (VTC) complex, and VTC-complemented strains. Wildtype C. reinhardtii assimilated PO43- and stored polyP within minutes of adding PO43- to cultures that were P-deprived, demonstrating that these cells were metabolically primed to assimilate and store PO43- . In contrast, vtc1 and vtc4 mutant lines assayed under the same conditions never accumulated polyP, and PO43- assimilation was considerably decreased in comparison with the wildtypes. In addition, to confirm the bioinformatics inferences and previous experimental work that the VTC complex of C. reinhardtii has a polyP polymerase function, these results evidence the influence of polyP synthesis on PO43- assimilation in C. reinhardtii. RNA-sequencing was carried out on C. reinhardtii cells that were either P-depleted (control) or supplied with PO43- following P depletion (treatment) in order to identify changes in the levels of mRNAs correlated with the P status of the cells. This analysis showed that the levels of VTC1 and VTC4 transcripts were strongly reduced at 5 and 24 h after the addition of PO43- to the cells, although polyP granules were continuously synthesized during this 24 h period. These results suggest that the VTC complex remains active for at least 24 h after supplying the cells with PO43- . Further bioassays and sequence analyses suggest that inositol phosphates may control polyP synthesis via binding to the VTC SPX domain.

The oral microbiome and inflammation in mild cognitive impairment.

Inflammation and immune mechanisms are believed to play important roles in Alzheimer's disease pathogenesis. Research supports the link between poor oral health and Alzheimer's disease. Periodontal disease and dental caries represent the two most common infections of the oral cavity. This study focused on a precursor to Alzheimer's disease, mild cognitive impairment (MCI). Using 16S rRNA sequencing, we characterized and compared the oral microbiome of 68 older adults who met the criteria for MCI or were cognitively normal, then explored relationships between the oral microbiome, diagnostic markers of MCI, and blood markers of systemic inflammation. Two taxa, Pasteurellacae and Lautropia mirabilis were identified to be differentially abundant in this cohort. Although systemic inflammatory markers did not differentiate the two groups, differences in five cerebrospinal fluid inflammatory mediators were identified and had significant associations with MCI. Because inflammatory markers may reflect CNS changes, pursuing this line of research could provide opportunities for new diagnostic tools and illuminate mechanisms for prevention and mitigation of Alzheimer's disease.

Rapid Cis-Trans Coevolution Driven by a Novel Gene Retroposed from a Eukaryotic Conserved CCR4-NOT Component in Drosophila.

Young, or newly evolved, genes arise ubiquitously across the tree of life, and they can rapidly acquire novel functions that influence a diverse array of biological processes. Previous work identified a young regulatory duplicate gene in Drosophila, Zeus that unexpectedly diverged rapidly from its parent, Caf40, an extremely conserved component in the CCR4-NOT machinery in post-transcriptional and post-translational regulation of eukaryotic cells, and took on roles in the male reproductive system. This neofunctionalization was accompanied by differential binding of the Zeus protein to loci throughout the Drosophila melanogaster genome. However, the way in which new DNA-binding proteins acquire and coevolve with their targets in the genome is not understood. Here, by comparing Zeus ChIP-Seq data from D. melanogaster and D. simulans to the ancestral Caf40 binding events from D. yakuba, a species that diverged before the duplication event, we found a dynamic pattern in which Zeus binding rapidly coevolved with a previously unknown DNA motif, which we term Caf40 and Zeus-Associated Motif (CAZAM), under the influence of positive selection. Interestingly, while both copies of Zeus acquired targets at male-biased and testis-specific genes, D. melanogaster and D. simulans proteins have specialized binding on different chromosomes, a pattern echoed in the evolution of the associated motif. Using CRISPR-Cas9-mediated gene knockout of Zeus and RNA-Seq, we found that Zeus regulated the expression of 661 differentially expressed genes (DEGs). Our results suggest that the evolution of young regulatory genes can be coupled to substantial rewiring of the transcriptional networks into which they integrate, even over short evolutionary timescales. Our results thus uncover dynamic genome-wide evolutionary processes associated with new genes.

The Examination of Repeated Self-Mobilizations With Movement and Joint Mobilizations on Individuals With Chronic Ankle Instability.

CONTEXT: Chronic ankle instability (CAI) is one of the most common chronic conditions in the world, resulting in millions of dollars contributed to the health care system. Joint mobilizations have been shown to effectively improve patient and disease-specific impairments secondary to CAI. The ability for patients to complete an effective manual therapy intervention without the need for continuous visits to a health care provider can alleviate burdens on the health care system and improve patient satisfaction. OBJECTIVE: To examine the effect of clinician-applied Maitland talocrural joint mobilization and self-mobilization (Self-Mob) on dorsiflexion range of motion (DFROM), dynamic balance, strength, and perceived function in those with CAI. DESIGN: Single-blind randomized trial. SETTING: Research laboratory. PARTICIPANTS: A total of 18 participants (7 males and 11 females; age = 20.78 [2.02] y, height = 67.66 [3.83] cm, limb length = 87.74 [5.05] cm) with self-reported CAI participated. INTERVENTIONS: The participants received 6 interventions over a 2-week period. The participants received either Maitland grade III anterior-to-posterior talocrural joint mobilizations or weight-bearing lunge Self-Mob. Each intervention consisted of four 2-minute sets, with a 1-minute rest between sets. MAIN OUTCOME MEASURES: The DFROM (weight-bearing lunge), dynamic balance (Y-Balance Test), isometric strength, Foot and Ankle Ability Measure Quick, Disablement of the Physically Active modified, Fear Avoidance Beliefs Questionnaire, and Tampa Scale of Kinesiophobia-11 were measured preintervention and postintervention. RESULTS: Dynamic balance, isometric strength, and perceived function significantly improved in both groups at postintervention. The DFROM significantly improved in the Self-Mob group. Higher individual responder rates were demonstrated within the Self-Mob group compared with clinician-applied mobilizations. CONCLUSIONS: Clinician-applied mobilizations and Self-Mobs are effective interventions for improving dynamic balance, isometric strength, and perceived function. Application of Self-Mobs can effectively improve DFROM compared with joint mobilization. Self-Mobs may be an effective intervention to incorporate into a home care plan.