Abstract
Broadly neutralizing antibodies (bnAbs) targeting conserved influenza A virus (IAV) hemagglutinin (HA) epitopes can provide valuable information for accelerating universal vaccine designs. ...Here, we report structural details for heterosubtypic recognition of HA from circulating and emerging IAVs by the human antibody 3I14. Somatic hypermutations play a critical role in shaping the HCDR3, which alone and uniquely among
V
H
3-30
derived antibodies, forms contacts with five sub-pockets within the HA-stem hydrophobic groove. 3I14 light-chain interactions are also key for binding HA and contribute a large buried surface area spanning two HA protomers. Comparison of 3I14 to bnAbs from several defined classes provide insights to the bias selection of
V
H
3-30
antibodies and reveals that 3I14 represents a novel structural solution within the
V
H
3-30
repertoire. The structures reported here improve our understanding of cross-group heterosubtypic binding activity, providing the basis for advancing immunogen designs aimed at eliciting a broadly protective response to IAV.
Mild Traumatic Brain Injury (mTBI), or concussion, is a major public health concern. There is controversy in the literature regarding the true incidence of postconcussion syndrome (PCS), with the ...constellation of physical, cognitive, emotional, and sleep symptoms after mTBI. In the current study, we report on the incidence and evolution of PCS symptoms and patient outcomes after mTBI at 3, 6, and 12 months in a large, prospective cohort of mTBI patients. Participants were identified as part of the prospective, multi-center Transforming Research and Clinical Knowledge in Traumatic Brain Injury Study. The study population was mTBI patients (Glasgow Coma Scale score of 13-15) presenting to the emergency department, including patients with a negative head computed tomography discharged to home without admission to hospital; 375 mTBI subjects were included in the analysis. At both 6 and 12 months after mTBI, 82% (n=250 of 305 and n=163 of 199, respectively) of patients reported at least one PCS symptom. Further, 44.5 and 40.3% of patients had significantly reduced Satisfaction With Life scores at 6 and 12 months, respectively. At 3 months after injury, 33% of the mTBI subjects were functionally impaired (Glasgow Outcome Scale-Extended score ≤6); 22.4% of the mTBI subjects available for follow-up were still below full functional status at 1 year after injury. The term "mild" continues to be a misnomer for this patient population and underscores the critical need for evolving classification strategies for TBI for targeted therapy.
Summary
Glutamate decarboxylase (GAD) is a Ca
2+
‐calmodulin‐activated, cytosolic enzyme that produces γ‐aminobutyrate (GABA) as the committed step of the GABA shunt. This pathway bypasses the ...2‐oxoglutarate to succinate reactions of the tricarboxylic acid (TCA) cycle. GABA also accumulates during many plant stresses.
We tested the hypothesis that AtGAD1 (At5G17330) facilitates
Arabidopsis
acclimation to Pi deprivation. Quantitative RT‐PCR and immunoblotting revealed that AtGAD1 transcript and protein expression is primarily root‐specific, but inducible at lower levels in shoots of Pi‐deprived (−Pi) plants.
Pi deprivation reduced levels of the 2‐oxoglutarate dehydrogenase (2‐OGDH) cofactor thiamine diphosphate (ThDP) in shoots and roots by > 50%. Growth of −Pi
atgad1
T‐DNA mutants was significantly attenuated relative to wild‐type plants. This was accompanied by: (i) an > 60% increase in shoot and root GABA levels of −Pi wild‐type, but not
atgad1
plants, and (ii) markedly elevated anthocyanin and reduced free and total Pi levels in leaves of −Pi
atgad1
plants. Treatment with 10 mM GABA reversed the deleterious development of −Pi
atgad1
plants.
Our results indicate that AtGAD1 mediates GABA shunt upregulation during Pi deprivation. This bypass is hypothesized to circumvent ThDP‐limited 2‐OGDH activity to facilitate TCA cycle flux and respiration by −Pi
Arabidopsis
.
Brain lesions are subtle or absent in most patients with mild traumatic brain injury (mTBI) and the standard clinical criteria are not reliable for predicting long-term outcome. This study ...investigates resting-state functional MRI (rsfMRI) to assess semiacute alterations in brain connectivity and its relationship with outcome measures assessed 6 months after injury. Seventy-five mTBI patients were recruited as part of the prospective multicenter Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) pilot study and compared with matched 47 healthy subjects. Patients were classified following radiological criteria: CT/MRI positive, evidence of lesions; CT/MRI negative, without evidence of brain lesions. rsfMRI data were acquired and then processed using probabilistic independent component analysis. We compared the functional connectivity of the resting-state networks (RSNs) between patients and controls, as well as group differences in the interactions between RSNs, and related both to cognitive and behavioral performance at 6 months post-injury. Alterations were found in the spatial maps of the RSNs between mTBI patients and healthy controls in networks involved in behavioral and cognition processes. These alterations were predictive of mTBI patients' outcomes at 6 months post-injury. Moreover, different patterns of reduced network interactions were found between the CT/MRI positive and CT/MRI negative patients and the control group. These rsfMRI results demonstrate that even mTBI patients not showing brain lesions on conventional CT/MRI scans can have alterations of functional connectivity at the semiacute stage that help explain their outcomes. These results suggest rsfMRI as a sensitive biomarker both for early diagnosis and for prediction of the cognitive and behavioral performance of these patients.
Traumatic brain injury (TBI) is a complex disorder that is traditionally stratified based on clinical signs and symptoms. Recent imaging and molecular biomarker innovations provide unprecedented ...opportunities for improved TBI precision medicine, incorporating patho-anatomical and molecular mechanisms. Complete integration of these diverse data for TBI diagnosis and patient stratification remains an unmet challenge.
The Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) Pilot multicenter study enrolled 586 acute TBI patients and collected diverse common data elements (TBI-CDEs) across the study population, including imaging, genetics, and clinical outcomes. We then applied topology-based data-driven discovery to identify natural subgroups of patients, based on the TBI-CDEs collected. Our hypothesis was two-fold: 1) A machine learning tool known as topological data analysis (TDA) would reveal data-driven patterns in patient outcomes to identify candidate biomarkers of recovery, and 2) TDA-identified biomarkers would significantly predict patient outcome recovery after TBI using more traditional methods of univariate statistical tests. TDA algorithms organized and mapped the data of TBI patients in multidimensional space, identifying a subset of mild TBI patients with a specific multivariate phenotype associated with unfavorable outcome at 3 and 6 months after injury. Further analyses revealed that this patient subset had high rates of post-traumatic stress disorder (PTSD), and enrichment in several distinct genetic polymorphisms associated with cellular responses to stress and DNA damage (PARP1), and in striatal dopamine processing (ANKK1, COMT, DRD2).
TDA identified a unique diagnostic subgroup of patients with unfavorable outcome after mild TBI that were significantly predicted by the presence of specific genetic polymorphisms. Machine learning methods such as TDA may provide a robust method for patient stratification and treatment planning targeting identified biomarkers in future clinical trials in TBI patients.
ClinicalTrials.gov Identifier NCT01565551.
Traumatic brain injury (TBI) is among the leading causes of death and disability worldwide, with enormous negative social and economic impacts. The heterogeneity of TBI combined with the lack of ...precise outcome measures have been central to the discouraging results from clinical trials. Current approaches to the characterization of disease severity and outcome have not changed in more than three decades. This prospective multicenter observational pilot study aimed to validate the feasibility of implementing the TBI Common Data Elements (TBI-CDEs). A total of 650 subjects who underwent computed tomography (CT) scans in the emergency department within 24 h of injury were enrolled at three level I trauma centers and one rehabilitation center. The TBI-CDE components collected included: 1) demographic, social and clinical data; 2) biospecimens from blood drawn for genetic and proteomic biomarker analyses; 3) neuroimaging studies at 2 weeks using 3T magnetic resonance imaging (MRI); and 4) outcome assessments at 3 and 6 months. We describe how the infrastructure was established for building data repositories for clinical data, plasma biomarkers, genetics, neuroimaging, and multidimensional outcome measures to create a high quality and accessible information commons for TBI research. Risk factors for poor follow-up, TBI-CDE limitations, and implementation strategies are described. Having demonstrated the feasibility of implementing the TBI-CDEs through successful recruitment and multidimensional data collection, we aim to expand to additional study sites. Furthermore, interested researchers will be provided early access to the Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) data set for collaborative opportunities to more precisely characterize TBI and improve the design of future clinical treatment trials. (ClinicalTrials.gov Identifier NCT01565551.).
To provide an overview of a series of projects that used a structured self-report screening tool in diverse settings and samples to screen for lifetime history of traumatic brain injury (TBI).
...Diverse community settings.
Homeless persons (n = 111), individuals with HIV seeking vocational rehabilitation (n = 173), youth in the juvenile justice system (n = 271), public schoolchildren (n = 174), substance users (n = 845), intercollegiate athletes (n = 90), and other community-based samples (n = 396).
Cross-sectional.
Brain Injury Screening Questionnaire.
Screening using the Brain Injury Screening Questionnaire finds that 27% to 54% of those in high-risk populations report a history of TBI with chronic symptoms. Associations between TBI and social, academic, or other problems are evident in several studies. In non-high-risk community samples, 9% to 12% of individuals report TBI with chronic symptoms.
Systematic TBI screening can be implemented efficiently and inexpensively in a variety of settings. Lifetime TBI history data gathered using a structured self-report instrument can augment existing estimates of the prevalence of TBI, both as an acute event and as a chronic condition. Identification of individuals with TBI can facilitate primary prevention efforts, such as reducing risk for reinjury in high-risk groups, and provide access to appropriate interventions that can reduce the personal and societal costs of TBI (tertiary prevention).
Objective: The objective of this study was to examine the benefits of long-term inpatient rehabilitation for individuals with moderate-to-severe traumatic brain injuries (TBIs).
Methods: ...Retrospective database review of 67 individuals with moderate-to-severe TBI admitted to a specialised inpatient TBI program. Outcome measures are as follows: (1) functional independence measure + functional assessment measure (FIM+FAM; admission, discharge, change scores); (2) discharge designation (community vs. long-term care (LTC)).
Results: There was a mean improvement on FIM+FAM of 54.19 points (SD = 35.63) or 67% between admission and discharge (t(66) = −12.45, p < 0.001). Mean time post-injury upon completion of therapy was 409.59 days (SD = 343.93). Upon completion of rehabilitation, 50 (75%) participants were discharged to community and 17 to LTC. Among those returning to community, those with longer length of stays were more severely disabled on admission (t(35.9) = −4.86, p < 0.001). Controlling for admission functional status, individuals returning to community following >90 days of therapy required a mean of 378.94 days (SD = 298.86) to achieve comparable gains to those less impaired who received shorter periods of rehabilitation (F(1) = 0.530, p = 0.47).
Conclusion: Continued specialised inpatient services following acute inpatient rehabilitation for individuals with moderate-to-severe TBI can reduce the level of dependency and enhance the likelihood of return to community living.
Molecular subtypes of serous ovarian cancer have been recently described. Using data from independent datasets including over 900 primary tumour samples, we show that deregulation of the Let-7 ...pathway is specifically associated with the C5 molecular subtype of serous ovarian cancer. DNA copy number and gene expression of HMGA2, alleles of Let-7, LIN28, LIN28B, MYC, MYCN, DICER1, and RNASEN were measured using microarray and quantitative reverse transcriptase PCR. Immunohistochemistry was performed on 127 samples using tissue microarrays and anti-HMGA2 antibodies. Fluorescence in situ hybridisation of bacterial artificial chromosomes hybridized to 239 ovarian tumours was used to measure translocation at the LIN28B locus. Short interfering RNA knockdown in ovarian cell lines was used to test the functionality of associations observed. Four molecular subtypes (C1, C2, C4, C5) of high-grade serous ovarian cancers were robustly represented in each dataset and showed similar pattern of patient survival. We found highly specific activation of a pathway involving MYCN, LIN28B, Let-7 and HMGA2 in the C5 molecular subtype defined by MYCN amplification and over-expression, over-expression of MYCN targets including the Let-7 repressor LIN28B, loss of Let-7 expression and HMGA2 amplification and over-expression. DICER1, a known Let-7 target, and RNASEN were over-expressed in C5 tumours. We saw no evidence of translocation at the LIN28B locus in C5 tumours. The reported interaction between LIN28B and Let-7 was recapitulated by siRNA knockdown in ovarian cancer cell lines. Our results associate deregulation of MYCN and downstream targets, including Let-7 and oncofetal genes, with serous ovarian cancer. We define for the first time how elements of an oncogenic pathway, involving multiple genes that contribute to stem cell renewal, is specifically altered in a molecular subtype of serous ovarian cancer. By defining the drivers of a molecular subtype of serous ovarian cancers we provide a novel strategy for targeted therapeutic intervention.
Although the majority of patients with mild traumatic brain injury (mTBI) recover completely, some still suffer from disabling ailments at 3 or 6 months. We validated existing prognostic models for ...mTBI and explored predictors of poor outcome after mTBI. We selected patients with mTBI from TRACK-TBI Pilot, an unselected observational cohort of TBI patients from three centers in the United States. We validated two prognostic models for the Glasgow Outcome Scale Extended (GOS-E) at 6 months after injury. One model was based on the CRASH study data and another from Nijmegen, The Netherlands. Possible predictors of 3- and 6-month GOS-E were analyzed with univariate and multi-variable proportional odds regression models. Of the 386 of 485 patients included in the study (median age, 44 years; interquartile range, 27-58), 75% (n=290) presented with a Glasgow Coma Score (GCS) of 15. In this mTBI population, both previously developed models had a poor performance (area under the receiver operating characteristic curve, 0.49-0.56). In multivariable analyses, the strongest predictors of lower 3- and 6-month GOS-E were older age, pre-existing psychiatric conditions, and lower education. Injury caused by assault, extracranial injuries, and lower GCS were also predictive of lower GOS-E. Existing models for mTBI performed unsatisfactorily. Our study shows that, for mTBI, different predictors are relevant as for moderate and severe TBI. These include age, pre-existing psychiatric conditions, and lower education. Development of a valid prediction model for mTBI patients requires further research efforts.
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