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1.  Increasing AIP Macrocycle Size Reveals Key Features of agr Activation in S. aureus 
The agr locus in the commensal human pathogen, Staphylococcus aureus, is a two-promoter regulon with allelic variability that produces a quorum-sensing circuit involved in regulating virulence within the bacterium. Secretion of unique autoinducing peptides (AIPs) and detection of their concentration via AgrC, a transmembrane receptor histidine kinase, coordinates local bacterial population density with global changes in gene expression. The finding that staphylococcal virulence can be inhibited through antagonism of this quorum-sensing pathway has fueled tremendous interest in understanding the structure-activity relationships underlying the AIP-AgrC interaction. The defining structural feature of the AIP is a 16-membered, thiolactone-containing macrocycle. Surprisingly, the importance of ring size on agr activation or inhibition has not been explored. In this study, we address this deficiency through the synthesis and functional analysis of AIP analogs featuring enlarged and reduced macrocycles. Notably, this study is the first to interrogate AIP function using both established cell-based reporter gene assays and newly developed in vitro AgrC-I binding and autophosphorylation activity assays. Based on our data, we present a model for robust agr activation involving a cooperative, 3-points-of-contact interaction between the AIP macrocycle and AgrC.
doi:10.1002/cbic.201500006
PMCID: PMC4589298  PMID: 25801678
Quorum Sensing; Autoinducing Peptides; Structure-activity relationships; Biological activity; Bacterial virulence
2.  A Global and Local Desymmetrization Approach to the Synthesis of Steroidal Alkaloids: Stereocontrolled Total Synthesis of Paspaline 
A stereocontrolled total synthesis of the indole diterpenoid natural product paspaline is described. Key steps include a highly diastereoselective enzymatic desymmetrization, substrate-directed epoxidation, Ireland-Claisen rearrangement, and diastereotopic group selective C–H acetoxylation to assemble the target with excellent stereofidelity. The route and results described herein outline complementary conceptual disconnections in the arena of steroid natural product synthesis.
doi:10.1021/jacs.5b02631
PMCID: PMC4409926  PMID: 25856767
3.  Preparation and biological evaluation of synthetic and polymer-encapsulated congeners of the antitumor agent pactamycin: Insight into functional group effects and biological activity 
Bioorganic & medicinal chemistry  2015;23(8):1849-1857.
The synthesis and biological analysis of a number of novel congeners of the aminocyclopentitol pactamycin is described. Specific attention was paid to the preparation of derivatives at crucial synthetic branch points of the parent structure, and biological assays revealed a number of insights into the source of pactamycin’s biological activity. Additionally, the encapsulation of pactamycin and select derivatives into the PRINT© nanoparticle technology was investigated as a proof-of-concept, and evidence of bioactivity modulation through nanoparticle delivery is demonstrated. This work has provided heretofore unrealized access to a large number of novel compounds for further evaluation.
doi:10.1016/j.bmc.2015.02.022
PMCID: PMC4380168  PMID: 25792144
Pactamycin; Nanoparticles; Structure activity relationships; Structural derivatization
4.  NF-κB activating complex engaged in response to EGFR oncogene inhibition drives tumor cell survival and residual disease in lung cancer 
Cell reports  2015;11(1):98-110.
Summary
Although oncogene-targeted therapy often elicits profound initial tumor responses in patients, responses are generally incomplete because some tumor cells survive initial therapy as residual disease that enables eventual acquired resistance. The mechanisms underlying tumor cell adaptation and survival during initial therapy are incompletely understood. Here, through the study of EGFR-mutant lung adenocarcinoma we show that NF-κB signaling is rapidly engaged upon initial EGFR inhibitor treatment to promote tumor cell survival and residual disease. EGFR oncogene inhibition induced an EGFR-TRAF2-RIP1-IKK complex that stimulated an NF-κB-mediated transcriptional survival program. The direct NF-κB inhibitor PBS-1086 suppressed this adaptive survival program and increased the magnitude and duration of initial EGFR inhibitor response in multiple NSCLC models, including a patient-derived xenograft. These findings unveil NF-κB activation as a critical adaptive survival mechanism engaged by EGFR oncogene inhibition and provide rationale for EGFR and NF-κB co-inhibition to eliminate residual disease and enhance patient responses.
doi:10.1016/j.celrep.2015.03.012
PMCID: PMC4394036  PMID: 25843712
5.  WHITE MATTER INTEGRITY IN TRAUMATIC BRAIN INJURY: EFFECTS OF PERMISSIBLE FIBER TURNING ANGLE 
Traumatic brain injury (TBI) is the leading cause of death and disability in children. Diffusion weighted imaging (DWI) methods have been shown to be especially sensitive to white matter abnormalities in TBI. We used our newly developed autoMATE algorithm (automated multi-atlas tract extraction) to map altered WM integrity in TBI. Even so, tractography methods include a free parameter that limits the maximum permissible turning angles for extracted fibers, with little investigation of how this may affect statistical group comparisons. Here, we examined WM integrity calculated over a range of fiber turning angles to determine to what extent this parameter affects our ability to detect group differences. Fiber turning angle threshold has a subtle, but sometimes significant, effect on the differences we were able to detect between TBI and healthy children.
doi:10.1109/ISBI.2015.7164023
PMCID: PMC4578174  PMID: 26413206
High angular resolution diffusion imaging (HARDI); traumatic brain injury; tractography; fiber turning angle
6.  Critical Role of Acetylation in Tau-Mediated Neurodegeneration and Cognitive Deficits 
Nature medicine  2015;21(10):1154-1162.
Tauopathies, including frontotemporal dementia (FTD) and Alzheimer’s disease (AD), are neurodegenerative diseases in which tau fibrils accumulate. Recent evidence supports soluble tau species as the major toxic species. How soluble tau accumulates and how it causes neurodegeneration remains unclear. Here we identified tau acetylation at K174 as an early change in AD brains and as a critical determinant in tau homeostasis and toxicity in mice. An acetyl-mimicking mutant (K174Q) slows down tau turnover and induces cognitive deficits in vivo. The acetyltransferase p300-induced tau acetylation is inhibited by a prescription drug salsalate/salicylate, which enhances tau turnover and reduces tau levels. In the PS19 transgenic mouse model of FTD, administering salsalate after disease onset inhibited p300 activity, lowered ac-K174 and total tau levels, rescued tau-induced memory deficits and prevented hippocampal atrophy. The tau-lowering and protective effects of salsalate/salicylate are diminished in neurons expressing K174Q tau. Targeting tau acetylation could be a new therapeutic strategy against human tauopathies.
doi:10.1038/nm.3951
PMCID: PMC4598295  PMID: 26390242
7.  Therapy with bortezomib plus lenalidomide for relapsed/refractory mantle cell lymphoma: Final results of a phase II trial (CALGB 50501) 
Leukemia & lymphoma  2014;56(4):958-964.
CALGB designed a phase II trial of lenalidomide+bortezomib for relapsed/refractory mantle cell lymphoma (MCL). Induction therapy was lenalidomide (days 1-14) plus bortezomib (days 1/4/8/11), every 21 days for eight cycles. Complete and partial responders (CR, PR) received maintenance lenalidomide (days 1-14) and bortezomib (days 1/8), every 21 days. Primary endpoint was overall response rate; secondary endpoints were CR rate, progression-free- (PFS), event-free- (EFS), and overall survival (OS). Fifty-three eligible patients, median age 67 years, were accrued. Median number of cycles received was 4 (range, 1-82). Median follow-up is 46 (range, 12-67) months. Best response was CR (n=8, 15%), PR (n=13, 25%). 5/8 CR and 4/13 PR patients received maintenance therapy. Of responders, 6 CR/1 PR patients remain in remission at a median of 3.2 years. Thirty-three (62%) patients have died. One-year PFS, EFS, OS are 40%, 25%, and 68%, respectively. This combination will not be pursued further at this dose/schedule.
doi:10.3109/10428194.2014.938333
PMCID: PMC4725701  PMID: 24996441
mantle cell lymphoma; bortezomib; lenalidomide
8.  Prb1 Protease Activity Is Required for Its Recognition by the F-Box Protein Saf1 
Biochemistry  2015;54(29):4423-4426.
The SCF ubiquitin ligase associates with substrates through its F-box protein adaptor. Substrates are typically recognized through a defined phosphodegron. Here, we characterize the interaction of the F-box protein Saf1 with Prb1, one of its vacuolar protease substrates. We show that Saf1 binds the mature protein but ubiquitinates only the zymogen precursor. The ubiquitinated lysine was found to be in a peptide eliminated from the mature protein. Mutations that eliminate the catalytic activity of Prb1, or the related substrate Prc1, block Saf1 targeting of the zymogen precursor. Our data suggest that Saf1 does not require a conventional degron as do other F-box proteins but instead recognizes the catalytic site itself.
doi:10.1021/acs.biochem.5b00504
PMCID: PMC4816488  PMID: 26161950
9.  FOXC1 Activates Smoothened-Independent Hedgehog Signaling in Basal-like Breast Cancer 
Cell reports  2015;13(5):1046-1058.
Summary
The mesoderm- and epithelial-mesenchymal transition-associated transcription factor FOXC1 is specifically overexpressed in basal-like breast cancer (BLBC), but its biochemical function is not understood. Here we demonstrate that FOXC1 controls cancer stem cell (CSC) properties enriched in BLBC cells via activation of Smoothened (SMO)-independent Hedgehog (Hh) signaling. This non-canonical activation of Hh is specifically mediated by Gli2. We further show that the N-terminal domain of FOXC1 (aa 1–68) binds directly to an internal region (aa 898–1168) of Gli2, enhancing the DNA-binding and transcription-activating capacity of Gli2. FOXC1 expression correlates with that of Gli2 and its targets in human breast cancers. Moreover, FOXC1 overexpression reduces sensitivity to anti-Hedgehog (Hh) inhibitors in BLBC cells and xenograft tumors. Together, these findings reveal FOXC1-mediated non-canonical Hh signaling that determines the BLBC stem-like phenotype and anti-Hh sensitivity, supporting inhibition of FOXC1 pathways as potential approaches for improving BLBC treatment.
doi:10.1016/j.celrep.2015.09.063
PMCID: PMC4806384  PMID: 26565916
basal-like breast cancer; cancer stem cells; FOXC1; Gli2; Hedgehog; Smoothened
11.  Asymmetric Total Syntheses of Megacerotonic Acid and Shimobashiric Acid A 
Organic letters  2015;17(5):1188-1191.
The asymmetric total syntheses of the α-benzylidene-γ-butyrolactone natural products megacerotonic acid and shimobashiric acid A have been accomplished in nine and 11 steps, respectively, from simple, commercially available starting materials. The key step for each synthesis is the (arene)RuCl(monosulfonamide)-catalyzed dynamic kinetic resolution-asymmetric transfer hydrogenation (DKR-ATH) of racemic α,δ-diketo-β-aryl esters to establish the absolute stereochemistry. Intramolecular diastereoselective Dieckmann cyclization forms the lactone core, and ketone reduction/alcohol elimination installs the α-arylidene.
doi:10.1021/acs.orglett.5b00140
PMCID: PMC4411184  PMID: 25699999
12.  Randomized Controlled Trial of Supplemental Augmentative and Alternative Communication versus Voice Rest Alone after Phonomicrosurgery 
Objective
This randomized trial investigated voice rest and supplemental text-to-speech communication versus voice rest alone on visual analog scale measures of communication effectiveness and magnitude of voice use.
Study Design
Randomized clinical trial.
Setting
Multicenter outpatient voice clinics.
Subjects
Thirty-seven patients undergoing phonomicrosurgery.
Methods
Patients undergoing phonomicrosurgery were randomized to voice rest and supplemental text-to-speech communication or voice rest alone. The primary outcome measure was the impact of voice rest on ability to communicate effectively over a seven-day period. Pre- and post-operative magnitude of voice use was also measured as an observational outcome.
Results
Patients randomized to voice rest and supplemental text-to-speech communication reported higher median communication effectiveness on each post-operative day compared to those randomized to voice rest alone, with significantly higher median communication effectiveness on post-operative day 3 (p = 0.03) and 5 (p = 0.01). Magnitude of voice use did not differ on any pre-operative (p > 0.05) or post-operative day (p > 0.05), nor did patients significantly decrease voice use as the surgery date approached (p > 0.05). However, there was a significant reduction in median voice use pre- to post-operatively across patients (p < 0.001) with median voice use ranging from 0–3 throughout the post-operative week.
Conclusion
Supplemental text-to-speech communication increased patient perceived communication effectiveness on post-operative days 3 and 5 over voice rest alone. With the prevalence of smartphones and the widespread use of text messaging, supplemental text-to-speech communication may provide an accessible and cost-effective communication option for patients on vocal restrictions.
doi:10.1177/0194599814566601
PMCID: PMC4617180  PMID: 25605690
randomized controlled trial; voice; voice disorders; voice rest; text-to-speech; augmentative and alternative communication
13.  Increased AD-like pathology in the APP/ PS1ΔE9 mouse model lacking Nrf2 through modulation of autophagy 
Neurobiology of aging  2014;36(2):664-679.
The presence of senile plaques is one of the major pathological hallmarks of the Alzheimer’s disease (AD) brain. The plaques predominantly contain insoluble amyloid β-peptide; a cleavage product of the larger amyloid precursor protein (APP). Two enzymes named β and γ secretase generate the neurotoxic amyloid-β peptide from APP. Mature APP is also turnovered endogenously by autophagy, more specifically by the endosomal-lysosomal pathway. A defective lysosomal system is known to be pathogenic in AD. Modulation of NF-E2 related factor 2 (Nrf2) has been shown in several neurodegenerative disorders and Nrf2 has become a potential therapeutic target for various neurodegenerative disorders including AD, Parkinson’s disease, and amyotrophic lateral sclerosis. In the current study, we explored the effect of genetic ablation of Nrf2 on APP/Aβ processing and/or aggregation as well as changes in autophagic dysfunction in APP/PS1 mice. There was a significant increase in inflammatory response in APP/PS1 mice lacking Nrf2. This was accompanied by increased intracellular levels of APP, Aβ (1-42), and Aβ (1-40), without a change total full-length APP. There was a shift of APP and Aβ into the insoluble fraction, as well as increased poly-ubiquitin conjugated proteins in mice lacking Nrf2. APP/PS1-mediated autophagic dysfunction is also enhanced in Nrf2 deficient mice. Finally, neurons in the APP/PS1/Nrf2−/− mice had increased accumulation of multivesicular bodies, endosomes and lysosomes. These outcomes provide a better understanding of the role of Nrf2 in modulating autophagy in an AD mouse model and may help design better Nrf2 targeted therapeutics that could be efficacious in the treatment of AD.
doi:10.1016/j.neurobiolaging.2014.09.004
PMCID: PMC4315753  PMID: 25316599
14.  Worry is Associated with Impaired Gating of Threat from Working Memory 
Emotion (Washington, D.C.)  2014;15(1):6-11.
Dispositional anxiety is a well-established risk factor for the development of anxiety and other emotional disorders. These disorders are common, debilitating, and challenging to treat, pointing to the need to understand the more elementary neurocognitive mechanisms that confer elevated risk. Importantly, many of the maladaptive behaviors characteristic of anxiety, such as worry, occur when threat is absent. This raises the possibility that worry reflects difficulties gating threat-related information from working memory, a limited capacity workspace that supports the maintenance, recall, and manipulation of information, and facilitates goal-directed thoughts and actions. Here, we tested for the first time whether trait-like individual differences in worry, a key facet of the anxious phenotype, reflect difficulties gating threat and neutral-related distracters from working memory. Results indicated that both dispositional worry and anxiety individually predicted the combined filtering cost of threat and neutral distracters. Importantly, worry was associated with inefficient filtering of threat-related but not neutral distracters from working memory. In contrast, dispositional anxiety was related to a similar level of threat and neutral filtering cost. Furthermore, dispositional anxiety’s relationship to filtering of threat was predominantly driven by differences in worry. These results suggest that the propensity to worry is characterized by a failure to gate task-irrelevant threat from working memory. These results provide a framework for understanding the mechanisms underlying chronic worry and more broadly, the cognitive architecture of dispositional anxiety.
doi:10.1037/emo0000015
PMCID: PMC4324005  PMID: 25151519
worry; anxiety; working memory; attention; cognition-emotion interactions
15.  Global mapping of herpesvirus-host protein complexes reveals a novel transcription strategy for late genes 
Molecular cell  2014;57(2):349-360.
SUMMARY
Mapping host-pathogen interactions has proven instrumental for understanding how viruses manipulate host machinery and how numerous cellular processes are regulated. DNA viruses such as herpesviruses have relatively large coding capacity and thus can target an extensive network of cellular proteins. To identify the host proteins hijacked by this pathogen, we systematically affinity tagged and purified all 89 proteins of Kaposi’s sarcoma-associated herpesvirus (KSHV) from human cells. Mass spectrometry of this material identified over 500 virus-host interactions. KSHV causes AIDS-associated cancers and its interaction network is enriched for proteins linked to cancer and overlaps with proteins that are also targeted by HIV-1. We found that the conserved KSHV protein ORF24 binds to RNA polymerase II and brings it to viral late promoters by mimicking and replacing cellular TATA-box-binding protein (TBP). This is required for herpesviral late gene expression, a complex and poorly understood phase of the viral lifecycle.
doi:10.1016/j.molcel.2014.11.026
PMCID: PMC4305015  PMID: 25544563
16.  A Combined Proteomics/Genomics Approach Links Hepatitis C Virus Infection with Nonsense-Mediated mRNA Decay 
Molecular cell  2015;57(2):329-340.
SUMMARY
Hepatitis C virus (HCV) is a leading cause of liver disease, but insight into virus-host interactions remains limited. We systematically used affinity purification/mass spectrometry to define the host interactions of all 10 HCV proteins in hepatoma cells. We combined these studies with RNAi knockdown of corresponding genes using a two-step scoring approach to generate a map of 139 high-confidence HCV-host protein-protein interactions. We found mitochondrial proteins highly involved in HCV infection and characterized a new interaction between the viral core protein and host protein within bgcn homolog (WIBG). Expression of core prevents WIBG from binding its regular interaction partners Y14 and Magoh, two known mediators of the nonsense-mediated mRNA decay pathway. We discovered that this surveillance pathway is disrupted in HCV-infected cells, causing potentially harmful transcripts to accumulate. Our study provides the first comprehensive view of HCV-host interactions and uncovers new mechanisms for how HCV perturbs host functions during infection.
doi:10.1016/j.molcel.2014.12.028
PMCID: PMC4305532  PMID: 25616068
17.  Callosal Function in Pediatric Traumatic Brain Injury Linked to Disrupted White Matter Integrity 
The Journal of Neuroscience  2015;35(28):10202-10211.
Traumatic brain injury (TBI) often results in traumatic axonal injury and white matter (WM) damage, particularly to the corpus callosum (CC). Damage to the CC can lead to impaired performance on neurocognitive tasks, but there is a high degree of heterogeneity in impairment following TBI. Here we examined the relation between CC microstructure and function in pediatric TBI. We used high angular resolution diffusion-weighted imaging (DWI) to evaluate the structural integrity of the CC in humans following brain injury in a sample of 32 children (23 males and 9 females) with moderate-to-severe TBI (msTBI) at 1–5 months postinjury, compared with well matched healthy control children. We assessed CC function through interhemispheric transfer time (IHTT) as measured using event-related potentials (ERPs), and related this to DWI measures of WM integrity. Finally, the relation between DWI and IHTT results was supported by additional results of neurocognitive performance assessed using a single composite performance scale. Half of the msTBI participants (16 participants) had significantly slower IHTTs than the control group. This slow IHTT group demonstrated lower CC integrity (lower fractional anisotropy and higher mean diffusivity) and poorer neurocognitive functioning than both the control group and the msTBI group with normal IHTTs. Lower fractional anisotropy—a common sign of impaired WM—and slower IHTTs also predicted poor neurocognitive function. This study reveals that there is a subset of pediatric msTBI patients during the post-acute phase of injury who have markedly impaired CC functioning and structural integrity that is associated with poor neurocognitive functioning.
SIGNIFICANCE STATEMENT Traumatic brain injury (TBI) is the primary cause of death and disability in children and adolescents. There is considerable heterogeneity in postinjury outcome, which is only partially explained by injury severity. Imaging biomarkers may help explain some of this variance, as diffusion weighted imaging is sensitive to the white matter disruption that is common after injury. The corpus callosum (CC) is one of the most commonly reported areas of disruption. In this multimodal study, we discovered a divergence within our pediatric moderate-to-severe TBI sample 1–5 months postinjury. A subset of the TBI sample showed significant impairment in CC function, which is supported by additional results showing deficits in CC structural integrity. This subset also had poorer neurocognitive functioning. Our research sheds light on postinjury heterogeneity.
doi:10.1523/JNEUROSCI.1595-15.2015
PMCID: PMC4502260  PMID: 26180196
corpus callosum; DTI; ERP; interhemispheric transfer time; traumatic brain injury
18.  Numerical simulation of the environmental impact of hydraulic fracturing of tight/shale gas reservoirs on near-surface groundwater: Background, base cases, shallow reservoirs, short-term gas, and water transport 
Water Resources Research  2015;51(4):2543-2573.
Hydrocarbon production from unconventional resources and the use of reservoir stimulation techniques, such as hydraulic fracturing, has grown explosively over the last decade. However, concerns have arisen that reservoir stimulation creates significant environmental threats through the creation of permeable pathways connecting the stimulated reservoir with shallower freshwater aquifers, thus resulting in the contamination of potable groundwater by escaping hydrocarbons or other reservoir fluids. This study investigates, by numerical simulation, gas and water transport between a shallow tight-gas reservoir and a shallower overlying freshwater aquifer following hydraulic fracturing operations, if such a connecting pathway has been created. We focus on two general failure scenarios: (1) communication between the reservoir and aquifer via a connecting fracture or fault and (2) communication via a deteriorated, preexisting nearby well. We conclude that the key factors driving short-term transport of gas include high permeability for the connecting pathway and the overall volume of the connecting feature. Production from the reservoir is likely to mitigate release through reduction of available free gas and lowering of reservoir pressure, and not producing may increase the potential for release. We also find that hydrostatic tight-gas reservoirs are unlikely to act as a continuing source of migrating gas, as gas contained within the newly formed hydraulic fracture is the primary source for potential contamination. Such incidents of gas escape are likely to be limited in duration and scope for hydrostatic reservoirs. Reliable field and laboratory data must be acquired to constrain the factors and determine the likelihood of these outcomes.
Key Points:
Short-term leakage fractured reservoirs requires high-permeability pathways Production strategy affects the likelihood and magnitude of gas release Gas release is likely short-term, without additional driving forces
doi:10.1002/2014WR016086
PMCID: PMC4691323  PMID: 26726274
hydraulic fracturing; contaminant transport; shale gas
19.  Enantioconvergent Synthesis of Functionalized γ-Butyrolactones via (3 + 2)-Annulation 
A dynamic kinetic resolution of β-halo α-keto esters in an asymmetric homoenolate reaction is described. A chiral N-hetereocyclic carbene catalyzes the a3 → d3-umpolung addition of α,β-enals to racemic α-keto esters, forming γ-butyrolactones with three contiguous stereocenters. The addition occurs with high regio-, diastereo-, and enantiocontrol. This methodology constitutes an intermolecular DKR process to set three stereocenters during the key bond forming event.
doi:10.1021/ja511701j
PMCID: PMC4304455  PMID: 25533016
20.  Activation of the Nrf2-ARE Pathway in Hepatocytes Protects Against Steatosis in Nutritionally Induced Non-alcoholic Steatohepatitis in Mice 
Toxicological Sciences  2014;142(2):361-374.
Oxidative stress is implicated in the development of non-alcoholic steatohepatitis (NASH). The Nrf2-antioxidant response element pathway protects cells from oxidative stress. Studies have shown that global Nrf2 deficiency hastens the progression of NASH. The purpose of this study was to determine whether long-term hepatocyte-specific activation of Nrf2 mitigates NASH progression. Transgenic mice expressing a constitutively active Nrf2 construct in hepatocytes (AlbCre+/caNrf2+) and littermate controls were generated. These mice were fed standard or methionine-choline-deficient (MCD) diet, a diet used to induce NASH development in rodents. After 28 days of MCD dietary feeding, mice developed significant increases in steatosis, inflammation, oxidative stress, and HSC activation compared with those mice on standard diet. AlbCre+/caNrf2+ animals had significantly decreased serum transaminases and reduced steatosis when compared with the AlbCre+/caNrf2− animals. This significant reduction in steatosis was associated with increased expression of genes involved in triglyceride export (MTTP) and β-oxidation (CPT2). However, there were no differences in the increased oxidative stress, inflammation, and HSC activation from MCD diet administration between the AlbCre+/caNrf2− and AlbCre+/caNrf2+ animals. We conclude that hepatocyte-specific activation of Nrf2-mediated gene expression decreased hepatocellular damage and steatosis in a dietary model of NASH. However, hepatocyte-specific induction of Nrf2-mediated gene expression alone is insufficient to mitigate inflammation, oxidative stress, and HSC activation in this nutritional NASH model.
doi:10.1093/toxsci/kfu184
PMCID: PMC4250843  PMID: 25294219
liver; Nrf2; antioxidants; steatosis; NASH; transgenic mice
21.  Kinematics and Kinetics of Single-Limb Heel Rise in Diabetes Related Medial Column Foot Deformity 
Background
Diabetes-related medial column foot deformities contribute to high plantar pressure, joint instability, ulceration and amputation. Impaired foot function may be an early indicator of foot structural incompetence and contribute to deformity progression. This study examines the ability of single-limb heel rise multi-segmental kinematics and kinetics to identify midfoot and hindfoot dysfunction in those with diabetes-related medial column foot deformity.
Methods
Single-limb heel rise foot kinematics and kinetics were examined in adults with diabetes mellitus and peripheral neuropathy with and without medial column foot deformity and age-, weight-matched controls.
Findings
Hindfoot relative to shank plantarflexion, peak and excursion, were reduced in bothdiabetes groups compared to controls (P<0.017). Controls' initial forefoot relative to hindfoot position was plantarflexed 31 degrees and plantarflexed an additional 13 degrees during heel rise. The initial forefoot relative to hindfoot position for the diabetes group without deformity was similarly plantarflexed as controls (34 degrees) while the diabetes deformity group was less plantarflexed (lower arch position: 23 degrees, P<0.017). During the heel rise task both diabetes groups demonstrated less ability to plantarflex the forefoot relative to the hindfoot compared to controls (2 and 5 degrees respectively, P<0.017). Ankle plantarflexion power was reduced in the diabetes deformity group compared to controls (P<0.017).
Interpretation
The single-limb heel rise task identified movement dysfunction in those with diabetes mellitus and peripheral neuropathy. Failure to plantarflex the forefoot relative to hindfoot may compromise midfoot joint stability and increase the risk of injury and arch collapse.
doi:10.1016/j.clinbiomech.2014.08.011
PMCID: PMC4253905  PMID: 25218437
Plantarflexion; midfoot; kinematics; kinetics; diabetes
22.  Neural hypernetwork approach for pulmonary embolism diagnosis 
BMC Research Notes  2015;8:617.
Background
Hypernetworks are based on topological simplicial complexes and generalize the concept of two-body relation to many-body relation. Furthermore, Hypernetworks provide a significant generalization of network theory, enabling the integration of relational structure, logic and analytic dynamics. A pulmonary embolism is a blockage of the main artery of the lung or one of its branches, frequently fatal.
Results
Our study uses data on 28 diagnostic features of 1427 people considered to be at risk of pulmonary embolism enrolled in the Department of Internal and Subintensive Medicine of an Italian National Hospital “Ospedali Riuniti di Ancona”. Patients arrived in the department after a first screening executed by the emergency room. The resulting neural hypernetwork correctly recognized 94 % of those developing pulmonary embolism. This is better than previous results obtained with other methods (statistical selection of features, partial least squares regression, topological data analysis in a metric space).
Conclusion
In this work we successfully derived a new integrative approach for the analysis of partial and incomplete datasets that is based on Q-analysis with machine learning. The new approach, called Neural Hypernetwork, has been applied to a case study of pulmonary embolism diagnosis. The novelty of this method is that it does not use clinical parameters extracted by imaging analysis.
doi:10.1186/s13104-015-1554-5
PMCID: PMC4627406  PMID: 26515513
TOPDRIM; Hypernetworks; Q-analysis; Pulmonary embolism; Topology of data; Machine learning; Artificial neural network
23.  Dynamic Kinetic Asymmetric Cross-Benzoin Additions of β-Stereogenic α-Keto Esters 
Journal of the American Chemical Society  2014;136(42):14698-14701.
The dynamic kinetic resolution of β-halo α-keto esters via an asymmetric cross-benzoin reaction is described. A chiral N-heterocyclic carbene catalyzes the umpolung addition of aldehydes to racemic α-keto esters. The resulting fully substituted β-halo glycolic ester products are obtained with high levels of enantio- and diastereocontrol. The high chemoselectivity observed is a result of greater electrophilicity of the α-keto ester toward the Breslow intermediate. The reaction products are shown to undergo highly diastereoselective substrate-controlled reduction to give highly functionalized stereotriads.
doi:10.1021/ja508521a
PMCID: PMC4210110  PMID: 25299730
24.  Longitudinal Detection and Persistence of Minority Drug-Resistant Populations and Their Effect on Salvage Therapy 
PLoS ONE  2015;10(9):e0135941.
Background
Drug-resistant HIV are more prevalent and persist longer than previously demonstrated by bulk sequencing due to the ability to detect low-frequency variants. To clarify a clinical benefit to monitoring minority-level drug resistance populations as a guide to select active drugs for salvage therapy, we retrospectively analyzed the dynamics of low-frequency drug-resistant population in antiretroviral (ARV)-exposed drug resistant individuals.
Materials and Methods
Six HIV-infected individuals treated with ARV for more than five years were analyzed. These individuals had difficulty in controlling viremia, and treatment regimens were switched multiple times guided by standard drug resistance testing using bulk sequencing. To detect minority variant populations with drug resistance, we used a highly sensitive allele-specific PCR (AS-PCR) with detection thresholds of 0.3–2%. According to ARV used in these individuals, we focused on the following seven reverse transcriptase inhibitor-resistant mutations: M41L, K65R, K70R, K103N, Y181C, M184V, and T215F/Y. Results of AS-PCR were compared with bulk sequencing data for concordance and presence of additional mutations. To clarify the genetic relationship between low-frequency and high-frequency populations, AS-PCR amplicon sequences were compared with bulk sequences in phylogenetic analysis.
Results
The use of AS-PCR enabled detection of the drug-resistant mutations, M41L, K103N, Y181C, M184V and T215Y, present as low-frequency populations in five of the six individuals. These drug resistant variants persisted for several years without ARV pressure. Phylogenetic analysis indicated that pre-existing K103N and T215I variants had close genetic relationships with high-frequency K103N and T215I observed during treatment.
Discussion and Conclusion
Our results demonstrate the long-term persistence of drug-resistant viruses in the absence of drug pressure. The rapid virologic failures with pre-existing mutant viruses detectable by AS-PCR highlight the clinical importance of low-frequency drug-resistant viruses. Thus, our results highlight the usefulness of AS-PCR and support its expanded evaluation in ART clinical management.
doi:10.1371/journal.pone.0135941
PMCID: PMC4567277  PMID: 26360259
25.  The association of spiritual care providers’ activities with family members’ satisfaction with care after a death in the ICU 
Critical care medicine  2014;42(9):1991-2000.
Objective
Spiritual distress is common in the ICU, and spiritual care providers are often called upon to provide care for patients and their families. Our goal was to evaluate the activities spiritual care providers’ conduct to support patients and families, and whether those activities are associated with family satisfaction with ICU care.
Design
Prospective cohort study.
Setting
350-bed, 65-ICU bed tertiary care teaching hospital.
Subjects
Spiritual care providers and family members of patients who died in the ICU or within 30 hours of transfer from the ICU.
Measurements
Spiritual care providers completed surveys reporting their activities. Family members completed validated measures of satisfaction with care and satisfaction with spiritual care. Clustered regression was used to assess the association between activities completed by spiritual care providers and family ratings of care.
Results
Of 494 eligible patients, 275 family members completed surveys (response rate, 56%). Fifty-seven spiritual care providers received surveys relating to 268 patients, completing 285 surveys for 244 patients (response rate, 91%). Spiritual care providers commonly reported activities related to supporting religious and spiritual needs (>=90%) and providing support for family feelings (90%). Discussions about the patient’s wishes for end-of-life care and a greater number of spiritual care activities performed were both associated with increased overall family satisfaction with ICU care (p<0.05). Discussions about a patient’s end-of-life wishes, preparation for a family conference, and total number of activities performed were associated with improved family satisfaction with decision-making in the ICU (p<0.05).
Conclusions
Spiritual care providers engage in a variety of activities with families of ICU patients; several are associated with increased family satisfaction with ICU care in general and decision-making in the ICU specifically. These findings provide insight into spiritual care provider activities and provide guidance for interventions to improve spiritual care delivered to families of critically ill patients.
doi:10.1097/CCM.0000000000000412
PMCID: PMC4134753  PMID: 24797373
intensive care; critical care; spiritual care; end-of-life care; dying; death; palliative care

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