bluuebunny/crossref_metadata_2025_split huggingface dataset:
MCR-1 Inhibition with Peptide-Conjugated Phosphorodiamidate Morpholino Oligomers Restores Sensitivity to Polymyxin in
Escherichia coli
Authors: Daly Seth M. , Sturge Carolyn R. , Felder-Scott Christina F. , Geller Bruce L. , Greenberg David E. 
Published: November 2017

ABSTRACT

In late 2015, the first example of a transferrable polymyxin resistance mechanism in Gram-negative pathogens, MCR-1, was reported. Since that report, MCR-1 has been described to occur in many Gram-negative pathogens, and the mechanism of MCR-1-mediated resistance was rapidly determined: an ethanolamine is attached to lipid A phosphate groups, rendering the membrane more electropositive and repelling positively charged polymyxins. Acquisition of MCR-1 is clinically significant because polymyxins are frequently last-line antibiotics used to treat extensively resistant organisms, so acquisition of this mechanism might lead to pan-resistant strains. Therefore, the ability to inhibit MCR-1 and restore polymyxin sensitivity would be an important scientific advancement. Peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) are antisense molecules that were designed to target mRNA, preventing translation. Peptide conjugation enhances cellular entry, but they are positively charged, so we tested our lead antibacterial PPMOs by targeting an essential
Escherichia coli
gene,
acpP
, and demonstrated that they were still effective in
mcr
-
1
-positive
E. coli
strains. We then designed and synthesized two PPMOs targeted to
mcr-1
mRNA. Five clinical
mcr-1
-positive
E. coli
strains were resensitized to polymyxins by MCR-1 inhibition, reducing MICs 2- to 16-fold. Finally, therapeutic dosing of BALB/c mice with MCR-1 PPMO combined with colistin in a sepsis model reduced morbidity and bacterial burden in the spleen at 24 h and offered a survival advantage out to 5 days. This is the first example of a way to modulate colistin resistance with an antisense approach and may be a viable strategy to combat this globally emerging antibiotic resistance threat.

IMPORTANCE
Polymyxin use has been increasing as a last line of defense against Gram-negative pathogens with high-level resistance mechanisms, such as carbapenemases. The recently described MCR-1 is a plasmid-mediated mechanism of resistance to polymyxins. MCR-1 is currently found in Gram-negative organisms already possessing high-level resistance mechanisms, leaving clinicians few or no antibacterial options for infections caused by these strains. This study utilizes antisense molecules that target mRNA, preventing protein translation. Herein we describe antisense molecules that can be directly antibacterial because they target genes essential to bacterial growth or blockade of MCR-1, restoring polymyxin sensitivity. We also demonstrate that MCR-1 antisense molecules restore the efficacies of polymyxins in mouse models of
E. coli
septicemia. Considering all things together, we demonstrate that antisense molecules may be effective therapeutics either alone when they target an essential gene or combined with antibiotics when they target specific resistance mechanisms, such as those seen with MCR-1.
The First Microbial Colonizers of the Human Gut: Composition, Activities, and Health Implications of the Infant Gut Microbiota
Authors: Milani Christian , Duranti Sabrina , Bottacini Francesca , Casey Eoghan , Turroni Francesca , Mahony Jennifer , Belzer Clara , Delgado Palacio Susana , Arboleya Montes Silvia , Mancabelli Leonardo , Lugli Gabriele Andrea , Rodriguez Juan Miguel , Bode Lars , de Vos Willem , Gueimonde Miguel , Margolles Abelardo , van Sinderen Douwe , Ventura Marco 
Published: November 2017

SUMMARYThe human gut microbiota is engaged in multiple interactions affecting host health during the host's entire life span. Microbes colonize the neonatal gut immediately following birth. The establishment and interactive development of this early gut microbiota are believed to be (at least partially) driven and modulated by specific compounds present in human milk. It has been shown that certain genomes of infant gut commensals, in particular those of bifidobacterial species, are genetically adapted to utilize specific glycans of this human secretory fluid, thus representing a very intriguing example of host-microbe coevolution, where both partners are believed to benefit. In recent years, various metagenomic studies have tried to dissect the composition and functionality of the infant gut microbiome and to explore the distribution across the different ecological niches of the infant gut biogeography of the corresponding microbial consortia, including those corresponding to bacteria and viruses, in healthy and ill subjects. Such analyses have linked certain features of the microbiota/microbiome, such as reduced diversity or aberrant composition, to intestinal illnesses in infants or disease states that are manifested at later stages of life, including asthma, inflammatory bowel disease, and metabolic disorders. Thus, a growing number of studies have reported on how the early human gut microbiota composition/development may affect risk factors related to adult health conditions. This concept has fueled the development of strategies to shape the infant microbiota composition based on various functional food products. In this review, we describe the infant microbiota, the mechanisms that drive its establishment and composition, and how microbial consortia may be molded by natural or artificial interventions. Finally, we discuss the relevance of key microbial players of the infant gut microbiota, in particular bifidobacteria, with respect to their role in health and disease.
Chronic inflammation is a feature of Achilles tendinopathy and rupture
Authors: Dakin Stephanie Georgina , Newton Julia , Martinez Fernando O , Hedley Robert , Gwilym Stephen , Jones Natasha , Reid Hamish A B , Wood Simon , Wells Graham , Appleton Louise , Wheway Kim , Watkins Bridget , Carr Andrew Jonathan 
Published: November 2017

BackgroundRecent investigation of human tissue and cells from positional tendons such as the rotator cuff has clarified the importance of inflammation in the development and progression of tendon disease. These mechanisms remain poorly understood in disease of energy-storing tendons such as the Achilles. Using tissue biopsies from patients, we investigated if inflammation is a feature of Achilles tendinopathy and rupture.MethodsWe studied Achilles tendon biopsies from symptomatic patients with either mid-portion tendinopathy or rupture for evidence of abnormal inflammatory signatures. Tendon-derived stromal cells from healthy hamstring and diseased Achilles were cultured to determine the effects of cytokine treatment on expression of inflammatory markers.ResultsTendinopathic and ruptured Achilles highly expressed CD14+ and CD68+ cells and showed a complex inflammation signature, involving NF-κB, interferon and STAT-6 activation pathways. Interferon markers IRF1 and IRF5 were highly expressed in tendinopathic samples. Achilles ruptures showed increasedPTGS2andinterleukin-8expression. Tendinopathic and ruptured Achilles tissues expressed stromal fibroblast activation markers podoplanin and CD106. Tendon cells isolated from diseased Achilles showed increased expression of pro-inflammatory and stromal fibroblast activation markers after cytokine stimulation compared with healthy hamstring tendon cells.ConclusionsTissue and cells derived from tendinopathic and ruptured Achilles tendons show evidence of chronic (non-resolving) inflammation. The energy-storing Achilles shares common cellular and molecular inflammatory mechanisms with functionally distinct rotator cuff positional tendons. Differences seen in the profile of ruptured Achilles are likely to be attributable to a superimposed phase of acute inflammation and neo-vascularisation. Strategies that target chronic inflammation are of potential therapeutic benefit for patients with Achilles tendon disease.
Vitamin D status in chronic fatigue syndrome/myalgic encephalomyelitis: a cohort study from the North-West of England
Authors: Earl Kate E , Sakellariou Giorgos K , Sinclair Melanie , Fenech Manuel , Croden Fiona , Owens Daniel J , Tang Jonathan , Miller Alastair , Lawton Clare , Dye Louise , Close Graeme L , Fraser William D , McArdle Anne , Beadsworth Michael B J 
Published: November 2017

ObjectiveSevere vitamin D deficiency is a recognised cause of skeletal muscle fatigue and myopathy. The aim of this study was to examine whether chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is associated with altered circulating vitamin D metabolites.DesignCohort study.SettingUK university hospital, recruiting from April 2014 to April 2015.ParticipantsNinety-two patients with CFS/ME and 94 age-matched healthy controls (HCs).Main outcome measuresThe presence of a significant association between CFS/ME, fatigue and vitamin D measures.ResultsNo evidence of a deficiency in serum total 25(OH) vitamin D (25(OH)D2and 25(OH)D3metabolites) was evident in individuals with CFS/ME. Liquid chromatography tandem mass spectrometry (LC–MS/MS) analysis revealed that total 25(OH)D was significantly higher (p=0.001) in serum of patients with CFS/ME compared with HCs (60.2 and 47.3 nmol/L, respectively). Analysis of food/supplement diaries with WinDiets revealed that the higher total 25(OH) vitamin D concentrations observed in the CFS/ME group were associated with increased vitamin D intake through use of supplements compared with the control group. Analysis of Chalder Fatigue Questionnaire data revealed no association between perceived fatigue and vitamin D levels.ConclusionsLow serum concentrations of total 25(OH)D do not appear to be a contributing factor to the level of fatigue of CFS/ME.
Efficacy of platelet-rich plasma injections for symptomatic tendinopathy: systematic review and meta-analysis of randomised injection-controlled trials
Authors: Miller Larry E , Parrish William R , Roides Breana , Bhattacharyya Samir 
Published: November 2017

AimTo determine the efficacy of platelet-rich plasma (PRP) injections for symptomatic tendinopathy.DesignSystematic review of randomised, injection-controlled trials with meta-analysis.Data sourcesSystematic searches of MEDLINE and EMBASE, supplemented by manual searches.Eligibility criteria for selecting studiesRandomised controlled trials with 3 months minimum follow-up that evaluated pain reduction with PRP versus control (saline, local anaesthetic, corticosteroid) injections in patients with symptomatic tendinopathy.ResultsA total of 16 randomised controlled trials (18 groups) of PRP versus control were included. Median sample size was 35 patients, a study size that would require an effect size ≥1.0 to achieve statistical significance. PRP was more efficacious than control in reducing tendinopathy pain, with an effect size of 0.47 (95% CI 0.22 to 0.72, p<0.001), signifying a moderate treatment effect. Heterogeneity among studies was moderate (I2=67%, p<0.001). In subgroup analysis and meta-regression, studies with a higher proportion of female patients were associated with greater treatment benefits with PRP.ConclusionsInjection of PRP is more efficacious than control injections in patients with symptomatic tendinopathy.
Involvement of N-methyl-d-aspartate receptors in plasticity induced by paired corticospinal-motoneuronal stimulation in humans
Authors: Dongés Siobhan C. , D’Amico Jessica M. , Butler Jane E. , Taylor Janet L. 
Published: November 2017

Plasticity can be induced at human corticospinal-motoneuronal synapses by delivery of repeated, paired stimuli to corticospinal axons and motoneurons in a technique called paired corticospinal-motoneuronal stimulation (PCMS). To date, the mechanisms of the induced plasticity are unknown. To determine whether PCMS-induced plasticity is dependent on N-methyl-d-aspartate receptors (NMDARs), the effect of the noncompetitive NMDAR antagonist dextromethorphan on PCMS-induced facilitation was assessed in a 2-day, double-blind, placebo-controlled experiment. PCMS consisted of 100 pairs of stimuli, delivered at an interstimulus interval that produces facilitation at corticospinal-motoneuronal synapses that excite biceps brachii motoneurons. Transcranial magnetic stimulation elicited corticospinal volleys, which were timed to arrive at corticospinal-motoneuronal synapses just before antidromic potentials elicited in motoneurons with electrical brachial plexus stimulation. To measure changes in the corticospinal pathway at a spinal level, biceps responses to cervicomedullary stimulation (cervicomedullary motor evoked potentials, CMEPs) were measured before and for 30 min after PCMS. Individuals who displayed a ≥10% increase in CMEP size after PCMS on screening were eligible to take part in the 2-day experiment. After PCMS, there was a significant difference in CMEP area between placebo and dextromethorphan days ( P = 0.014). On the placebo day PCMS increased average CMEP areas to 127 ± 46% of baseline, whereas on the dextromethorphan day CMEP area was decreased to 86 ± 33% of baseline (mean ± SD; placebo: n = 11, dextromethorphan: n = 10). Therefore, dextromethorphan suppressed the facilitation of CMEPs after PCMS. This indicates that plasticity induced at synapses in the human spinal cord by PCMS may be dependent on NMDARs. NEW & NOTEWORTHY Paired corticospinal-motoneuronal stimulation can strengthen the synaptic connections between corticospinal axons and motoneurons at a spinal level in humans. The mechanism of the induced plasticity is unknown. In our 2-day, double-blind, placebo-controlled study we show that the N-methyl-d-aspartate receptor (NMDAR) antagonist dextromethorphan suppressed plasticity induced by paired corticospinal-motoneuronal stimulation, suggesting that an NMDAR-dependent mechanism is involved.
Rapid feedback responses are flexibly coordinated across arm muscles to support goal-directed reaching
Authors: Weiler Jeffrey , Gribble Paul L. , Pruszynski J. Andrew 
Published: November 2017

A transcortical pathway helps support goal-directed reaching by processing somatosensory information to produce rapid feedback responses across multiple joints and muscles. Here, we tested whether such feedback responses can account for changes in arm configuration and for arbitrary visuomotor transformations—two manipulations that alter how muscles at the elbow and wrist need to be coordinated to achieve task success. Participants used a planar three degree-of-freedom exoskeleton robot to move a cursor to a target following a mechanical perturbation that flexed the elbow. In our first experiment, the cursor was mapped to the veridical position of the robot handle, but participants grasped the handle with two different hand orientations (thumb pointing upward or thumb pointing downward). We found that large rapid feedback responses were evoked in wrist extensor muscles when wrist extension helped move the cursor to the target (i.e., thumb upward), and in wrist flexor muscles when wrist flexion helped move the cursor to the target (i.e., thumb downward). In our second experiment, participants grasped the robot handle with their thumb pointing upward, but the cursor’s movement was either veridical or was mirrored such that flexing the wrist moved the cursor as if the participant extended their wrist, and vice versa. After extensive practice, we found that rapid feedback responses were appropriately tuned to the wrist muscles that supported moving the cursor to the target when the cursor was mapped to the mirrored movement of the wrist, but were not tuned to the appropriate wrist muscles when the cursor was remapped to the wrist’s veridical movement. NEW & NOTEWORTHY We show that rapid feedback responses were evoked in different wrist muscles depending on the arm’s orientation, and this muscle activity was appropriate to generate the wrist motion that supported a reaching action. Notably, we also show that these rapid feedback responses can be evoked in wrist muscles that are detrimental to a reaching action if a nonveridical mapping between wrist and hand motion is extensively learned.
Inflow of oxygen and glucose in brain tissue induced by intravenous norepinephrine: relationships with central metabolic and peripheral vascular responses
Authors: Bola R. Aaron , Kiyatkin Eugene A. 
Published: November 2017

As an essential part of sympathetic activation that prepares the organism for “fight or flight,” peripheral norepinephrine (NE) plays an important role in regulating cardiac activity and the tone of blood vessels, increasing blood flow to the heart and the brain and decreasing blood flow to the organs not as necessary for immediate survival. To assess whether this effect is applicable to the brain, we used high-speed amperometry to measure the changes in nucleus accumbens (NAc) levels of oxygen and glucose induced by intravenous injections of NE in awake freely moving rats. We found that NE at low doses (2–18 μg/kg) induces correlative increases in NAc oxygen and glucose, suggesting local vasodilation and enhanced entry of these substances in brain tissue from the arterial blood. By using temperature recordings from the NAc, temporal muscle, and skin, we show that this central effect is associated with strong skin vasoconstriction and phasic increases in intrabrain heat production, indicative of metabolic neural activation. A tight direct correlation between NE-induced changes in metabolic activity and NAc levels of oxygen and glucose levels suggests that local cerebral vasodilation is triggered via a neurovascular coupling mechanism. Our data suggest that NE, by changing vascular tone and cardiac activity, triggers a visceral sensory signal that rapidly reaches the central nervous system via sensory nerves and induces neural activation. This neural activation leads to a chain of neurovascular events that promote entry of oxygen and glucose in brain tissue, thus preventing any possible metabolic deficit during functional activation.NEW & NOTEWORTHY Using high-speed amperometry and thermorecording in freely moving rats, we demonstrate that intravenous norepinephrine at physiological doses induces rapid correlative increases in nucleus accumbens oxygen and glucose levels coupled with increased intrabrain heat production. Although norepinephrine cannot cross the blood-brain barrier, by changing cardiac activity and vascular tone, it creates a sensory signal that reaches the central nervous system via sensory nerves, induces neural activation, and triggers a chain of neurovascular events that promotes intrabrain entry of oxygen and glucose.
Bayesian optimal adaptation explains age-related human sensorimotor changes
Authors: Karmali Faisal , Whitman Gregory T. , Lewis Richard F. 
Published: November 2017

The brain uses information from different sensory systems to guide motor behavior, and aging is associated with simultaneous decline in the quality of sensory information provided to the brain and deterioration in motor control. Correlations between age-dependent decline in sensory anatomical structures and behavior have been demonstrated in many sensorimotor systems, and it has recently been suggested that a Bayesian framework could explain these relationships. Here we show that age-dependent changes in a human sensorimotor reflex, the vestibuloocular reflex, are explained by a Bayesian optimal adaptation in the brain occurring in response to death of motion-sensing hair cells. Specifically, we found that the temporal dynamics of the reflex as a function of age emerge from ( r = 0.93, P < 0.001) a Kalman filter model that determines the optimal behavioral output when the sensory signal-to-noise characteristics are degraded by death of the transducers. These findings demonstrate that the aging brain is capable of generating the ideal and statistically optimal behavioral response when provided with deteriorating sensory information. While the Bayesian framework has been shown to be a general neural principle for multimodal sensory integration and dynamic sensory estimation, these findings provide evidence of longitudinal Bayesian processing over the human life span. These results illuminate how the aging brain strives to optimize motor behavior when faced with deterioration in the peripheral and central nervous systems and have implications in the field of vestibular and balance disorders, as they will likely provide guidance for physical therapy and for prosthetic aids that aim to reduce falls in the elderly.NEW & NOTEWORTHY We showed that age-dependent changes in the vestibuloocular reflex are explained by a Bayesian optimal adaptation in the brain that occurs in response to age-dependent sensory anatomical changes. This demonstrates that the brain can longitudinally respond to age-related sensory loss in an ideal and statistically optimal way. This has implications for understanding and treating vestibular disorders caused by aging and provides insight into the structure-function relationship during aging.
Venetoclax Is Effective in Small-Cell Lung Cancers with High BCL-2 Expression
Authors: Lochmann Timothy L. , Floros Konstantinos V. , Naseri Mitra , Powell Krista M. , Cook Wade , March Ryan J. , Stein Giovanna T. , Greninger Patricia , Maves Yuki Kato , Saunders Laura R. , Dylla Scott J. , Costa Carlotta , Boikos Sosipatros A. , Leverson Joel D. , Souers Andrew J. , Krystal Geoffrey W. , Harada Hisashi , Benes Cyril H. , Faber Anthony C. 
Published: November 2017

Abstract
Purpose: Small-cell lung cancer (SCLC) is an often-fatal neuroendocrine carcinoma usually presenting as extensive disease, carrying a 3% 5-year survival. Despite notable advances in SCLC genomics, new therapies remain elusive, largely due to a lack of druggable targets.
Experimental Design: We used a high-throughput drug screen to identify a venetoclax-sensitive SCLC subpopulation and validated the findings with multiple patient-derived xenografts of SCLC.
Results: Our drug screen consisting of a very large collection of cell lines demonstrated that venetoclax, an FDA-approved BCL-2 inhibitor, was found to be active in a substantial fraction of SCLC cell lines. Venetoclax induced BIM-dependent apoptosis in vitro and blocked tumor growth and induced tumor regressions in mice bearing high BCL-2–expressing SCLC tumors in vivo. BCL-2 expression was a predictive biomarker for sensitivity in SCLC cell lines and was highly expressed in a subset of SCLC cell lines and tumors, suggesting that a substantial fraction of patients with SCLC could benefit from venetoclax. Mechanistically, we uncover a novel role for gene methylation that helped discriminate high BCL-2–expressing SCLCs.
Conclusions: Altogether, our findings identify venetoclax as a promising new therapy for high BCL-2–expressing SCLCs. Clin Cancer Res; 24(2); 360–9. ©2017 AACR.