bluuebunny/crossref_metadata_2025 huggingface dataset:
Positional Testing in Acute Vestibular Syndrome: a Transversal and Longitudinal Study
Authors: Lemos João , Martins Ana Inês , Duque Cristina , Pimentel Sara , Nunes César , Gonçalves António F.
Published: January 2019

Objective:

To evaluate the utility of positional testing in peripheral and central acute vestibular syndrome (pAVS, cAVS, respectively).

Study design:

Prospective; observational.

Setting:

Tertiary referral center.

Patients:

Consecutive AVS patients.

Interventions:

Video-oculography in upright, supine and head hanging positions at presentation, 3-month and 1-year follow-up.

Main Outcome Measures:

Positional modulation of spontaneous nystagmus; co-occurrence of central paroxysmal positional nystagmus (CPPN).

Results:

Fifteen pAVS [mean age (SD), 53.3 (16.6) (11 males)] and 15 cAVS [mean age (SD), 56.5 (17.8) (11 males)] patients were included (p=0.49). Acutely, in supine, in patients whose nystagmus was present in both head rotation sides, 12 of 13 (93%) pAVS and only 4 of 12 (33%) cAVS patients showed direction-fixed positional nystagmus which was stronger when turning the head to the slow phase side. The remaining cAVS patients showed either direction-fixed positional nystagmus which was stronger when turning the head to the fast phase side (5), or direction-changing positional geotropic nystagmus (2). One patient in each group showed direction-changing positional apogeotropic nystagmus. During follow-up, direction-changing positional apogeotropic and geotropic nystagmus became common in both groups. Acutely, in head hanging, 5 (33%) cAVS patients showed vertical CPPN and 2 showed positional saccadic intrusions. Positional downbeat nystagmus and saccadic intrusions became chronic.

Conclusions:

The presence of acute direction-changing positional geotropic nystagmus, stronger direction-fixed positional nystagmus when turning the head to the fast phase side, and acute or chronic head hanging vertical CPPN should raise the suspicion for central AVS. Chronic geotropic and apogeotropic nystagmus following AVS constitute an underrecognized manifestation of vestibular compensation.
Long-Term Audiometric and Clinical Outcomes Following Stapedectomy With the Shape Memory Nitinol Stapes Prosthesis
Authors: Heywood Rebecca L. , Quick Mark E. , Atlas Marcus D.
Published: January 2019

Objective:

To assess long-term hearing outcomes following stapedectomy using a self-crimping shape memory nitinol prosthesis. The results were compared with those of a group of patients who received a conventional prosthesis.

Study Design:

Retrospective case review.

Setting:

Tertiary referral center.

Patients:

All patients who underwent stapedectomy for otosclerosis between July 2001 and November 2008 with a minimum dataset of preoperative, early postoperative (≤2 yr), and late postoperative (≥6 yr) audiometry were included. Fifty-six patients with a nitinol prosthesis and 27 patients with a titanium prosthesis met the inclusion criteria.

Intervention:

Stapedectomy using a nitinol or conventional prosthesis.

Main Outcome Measure(s):

Hearing outcomes by audiological assessment.

Results:

Mean duration of follow up was 9.5 (standard deviation [SD] 1.4) years in the nitinol group and 12.6 (SD 2.1) years in the titanium group. The early and late mean postoperative air-bone gaps (ABGs) were 9.7 and 9.8 dB in the nitinol group and 11.0 and 12.6 dB in the titanium group, respectively. The proportion of patients achieving an ABG less than or equal to 20 dB at early and late follow up was 96% and 96% in the nitinol group and 92% and 86% in the titanium group respectively.

Conclusions:

The excellent closure of the ABG achieved at early follow up remains remarkably stable up to 12 years using a self-crimping shape memory nitinol prosthesis. There is no evidence that firm fixation of the hook around the long process of incus has a detrimental effect in the long-term.
Novel Use of Portable Audiometry to Track Hearing Fluctuations in Menière's Disease: A Pilot Study
Authors: Tse Darren , Ramsay Tim , Lelli Daniel A.
Published: January 2019

Introduction:

Menière's Disease (MD) is a disorder of the inner ear consisting of episodic attacks of vertigo associated with aural fullness, tinnitus, and fluctuating hearing loss. Hearing levels in MD can often fluctuate over time, and may eventually decline permanently in a step-wise fashion. There are no current studies examining daily hearing fluctuations for prolonged periods in patients with MD. Portable audiometry has the potential to allow the patient to monitor their hearing on a daily basis without attending a center for formal audiology. The objective of this pilot study was to assess feasibility of using iPad-based audiometry on a daily basis to capture hearing fluctuations in a small sample of adult patients with active MD.

Methods:

We recruited five patients with active MD as defined by current diagnostic criteria (International Classification of Vestibular Disease 2015). “Active” MD was defined as the patient having had at least one typical Menière's episode within the last 4 weeks. Patients were trained on how to use the portable audiometer and asked to perform at least daily audiograms for 3 months. Patients were asked to manually track vertigo attacks in a diary. Qualitative feedback was obtained from each patient at each monthly visit. For each patient, individual pure tone thresholds at each frequency and pure-tone averages (PTA) were analyzed for maximum and minimum values and interquartile ranges.

Results:

There were four women and one man, with an average age of 49.8 years. Duration of MD ranged from 4 months to 5 years. None of the patients experienced any technical difficulties performing the testing at home. The average duration of each test was 4.2 minutes, with the longest test taking 19.2 minutes. Patients completed between 45 and 102 tests, with an average of 72. The interquartile range for the PTA ranged from 2.5 to 25 dB for affected ears, and 0 to 6.25 dB for unaffected ears with maximums ranging from 5 to 35 dB in affected ears, and 0 to 10 dB in unaffected ears.

Conclusions:

Daily portable audiometry is feasible in patients with MD. Future studies are planned to further analyze hearing fluctuations in MD with respect to frequencies affected, relationship to vertigo attacks, and response to treatments. Understanding hearing fluctuations in MD may aid refinement of diagnostic criteria and improve prognostication for long-term hearing loss, with a goal of informing treatments that might improve final hearing outcome.
Stüve–Wiedemann syndrome: recurrent neonatal infections caused by impairment of JAK/STAT 3 pathway
Authors: Van De Maele Karolien , Smulders Charlotte , Ecury-Goossen Ginette , Rosina-Angelista Irsa , Redeker Egbert , van Haelst Mieke
Published: January 2019

Stüve–Wiedemann syndrome (OMIM #601559) is a rare, autosomal recessive disorder characterized by skeletal dysplasia, consecutive infections, feeding difficulties and autonomic dysregulation. We present an Afro-Caribbean family with two siblings diagnosed with Stüve–Wiedemann syndrome. The underlying loss-of-function mutation in the leukemia inhibitory factor receptor gene is thought to impair proper functioning of the JAK/STAT 3 pathway. As this affects normal functioning of T-helper cells, these patients are prone to infections with uncommon pathogens as illustrated by this case.
Clinical Outcomes Based on the Timing of Appearance of Visible Lesions in Barrett’s Esophagus During Endoscopic Eradication Therapy
Authors: Thota Prashanthi N. , Benjamin Tanmayee , Sanaka Madhusudhan R. , Goldblum John R. , Vargo John , Jang Sunguk , Lopez Rocio
Published: January 2019

Background and Goals:

Visible lesions (VLs) in Barrett’s esophagus (BE) are seen in 70% to 90% of patients presenting for endoscopic eradication therapy (EET). It is not known if there are any differences in outcomes of patients with flat dysplasia versus patients with VL. Our aim was to assess outcomes of EET in BE patients with VL and BE patients with flat dysplasia.

Study:

This is a single center study with data drawn from a prospective registry of patients referred for EET of BE between 2011 and 2015. Demographic data, endoscopic findings, histologic findings, and response to EET were analyzed.

Results:

There were 264 patients of which 34 had flat dysplasia, 180 had VL before initiating EET (prevalent lesions) and 50 who developed VL during EET (incident lesions). Compared with patients with flat dysplasia, patients with VL had longer segments of BE (5 vs. 4 cm, P=0.002) and greater prevalence of high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) (63.6% vs. 29.4%, P<0.001). Incident lesions are less likely to harbor HGD/EAC compared with prevalent lesions (28.1% vs. 61.8%, P<0.001). There were no significant differences in eradication of metaplasia/dysplasia between the groups. No progression or recurrences were observed in flat dysplasia group. In VL group, 14 patients progressed (prevalent VL=11, incident VL=3) and 15 had recurrences (prevalent VL=11, incident VL=4).

Conclusions:

About 19% of BE patients developed VL during EET. There is higher prevalence of HGD/EAC in prevalent VL compared with incident VL. However, the outcomes did not differ.
CAM-ICU may not be the optimal screening tool for early delirium screening in older emergency department patients: a prospective cohort study
Authors: Lucke Jacinta A. , De Gelder Jelle , Blomaard Laura C. , Fogteloo Anne J. , Alsma Jelmer , Schuit Stephanie C.E. , Brink Anniek , De Groot Bas , Blauw Gerard J. , Mooijaart Simon P.
Published: January 2019

Objectives

Delirium is a frequent problem among older patients in the emergency department (ED) and early detection is important to prevent its associated adverse outcomes. Several screening tools for delirium have been proposed for the ED, such as the 6-Item Cognitive Impairment Test (6-CIT) and the Confusion Assessment Method-ICU (CAM-ICU). Previous validation of the CAM-ICU for use in the ED showed varying results, possibly because it was administered at different or unknown time points. The aim was to study the prevalence of delirium in older ( ≥ 70 years) ED patients using the CAM-ICU and 6-CIT.

Participants and methods

A prospective cohort study was carried out in one tertiary care and one secondary care hospital in the Netherlands. Patients aged 70 years and older attending the ED were included. Delirium screening was performed within 1 h after ED registration using the CAM-ICU. The 6-CIT was determined for comparison using a cut-off point of at least 14 points indicating possible delirium.

Results

A total of 997 patients were included in the study, with a median age of 78 years (interquartile range 74–84). Delirium as assessed with CAM-ICU was positive in only 13 (1.3%, 95% confidence interval: 0.8–2.2) patients. Ninety-five (9.5% 95% confidence interval: 7.9–11.5) patients had 6-CIT more than or equal to 14.

Conclusion

We found a delirium prevalence of 1.3% using the CAM-ICU, which was much lower than the expected prevalence of around 10% as being frequently reported in the literature and what we found when using the 6-CIT. On the basis of these results, caution is warranted to use the CAM-ICU for early screening in the ED.
Multimodal Management of Congenital Orbital Malignant Rhabdoid Tumor: Review of Literature and Report of a Rare Case
Authors: Biswas Ahitagni , Kumar Ritesh , Bakhshi Sameer , Sen Seema , Sharma Mehar C.
Published: January 2019

Background:

Malignant rhabdoid tumor (MRT) is a rare and aggressive tumor with a dismal prognosis. It commonly arises in the brain (65%), soft tissues (26%), and the kidney (9%). Primary orbital involvement is extremely rare. Although it has been mostly described in children below 2 years old, presentation at birth is sparsely reported.

Observation:

We have described a case of congenital orbital MRT, who presented with rapidly progressive right-sided proptosis and was initially treated with subtotal resection and postoperative chemotherapy with ICE (Ifosfamide, Carboplatin, Etoposide) regimen. On local progression the child was treated with palliative radiotherapy (20 Gy) to the right orbit and second-line chemotherapy with VAC (Vincristine, Adriamycin, Cyclophosphamide) regimen. Unfortunately he died due to progressive disease 4 months after the initial diagnosis.

Conclusions:

This report highlights the importance of awareness of orbital MRT as a differential diagnosis of rapidly progressing proptosis in the neonatal period. This tumor is often refractory to conventional multimodality treatment and more intensive and innovative treatment approaches are clearly needed in future.
Comparisons of Functional Apical Support After Sacral Hysteropexy Versus Sacral Colpopexy: A Cadaveric Study
Authors: Maldonado Pedro A. , Jackson Lindsey A. , Florian-Rodriguez Maria E. , Wai Clifford Y.
Published: January 2019

Objectives

Prolapse procedures with uterine preservation offer an alternative to colpopexy with hysterectomy. Few studies have examined the differences in anatomic or subjective outcomes following sacral hysteropexy versus sacral colpopexy with hysterectomy. This study sought to compare the ability of sacral hysteropexy and sacral colpopexy with hysterectomy to resist downward traction as an estimate of apical support in human cadavers.

Methods

Sacral hysteropexy was performed on unembalmed female cadavers. A metal bolt/washer was threaded through the uterine fundus, down the cervical canal. and out the vagina and fastened to a waxed surgical filament, which ran over a fixed pulley at the table's end. Successive weights were added to provide increasing loads on the uterine fundus, and the distances traversed by the fundus were recorded. The same process was repeated after completion of a total hysterectomy (with vaginal cuff closure) and subsequent sacral colpopexy in the same specimen. Data were analyzed using paired-sample t test and repeated-measures analysis of variance (Sigma Plot version 13.0), with P ≤ 0.05 considered statistically significant.

Results

Eight female cadavers were utilized. With the addition of each weight, the average distance traversed by the uterine fundus or vaginal cuff gradually increased. There were no statistical differences in the distances moved by the apex between sacral hysteropexy and total hysterectomy/sacral colpopexy.

Conclusions

These results suggest that functional support provided by sacral hysteropexy and sacral colpopexy with hysterectomy may be similar. Further studies are needed to correlate these findings with patient satisfaction, which may vary despite similar anatomic results.
Reciprocal control of motility and biofilm formation by the PdhS2 two-component sensor kinase of Agrobacterium tumefaciens
Authors: Heindl Jason E. , Crosby Daniel , Brar Sukhdev , Pinto John F. , Singletary Tiyan , Merenich Daniel , Eagan Justin L. , Buechlein Aaron M. , Bruger Eric L. , Waters Christopher M. , Fuqua Clay
Published: January 2019

A core regulatory pathway that directs developmental transitions and cellular asymmetries in

Agrobacterium tumefaciens

involves two overlapping, integrated phosphorelays. One of these phosphorelays putatively includes four histidine sensor kinase homologues, DivJ, PleC, PdhS1 and PdhS2, and two response regulators, DivK and PleD. In several different alphaproteobacteria, this pathway influences a conserved downstream phosphorelay that ultimately controls the phosphorylation state of the CtrA master response regulator. The PdhS2 sensor kinase reciprocally regulates biofilm formation and swimming motility. In the current study, the mechanisms by which the

A. tumefaciens

sensor kinase PdhS2 directs this regulation are delineated. PdhS2 lacking a key residue implicated in phosphatase activity is markedly deficient in proper control of attachment and motility phenotypes, whereas a kinase-deficient PdhS2 mutant is only modestly affected. A genetic interaction between DivK and PdhS2 is revealed, unmasking one of several connections between PdhS2-dependent phenotypes and transcriptional control by CtrA. Epistasis experiments suggest that PdhS2 may function independently of the CckA sensor kinase, the cognate sensor kinase for CtrA, which is inhibited by DivK. Global expression analysis of the pdhS2 mutant reveals a restricted regulon, most likely functioning through CtrA to separately control motility and regulate the levels of the intracellular signal cyclic diguanylate monophosphate (cdGMP), thereby affecting the production of adhesive polysaccharides and attachment. We hypothesize that in

A. tumefaciens

the CtrA regulatory circuit has expanded to include additional inputs through the addition of PdhS-type sensor kinases, likely fine-tuning the response of this organism to the soil microenvironment.
A Reaction Norm Perspective on Reproducibility
Authors: Voelkl Bernhard , Würbel Hanno
Published: January 2019

Reproducibility in biomedical research, and more specifically in preclinical animal research, has been seriously questioned. Several cases of spectacular failures to replicate findings published in the primary scientific literature have led to a perceived reproducibility crisis. Diverse threats to reproducibility have been proposed, including lack of scientific rigour, low statistical power, publication bias, analytical flexibility and fraud. An important aspect that is generally overlooked is the lack of external validity caused by rigorous standardization of both the animals and the environment. Here, we argue that a reaction norm approach to phenotypic variation, acknowledging gene-by-environment interactions, can help us seeing reproducibility of animal experiments in a new light. We illustrate how dominating environmental effects can affect inference and effect size estimates of studies and how elimination of dominant factors through standardization affects the nature of the expected phenotype variation through the reaction norms of small effect. Finally, we discuss the consequences of reaction norms of small effect for statistical analysis, specifically for random effect latent variable models and the random lab model.
Internally coupled middle ears enhance the range of interaural time differences heard by the chicken
Authors: Köppl Christine
Published: January 2019

Interaural time differences (ITD) are one of several principle cues for localizing sounds. However, ITD are in the sub-millisecond range for most animals. Because the neural processing of such small ITDs pushes the limit of temporal resolution, the precise ITD-range for a given species and its usefulness - relative to other localization cues - was a powerful selective force in the evolution of the neural circuits involved. Birds and other non-mammals have internally coupled middle ears working as pressure-difference receivers that may significantly enhance ITD, depending on the precise properties of the interaural connection. Here, the extent of this internal coupling was investigated in chickens, specifically under the same experimental conditions as typically used in neurophysiology of ITD-coding circuits, i.e. with headphone stimulation. Cochlear microphonics (CM) were recorded simultaneously from both ears of anesthetized chickens under monaural and binaural stimulation, using pure tones from 0.1 to 3 kHz. Interaural transmission peaked at 1.5 kHz at a loss of only −5.5 dB; the mean interaural delay was 264 μs. CM amplitude strongly modulated as a function of ITD, confirming significant interaural coupling. The “ITD heard” derived from the CM phases in both ears showed enhancement, compared to the acoustic stimuli, by a factor of up to 1.8. However, the closed sound delivery systems impaired interaural transmission at low frequencies (< 1 kHz). We identify factors that need to be considered when interpreting neurophysiological data obtained under these conditions, and relating them to the natural free-field condition.

Summary statement

The interaural time differences that chickens can use for sound localization are significantly greater than their small head size suggests. Closed-system sound stimulation can, however, produce complex artefacts.
In-silico Exploration of Mouse Brain Dynamics by Stimulation explains Functional Networks and Sensory Processing
Authors: Spiegler Andreas , Abadchi Javad Karimi , Mohajerani Majid , Jirsa Viktor K.
Published: January 2019

Sensory and direct stimulation of the brain probes its functional repertoire and the information processing capacity of networks. However, a systematic exploration can only be performed in silico. Stimulation takes the system out of its attractor states and samples the environment of the flow to gain insight into the stability and multiplicity of trajectories. It is the only means of obtaining a complete understanding of the healthy brain network’s dynamic properties. We built a whole mouse brain model with connectivity derived from tracer studies. We systematically varied the stimulation location, the ratio of long- to short-range interactions, and the range of short connections. Functional networks appeared in the spatial motifs of simulated brain activity. Several motifs included the default mode network, suggesting a junction of functional networks. The model explains processing in sensory systems and replicates the in vivo dynamics after stimulation without parameter tuning, emphasizing the role of connectivity.
VGF in cerebrospinal fluid, when combined with conventional biomarkers, enhances prediction of conversion from mild cognitive impairment to Alzheimer’s Disease
Authors: Llano Daniel A. , Devanarayan Priya , Devanarayan Viswanath ,   for the Alzheimer’s Disease Neuroimaging Initiative (ADNI)
Published: January 2019

Sensitive and accurate biomarkers for the prediction of conversion from mild cognitive impairment (MCI) to Alzheimer’s Disease (AD) are needed to both support clinical care and enhance clinical trial design. Here, we examined the potential of cerebrospinal fluid (CSF) levels of a peptide derived from a neural protein involved in synaptic transmission, VGF (a non-initialism), to enhance accuracy of prediction of conversion from MCI to AD. The performance of conventional biomarkers (CSF Aβ1-42 and phosphorylated tau +/− hippocampal volume) was compared to the same biomarkers with CSF VGF peptide levels. It was observed that VGF peptides are lowered in patients with AD compared to controls and that combinations of CSF Aβ1-42 and phosphorylated tau, hippocampal volume and VGF peptide levels outperformed conventional biomarkers alone (hazard ratio = 2.2 vs. 3.9). VGF peptide levels were correlated most strongly with total tau levels, but not hippocampal volume, suggesting that they serve as a marker for neuronal degradation, but not necessarily in the hippocampus. The latter point suggests that VGF may serve as a more general marker of neurodegeneration. Future work will be needed to determine the specificity of VGF for AD vs. other neurodegenerative diseases.
Divergent selection following speciation in two ectoparasitic honey bee mites
Authors: Techer Maeva A. , Rane Rahul V. , Grau Miguel L. , Roberts John M. K. , Sullivan Shawn T. , Liachko Ivan , Childers Anna K. , Evans Jay D. , Mikheyev Alexander S.
Published: January 2019

Multispecies host-parasite evolution is common, but how parasites evolve after speciating remains poorly understood. Shared evolutionary history and physiology may propel species along similar evolutionary trajectories whereas pursuing different strategies can reduce competition. We test these scenarios in the economically important association between honey bees and ectoparasitic mites by sequencing the genomes of the sister mite speciesVarroa destructorandVarroa jacobsoni. These genomes were closely related, with 99.7% sequence identity. Among the 9,628 orthologous genes, 4.8% showed signs of positive selection in at least one species. Divergent selective trajectories were discovered in conserved chemosensory gene families (IGR, SNMP), and Halloween genes (CYP) involved in moulting and reproduction. However, there was little overlap in these gene sets and associated GO terms, indicating different selective regimes operating on each of the parasites. Based on our findings, we suggest that species-specific strategies may be needed to combat evolving parasite communities.
Buckling of epithelium growing under spherical confinement
Authors: Trushko Anastasiya , Di Meglio Ilaria , Merzouki Aziza , Blanch-Mercader Carles , Abuhattum Shada , Guck Jochen , Alessandri Kevin , Nassoy Pierre , Kruse Karsten , Chopard Bastien , Roux Aurélien
Published: January 2019

Many organs, such as the gut or the spine are formed through folding of an epithelium. This change in shape is usually attributed to tissue heterogeneities, for example, local apical contraction. In contrast, compressive stresses have been proposed to fold a homogeneous epithelium by buckling. While buckling is an appealing mechanism, demonstrating that it underlies folding requires to measure the stress field and the material properties of the tissue, which is currently inaccessiblein vivo. Here we show that monolayers of identical cells proliferating on the inner surface of elastic spherical shells can spontaneously fold. By measuring the elastic deformation of the shell, we infer the forces acting within the monolayer and its elastic modulus. Using analytical and numerical theories linking forces to shape, we find that buckling quantitatively accounts for the shape changes of our monolayers. Our study shows that forces arising from epithelium growth in three-dimensional confinement are sufficient to drive folding by buckling.
NOTCH assembles a transcriptional repressive complex containing NuRD and PRC1 to repress genes involved in cell proliferation and differentiation
Authors: Doyen Cecile M. , Depierre David , Yatim Ahmad , Heurteau Alex , Lelievre Jean Daniel , Levy Yves , Cuvier Olivier , Benkirane Monsef
Published: January 2019

NOTCH1 is best known as a master regulator of T-cell development with a strong oncogenic potential in developing T-cells. Upon induction of Notch, cells go through major transcriptional reprogramming that involves both activation and repression of gene expression. Although much is known about the transcriptional programs activated by Notch, the identity of the genes silenced downstream of Notch signaling and the mechanisms by which Notch down-regulates their expression remain unclear. Here, we show that upon induction of Notch signaling, ICN1-CSL-MAML1 ternary complex assembles a transcriptional Notch Repressive Complex (NRC) containing NuRD and PRC1. Genome wide analysis revealed set of genes bound and transcriptionally repressed by the NRC. Remarkably, among those genes, we found master regulators of cell differentiation and cell proliferation such as PAX5, master B-cell regulator and the DNA-binding transcriptional repressor MAD4. We propose that Notch possesses a dual role as direct activator and repressor by serving as a platform for the recruitment of co-activators and co-repressors on target genes and that both activities are required for Notch nuclear functions.
Species-specific enhancement of enterohemorrhagic E. Coli pathogenesis mediated by microbiome metabolites
Authors: Tovaglieri Alessio , Sontheimer-Phelps Alexandra , Geirnaert Annelies , Prantil-Baun Rachelle , Camacho Diogo M. , Chou David B. , Jalili-Firoozinezhad Sasan , de Wouters Tomás , Kasendra Magdalena , Super Michael , Cartwright Mark , Richmond Camilla A. , Breault David T. , Lacroix Christophe , Ingber Donald E.
Published: January 2019

Background

Species-specific differences in tolerance to infection are exemplified by the high susceptibility of humans to enterohemorrhagic E. coli (EHEC) infection whereas mice are relatively resistant to this pathogen. This intrinsic species-specific difference in EHEC infection limits the translation of murine research to human. Furthermore, studying the mechanisms underlying this differential susceptibility is a difficult problem due to complex in vivo interactions between the host, pathogen, and disparate commensal microbial communities.

Results

We utilize organ-on-a-chip (Organ Chip) microfluidic culture technology to model damage of the human colonic epithelium induced by EHEC infection, and show that epithelial injury is greater when exposed to metabolites derived from the human gut microbiome compared to mouse. Using a multi-omics approach, we discovered four human microbiome metabolites — 4-methyl benzoic acid, 3,4-dimethylbenzoic acid, hexanoic acid, and heptanoic acid — that are sufficient to mediate this effect. The active human microbiome metabolites preferentially induce expression of flagellin, a bacterial protein associated with motility of EHEC and increased epithelial injury. Thus, the decreased tolerance to infection observed in humans versus other species may be due in part to the presence of compounds produced by the human intestinal microbiome that actively promote bacterial pathogenicity.

Conclusion

Organ on chip technology allowed the identification of specific human microbiome metabolites modulating EHEC pathogenesis. These identified metabolites are sufficient to increase susceptibility to EHEC in our human Colon Chip model and they contribute to species-specific tolerance. This work suggests that higher concentrations of these metabolites could be the reason for higher susceptibility to EHEC infection in certain human populations, such as children. Furthermore, this research lays the foundation for therapeutic-modulation of microbe products in order to prevent and treat human bacterial infection.
CHCHD4 confers metabolic vulnerabilities to tumour cells through its control of the mitochondrial respiratory chain
Authors: Thomas Luke W. , Stephen Jenna M. , Esposito Cinzia , Hoer Simon , Antrobus Robin , Ahmed Afshan , Al-Habib Hasan , Ashcroft Margaret
Published: January 2019

BACKGROUND

Tumour cells rely on glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) to survive. Thus mitochondrial OXPHOS has become an increasingly attractive area for therapeutic exploitation in cancer. However, mitochondria are required for intracellular oxygenation and normal physiological processes, and it remains unclear which mitochondrial molecular mechanisms might provide therapeutic benefit. Previously, we discovered that coiled-coil helix coiled-coil helix domain-containing protein 4 (CHCHD4) is critical for maintaining intracellular oxygenation and required for the cellular response to hypoxia (low oxygenation) in tumour cells through molecular mechanisms that we do not yet fully understand. Overexpression of CHCHD4 in human cancers, correlates with increased tumour progression and poor patient survival.

RESULTS

Here, we show that elevated CHCHD4 expression provides a proliferative and metabolic advantage to tumour cells in normoxia and hypoxia. Using stable isotope labelling with amino acids in cell culture (SILAC) and analysis of the whole mitochondrial proteome, we show that CHCHD4 dynamically affects the expression of a broad range of mitochondrial respiratory chain subunits from complex I-V, including multiple subunits of complex I (CI) required for complex assembly that are essential for cell survival. We found that loss of CHCHD4 protects tumour cells from respiratory chain inhibition at CI, while elevated CHCHD4 expression in tumour cells leads to significantly increased sensitivity to CI inhibition, in part through the production of mitochondrial reactive oxygen species (ROS).

CONCLUSIONS

Our study highlights an important role for CHCHD4 in regulating tumour cell metabolism, and reveals that CHCHD4 confers metabolic vulnerabilities to tumour cells through its control of the mitochondrial respiratory chain and CI biology.
Recruitment and disruption of value encoding during alcohol seeking
Authors: Ottenheimer David , Wang Karen , Haimbaugh Alexandria , Janak Patricia H. , Richard Jocelyn M.
Published: January 2019

A critical area of inquiry in the neurobiology of alcohol abuse is the neural mechanisms by which cues gain the ability to elicit alcohol use. We previously showed that cue-evoked activity in rat ventral pallidum (VP) robustly encodes the value of cues trained under both Pavlovian and instrumental contingencies, despite a stronger relationship between cue-evoked responses and behavioral latency after instrumental training. Here, we assessed VP neural representations of cue value in rats trained with a Pavlovian conditioned stimulus (CS+) that predicted alcohol delivery, and in rats trained with an instrumental discriminative stimulus (DS) that predicted alcohol availability if the rat entered the reward port during the cue. We also examined the impact of alcohol exposure itself on the integrity of this type of signaling in rats trained with sucrose. Decoding of cue value based on VP firing was blunted for an alcohol CS+ versus an alcohol DS, as well as in comparison to a sucrose DS or CS+. Further, homecage alcohol exposure had opposing effects on VP encoding of cue value for a sucrose DS versus a sucrose CS+, enhancing decoding accuracy for the DS and reducing decoding accuracy for the CS+. These findings suggest that problem alcohol seeking may result from biased engagement of specific reward-related processes via changes in VP signaling.
Collagen Density Modulates the Immunosuppressive Functions of Tumor-Associated Macrophages
Authors: Larsen Anne Mette H. , Kuczek Dorota E. , Kalvisa Adrija , Siersbæk Majken S. , Thorseth Marie-Louise , Johansen Astrid Zedlitz , Carretta Marco , Grøntved Lars , Vang Ole , Madsen Daniel H.
Published: January 2019

Tumor-associated macrophages (TAMs) support tumor growth by suppressing the activity of tumor infiltrating T cells. Consistently, the number of TAMs has been correlated with a poor prognosis of cancer. The immunosuppressive TAMs are also considered a major limitation for the efficacy of cancer immunotherapy. However, the molecular reason behind the acquisition of an immunosuppressive TAM phenotype is still not completely understood. During solid tumor growth, the extracellular matrix (ECM) is degraded and substituted with a tumor specific collagen-rich ECM. The collagen density of this tumor ECM has been associated with a poor prognosis of several cancers, but the underlying reason for this correlation is not well understood. Here, we have investigated whether the collagen density could modulate the immunosuppressive activity of TAMs and thereby promote tumor progression.

In this study, the macrophage cell line RAW 264.7 was 3D cultured in collagen matrices of low- and high collagen densities mimicking healthy and tumor tissue, respectively. The effects of collagen density on macrophage phenotype and function were investigated by confocal microscopy, flow cytometry, RNA sequencing, qRT-PCR, and ELISA analysis. To investigate the effect of collagen density on the immune modulatory activity of macrophages, co-culture assays with primary T cells to assess T cell chemotaxis and proliferation were conducted. Lastly, the effects of collagen density on primary cells were investigated using murine bone-marrow derived macrophages (BMDMs) and TAMs isolated from murine 4T1 breast tumors.

Collagen density did not affect the proliferation, viability or morphology of macrophages. However, whole-transcriptome analysis revealed a striking response to the surrounding collagen density including the differential regulation of many immune regulatory genes and genes encoding chemokines. The transcriptional changes in RAW 264.7 macrophages were shown to be similar in murine BMDMs and TAMs. Strikingly, the collagen density-induced changes in the gene expression profile had functional consequences for the macrophages. Specifically, macrophages cultured in high density collagen were less efficient at attracting cytotoxic T cells and also capable of inhibiting T cell proliferation to a greater extent than macrophages cultured in low density collagen.

Our study demonstrates that a high collagen density can instruct TAMs to acquire an immunosuppressive phenotype. This could be one of the mechanisms decreasing the efficacy of immunotherapy and linking increased collagen density to poor patient prognosis.
NRF2-dependent metabolic reprogramming is required for tumor recurrence following oncogene inhibition
Authors: Fox Douglas B. , Lupo Ryan , Noteware Laura C. , Newcomb Rachel , Liu Juan , Locasale Jason W. , Hirschey Matthew D. , Alvarez James V.
Published: January 2019

Oncogenic signaling pathways both directly and indirectly regulate anabolic metabolism, and this is required for tumor growth. Targeted therapies that inhibit oncogenic signaling have dramatic impacts on cellular metabolism. However, it is not known whether the acquisition of resistance to these therapies is associated with – or driven by – alterations in cellular metabolism. To address this, we used a conditional mouse model of Her2-driven breast cancer to study metabolic adaptations following Her2 inhibition, during residual disease, and after tumor recurrence. We found that Her2 downregulation caused widespread changes in cellular metabolism, culminating in oxidative stress. Tumor cells adapted to this metabolic stress by upregulation of the antioxidant transcription factor, NRF2. Constitutive NRF2 expression persisted during residual disease and tumor recurrence, and NRF2 was both sufficient to promote tumor recurrence, and necessary for recurrent tumor growth. These results are supported by clinical data showing that the NRF2 transcriptional program is activated in recurrent breast tumors, and that NRF2 is associated with poor prognosis in patients with breast cancer. Mechanistically, NRF2 signaling in recurrent tumors induced metabolic reprogramming to re-establish redox homeostasis and upregulate de novo nucleotide synthesis. Finally, this NRF2-driven metabolic state rendered recurrent tumor cells sensitive to glutaminase inhibition, suggesting that NRF2-high recurrent tumors can be therapeutically targeted. Together, these data provide evidence that NRF2-driven metabolic reprogramming is required for breast cancer recurrence following oncogene inhibition.

Significance

Although tumor recurrence is the leading cause of mortality in breast cancer, the cellular properties that allow tumor cells to evade therapy and form recurrent tumors remain largely uncharacterized. Similarly, very little is known about how tumor metabolism changes following therapy, or whether alterations in cellular metabolism drive tumor recurrence. In this study, we identify the antioxidant transcription factor NRF2 as a critical positive regulator of breast cancer recurrence. We find that NRF2-dependent metabolic reprogramming is both sufficient and required to promote tumor recurrence. Additionally, we demonstrate that the NRF2-driven metabolic state renders recurrent tumors sensitive to glutaminase inhibitors, suggesting a novel therapeutic approach for the treatment of recurrent breast cancer.
Acceptability of active case finding with a seed-and-recruit model to improve tuberculosis case detection and linkage to treatment in Cambodia: a qualitative study
Authors: Tuot Sovannary , Teo Alvin Kuo Jing , Cazabon Danielle , Sok Say , Ung Mengieng , Ly Sangky , Choub Sok Chamreun , Yi Siyan
Published: January 2019

Background

With support of the national tuberculosis (TB) program, KHANA has implemented an innovative approach using a seed-and-recruit model to actively find TB cases in the community. The intervention engaged community members including TB survivors to recruit people with TB symptoms in a ‘snowball’ approach for screening and linkage to treatment. This study aims to explore the acceptability of active case finding with the seed-and-recruit model in detecting new TB cases and determine the characteristics of successful seeds.

Methods

This qualitative study was conducted in four provinces (Banteay Meanchey, Kampong Chhnang, Siem Reap, and Takeo) in Cambodia in 2017. Fifty six in-depth interviews and ten focus group discussions were conducted to gain insights into the acceptability, strengths, and challenges in implementing the model. Transcripts were coded and content analyses were performed.

Results

The seed-and-recruit active case finding model was generally well-received by the study participants. They saw the benefits of engaging TB survivors and utilize their social network to find new TB cases in the community. The social embeddedness of the model within the local community was one of the major strengths. The success of the model also hinges on the integration with existing health facilities. Having extensive social network, being motivated, and having good knowledge about TB were important characteristics of successful seeds. Study participants reported challenges in motivating the recruits for screening, logistic capacities, and high workload during implementation. However, there was a general consensus that the model ought to be expanded.

Conclusions

These findings indicate that the seed-and-recruit model should be fine-tuned and scaled up as part of the national TB Program to increase TB new case detection in Cambodia. Further studies are needed to more comprehensively evaluate the impacts and cost-effectiveness of the model in Cambodia as well as in other resource-limited settings.
Consideration of species-specific diatom indicators of anthropogenic stress in the Great Lakes
Authors: Reavie Euan D. , Cai Meijun
Published: January 2019

Robust inferences of environmental condition come from bioindicators that have strong relationships with stressors and are minimally confounded by extraneous environmental variables. These indicator properties are generally assumed for assemblage-based indicators such as diatom transfer functions that use species abundance data to infer environmental variables. However, failure of assemblage approaches necessitates the interpretation of individual dominant taxa when making environmental inferences. To determine whether diatom species from Laurentian Great Lakes sediment cores have the potential to provide unambiguous inferences of anthropogenic stress, we evaluated fossil diatom abundance against a suite of historical environmental gradients: human population, agriculture, mining, atmospheric nutrient deposition, atmospheric temperature and ice cover. Several diatom species, such asStephanodiscus parvus, had reliable relationships with anthropogenic stress such as human population. However, many species had little or no indicator value or had confusing relationships with multiple environmental variables, suggesting one should be careful when using those species to infer stress in the Great Lakes. Recommendations for future approaches to refining diatom indicators are discussed, including accounting for the effects of broad species geographic distributions to minimize region-specific responses that can weaken indicator power.
Parallel Visual Circuitry in a Basal Chordate
Authors: Kourakis Matthew J. , Borba Cezar , Zhang Angela , Newman-Smith Erin , Salas Priscilla , Manjunath B. , Smith William C.
Published: January 2019

A common CNS architecture is observed in all chordates, from vertebrates to basal chordates like the ascidian Ciona. Currently Ciona stands apart among chordates in having a complete larval CNS connectome. Starting with visuomotor circuits predicted by the Ciona connectome, we used expression maps of neurotransmitter use with behavioral assays and pharmacology to identify two parallel visuomotor circuits that are responsive to different components of visual stimuli. The first circuit is characterized by glutamatergic photoreceptors and responds to the direction of light. These photoreceptors project to cholinergic motor neurons, via two tiers of cholinergic interneurons. The second circuit is responsive to changes in ambient light and mediates an escape response. This circuit starts with novel GABAergic photoreceptors which project to GABAergic interneurons, and then to cholinergic interneurons shared with the first circuit. Our observations on neurotransmitter use and the behavior of larvae lacking photoreceptors indicate the second circuit is disinhibitory.
What drives phenotypic divergence among coral clonemates?
Authors: Baums Iliana B , Devlin-Durante Meghann K , Williams Dana W , Kemp Dustin
Published: January 2019

Evolutionary rescue of populations depends on their ability to produce phenotypic variation that is heritable and adaptive. DNA mutations are the best understood mechanisms to create phenotypic variation, but other, less well-studied mechanisms exist. Marine benthic foundation species provide opportunities to study these mechanisms because many are dominated by isogenic stands produced through asexual reproduction. For example, Caribbean acroporid corals are long lived and reproduce asexually via breakage of branches. Fragmentation is often the dominant mode of local population maintenance. Thus, large genets with many ramets (colonies) are common. Here, we observed phenotypic variation in stress response within genets following the coral bleaching events in 2014-and 2015 caused by high water temperatures. This was not due to genetic variation in their symbiotic dinoflagellates (Symbiodinium ‘fitti’) because each genet of this coral species typically harbors a single strain of S. ‘fitti’. Characterization of the microbiome via 16S tag sequencing did not provide evidence for a central role of microbiome variation in determining bleaching response. Instead, epigenetic changes were significantly correlated with the host’s genetic background, the position of the sampled polyps within the colonies (e.g. branch versus base of colony), and differences in the colonies’ condition during the bleaching event. We conclude that microenvironmental differences in growing conditions led to long-term changes in the way the ramets methylated their genomes contributing to, but not fully explaining, the differential bleaching response. This research provides novel data to understanding intra-genet variability in stress phenotypes of sessile marine species.
Efficacy and Safety of Immunosuppressive Treatment in IgA Nephropathy: A Meta-analysis of Randomized Controlled Trials
Authors: Zhang Zheng , Yang Yue , Jiang Shi-min , Li Wen-ge
Published: January 2019

Background

There is some controversy regarding the efficacy and safety of immunosuppressive agents for the treatment of kidney diseases. The recent STOP-IgAN and TESTING studies have focused attention on the application of immunosuppressive agents in IgA nephropathy (IgAN). This study investigated the benefits and risks of immunosuppressive agents in IgAN.

Methods

MEDLINE, EMBASE, the Cochrane Library, and article reference lists were searched for randomized controlled trials (RCTs) comparing immunosuppressive agents with any other non-immunosuppressive agents for treating IgAN. A meta-analysis was performed on the outcomes of proteinuria, creatinine (Cr), estimated glomerular filtration rate (eGFR), and adverse events in patients with IgAN, and trial sequential analyses were also performed for outcomes.

Results

Twenty-nine RCTs (1957 patients) that met our inclusion criteria were identified. Steroids (weighted mean difference [WMD] −0.70, 95% confidence interval [CI] −1.2 to −0.20), non-steroidal immunosuppressive agents (NSI) (WMD −0. 43, 95% CI −0.55 to −0.31), and combined steroidal and non-steroidal immunosuppressive agents (S&NSI) (WMD −1.46, 95% CI −2.13 to −0.79) therapy significantly reduced proteinuria levels in patients with IgAN. Steroid treatment significantly reduced the risk for end-stage renal disease (ESRD) (relative risk [RR] 0.39, CI 0.19 to 0.79). The immunosuppressive therapy group showed significant increases in gastrointestinal, hematological, dermatological, and genitourinary side effects, as well as impaired glucose tolerance or diabetes. Hyperkalemia was more common in the control group.

Conclusion

Immunosuppressive therapy can significantly reduce proteinuria and ESRD risk in patients with IgAN, but with a concomitant increase in adverse reactions. Therefore, care is required in the application of immunosuppressive agents in IgAN.