bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlation between kidney and peripheral nerve functions in Type 2 diabetes
Authors: Lai Y-R , Cheng B-C , Huang C-C , Chiu W-C , Tsai N-W , Chen J-F , Lu C-H
Published: September 2019

Background

Although greater impairments in nerve functions parameters are most likely to occur with a lower kidney function, there is a paucity of information on the relationship between the kidney and peripheral nerve functions parameters in Type 2 diabetes.

Aim

To address the impact of peripheral nerve functions in Type 2 diabetes patients in different stages of chronic kidney diseases (CKD).

Design

This prospective study enrolled 238 patients with Type 2 diabetes at a tertiary medical center.

Method

We designed composite amplitude scores of nerve conductions (CAS) as a measure of severity of peripheral neuropathy (PN), and used estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (UACR) parameters to stage CKD in Type 2 diabetes patients. The intrapersonal mean, standard deviation and coefficient of variation of eGFR for 238 patients were obtained in the 3 years prior to the study.

Results

The patients who had lower eGFR and higher UACR were older, with longer diabetes duration, a greater percentage of retinopathy and PN and higher CAS. Multiple linear regression analysis revealed that diabetes duration and eGFR were independently associated with CAS, and a cut-off value of eGFR in the presence of PN was 65.3 ml/min/1.73 m2.

Conclusion

We observed a close relationship between the severity of kidney and peripheral nerve function in patients with diabetes. If a patient’s eGFR value is below 65.3 ml/min/1.73 m2 or the UACR value is above 98.6 mg/dl, caution is needed with the presence of PN even in diabetic patients who are asymptomatic.
Perinatal use and discontinuation of disease-modifying anti-rheumatic drugs and biologics in women with rheumatoid arthritis: a cohort study
Authors: Rebić Nevena , Sayre Eric C , Zusman Enav Z , Amiri Neda , Baldwin Corisande , De Vera Mary A
Published: September 2019

Objectives

To characterize the utilization and discontinuation of medications before, during and after pregnancy among women with RA.

Methods

We used population-based administrative data to identify women with RA who had a singleton pregnancy ending in delivery between 1 January 2002 and 31 December 2012. We assessed the utilization of RA medications, namely, conventional synthetic DMARDs, biologics, glucocorticosteroids and NSAIDs, across six windows spanning 24 and 12 months before the start of pregnancy, each trimester of pregnancy and 12 months post-pregnancy. We defined medication discontinuation as no prescription in a given window following a prescription in the preceding window and evaluated predictors using logistic regression models, calculating adjusted odds ratios (ORs) and 95% CIs.

Results

We studied 1730 pregnancies in 1301 women with RA (mean age at delivery 31.4 ± 5.4 years). We observed substantial medication discontinuation, particularly in the first trimester, with discontinuation of antimalarials in 57.3% of patients, azathioprine 59.1%, sulfasalazine 69.5% and biologics 50.8%. Factors inversely associated with discontinuation of antimalarials in the first trimester were maternal age [OR 0.90 (95% CI 0.86, 0.95)] and number of rheumatology visits [OR 0.86 (95% CI 0.75, 0.97)] and for biologics, prior adverse birth outcome [OR 0.22 (95% CI 0.05, 0.95)].

Conclusion

Our population-based study shows frequent discontinuation of medications for RA, particularly in the first trimester. Findings indicate a need to educate women with RA who are planning pregnancy on the benefits and risks of medications during pregnancy.
CR10—A PUBLIC DATABASE OF COSMIC RADIATION MEASUREMENTS AT AVIATION ALTITUDES OF ABOUT 10 KM
Authors: Kákona Martin , Kyselová Dagmar , Ambrožová Iva , Kubančák Ján , Štěpán Václav , Langer Ronald , Kudela Karel , Ploc Ondřej
Published: September 2019

Long-term measurements using silicon radiation spectrometer Liulin on board commercial aircraft have been performed since 2001; results were put into a new database, which covers more than 4500 flights with more than 130 000 measurements. Methodology and tools were developed to normalize the data with respect to latitude and altitude and thus enable comparison with other radiation detectors and with model calculations. This capability is demonstrated using data from the neutron monitor at Lomnický štít. Instead of providing data files for individual measurement period, two software solutions are delivered. First is a web-based user interface for visualizing and downloading arbitrary time window of interest from the database hosted at http://cr10.odz.ujf.cas.cz. The second is a set of interactive Python notebooks available at GitHub. Those implement the calibration, normalization and visualization methods—so the outputs can be tailored to user needs. The software and data are provided under GNU/CC license.
Sleep-wake disturbances in hospitalized patients with traumatic brain injury: association with brain trauma but not with an abnormal melatonin circadian rhythm
Authors: Duclos Catherine , Dumont Marie , Paquet Jean , Blais Hélène , Van der Maren Solenne , Menon David K , Bernard Francis , Gosselin Nadia
Published: September 2019

Study Objectives

To test whether the sleep-wake cycle disruption in patients hospitalized with traumatic brain injury (TBI) (1) is also found in patients with traumatic injuries other than TBI (non-TBI) and (2) is associated with a weaker or abnormal circadian clock signal.

Methods

Forty-two non-mechanically ventilated and non-sedated patients hospitalized for moderate-to-severe TBI were compared to 34 non-TBI patients. They wore wrist actigraphs for 9.4 ± 4.2 days, starting 19.3 ± 12.6 days post-injury. Of these, 17 TBI and 14 non-TBI patients had their urine collected every hour for 25 hours, starting 18.3 ± 12.3 days post-injury. We calculated urinary 6-sulfatoxymelatonin concentration to obtain total 24-hour excretion, excretion onset, offset, duration, amplitude, and acrophase. Using Student’s t-tests, we compared groups on actigraphy (daytime activity ratio, nighttime total sleep time, and fragmentation index) and melatonin variables. We investigated associations between melatonin and actigraphy variables using Pearson’s correlations.

Results

TBI patients had poorer daytime activity ratio (TBI: 77.5 ± 9.4%; non-TBI: 84.6 ± 6.9%), shorter nighttime total sleep time (TBI: 353.5 ± 96.6 min; non-TBI: 421.2 ± 72.2 min), and higher fragmentation index (TBI: 72.2 ± 30.0; non-TBI: 53.5 ± 23.6) (all p-values < 0.01). A melatonin rhythm was present in both groups, and no group differences were found on melatonin variables. No associations were found between melatonin and actigraphy variables in TBI patients.

Conclusion

Moderate-to-severe TBI patients have more serious sleep-wake disturbances than non-TBI patients hospitalized in the same environment, suggesting that the brain injury itself alters the sleep-wake cycle. Despite their deregulated 24-hour sleep-wake cycle, TBI patients have a normal circadian clock signal.
Women Cabinet Ministers’ Substantive Representation in Africa
Authors: Nwankwor Chiedo
Published: September 2019

Research on women executives’ substantive representation is currently drawing serious attention given women’s increasing inclusion in cabinets globally. However, these studies rarely question whether women ministers across Africa represent women’s interests. Using primary semi-structured interview data conducted with forty-nine interviewees, including seventeen ministers in Nigeria and South Africa, this article explores whether women politicians advocate for women’s interests. It centers a critical understanding of the cabinet as an embedded institution, embraces a context-specific understanding of substantive representation, and demonstrates that women ministers’ representation of women’s interests occurs mostly in nonlegislative ways. It presents an expansive three-level conception of substantive representation.
Redistribution of EC‐SOD resolves bleomycin‐induced inflammation via increased apoptosis of recruited alveolar macrophages
Authors: Allawzi Ayed , McDermott Ivy , Delaney Cassidy , Nguyen Kianna , Banimostafa Laith , Trumpie Ashley , Hernandez‐Lagunas Laura , Riemondy Kent , Gillen Austin , Hesselberth Jay , Kasmi Karim El , Sucharov Carmen C. , Janssen William J. , Stenmark Kurt , Bowler Russell , Nozik‐Grayck Eva
Published: September 2019

A human single nucleotide polymorphism (SNP) in the matrix‐binding domain of extracellular superoxide dismutase (EC‐SOD), with arginine to glycine substitution at position 213 (R213G), redistributes EC‐SOD from the matrix into extracellular fluids. We reported that, following bleomycin (bleo), knockin mice harboring the human R213G SNP (R213G mice) exhibit enhanced resolution of inflammation and protection against fibrosis, compared with wild‐type (WT) littermates. In this study, we tested the hypothesis that the EC‐SOD R213G SNP promotes resolution via accelerated apoptosis of recruited alveolar macrophage (AM). RNA sequencing and Ingenuity Pathway Analysis 7 d postbleo in recruited AM implicated increased apoptosis and blunted inflammatory responses in the R213G strain exhibiting accelerated resolution. We validated that the percentage of apoptosis was significantly elevated in R213G recruited AM vs. WT at 3 and 7 d postbleo in vivo. Recruited AM numbers were also significantly decreased in R213G mice vs. WT at 3 and 7 d postbleo. ChaC glutathione‐specific γ‐glutamylcyclotransferase 1 (Chac1), a proapoptotic γ‐glutamyl cyclotransferase that depletes glutathione, was increased in the R213G recruited AM. Overexpression of Chac1 in vitro induced apoptosis of macrophages and was blocked by administration of cell‐permeable glutathione. In summary, we provide new evidence that redistributed EC‐SOD accelerates the resolution of inflammation through redox‐regulated mechanisms that increase recruited AM apoptosis.—Allawzi, A., McDermott, I., Delaney, C., Nguyen, K., Banimostafa, L., Trumpie, A., Hernandez‐Lagunas, L., Riemondy, K., Gillen, A., Hesselberth, J., ElKasmi, K., Sucharov, C. C., Janssen, W. J., Stenmark, K., Bowler, R., Nozik‐Grayck, E. Redistribution of EC‐SOD resolves bleomycin‐induced inflammation via increased apoptosis of recruited alveolar macrophages. FASEB J. 33, 13465–13475 (2019). www.fasebj.org
A modified cholera toxin B subunit containing an ER retention motif enhances colon epithelial repair via an unfolded protein response
Authors: Royal Joshua M. , Oh Young Jun , Grey Michael J. , Lencer Wayne I. , Ronquillo Nemencio , Galandiuk Susan , Matoba Nobuyuki
Published: September 2019

Cholera toxin B subunit (CTB) exhibits broad‐spectrum biologic activity upon mucosal administration. Here, we found that a recombinant CTB containing an endoplasmic reticulum (ER) retention motif (CTB‐KDEL) induces colon epithelial wound healing in colitis via the activation of an unfolded protein response (UPR) in colon epithelial cells. In a Caco2 cell wound healing model, CTB‐KDEL, but not CTB or CTB‐KDE, facilitated cell migration via interaction with the KDEL receptor, localization in the ER, UPR activation, and subsequent TGF‐β signaling. Inhibition of the inositol‐requiring enzyme 1/X‐box binding protein 1 arm of UPR abolished the cell migration effect of CTB‐KDEL, indicating that the pathway is indispensable for the activity. CTB‐KDEL's capacity to induce UPR and epithelial restitution or wound healing was corroborated in a dextran sodium sulfate‐induced acute colitis mouse model. Furthermore, CTB‐KDEL induced a UPR, up‐regulated wound healing pathways, and maintained viable crypts in colon explants from patients with inflammatory bowel disease (IBD). In summary, CTB‐KDEL exhibits unique wound healing effects in the colon that are mediated by its localization to the ER and subsequent activation of UPR in epithelial cells. The results provide implications for a novel therapeutic approach for mucosal healing, a significant unmet need in IBD treatment.—Royal, J. M., Oh, Y. J., Grey, M. J., Lencer, W. I., Ronquillo, N., Galandiuk, S., Matoba, N. A modified cholera toxin B subunit containing an ER retention motif enhances colon epithelial repair via an unfolded protein response. FASEB J. 33, 13527‐13545 (2019). www.fasebj.org
Contribution of Marijuana Legalization to the U.S. Opioid Mortality Epidemic: Individual and Combined Experience of 27 States and District of Columbia
Authors: Bleyer Archie , Barnes Brian
Published: September 2019

Background

Prior studies of U.S. states as of 2013 and one state as of 2015 suggested that marijuana availability reduces opioid mortality (marijuana protection hypothesis). This investigation tested the hypothesis with opioid mortality trends updated to 2017 and by evaluating all states and the District of Columbia (D.C.).

Methods

Opioid mortality data obtained from the U.S. Centers for Disease Control and Prevention were used to compare opioid death rate trends in each marijuana-legalizing state and D.C. before and after medicinal and recreational legalization implementation and their individual and cumulative aggregate trends with concomitant trends in non-legalizing states. The Joinpoint Regression Program identified statistically-significant mortality trends and when they occurred.

Results

Of 23 individually evaluable legalizing jurisdictions, 78% had evidence for a statistically-significant acceleration of opioid death rates after medicinal or recreational legalization implementation at greater rates than their pre-legalization rate or the concurrent composite rate in non-legalizing states. All four jurisdictions evaluable for recreational legalization had evidence (p <0.05) for subsequent opioid death rate increases, one had a distinct acceleration, and one a reversal of prior decline. Since 2009-2012, when the cumulative-aggregate opioid death rate in the legalizing jurisdictions was the same as in the non-legalizing group, the legalizing group’s rate accelerated increasingly faster (p=0.009). By 2017 it was 67% greater than in the non-legalizing group (p <<0.05).

Conclusions

The marijuana protection hypothesis is not supported by recent U.S. data on opioid mortality trends. Instead, legalizing marijuana appears to have contributed to the nation’s opioid mortality epidemic.
Patterns of Autism Symptoms: Hidden Structure in the ADOS and ADI-R instruments
Authors: Lefort-Besnard Jérémy , Vogeley Kai , Schilbach Leonhard , Varoquaux Gaël , Thirion Bertrand , Dumas Guillaume , Bzdok Danilo
Published: September 2019

We simultaneously revisited the ADI-R and ADOS with a comprehensive data-analytics strategy. Here, the combination of pattern analysis algorithms and an extensive data resources (n=266 patients aged 7 to 49 years) allowed identifying coherent clinical constellations in and across ADI-R and ADOS assessments widespread in clinical practice. The collective results of the clustering and sparse regression approaches suggest that identifying autism subtypes and severity for a given individual may be most manifested in the social and communication domains of the ADI-R. Additionally, our quantitative investigation revealed that disease-specific patterns of ADI-R and ADOS scores can be uncovered when studying sex, age or level of FIQ in patients.
Genetic Diversity of thecagAgene ofHelicobacter pyloristrains from Sudanese Patients with Different Gastroduodenal Diseases
Authors: Hassan Hadeel Gassim , Idris Abeer Babiker , Hassan Mohamed A. , Altayb Hisham N. , Yasin Kyakonye , Beirage Nazar , Abdel Hamid Muzamil M.
Published: September 2019

Background

There is an increase in the prevalence ofHelicobacter pyloriinfection in Sudan, accompanied by a high incidence of upper gastrointestinal malignancy. The cytotoxin-associated genecagAgene is a marker of a pathogenicity island (PAI) inH. pyloriand plays a crucial role in determining the clinical outcome ofHelicobacterinfections.

Objective

This study aimed to determine the frequency and heterogeneity of thecagAgene ofH. pyloriand correlate the presence ofcagAgene with clinical outcomes.

Materials and methods

Fifty endoscopy biopsies were collected from Fedail and Soba hospitals in Khartoum state. DNA was extracted using the Guanidine chloride method followed by PCR to amplify16S rRNAandcagAgene ofH. pyloriusing specific primers. DNA amplicons ofcagAgene were purified and sequenced. Bioinformatics and statistical analysis were done to characterize and to test the association betweencagAgene and gastric complications.

Results

CagAgene was detected in 20/37(54%) of the samples that were found positive forH. pylori. There was no association between endoscopy finding and the presence of thecagAgene (p = 0.225). Specific amino acid variations were found at seven loci related to strains from a patient with duodenitis, gastric ulcer, and gastric atrophy (R448H, T457K, S460L, IT463-464VA, D470E, A482Q, KNV490-491-492TKT) while mutations in cancerous strain were A439P, T457P, and H500Y.

Conclusion

Disease-specific variations ofcagAofH. pyloristrains, in the region of amino acid residues 428-510, were evident among Sudanese patients with different gastroduodenal diseases. A novel mutation (K458N) was detected in a patient with duodenitis, which affects the positive electrostatic surface ofcagA. Phylogenetic analysis showed a high level of diversity ofcagAfrom SudaneseH. pyloristrains.
Tumor Necrosis Factor (TNF) Blocking Agents are Associated with Lower Risk for Alzheimer’s Disease in Patients with Rheumatoid Arthritis and Psoriasis
Authors: Zhou Mengshi , Xu Rong , Kaelber David C. , Gurney Mark E.
Published: September 2019

This large, retrospective case-control study of electronic health records from 56 million unique adult patients examined whether or not treatment with a Tumor Necrosis Factor (TNF) blocking agent is associated with lower risk for Alzheimer’s disease (AD) in patients with rheumatoid arthritis (RA), psoriasis, and other inflammatory diseases which are mediated in part by TNF and for which a TNF blocker is an approved treatment. The analysis compared the diagnosis of AD as an outcome measure in patients receiving at least one prescription for a TNF blocking agent (etanercept, adalimumab, and infliximab) or for methotrexate. Adjusted odds ratios (AORs) were estimated using the Cochran-Mantel-Haenszel (CMH) method and presented with 95% confidence intervals (CIs) and p-values. RA was associated with a higher risk for AD (Adjusted Odds Ratio (AOR) = 2.06, 95% Confidence Interval: (2.02-2.10), P-value <0.0001) as did psoriasis (AOR = 1.37 (1.31-1.42), P <0.0001), ankylosing spondylitis (AOR = 1.57 (1.39-1.77), P <0.0001), inflammatory bowel disease (AOR = 2.46 (2.33-2.59), P < 0.0001), ulcerative colitis (AOR = 1.82 (1.74-1.91), P <0.0001), and Crohn’s disease (AOR = 2.33 (2.22-2.43), P <0.0001). The risk for AD in patients with RA was lower among patients treated with etanercept (AOR = 0.34 (0.25-0.47), P <0.0001), adalimumab (AOR = 0.28 (0.19-0.39), P < 0.0001), or infliximab (AOR = 0.52 (0.39-0.69), P <0.0001). Methotrexate was also associated with a lower risk for AD (AOR = 0.64 (0.61-0.68), P <0.0001), while lower risk was found in patients with a prescription history for both a TNF blocker and methotrexate. Etanercept and adalimumab also were associated with lower risk for AD in patients with psoriasis: AOR = 0.47 (0.30-0.73 and 0.41 (0.20-0.76), respectively. There was no effect of gender or race, while younger patients showed greater benefit from a TNF blocker than did older patients. This study identifies a subset of patients in whom systemic inflammation contributes to risk for AD through a pathological mechanism involving TNF and who therefore may benefit from treatment with a TNF blocking agent.
Machine learning-based prediction of response to PARP inhibition across cancer types
Authors: Hill Katherine E. , Rattani Ahmed , Lietz Christopher E. , Garbutt Cassandra , Choy Edwin , Cote Gregory M. , Culhane Aedin , Kelly Andrew D. , Haibe-Kains Benjamin , Spentzos Dimitrios
Published: September 2019

PARP inhibitors (PARPi) are FDA approved for the treatment of BRCA1/2 deficient breast and ovarian cancer, but a growing body of pre-clinical evidence suggests the drug class holds therapeutic potential in other cancer types, independent of BRCA1/2 status. Large-scale pharmacogenomic datasets offer the opportunity to develop predictors of response to PARPi’s in many cancer types, expanding their potential clinical applicability. Response to the PARPi olaparib was used to identify a multi-gene PARPi response signature in a largein vitrodataset including multiple cancer types, such as breast, ovarian, pancreatic, lung cancer, osteosarcoma and Ewing sarcoma, using machine learning approaches. The signature was validated on multiple independentin vitrodatasets, also testing for response to another PARPi, rucaparib, as well as two clinical datasets using the cisplatin response as a surrogate for PARPi response. Finally, integrative pharmacogenomic analysis was performed to identify drugs which may be effective in PARPi resistant tumors. A PARPi response signature was defined as the 50 most differentially transcribed genes between PARPi resistant and sensitive cell lines from several different cancer types. Cross validated predictors generated with LASSO logistic regression using the PARPi signature genes accurately predicted PARPi response in a training set of olaparib treated cell lines (80-89%), an independent olaparib treatedin vitrodataset (66-77%), and an independent rucaparib treatedin vitrodataset (80-87%). The PARPi signature also significantly predictedin vitrobreast cancer response to olaparib in another separate experimental dataset. The signature also predicted clinical response to cisplatin and survival in human ovarian cancer and osteosarcoma datasets. Robust transcriptional differences between PARPi sensitive and resistant tumors accurately predict PARPi responsein vitroand cisplatin responsein vivofor multiple tumor types with or without known BRCA1/2 deficiency. These signatures may prove useful for predicting response in patients treated with PARP inhibitors.
Differential effects of opioid receptor modulators on motivational and stress-coping behaviors in the back-translational rat IFN-α depression model
Authors: Callaghan Charlotte K. , Rouine Jennifer , Islam Md Nurul , Eyerman David J. , Smith Karen L. , Blumberg Laura , Sanchez Connie , O’Mara Shane M.
Published: September 2019

Rationale

Many patients respond inadequately to antidepressant drug treatment; the search for alternate pharmacological treatment mechanisms is ongoing. Until the 1950’s, opium was sometimes used to treat depression, but eventually abandoned due to addiction risk. Recent insights into opioid biology have sparked a renewed interest in the potential antidepressant properties of opioids.

Objective

We studied how mu (MOR), kappa (KOR) and delta (DOR) opioid receptor ligands affect the dysregulation of motivated behavior (progressive ratio responding; PR), stress-coping behavior (forced swim test; FST) and hippocampal neurogenesis in rats, all induced by the back-translational interferon-alpha (IFN-α)-induced depression model.

Methods

Male Wistar rats (3-months old, 8/group) were treated with recombinant human IFN-α (170,000 IU/kg, 3 times/week) or saline. Ligands of the MOR, KOR and DOR receptors were administered as follows: a single subcutaneous dose, 30min before PR and 1h before FST, of the MOR agonist morphine (full agonist; 5mg/kg), the partial agonist RDC 2944 (0.1mg/kg) and the antagonist, cyprodime (10mg/kg); of the KOR agonist, U50 488 (5mg/kg), the antagonist, DIPPA (10mg/kg); and the DOR agonist, SNC 80 (20mg/kg) and antagonist naltrindole (10mg/kg). After 4 days of treatment with the mitotic BrdU marker, hippocampi were harvested and analysed for neurogenesis. Fluoxetine (10 mg/kg/day for 4 weeks, orally) served as control for assay sensitivity in the FST.

Results

The KOR antagonist, DIPPA, the DOR agonist SNC 80 and fluoxetine reversed the IFN-α-induced immobility increase in the FST. The MOR agonist, morphine, the KOR antagonist DIPPA, and the KOR agonist U50 488 reduced the IFN-α-induced increase in the breakpoint in the PR. The DOR agonist SNC 80 recovered the IFN-α-induced decrease in BrdU+ hippocampal cells.

Conclusion

Opioid receptors mediate different aspects of the IFN-α-induced dysregulation of motivational and stress-coping behaviors and hippocampal neurogenesis in a back-translational model of depression. KORs and DORs appear to play more prominent roles in torpor–inertia-type behaviors, whereas DORs appear more involved in the regulation of neurogenesis.
Convergent neural representations of acute nociceptive pain in healthy volunteers: A large-scale fMRI meta-analysis
Authors: Xu Anna , Larsen Bart , Baller Erica B. , Scott J. Cobb , Sharma Vaishnavi , Adebimpe Azeez , Basbaum Allan I. , Dworkin Robert H. , Edwards Robert R. , Woolf Clifford J. , Eickhoff Simon B. , Eickhoff Claudia R. , Satterthwaite Theodore D.
Published: September 2019

Characterizing a reliable, pain-related neural signature is critical for translational applications. Many prior fMRI studies have examined acute pain-related brain activation in healthy participants. However, synthesizing these data to identify convergent patterns of activation can be challenging due to the heterogeneity of experimental designs and samples. To address this challenge, we conducted a comprehensive meta-analysis of fMRI studies of stimulus-induced pain in healthy participants. Following pre-registration, two independent reviewers evaluated 4,927 abstracts returned from a search of 8 databases, with 222 fMRI experiments meeting inclusion criteria. We analyzed these experiments using Activation Likelihood Estimation with rigorous type I error control (voxel height p < 0.001, cluster p < 0.05 FWE-corrected) and found a convergent, largely bilateral pattern of pain-related activation in the secondary somatosensory cortex, insula, midcingulate cortex, and thalamus. Notably, these regions were consistently recruited regardless of stimulation technique, location of induction, and participant sex. These findings suggest a highly-conserved core set of pain-related brain areas, encouraging applications as a biomarker for novel therapeutics targeting acute pain.

HIGHLIGHTS

Pain stimulation recruits a core set of pain-related brain regions.

This core set includes thalamus, SII, insula and mid-cingulate cortex.

These regions were recruited regardless of stimulus modality and stimulus location.
An open source microfluidic sorter for Caenorhabditis nematodes
Authors: Timmermeyer Nadine , Banse Stephen A. , North Joseph H. , Sottile Matthew , Lockery Shawn R. , Phillips Patrick C.
Published: September 2019

Rapid and accurate sorting of biological samples is extremely useful in a wide variety of applications. The model nematode Caenorhabditis elegans lends itself to automated fluid-flow based sorting because of its ability to live in aqueous solutions. Here, we build upon previous developments to construct a microfluidic device capable of sorting individuals based on a variety of characteristics, with a specific application toward differentiating fluorescently marked individuals. We find that our new design generates highly repeatable pools of sorted individuals. In general, there tends to be a tradeoff between precision and speed that can be optimized based on several different factors. Importantly, sorting does not decrease offspring production, and individuals can be sorted multiple times for increased precision. We provide detailed parts lists, schematics and software to allow implementation of these methods in other laboratories. Our results demonstrate that custom-made sorter chips can be a flexible and versatile addition to the nematode experimental toolbox.
Zinc can counteract selection for ciprofloxacin resistance
Authors: Vos Michiel , Sibleyras Louise , Lo Lai Ka , Hesse Elze , Gaze William , Klümper Uli
Published: September 2019

Antimicrobial resistance (AMR) has emerged as one of the most pressing global threats to public health. AMR evolution occurs in the clinic but also in the environment, where low concentrations of antibiotics and heavy metals can respectively select and co-select for resistance. While the selective potential for AMR of both antibiotics and metals is increasingly well-characterized, studies exploring the combined effect of both types of selective agents are rare. It has previously been demonstrated that fluoroquinolone antibiotics such as ciprofloxacin can chelate metal ions. To investigate how ciprofloxacin resistance is affected by the presence of metals, we quantified selection dynamics between a ciprofloxacin-susceptible and an isogenic ciprofloxacin-resistantEscherichia coliMG1655 strain across a gradient of ciprofloxacin concentrations in the presence and absence of Zinc cations (Zn2+). The minimal selective concentration (MSC) for ciprofloxacin resistance significantly increased up to 5-fold in the presence of Zn2+. No such effect on the MSC was found for gentamicin, an antibiotic not known to chelate zinc cations. Environmental pollution usually consists of complex mixtures of antimicrobial agents. Our findings highlight the importance of taking antagonistic as well as additive or synergistic interactions between different chemical compounds into account when considering their effect on bacterial resistance evolution.

Graphical abstract

One sentence summary

The minimal selective concentration for a ciprofloxacin resistantE. colistrain increases up to 5-fold in the presence of Zinc cations.
An integrated approach unravels a crucial structural property for the function of the insect steroidogenic Halloween protein Noppera-bo
Authors: Koiwai Kotaro , Inaba Kazue , Morohashi Kana , Enya Sora , Arai Reina , Kojima Hirotatsu , Okabe Takayoshi , Fujikawa Yuuta , Inoue Hideshi , Yoshino Ryunosuke , Hirokawa Takatsugu , Kato Koichiro , Fukuzawa Kaori , Shimada-Niwa Yuko , Nakamura Akira , Yumoto Fumiaki , Senda Toshiya , Niwa Ryusuke
Published: September 2019

Ecdysteroids are the principal insect steroid hormones essential for insect development and physiology. In the last 18 years, several enzymes responsible for ecdysteroid biosynthesis, encoded by Halloween genes, have been identified and well characterized, both genetically and biochemically. However, none of these proteins have yet been characterized at the tertiary structure level. Here, we report an integratedin silico,in vitro, andin vivoanalyses of the Halloween glutathioneS-transferase (GST) protein, Noppera-bo (Nobo). We determine crystal structures ofDrosophila melanogasterNobo (DmNobo) complexed with glutathione and 17β-estradiol, a DmNobo inhibitor. 17β-estradiol almost fully occupied the putative ligand-binding pocket, and a prominent hydrogen bond formed between Asp113 of DmNobo and 17β-estradiol. Asp113 is essential for inhibiting DmNobo enzymatic activity by 17β-estradiol, as 17β-estradiol does not inhibit and physically interacts less with the Asp113Ala DmNobo point mutant. Asp113 is highly conserved among Nobo proteins, but not among other GSTs, implying that Asp113 is important for endogenous Nobo function. Indeed, a homozygousnoboallele possessing the Asp113Ala point mutation exhibits embryonic lethality with undifferentiated cuticle structure, a phenocopy of complete loss-of-functionnobohomozygotes. These results suggest that thenobofamily of GST proteins has acquired a unique amino acid residue, which seems to be essential for binding an endogenous sterol substrate to regulate ecdysteroid biosynthesis. This is the first study to reveal the structural characteristics of insect steroidogenic Halloween proteins. This study also provides basic insight into applied entomology for developing a new type of insecticides that specifically inhibit ecdysteroid biosynthesis.

Significance Statement

Insect molting and metamorphosis are drastic and dynamic biological processes and, therefore, have fascinated many scientists. Ecdysteroids represent one class of insect hormones that are indispensable for inducing molting and metamorphosis. It is well known that proteins responsible for catalyzing ecdysteroid biosynthesis reactions are encoded by “Halloween” genes, most of which have names of ghosts and phantoms. However, no studies have focused on the structural properties of these biosynthetic proteins. In this study, we addressed this unsolved issue and successfully unraveled a structural property that is crucial for the function of the fruit fly Halloween protein, Noppera-bo (a Japanese faceless ghost). This is the first study to reveal the structural characteristics of an insect steroidogenic Halloween protein.
Glutamatergic and GABAergic neuronal populations in the dorsolateral Periacqueductual Gray have different functional roles in fear conditioning
Authors: Montardy Quentin , Zhou Zheng , Liu Xuemei , Lei Zhuogui , Zeng Pengyu , Chen Chen , Liu Yuanming , Huang Kang , Wei Mengxia , Wang Liping
Published: September 2019

It is though that only a subset of brain structures can encode emotional states. This can be investigated though a set of properties, including the ability of neurons to respond to a conditioned stimulus (CS) preceding an aversive unconditioned stimulus (US). The dorsolateral periacqueductal gray (dPAG) is a midbrain structure though to have an essential role in coordinating defensive behaviors in response to aversive stimulation. But its ability of dPAG neurons to encode a CS following fear conditioning as not been sufficiently studied.

Here we used calcium imaging by fiber photometry to record the activity of dPAGVGluT2+ and dPAGGAD2+ neuronal populations during unconditioned and conditioned aversive stimulation. Then, following an unconditioned stimulation we performed a retrieval experiment to quantify memory-like responses of dPAG neurons. This shown that whilst both dPAGVGluT2+ and dPAGGAD2+ neuronal populations respond to direct US stimulation, and to CS stimulation during conditioning, only the dPAGVGluT2+ population persisted in responding to the CS stimulation during retrieval. Finally, to better understand dPAGVGluT2+ and dPAGGAD2+ connectivity patterns, we performed a cell specific monosynaptic retrograde rabies virus tracing experiment. This revealed that different patterns of fibers projects to dPAGVGluT2+ and dPAGGAD2+, further complementing our recording showing divergences between PAGVGluT2+ and dPAGGAD2+ populations.
Data-Driven Classification of Spectral Profiles Reveals Brain Region-Specific Plasticity
Authors: Lubinus Christina , Orpella Joan , Keitel Anne , Gudi-Mindermann Helene , Engel Andreas K. , Roeder Brigitte , Rimmele Johanna M.
Published: September 2019

Congenital blindness has been shown to result in behavioral adaptation and neuronal reorganization, but the underlying neuronal mechanisms are largely unknown. Brain rhythms are characteristic for anatomically defined brain regions and provide a putative mechanistic link to cognitive processes. In a novel approach, using magnetoencephalography resting state data of congenitally blind and sighted humans, deprivation-related changes in spectral profiles were mapped to the cortex using clustering and classification procedures. Altered spectral profiles in visual areas suggest changes in visual alpha-gamma band inhibitory-excitatory circuits. Remarkably, spectral profiles were also altered in auditory and right frontal areas showing increased power in theta-to-beta frequency bands in blind compared to sighted individuals, possibly related to adaptive auditory and higher-cognitive processing. Moreover, occipital alpha correlated with microstructural white matter properties extending bilaterally across posterior parts of the brain. We provide evidence that visual deprivation selectively modulates spectral profiles, possibly reflecting structural and functional adaptation.
Dynamic reconfiguration, fragmentation and integration of whole-brain modular structure across depths of unconsciousness
Authors: Standage Dominic , Areshenkoff Corson N. , Nashed Joseph Y. , Hutchison R. Matthew , Hutchison Melina , Heinke Dietmar , Menon Ravi S. , Everling Stefan , Gallivan Jason P.
Published: September 2019

General anesthetics are routinely used to induce unconsciousness, and much is known about their effects on receptor function and single neuron activity. Much less is known about how these local effects are manifest at the whole-brain level, nor how they influence network dynamics, especially past the point of induced unconsciousness. Using resting-state functional magnetic resonance imaging (fMRI) with nonhuman primates, we investigated the dose-dependent effects of anesthesia on whole-brain temporal modular structure, following loss of consciousness. We found that higher isoflurane dose was associated with an increase in both the number and isolation of whole-brain modules, as well as an increase in the uncoordinated movement of brain regions between those modules. Conversely, we found that higher dose was associated with a decrease in the cohesive movement of brain regions between modules, as well as a decrease in the proportion of modules in which brain regions participated. Moreover, higher dose was associated with a decrease in the overall integrity of networks derived from the temporal modules, with the exception of a single, sensory-motor network. Together, these findings suggest that anaesthesia-induced unconsciousness results from the hierarchical fragmentation of dynamic whole-brain network structure, leading to the discoordination of temporal interactions between cortical modules.
LRR-extensins of vegetative tissues are a functionally conserved family of RALF1 receptors interacting with the receptor kinase FERONIA
Authors: Herger Aline , Gupta Shibu , Kadler Gabor , Franck Christina Maria , Boisson-Dernier Aurélien , Ringli Christoph
Published: September 2019

Plant cell growth requires the coordinated expansion of the protoplast and the cell wall that confers mechanical stability to the cell. An elaborate system of cell wall integrity sensors monitors cell wall structures and conveys information on cell wall composition and growth factors to the cell. LRR-extensins (LRXs) are cell wall-attached extracellular regulators of cell wall formation and high-affinity binding sites for RALF (rapid alkalinization factor) peptide hormones that trigger diverse physiological processes related to cell growth. RALF peptides are also perceived by receptors at the plasma membrane and LRX4 ofArabidopsis thalianahas been shown to also interact with one of these receptors, FERONIA (FER). Here, we demonstrate that several LRXs, including the main LRX protein of root hairs, LRX1, interact with FER and RALF1 to coordinate growth processes. Membrane association of LRXs correlate with binding to FER, indicating that LRXs represent a physical link between intra- and extracellular compartments via interaction with membrane-localized proteins. Finally, despite evolutionary diversification of the LRR domains of various LRX proteins, many of them are functionally still overlapping, indicative of LRX proteins being central players in regulatory processes that are conserved in very different cell types.

Author Summary

Cell growth in plants requires the coordinated enlargement of the cell and the surrounding cell wall, which is ascertained by an elaborate system of cell wall integrity sensors, proteins involved in the exchange of information between the cell and the cell wall. InArabidopsis thaliana, LRR-extensins (LRXs) are localized in the cell wall and are binding RALF peptides, hormones that regulate cell growth-related processes. LRX4 also binds the plasma membrane-localized receptor kinase FERONIA (FER), establishing a link between the cell and the cell wall. It is not clear, however, whether the different LRXs of Arabidopsis have similar functions and how they interact with their binding partners. Here, we demonstrate that interaction with FER and RALFs requires the LRR domain of LRXs and several but not all LRXs can bind these proteins. This explains the observation that mutations in several of theLRXsinduce phenotypes comparable to afermutant, establishing that LRX-FER interaction is important for proper cell growth. Some LRXs, however, appear to influence cell growth processes in different ways, which remain to be identified.
Goal-directed action transiently depends on action space
Authors: Bradfield Laura A. , Leung Beatrice K. , Boldt Susan , Balleine Bernard W.
Published: September 2019

Rats use spatiotemporal features of the environment to navigate to a goal, but whether representations of ‘action space’ are necessary for non-navigational goal-directed actions is unknown. We addressed this question by assessing goal-directed action control across contexts and under hippocampal inactivation and found that such actions do indeed rely on a representation of action space but only immediately after initial acquisition.

One Sentence Summary

Goal-directed actions depend on a hippocampal representation of action space immediately after initial encoding but not after a delay.
Crystal structure of human PACRG in complex with MEIG1
Authors: Khan Nimra , Pelletier Dylan , Veyron Simon , Croteau Nathalie , Ichikawa Muneyoshi , Black Corbin , Khalifa Ahmad Abdelzaher Zaki , Chaaban Sami , Kurinov Igor , Brouhard Gary , Bui Khanh Huy , Trempe Jean-François
Published: September 2019

In human, the Parkin Co-Regulated Gene (PACRG) shares a bidirectional promoter with Parkin, a gene involved in Parkinson’s disease, mitochondrial quality control and inflammation. The PACRG protein is essential to the formation of the inner junction between doublet microtubules of the axoneme, a structure found in flagella and cilia. PACRG interacts with tubulin as well as the meiosis expressed gene 1 (MEIG1) protein, which is essential for spermiogenesis in mice. However, the 3D structure of human PACRG is unknown. Here, we report the crystal structure of the C-terminal domain of human PACRG in complex with MEIG1 at 2.1 Å resolution. PACRG adopts an α-helical structure with a loop insertion that mediates a conserved network of interactions with MEIG1. Using the cryo-electron tomography structure of the axonemal doublet microtubule from the flagellated protozoan Chlamydomonas reinhardtii, we generate a model of a mammalian microtubule doublet inner junction, which reveals how PACRG interacts with tubulin subunits in both the A- and B-tubules. Furthermore, the model shows that MEIG1 interacts with β-tubulin on the outer surface of the B-tubule, facing towards the central pair of the axoneme. We also model the PACRG-like protein (PACRGL), a homolog of PACRG with potential roles in microtubule remodelling and axonemal inner junction formation. Finally, we explore the evolution of the PACRG and Parkin head-to-head gene structure and analyze the tissue distribution of their transcripts. Our work establishes a framework to assess the function of the PACRG family of proteins and its adaptor proteins in the function of motile and non-motile cilia.
How to define and optimize axial resolution in light-sheet microscopy: a simulation-based approach
Authors: Remacha Elena , Friedrich Lars , Vermot Julien , Fahrbach Florian O.
Published: September 2019

“How thick is your light sheet?” is a question that has been asked frequently after talks showing impressive renderings of 3D data acquired by a light-sheet microscope. This question is motivated by the fact that most of the time the thickness of the light-sheet is uniquely associated to the axial resolution of the microscope. However, the link between light-sheet thickness and axial resolution has never been systematically assessed and it is still unclear how both are connected. The question is not trivial because commonly employed measures cannot readily be applied or do not lead to easily interpretable results for the many different types of light sheet. Here, by using simulation data we introduce a set of intuitive measures that helps to define the relationship between light sheet thickness and axial resolution. Unexpectedly, our analysis revealed a trade-off between better axial resolution and thinner light-sheet thickness. Our results are surprising because thicker light-sheets that provide lower image contrast have previously not been associated with better axial resolution. We conclude that classical Gaussian illumination beams should be used when image contrast is most important, and more advanced types of illumination represent a way to optimize axial resolution at the expense of image contrast.
Pre-stress of actin cortices is important for the viscoelastic response of living cells
Authors: Cordes Andrea , Witt Hannes , Gallemí-Pérez Aina , Brückner Bastian , Grimm Florian , Vache Marian , Oswald Tabea , Flormann Daniel , Lautenschläger Franziska , Tarantola Marco , Janshoff Andreas
Published: September 2019

Shape, dynamics, and viscoelastic properties of eukaryotic cells are primarily governed by a thin, reversibly cross-linked actomyosin cortex located directly beneath the plasma membrane. We obtain time-dependent rheological responses of fibroblasts and MDCK II cells from deformation-relaxation curves using an atomic force microscope to access the dependence of cortex fluidity on pre-stress. We introduce a viscoelastic model that treats the cell as a composite shell and assumes that relaxation of the cortex follows a power law giving access to cortical pre-stress, area compressibility modulus, and the power law (fluidity) exponent. Cortex fluidity is modulated by interfering with myosin activity. We find that the power law exponent of the cell cortex decreases with increasing intrinsic pre-stress and area compressibility modulus, in accordance with previous finding for isolated actin networks subject to external stress. Extrapolation to zero tension returns the theoretically predicted power law exponent for transiently cross-linked polymer networks. In contrast to the widely used Hertzian mechanics, our model provides viscoelastic parameters independent of indenter geometry and compression velocity.