bluuebunny/crossref_metadata_2025 huggingface dataset:
Dose Escalation of Naltrexone to Reduce Stress Responses Associated With Opioid Antagonist Induction: A Double-blind Randomized Trial
Authors: Badaras Robertas , Jovaisa Tomas , Lapinskiene Indre , Ivaskevicius Juozas
Published: October 2019

Context:

To describe the role of opioid antagonist induction in reducing stress response and withdrawal symptoms.

Objective:

Complexity of naltrexone induction is limiting broader applicability of opioid antagonist-assisted abstinence. The aim of this clinical trial was to assess the stress response to 2 low-dose naltrexone induction protocols under minimal oral sedation.

Design:

Double-blind randomized controlled trial.

Setting:

Open setting in-patient unit.

Participants:

Adults with opioid use disorder, and at least a year-long history of opioid use.

Intervention protocol:

Patients received either a single 12.5 mg naltrexone oral dose (SI group) or escalating dosage regimen starting from 50 μg up to a cumulative dose of 12.5 mg (ED group).

Main outcome measure:

Differences in cortisol and adrenocorticotropic hormone (ACTH) concentrations 1 hour after the start of naltrexone induction.

Results:

In all, 124 patients were enrolled and 68 remained in the trial at the point of randomization—33 in SI and 35 in ED group. Eight patients were excluded from final analysis. Plasma cortisol and ACTH concentrations were significantly higher in SI group; mean difference between groups 313 nmol/L (95% confidence interval [CI] 182–444,P < 0.001) and 36.9 pg/mL (95% CI 12.3–61.4,P = 0.004), respectively. Secondary outcomes: SI patients experienced significant increases in plasma cortisol and ACTH concentrations, and withdrawal scores. In ED group these measures remained at or below baseline throughout the 24-hour period from start of naltrexone induction.

Conclusions:

Contrary to a single 12.5-mg dose, the escalating naltrexone dosing regimen produced no significant increase in stress response and withdrawal scores during antagonist induction.
Management of Behçet syndrome
Authors: Yazici Yusuf
Published: October 2019

Purpose of review

New treatment options have been studied over the last several years, with a recent approval, a first for Behçet syndrome, in the United States. New management guidelines have also been published, helping with this nowadays more commonly recognized condition's management. The goal of this review is to summarize the most important and potentially clinically relevant recent developments and discuss their impact in the management of patients with Behçet syndrome.

Recent findings

Apremilast is now approved for the treatment of oral ulcer of Behçet syndrome in the United States. It's possible benefits in controlling nonoral ulcer features of the syndrome are awaited. Long-term use of tumor necrosis factor inhibitors for the treatment of especially eye disease in Behçet syndrome seems to be safe and efficacious. New treatment options such as ustekinumab, secukinumab, tocilizumab and others have early promising data but more studies are needed to better clarify their role in Behçet management.

The last 2 years have not only seen the approval of the first drug specifically labeled for the treatment of Behçet syndrome in the case of apremilast, many groups have also presented and published their findings on promising new therapeutic agents, which may soon be added to our tools in treating this condition. We also know more about other drugs, such as tumor necrosis factor inhibitors as many patients have been on these for long periods of time, and long-term follow-up data seem to confirm their role in Behçet treatment. Lack of placebo controlled, randomized trials, for the most part, are still outstanding issues.
The let-7c/HoxB7 axis regulates the cell proliferation, migration and apoptosis in hepatocellular carcinoma
Authors: Cai Lijun , Wang Zhangliu , Zheng Huajun , Xu Lei
Published: October 2019

Ectopic expression of HOX-containing genes is closely related to carcinogenesis, acting as either tumor suppressors or oncogenes. A preliminary bioinformatics analysis showed that HoxB7 is a possible target of let-7c. In this study, we aimed to investigate the relationship between HoxB7 and let-7c in liver carcinogenesis. We found that HoxB7 was upregulated in hepatocellular carcinoma (HCC) tissues and cells and negatively correlated with survival time, whereas let-7c was downregulated and positively correlated with survival time in patients with HCC. Let-7c overexpression suppressed proliferation, migration but promoted cell apoptosis in HCC cells. We validated that HoxB7 is a target of let-7c. Consistently, let-7c overexpression reversed the promotional effects of HoxB7 on proliferation and migration in HCC cells, and increased the cell apoptotic rate reduced by HoxB7. Furthermore, let-7c overexpression reversed the promotional effect of HoxB7 on tumor growth in subcutaneous HCC tumor model. Our data suggest that the let-7c/HoxB7 axis regulates HCC development, which may provide a novel therapeutic strategy for the treatment of HCC.
Pilot Randomized Trial of a Recovery Navigator Program for Survivors of Critical Illness With Problematic Alcohol Use
Authors: Clark Brendan J. , Sorrell Tanya , Hodapp Rachel M. , Reed Kathryne , Moss Marc , Aagaard Laurra , Cook Paul F.
Published: October 2019

Objective:

Many survivors of critical illness have problematic alcohol use, associated with risk of death and hospital readmission. We tested the feasibility, acceptability, treatment fidelity, and potential efficacy of a customized alcohol intervention for patients in ICUs. The intervention was delivered by a Recovery Navigator using principles of motivational interviewing and shared decision-making.

Design:

Pilot randomized trial.

Setting:

Two urban ICUs in Denver, CO.

Patients:

Patients with problematic alcohol use were enrolled prior to hospital discharge.

Interventions:

Patients were randomly assigned to usual care, single-session motivational interviewing and shared decision-making, or multisession motivational interviewing and shared decision-making.

Measurements and Main Results:

We assessed feasibility via enrollment and attrition, acceptability via patient satisfaction (Client Satisfaction Questionnaire-8), fidelity via observation and questionnaires, and potential efficacy via group means and CIs on measures of alcohol use, psychiatric symptoms, cognition, and other alcohol-related problems. Over 18 months, we offered the study to 111 patients, enrolled 47, and randomized 36; refusals were mainly due to stigma or patients' desire to handle problems on their own. Groups were similar at baseline, and 67% of patients met criteria for alcohol use disorder. Average patient satisfaction was high (mean = 28/32) regardless of group assignment. Sessions were delivered with 98% adherence to motivational interviewing principles and excellent motivational interviewing spirit; patients perceived the intervention to be more autonomy supportive than usual care. Group means after 6 months suggested that patients receiving the intervention might improve on measures such as alcohol use, psychiatric symptoms, legal problems, and days of paid work; however, they did not receive more substance use treatment. All results were nonsignificant due to small sample size.

Conclusions:

A Recovery Navigator intervention was feasible and acceptable for delivering high-fidelity brief interventions to ICU patients. Changes in alcohol-related problems with motivational interviewing and shared decision-making were nonsignificant but clinically meaningful in size. A full-scale randomized trial of motivational interviewing and shared decision-making is warranted.
Circular RNA Pleiotrophin promotes carcinogenesis in glioma via regulation of microRNA-122/SRY-box transcription factor 6 axis
Authors: Chen Chen , Deng Lu , Nie De-Kang , Jia Feng , Fu Lin-Shan , Wan Zheng-Qiang , Lan Qing
Published: October 2019

Background:

Circular RNAs (circRNAs) are recently identified as gene regulators in mammals and play important roles in carcinogenesis of cancer. For example, circRNA_PTN has been recognized as a biomarker of human cancer and is overexpressed in glioma. The molecular function of circRNA_PTN and its downstream targets in glioma, however, remains elusive.

Methods:

Quantitative polymerase chain reaction analysis was used to measure the expression of circular RNA pleiotrophin (circ_PTN) and miR-122. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, propidium iodide and Annexin-V/propidium iodide assay were performed to determine cell proliferation and apoptosis of glioma cells. Circular RNA Interactome and TargetScan were used to predict the potential microRNA targeting of circ_PTN and the potential targets of miR-122, respectively. Luciferase activity assay was used to validate these interactions. Downstream molecular mechanisms, including SRY-box transcription factor 6 (SOX6), extracellular regulated protein kinases (ERK), Cyclin D1, B-cell lymphoma-2 (BCL-2) and BCL2 associated X, apoptosis regulator (BAX), were determined by western blot.

Results:

Circ_PTN was overexpressed in glioma cells, and its knockdown induced cell proliferation inhibition, cell cycle arrest and apoptosis in glioma cells. The target microRNA of circ_PTN was predicted to be miR-122, the expression of which was negatively correlated with circ_PTN in glioma cells. Moreover, SOX6 was predicted as a potential target of miR-122, and miR-122 overexpression decreased SOX6 expression. MiR-122 inhibitor reversed the tumor-suppressing effects of circ_PTN knockdown, while overexpression of SOX6 impaired the miR-122 overexpression-induced cell growth inhibition and apoptosis. In addition, mitogen activated kinase-like protein (MAPK)/ERK pathway was involved in circ_PTN/miR-122/SOX6 axis.

Conclusions:

Circ_PTN acted as a sponge of miR-122 and upregulated miR-122 target SOX6, thus promoting carcinogenesis of glioma cells.
Navigating Barriers to Patient Access and Reimbursement in Mohs Micrographic Surgery
Authors: Krausz Aimee E. , Manning Jamie R. , Vinelli Gian L. , Ciocon David H.
Published: October 2019

BACKGROUND

Insurance companies have implemented new policies including excessive prior authorization (PA) requirements, high-deductible plans, and complicated billing structures in an effort to curb rising health care costs. Studies investigating the real-time impact on providers and patients are emerging, but few within the field of dermatology have been published.

OBJECTIVE

To assess the impact of cost-cutting policies on patients and physicians.

METHODS

A survey was electronically distributed to members of the American College of Mohs Surgery (ACMS).

RESULTS

The majority of respondents (78.2%) practiced in a private setting, with no other demographic differences. The majority of respondents (70%) dedicated 1 to 2 employees to obtaining PAs. Fifty percent reported an average time of 30 minutes spent per PA. Fifty-six percent of respondents obtained PA from private insurance before Mohs surgery, whereas only 24.5% obtained PA from Medicare. Forty-nine percent of practitioners provided patients with a financial disclosure prior to Mohs surgery. Moreover, many practitioners reported screening patients for high-deductible policies and request an advanced deposit against the deductible. Sixty percent reported difficulty obtaining payment for service in the absence of an advanced deposit.

CONCLUSION

The burden of restrictive health care policies will have long-term consequences for the patient–provider interaction and patient outcomes.
Pelvic floor physical therapy in the treatment of pelvic floor dysfunction in women
Authors: Wallace Shannon L. , Miller Lucia D. , Mishra Kavita
Published: October 2019

Purpose of review

To describe the principles of pelvic floor physical therapy (PFPT), review the evidence for PFPT as a treatment for pelvic floor dysfunction, and summarize the current recommendations for PFPT as a first-line conservative treatment option for pelvic floor disorders.

Recent findings

Pelvic floor dysfunction can cause voiding and defecation problems, pelvic organ prolapse (POP), sexual dysfunction, and pelvic pain. PFPT is a program of functional retraining to improve pelvic floor muscle strength, endurance, power, and relaxation in patients with pelvic floor dysfunction. Based on the available evidence, PFPT with or without supplemental modalities can improve or cure symptoms of urinary incontinence, POP, fecal incontinence, peripartum and postpartum pelvic floor dysfunction, and hypertonic pelvic floor disorders, including pelvic floor myofascial pain, dyspareunia, vaginismus, and vulvodynia. Currently, there is conflicting evidence regarding the effectiveness of perioperative PFPT before or after POP and urinary incontinence surgery.

PFPT has robust evidence-based support and clear benefit as a first-line treatment for most pelvic floor disorders. Standards of PFPT treatment protocols, however, vary widely and larger well designed trials are recommended to show long-term effectiveness.
Innovation in Medical Devices—Lessons from the Past, Planning for the Future: Hastings Lecture 2019
Authors: Holman William L.
Published: October 2019

The development of devices for cardiac and pulmonary support is an example of innovation that opened important therapeutic options for patients with life-limiting diseases. The history of this important advance provides guidance for future developments in the field. Integrity is fundamental to maintaining the trust necessary for success.
Tirofiban in Suspected Left Ventricular Assist Device Pump Thrombosis
Authors: Nei Scott D. , Wieruszewski Patrick M. , Orzel Libby A. , Ritchie Brianne M. , Stulak John M.
Published: October 2019

Antithrombotic optimization with a glycoprotein IIb/IIIa inhibitor has been used for the treatment of suspected pump thrombosis, but available literature with tirofiban is lacking. This study aims to describe the use of tirofiban for suspected pump thrombosis. This was a single-center cohort study of left ventricular assist device patients who received tirofiban for the treatment of suspected pump thrombosis from January 1, 2016 to July 31, 2017. Tirofiban was initiated at 0.1 μg/kg/min in patients with normal renal function and subsequent dose adjustments for altered renal function or history of bleeding were employed. Success was defined as resolution of lactate dehydrogenase back to patients’ known baseline. Fourteen patients were included for 16 total instances of tirofiban use during the time period. Tirofiban was continued for a median of 5 days (range: 0.3–35 days). Successful treatment was achieved in 12 of the 16 tirofiban uses (75%). Seven bleeding events occurred while on therapy, two major and five minor. This study showed a majority of patients achieved success with tirofiban for suspected pump thrombosis. For patients who are not current candidates for pump exchange or transplant, tirofiban may be considered a therapeutic medical management option.
Phenotypic variability in Muenke syndrome—observations from five Danish families
Authors: Öwall Louise , Kreiborg Sven , Dunø Morten , Hermann Nuno V. , Darvann Tron A. , Hove Hanne
Published: October 2019

Muenke syndrome is a craniosynostosis syndrome associated with the p.Pro250Arg mutation in FGFR3. An increasing number of individuals with this mutation are reported to not have craniosynostosis. The purpose of this report is to increase awareness of the high phenotypic variability seen in Muenke syndrome. DNA testing for the p.Pro250Arg mutation is routinely performed in Denmark, in children presenting with isolated coronal synostosis. Verified diagnosis entails detailed family history, drawing of family pedigree, DNA testing of the parents, genetic counseling, skull radiographs, clinical photographs, and follow-up. Sixteen individuals from 5 Danish families with Muenke syndrome are presented. Large phenotypic variation was seen both within and across families. The most striking observations were that 6/16 (38%) cases did not have craniosynostosis and one individual presented with a normal phenotype. In addition, 3 unrelated cases had incomplete cleft palate, submucous cleft palate, and bifid uvula, respectively. There is strong evidence for reduced penetrance of the craniosynostosis trait in Muenke syndrome. We argue that many studies on Muenke syndrome have been influenced by ascertainment bias in regard to craniosynostosis. In addition, it is suggested that oral clefting might be part of the clinical spectrum seen in Muenke syndrome.
Prevalence of pulmonary embolism in emergency department patients with isolated syncope: a prospective cohort study
Authors: Raynal Pierre-Alexis , Cachanado Marine , Truchot Jennifer , Damas-Perrichet Clara , Feral-Pierssens Anne-Laure , Goulet Hélène , Deltour Sandrine , Boussouar Samia , Donciu Victoria , Simon Tabassome , Freund Yonathan , Philippon Anne-Laure
Published: October 2019

Backgrounds

Paramount to guide the diagnostic strategy, the prevalence of pulmonary embolism in patients with syncope and no other symptoms is uncertain. We aimed to assess the pulmonary embolism prevalence in patients that present to the emergency department (ED) with syncope and no chest pain nor dyspnea.

Methods

Multicenter prospective cohort study in seven EDs in France. Adult patients who presented to the ED with syncope (transient loss of consciousness) were included. Patients with chest pain or dyspnea were excluded. Included patients underwent formal work-up for pulmonary embolism, including D-dimer testing and further imaging if positive. Cases of pulmonary embolism were adjudicated by two independent expert radiologists with the review of imaging studies. Secondary objectives included the pulmonary embolism prevalence in the subgroup of patients with cancer, in patients with negative Pulmonary Embolism Rule Out criteria (PERC) score, and according to the clinical probability assessed either by Wells or revised Geneva score.

Results

We analyzed 411 patients, in whom 128 (31%) underwent a computed tomographic pulmonary angiogram and 9 (2%) a ventilation-perfusion scan. A pulmonary embolism was confirmed in nine patients (prevalence of 2.2%, 95% confidence interval, 1.1–4.3%), including one subsegmental pulmonary embolism. This prevalence was of 18% (3–52%) in patients with cancer and 0.7% (0.1–4%) in PERC negative patients.

Conclusion

In our sample of patients with isolated syncope, the prevalence of pulmonary embolism was 2.2%. This value is not sufficiently low to negate the requirement for a formal work up in the ED, even in the absence of chest pain or dyspnea. However, the large confidence interval precludes any strong conclusion.
Insula Activity to Visceral Stimulation and Endocrine Stress Responses as Associated With Alexithymia in Patients With Irritable Bowel Syndrome
Authors: Kano Michiko , Muratsubaki Tomohiko , Yagihashi Mao , Morishita Joe , Mugikura Shunji , Dupont Patrick , Takase Kei , Kanazawa Motoyori , Van Oudenhove Lukas , Fukudo Shin
Published: October 2019

Objective

Few studies have investigated associations between alexithymia and physiological mechanisms in psychosomatic diseases. We examined associations between alexithymia and 1) perception and brain processing of visceral stimulation and 2) the endocrine responses to corticotrophin-releasing hormone (CRH) in healthy individuals and patients with irritable bowel syndrome (IBS).

Methods

The study included 29 patients with IBS and 35 age- and sex-matched healthy controls (HCs). Alexithymia was measured using the 20-item Toronto Alexithymia Scale (TAS-20). Brain responses to rectal distention and its anticipation were measured by functional magnetic resonance imaging and analyzed at a voxel-level threshold of p
uncorrected < .001 combined with a cluster-level threshold of p
FWE-corrected < .05. On a different day, plasma adrenocorticotropic hormone and cortisol responses after intravenous CRH administration were measured.

Results

TAS-20 scores did not differ significantly between patients with IBS and HCs (p = .18). TAS-20 scores correlated positively with the individual rectal discomfort thresholds (βrobust = 0.49, p = .03) and negatively with the rating of fear before rectal distention (βrobust = −1.63, p = .04) in patients with IBS but not in HCs. Brain responses to rectal distention in the right insula and other brain regions were positively associated with TAS-20 scores to a greater extent in patients with IBS than in HCs. Individuals with higher TAS-20 scores (both patients with IBS and HCs) demonstrated stronger adrenocorticotropic hormone responses to CRH administration (F(4,224) = 3.54, p = .008).

Conclusion

Higher alexithymia scores are associated with stronger physiological responses, but lower anticipatory fear ratings and higher discomfort thresholds, particularly in patients with IBS.
Surgical Treatment of Oral Cavity Nodular Fasciitis
Authors: Zhurakivska Khrystyna , Troiano Giuseppe , Montella Marco , Ronchi Andrea , Di Stasio Dario , Cicciù Marco , Laino Luigi
Published: October 2019

Background:

Nodular fascitiis is a myofibroblastic neoplasm of the soft tissue that rarely affects oral cavity. With a broad pattern of presentation, sometimes Nodular Fascitiis can have a rapid growth and appear highly cellular with local aggressiveness on biopsies, thus simulating a sarcoma. The aim of this paper is to present a case of troublesome diagnosis of nodular fascitiis mimicking a Malignant Fibrous Histiocytoma, with the purpose of alert clinicians and pathologists on the difficulties that can be met in the differential diagnosis between these 2 lesions. A 42-year-old male presented an exophytic lesion on the cheek. After the excisional biopsy, histological and immunohistochemical evaluations revealed a picture of doubtful significance. With a careful analysis, the diagnosis of nodular fasciitis was made and the patient was not further treated. At a 3-year follow-up, no recurrence was found. Differential diagnosis within myofibroblastic neoplasm can be a real challenge for both Clinicians and Pathologist. A coordinated team-work is mandatory to avoid clinical malpractice and unnecessarily aggressive treatment.
Maxillary Distraction Osteogenesis in a Patient With Osteogenesis Imperfecta
Authors: Kunkel Ryan , Kim Erinn , Tuncer Fatma Betul , Siddiqi Faizi , Gociman Barbu
Published: October 2019

Osteogenesis imperfecta (OI) is characterized by brittle bones, premature hearing loss, blue sclera, dental abnormalities, and short stature. Maxillofacial pathology is marked in many OI patients and includes a high incidence of class III malocclusion secondary to a retrusive maxilla relative to both the mandible and cranial base.

Review of literature shows that most of the orthognathic surgeries performed in the setting of OI are double jaw surgeries, in the form of maxillary advancement and mandibular setback. However, severe maxillary hypoplasia is usually not correctable with single-stage maxillary advancement. Distraction osteogenesis (DO) is a technique that relies on the normal healing process that occurs between controlled, surgically osteotomized bone segments and it is a relatively widely used technique in modern management of craniofacial conditions.

Distraction osteogenesis has been reported in only several patients with OI. There is only 1 previously documented case of maxillary distraction in the craniofacial literature. The authors present here the successful management of a patient with OI and severe class III malocclusion using LeFort I osteotomy and DO with an external rigid distractor.

At 12 months follow-up, the patient had no complications and maintained stable maxillary position with normal occlusion, improvement of facial appearance, obstructive airway symptoms, speech, and chewing.

This case serves to reinforce the safety and efficacy of DO in patients with OI. The authors did not significantly change our distraction protocol and did not have any complications, therefore the authors believe that DO should be the preferable treatment technique for severe malocclusion in OI patient population.
MetAP2 inhibition reduces food intake and body weight in a ciliopathy mouse model of obesity
Authors: Pottorf Tana S. , Fagan Micaella , Burkey Bryan , Cho David J. , Vath James E. , Tran Pamela V.
Published: October 2019

The ciliopathies Bardet-Biedl Syndrome and Alström Syndrome are genetically inherited pleiotropic disorders with primary clinical features of hyperphagia and obesity. Methionine aminopeptidase 2 inhibitors (MetAP2i) have been shown in preclinical and clinical studies to reduce food intake, body weight, and adiposity. Here we investigated the effects of MetAP2i administration in a mouse model of ciliopathy produced by conditional deletion of the Thm1 gene in adulthood (Thm1 cko). Thm1 cko mice show decreased hypothalamic pro-opiomelanocortin expression as well as hyperphagia, obesity, metabolic disease and hepatic steatosis. In obese Thm1 cko mice, two-week administration of MetAP2i reduced daily food intake and reduced body weight 17.1% from baseline (vs. 5% reduction for vehicle). This was accompanied with decreased levels of blood glucose, insulin and leptin. Further, MetAP2i reduced gonadal adipose depots and adipocyte size and improved liver morphology. This is the first report of MetAP2i reducing hyperphagia and body weight, and ameliorating metabolic indices in a mouse model of ciliopathy. These results support further investigation of MetAP2 inhibition as a potential therapeutic strategy for ciliary-mediated forms of obesity.
A mechanistic path to maximize biomass productivity while maintaining diversity
Authors: Godoy Oscar , Gómez-Aparicio Lorena , Matías Luis , Pérez-Ramos Ignacio M. , Allan Eric
Published: October 2019

With ongoing biodiversity loss, it is important to understand how the mechanisms that promote coexistence relate to those that increase functioning in diverse communities. Both coexistence and biodiversity functioning research have unified their mechanisms into two classes. However, despite seeming similarities, theory suggests that coexistence and biodiversity mechanisms do not necessarily map onto each other, yet direct empirical evidence for this prediction is lacking. We coupled field-parameterized models of competition between 10 plants with a biodiversity-functioning experiment measuring biomass production, litter decomposition, and soil nutrient content under contrasting environmental conditions. We related biodiversity mechanisms (complementarity and selection effects), to coexistence mechanisms (niche and fitness differences). As predicted by theory, complementarity effects were positively correlated with niche differences and differences in selection effects were correlated with fitness differences. However, we also found that niche differences contributed to selection effects and fitness differences to complementarity effects. Despite this complexity more stably coexisting communities (i.e. those in which niche differences offset fitness differences) produced more biomass, particularly under drought. This relationship was weaker for litter decomposition rates and soil nutrient acquisition, showing that the mechanisms promoting plant coexistence may differ from those promoting high levels of functions that are less directly related to plant performance. We provide the first empirical evidence that the mechanisms promoting stable coexistence correlate with those driving high biomass production. These findings establish a link between stable coexistence and functioning, which could allow better predictions of how diversity loss induced by global change translates to changes in ecosystem function.
Demographic performance of European tree species at their hot and cold climatic edges
Authors: Kunstler Georges , Guyennon Arnaud , Ratcliffe Sophia , Rüger Nadja , Ruiz-Benito Paloma , Childs Dylan Z. , Dahlgren Jonas , Lehtonen Aleksi , Thuiller Wilfried , Wirth Christian , Zavala Miguel A. , Salguero-Gomez Roberto
Published: October 2019

Species range limits are thought to result from a decline in demographic performance at range edges. However, recent studies reporting contradictory patterns in species demographic performance at their edges cast doubt on our ability to predict climate change demographic impacts. To understand these inconsistent demographic responses at the edges, we need to shift the focus from geographic to climatic edges and analyse how species responses vary with climatic constraints at the edge and species’ ecological strategy.

Here we parameterised integral projection models with climate and competition effects for 27 tree species using forest inventory data from over 90,000 plots across Europe. Our models estimate size-dependent climatic responses and evaluate their effects on two life trajectory metrics: lifespan and passage time – the time to grow to a large size. Then we predicted growth, survival, lifespan, and passage time at the hot and dry or cold and wet edges and compared them to their values at the species climatic centre to derive indices of demographic response at the edge. Using these indices, we investigated whether differences in species demographic response between hot and cold edges could be explained by their position along the climate gradient and functional traits related to their climate stress tolerance.

We found that at cold and wet edges of European tree species, growth and passage time were constrained, whereas at their hot and dry edges, survival and lifespan were constrained. Demographic constraints at the edge were stronger for species occurring in extreme conditions, i.e. in hot edges of hot-distributed species and cold edges of cold-distributed species. Species leaf nitrogen content was strongly linked to their demographic responses at the edge. In contrast, we found only weak links with wood density, leaf size, and xylem vulnerability to embolism.

Synthesis. Our study presents a more complicated picture than previously thought with demographic responses that differ between hot and cold edges. Predictions of climate change impacts should be refined to include edge and species characteristics.
A fully automated deep learning pipeline for high-throughput colony segmentation and classification
Authors: Carl Sarah H. , Duempelmann Lea , Shimada Yukiko , Bühler Marc
Published: October 2019

Background

Adenine auxotrophy is a commonly used non-selective genetic marker in yeast research. It allows investigators to easily visualize and quantify various genetic and epigenetic events by simply reading out colony color. However, manual counting of large numbers of colonies is extremely time-consuming, difficult to reproduce and possibly inaccurate.

Results

Using cutting-edge neural networks, we have developed a fully automated pipeline for colony segmentation and classification, which speeds up white/red colony quantification 100-fold over manual counting by an experienced researcher.

Conclusions

Our approach uses readily available training data and can be smoothly integrated into existing protocols, vastly speeding up screening assays and increasing the statistical power of experiments that employ adenine auxotrophy.
Root trait responses to drought depend on plant functional group
Authors: Lozano Y.M. , Aguilar-Trigueros C.A. , Flaig I.C. , Rillig M.C.
Published: October 2019

Drought can strongly modify plant diversity and ecosystem processes. As droughts are expected to intensify in the future, it is important to better understand plant responses to drought. We expect that roots traits constitute an overlooked but powerful predictor of plant responses as roots are in direct contact with the soil environment, taking up nutrients and water.

Here, we determine which root traits are sensitive to drought, the magnitude of that response, whether their predictive power and relationships with shoot biomass are affected by drought and whether all these responses depend on plant functional group. To do so, we conducted a glasshouse experiment with 24 plant species grown in pots (10 replicates per species), which represent three different functional groups: grasses, herbs and legumes. All replicates were well watered during the first month and then half of the replicates were kept under drought (30 % water holding capacity (WHC)) with the other half serving as control (kept at 70% WHC). After two months of the treatment, leaf and root traits were measured.

Leaf traits had a strong but more uniform response to drought compared to root traits. Root trait response was variable and differed by plant functional group. Most grasses had increased root diameter, specific root surface area (SRSA) while decreased root tissue density (RTD) with drought. Production of thicker roots with a low tissue density could allow grasses to achieve greater nutrient and water acquisition through mycotrophy and would be linked to an increase in the reserve of non-structural carbohydrates needed for osmoregulation. Herbs had decreased SRSA and specific root length (SRL) while increase root carbon allocation. Reduction of root elongation or sacrifice of fine roots would be compensated by an increase in root carbon allocation, which allow herbs to improve water uptake. Legumes did not alter root morphological traits but promote an early flowering in order to scape drought.

Our results identify changes in root morphological traits as mechanisms to likely face drought, a response that is species-specific and differed among functional groups.
Bacteria primed by antimicrobial peptides develop tolerance and persist
Authors: Rodríguez-Rojas Alexandro , Baeder Desiree Y. , Johnston Paul , Regoes Roland R. , Rolff Jens
Published: October 2019

Antimicrobial peptides (AMPs) are key components of innate immune defenses. Because of the antibiotic crisis, AMPs have also come into focus as new drugs. Here, we explore whether prior exposure to sublethal doses of AMPs increases bacterial survival and abets the evolution of resistance. We show thatEscherichia coliprimed by sublethal doses of AMPs develop tolerance and increase persistence by producing curli or colanic acid. We develop a population dynamic model that predicts that priming delays the clearance of infections and fuels the evolution of resistance. The effects we describe should apply to many AMPs and other drugs that target the cell surface. The optimal strategy to tackle tolerant or persistent cells requires high concentrations of AMPs and fast and long-lasting expression. Our findings also offer a new understanding of non-inherited drug resistance as an adaptive response and could lead to measures that slow the evolution of resistance.
Short interval intracortical inhibition as measured by TMS-EEG
Authors: Rawji Vishal , Kaczmarczyk Isabella , Rocchi Lorenzo , Rothwell John C. , Sharma Nikhil
Published: October 2019

The diagnosis of amyotrophic lateral sclerosis (ALS) relies on involvement of both upper (UMN) lower motor neurons (LMN). Yet, there remains no objective marker of UMN involvement, limiting early diagnosis of ALS. This study establishes whether TMS combined with EEG can be used to measure short-interval intracortical inhibition (SICI) via TMS evoked potentials (TEP) in healthy volunteers - an essential first step in developing an independent marker of UMN involvement in ALS.

We hypothesised that a SICI paradigm would result in characteristic changes in the TMS-evoked EEG potentials that directly mirror the changes in MEP.

TMS was delivered to the left motor cortex using single-pulse and three inhibitory stimulation paradigms. SICI was present in all three conditions. TEP peaks were reduced predominantly under the SICI 70 protocol but less so for SICI 80 and not at all for SICI 90. There was a significant negative correlation between MEPs and N45 TEP peak for SICI 70 (rho = −0.54, p = 0.04). In other words, as MEPs becomes inhibited the N45 increases. The same trend was maintained across SICI 80 and 90 (SICI 80, rho = −0.5, p = 0.06; SICI 90, rho = −0.48, p = 0.07). Additional experiments suggest these results cannot be explained by artefact.

We establish that motor cortical inhibition can be measured during a SICI 70 protocol expanding on previous work. We have carefully considered the role of artefact in TEPs and have taken a number of steps to show that artefact cannot explain these results and we suggesting the differences are cortical in origin. TMS-EEG has potential to aid early diagnosis and to further understand central and peripheral pathophysiology in MND.
Distinct spatiotemporal mechanisms underlie extra-classical receptive field modulation in macaque V1 microcircuits
Authors: Henry Christopher A. , Jazayeri Mehrdad , Shapley Robert M. , Hawken Michael J.
Published: October 2019

Complex scene perception depends upon the interaction between signals from the classical receptive field (CRF) and the extra-classical receptive field (eCRF) in primary visual cortex (V1) neurons. While much is known about V1 eCRF properties, it remains unknown how the underlying mechanisms map onto the cortical microcircuit. We probed the spatio-temporal dynamics of eCRF modulation using a reverse correlation paradigm, and found three principal eCRF mechanisms: tuned-facilitation, untuned-suppression, and tuned-suppression. Each mechanism had a distinct timing and spatial profile. Laminar analysis showed that the timing, orientation-tuning, and strength of eCRF mechanisms had distinct signatures within magnocellular and parvocellular processing streams in the V1 microcircuit. The existence of multiple eCRF mechanisms provides new insights into how V1 responds to spatial context. Modeling revealed that the differences in timing and scale of these mechanisms predicted distinct patterns of net modulation, reconciling many previous disparate physiological and psychophysical findings.
Aβ oligomers induce sex-selective differences in mGluR5 pharmacology and pathophysiological signaling in Alzheimer mice
Authors: Abd-Elrahman Khaled S. , Albaker Awatif , de Souza Jessica M. , Ribeiro Fabiola M. , Schlossmacher Michael G. , Tiberi Mario , Hamilton Alison , Ferguson Stephen S. G.
Published: October 2019

Sex is a key modifier of the prevalence and progression of Alzheimer’s disease (AD). β- Amyloid (Aβ) deposition is a pathological hallmark of AD and aberrant activation of metabotropic glutamate receptor 5 (mGluR5) by Aβ has been linked to AD progression. We find that mGluR5 exhibits distinct sex-dependent pharmacological profiles. Specifically, endogenous mGluR5 from male mouse cortex and hippocampus binds with high-affinity to Aβ oligomers whereas, female mGluR5 exhibits no affinity to Aβ oligomers. The binding affinity of mGluR5 to Aβ oligomer is dependent on its interaction with cellular prion protein (PrPC) as mGluR5 co-immunoprecipitates with PrPCfrom male, but not female, mouse brain. Aβ oligomers also bind with high-affinity to human mGluR5 in male, but not female, cortex. The mGluR5/Aβ oligomer/PrPCternary complex is essential to elicit mGluR5-dependent pathological signaling and as a consequence mGluR5-regulated GSK3β/ZBTB16 autophagic signaling is dysregulated in male, but not female, primary neuronal cultures. These sex-specific differences in mGluR5 signaling translate into in vivo differences in mGluR5-dependent pathological signaling between male and female AD mice. We show that the chronic inhibition of mGluR5 using a mGluR5-selective negative allosteric modulator reactivates GSK3β/ZBTB16-regulated autophagy, mitigates Aβ pathology and reverses cognitive decline in male, but not female, APPswe/PS1ΔE9 mice. Thus, it is evident that, unlike male brain, mGluR5 does not contribute to Aβ pathology in female AD mice. This study highlights the complexity of mGluR5 pharmacology and Aβ oligomer-activated pathological signaling and emphasizes the need for clinical trials redesign and analysis of sex-tailored treatment for AD.
Preexisting hippocampal network dynamics constrain optogenetically induced place fields
Authors: McKenzie Sam , Huszár Roman , English Daniel F. , Kim Kanghwan , Yoon Euisik , Buzsáki György
Published: October 2019

Neuronal circuits face a fundamental tension between maintaining existing structure and changing to accommodate new information. Memory models often emphasize the need to encode novel patterns of neural activity imposed by “bottom-up” sensory drive. In such models, learning is achieved through synaptic alterations, a process which potentially interferes with previously stored knowledge 1-3. Alternatively, neuronal circuits generate and maintain a preconfigured stable dynamic, sometimes referred to as an attractor, manifold, or schema 4-7, with a large reservoir of patterns available for matching with novel experiences 8-13. Here, we show that incorporation of arbitrary signals is constrained by pre-existing circuit dynamics. We optogenetically stimulated small groups of hippocampal neurons as mice traversed a chosen segment of a linear track, mimicking the emergence of place fields 1,14,15, while simultaneously recording the activity of stimulated and non-stimulated neighboring cells. Stimulation of principal neurons in CA1, but less so CA3 or the dentate gyrus, induced persistent place field remapping. Novel place fields emerged in both stimulated and non-stimulated neurons, which could be predicted from sporadic firing in the new place field location and the temporal relationship to peer neurons prior to the optogenetic perturbation. Circuit modification was reflected by altered spike transmission between connected pyramidal cell – inhibitory interneuron pairs, which persisted during post-experience sleep. We hypothesize that optogenetic perturbation unmasked sub-threshold, pre-existing place fields16,17. Plasticity in recurrent/lateral inhibition may drive learning through rapid exploration of existing states.
Exogenous supply of Hsp47 triggers fibrillar collagen deposition in skin cell cultures in vitro
Authors: Khan Essak S , Sankaran Shrikrishnan , LLontop Lorena , del Campo Aránzazu
Published: October 2019

Background

Collagen is a structural protein that provides mechanical stability and defined architectures to skin. In collagen-based skin disorders like Epidermolysis bullosa, EDS the ability to offer such stability is lost either due to mutations in collagens or defect in the chaperones involved in collagen assembly, which leads to chronic wounds, skin fragility, and blisters. Existing approaches to study and develop therapy against such conditions are the use of small molecules like 4-phenylbutyrate (4-PBA) or growth factors like TGF-β. However, these approaches are not collagen specific resulting in unsolicited responses. Therefore, a collagen specific booster is required to guide the correct folding and deposition of collagen in a highly regulated manner. Hsp47 is a chaperone with a major role in collagen biosynthesis. Expression levels of Hsp47 correlate with collagen production. This article explores the stimulation of collagen deposition by exogenously supplied Hsp47 (collagen specific chaperone) in skin cells, including specific collagen subtypes quantification.

Results

Here we quantify the collagen deposition level and the type of deposited collagens by different cell types from skin tissue (fibroblasts NHDF, L929 and MEF, keratinocytes HaCat and endothelial cells HDMEC) after Hsp47 stimulation. We find upregulated deposition of fibrillar collagen subtypes I, III and V after Hsp47 delivery. Network collagen IV deposition was enhanced in HaCat and HDMECs and fibril-associated collagen XII were not affected by the increased Hsp47 intracellular levels. The deposition levels of fibrillar collagen were cell-dependent i.e. Hsp47-stimulated fibroblasts deposited significantly higher amount of fibrillar collagen than Hsp47-stimulated HaCat and HDMECs.

Conclusions

A 3-fold enhancement of collagen deposition was observed in fibroblasts upon repeated dosage of Hsp47 within the first 6 days of culture. Our results provide fundamental understanding towards the idea of using Hsp47 as therapeutic protein to treat collagen disorders.
Multilevel power dynamics shaping employer anti-sexual harassment efforts in Lebanon
Authors: Karam Charlotte , Ghanem May
Published: October 2019

Purpose

The #MeToo movement against sexual harassment (SH) has sparked a sense of familiarity, and collective anger among women, highlighting it as a pervasive and common experience across the globe. The purpose of this paper is to argue that despite shared experiences and such transnational movements, the ways in which SH is actually understood and combated are likely to be different in disparate National Business Systems (NBS). Through the analysis, the authors unpack these differences by paying specific attention to the multilevel power dynamics shaping how employers and their key stakeholders understand and respond to SH in Lebanon.

Design/methodology/approach

Against the backdrop of the complex and inefficient Lebanese NBS, the authors adopt a cross-cultural feminist analytic framework and engage in an iterative qualitative analysis of over 208 pages of transcriptions from relevant multisector, multi-stakeholder interactive sessions. Based on the analysis, the authors propose a series of first- and second-order concepts and themes that help us to trace how power shapes local SH understandings and related efforts.

Findings

The findings highlight the simultaneous influence of power through geopolitical forces external to Lebanon (i.e. power over through North-centricism and othering; power to through comparative perspectives and SDG regulations), combined with local forces embedded within the specific NBS (i.e. power over through negative attitudes and NBS specificities; power to through positive business efforts and local multistakeholder mobilizing).

Originality/value

The findings demonstrate the importance of paying attention to the interaction between power, contextual embeddedness and geopolitical considerations in attempts to advance SH theorization.
A set of parameters for automatically annotating a Sentiment Arabic Corpus
Authors: Imane Guellil , Kareem Darwish , Faical Azouaou
Published: October 2019

Purpose

This paper aims to propose an approach to automatically annotate a large corpus in Arabic dialect. This corpus is used in order to analyse sentiments of Arabic users on social medias. It focuses on the Algerian dialect, which is a sub-dialect of Maghrebi Arabic. Although Algerian is spoken by roughly 40 million speakers, few studies address the automated processing in general and the sentiment analysis in specific for Algerian.

Design/methodology/approach

The approach is based on the construction and use of a sentiment lexicon to automatically annotate a large corpus of Algerian text that is extracted from Facebook. Using this approach allow to significantly increase the size of the training corpus without calling the manual annotation. The annotated corpus is then vectorized using document embedding (doc2vec), which is an extension of word embeddings (word2vec). For sentiments classification, the authors used different classifiers such as support vector machines (SVM), Naive Bayes (NB) and logistic regression (LR).

Findings

The results suggest that NB and SVM classifiers generally led to the best results and MLP generally had the worst results. Further, the threshold that the authors use in selecting messages for the training set had a noticeable impact on recall and precision, with a threshold of 0.6 producing the best results. Using PV-DBOW led to slightly higher results than using PV-DM. Combining PV-DBOW and PV-DM representations led to slightly lower results than using PV-DBOW alone. The best results were obtained by the NB classifier with F1 up to 86.9 per cent.

Originality/value

The principal originality of this paper is to determine the right parameters for automatically annotating an Algerian dialect corpus. This annotation is based on a sentiment lexicon that was also constructed automatically.