bluuebunny/crossref_metadata_2025 huggingface dataset:
Revertant somatic mosaicism as a cause of cancer
Authors: Inaba Toshiya , Nagamachi Akiko
Published: February 2021

Revertant (somatic) mosaicism is a spontaneous correction of a causative mutation in patients with congenital diseases. A relatively frequent event, revertant mosaicism may bring favorable outcomes that ameliorate disorders, and is therefore called “natural gene therapy.” However, it has been revealed recently that “overcorrection” of inherited bone marrow failure in patients with sterile alpha motif domain containing 9 (SAMD9)/9L syndromes by revertant mosaicism induces myelodysplastic syndrome (MDS) with monosomy 7 that occasionally proceeds to acute myelogenous leukemia (AML). In this review, we interpret very complex mechanisms underlying MDS/AML in patients with SAMD9/9L syndromes. This includes multiple myeloid tumor suppressors on the long arm of chromosome 7, all of which act in a haploinsufficient fashion, and a difference in sensitivity to interferon between cells carrying a mutation and revertants. Overcorrection of mutants by somatic mosaicism is likely a novel mechanism in carcinogenesis.
Does neoadjuvant FOLFOX chemotherapy improve the prognosis of high‐risk Stage II and III colon cancers? Three years' follow‐up results of the PRODIGE 22 phase II randomized multicentre trial
Authors: Karoui Mehdi , Gallois Claire , Piessen Guillaume , Legoux Jean‐Louis , Barbier Emilie , De Chaisemartin Cecile , Lecaille Cedric , Bouche Olivier , Ammarguellat Hanifa , Brunetti Francesco , Prudhomme Michel , Regimbeau Jean‐Marc , Glehen Olivier , Lievre Astrid , Portier Guillaume , Hartwig Johannes , Goujon Gael , Romain Benoit , Lepage Come , Taieb Julien ,   for PRODIGE 22 investigators/Collaborators
Published: February 2021

Aim

Neoadjuvant chemotherapy has proven valuable in locally advanced resectable colon cancer (CC) but its effect on oncological outcomes is uncertain. The aim of the present paper was to report 3‐year oncological outcomes, representing the secondary endpoints of the PRODIGE 22 trial.

Method

PRODIGE 22 was a randomized multicentre phase II trial in high‐risk T3, T4 and/or N2 CC patients on CT scan. Patients were randomized between 6 months of adjuvant FOLFOX (upfront surgery) or perioperative FOLFOX (four cycles before surgery and eight cycles after; FOLFOX perioperative). In wild‐type RAS patients, a third arm testing perioperative FOLFOX‐cetuximab was added. The primary endpoint was the tumour regression grade. Secondary endpoints were 3‐year overall survival (OS), disease‐free survival (DFS), recurrence‐free survival (RFS) and time to recurrence (TTR).

Results

Overall, 120 patients were enrolled. At interim analysis, the FOLFOX‐cetuximab arm was stopped for futility. The remaining 104 patients represented our intention‐to‐treat population. In the perioperative group, 96% received the scheduled four neoadjuvant cycles and all but one had adjuvant FOLFOX for eight cycles. In the control arm, 38 (73%) patients received adjuvant FOLFOX. The median follow‐up was 54.3 months. Three‐year OS was 90.4% in both arms [hazard ratio (HR) = 0.85], 3‐year DFS, RFS and TTR were, respectively, 76.8% and 69.2% (HR=0.94), 73% and 69.2% (HR = 0.86) and 82% and 72% (HR = 0.67) in the perioperative and control arms, respectively. Forest plots did not show any subgroup with significant difference for survival outcomes. No benefit from adding cetuximab was observed.

Conclusion

Perioperative FOLFOX has no detrimental effect on long‐term oncological outcomes and may be an option for some patients with locally advanced CC.
The relationship between carotid and coronary calcification in patients with coronary artery disease
Authors: Shenouda Rafik , Vancheri Sergio , Maria Bassi Emilio , Nicoll Rachel , Sobhi Mohammed , El Sharkawy Eman , Wester Per , Vancheri Federico , Henein Michael Y.
Published: February 2021

Background

Atherosclerosis is a multi‐system pathology with heterogeneous involvement.

We aimed to investigate the relationship between the presence and severity of carotid and coronary calcification in a group of patients with coronary artery disease.

Methods

Sixty‐three patients presenting with unstable angina or positive stress test for myocardial ischaemia were enrolled in this study. All patients underwent CT scanning of the carotid and coronary arteries using the conventional protocol and Agatston scoring system. Risk factors for atherosclerosis were also analyzed for correlation with the extent of arterial calcification.

Results

Total coronary artery calcium score (CAC) was several times higher than total carotid calcium score (1274 (1018) vs 6 (124), p = 0·0001, respectively). The left carotid calcium score correlated strongly with the right carotid calcium score (rho = 0·69, p < 0·0001). The total CAC score correlated modestly with the total carotid calcium score (rho = 0·34, p = 0·007), in particular with left carotid score (rho = 0·38, p = 0·002), but not with the right carotid score. The left coronary calcium score correlated with the right coronary calcium score (rho = 0·35, p = 0·004), left carotid calcium score (rho = 0·33, p = 0·007) and left carotid calcium score at the bifurcation (rho = 0·34, p = 0·006). While hypertension correlated with carotid calcium score, diabetes and dyslipidaemia correlated with left CAC score.

Conclusion

In patients with coronary disease, the carotid calcification pattern appeared to be similar between the right and left system in contrast to that of the coronary arteries. CAC correlated only modestly with the carotid score, despite being significantly higher. Hypertension was related to carotid calcium score while diabetes and dyslipidaemia correlated with coronary calcification.
Typical angina during exercise stress testing improves the prediction of future acute coronary syndrome
Authors: Lindow Thomas , Ekström Magnus , Brudin Lars , Carlén Anna , Elmberg Viktor , Hedman Kristofer
Published: February 2021

Introduction

The prognostic value of angina during exercise stress testing is controversial, possibly due to previous studies not differentiating typical from non‐typical angina. We aimed to assess the prognostic value of typical angina alone, or in combination with ST depression, during exercise stress testing for predicting cardiovascular events.

Methods

We conducted a prospective observational cohort study including all patients who performed a clinical exercise stress test at the department of Clinical Physiology, Kalmar County Hospital between 2005 and 2012. The association between typical angina/ST depression and incident acute coronary syndrome (ACS) and cardiovascular mortality were analysed using Cox regression for long‐term and 1‐year follow‐up.

Results

Out of 11605 patients (median follow‐up 6.7 years), 623 (5.4%) developed ACS and 319 (2.7%) died from cardiovascular causes. Compared to patients with no angina and no ST depression, typical angina and ST depression were associated with increased risk of future ACS; hazard ratio (HR) 3.5 ([95%CI] 2.6–4.7). This association was even stronger for ACS within one year (typical angina with and without concomitant ST depression; HR 20.8 (13.9–31.3) and 9.7 (6.1–15.4), respectively). Concordance statistics for ST depression in predicting ACS during long‐term follow‐up was 0.58 (0.56–0.60) and 0.69 (0.65–0.73) for ACS within one year, and 0.64 (0.62–0.66) and 0.77 (0.73–0.81), respectively, when typical angina was added to the model.

Conclusions

Typical angina during exercise stress testing is predictive of future ACS, especially in combination with ST depression, and during the first year after the test.
Using economics in conservation practice: Insights from a global environmental organization
Authors: Springer Nathaniel , Musengezi Jessica , Hunter Eric O. , Kaiser Charlotte , Shyamsundar Priya
Published: February 2021

Identifying and implementing successful strategies to conserve nature is a central goal of environmental practitioners. Conservation tools increasingly have an economic rationale to them, expanding the array of means available to trigger environmental actions. Missing is a comprehensive list of economic and financial instruments for conservation practitioners that highlights their current applicability, context, and relative success. To address this gap, we assembled such a list and surveyed units of The Nature Conservancy, a global conservation organization, to understand how these instruments are being used in varied contexts. We find that the majority of respondents have used economic or financial instruments, with the most common types being markets and price premiums, investments and funds, and payments for ecosystem services. A variety of factors influence the choice of instruments, including stakeholder interests, experience, and replication possibilities. Institutional constraints act as a significant barrier to implementation. These findings identify and offer insights on an expanded set of instruments that the non‐profit conservation sector can use, replicate, and develop to meet conservation goals.
Benefits, safety and side effects of tumescent local anesthesia in dermatologic surgery in infants
Authors: Roerden Alisa , Neunhoeffer Felix , Götz Angelika , Häfner Hans‐Martin , Kofler Lukas
Published: February 2021

Tumescent local anesthesia (TLA) plays an important role in dermatosurgical procedures. TLA has several benefits such as long‐lasting anesthesia, reduced bleeding during surgery and the avoidance of general anesthesia‐associated complications. Convenience and a favorable risk profile along with a broad spectrum of indications are further reasons why TLA is increasingly applied in infants as well. There are not only a variety of indications for surgical excisions in infancy, such as congenital nevi, but also substantial benefits when performing these excisions at an early age. These include the smaller size of the lesions as well as the unproblematic wound healing and tissue regeneration in infancy. Nevertheless, several aspects need to be considered when applying TLA in infants including dosing, altered plasma protein binding and the need for adequate and long‐lasting pain control.
Importance of diagnostics and risk of secondary malignancies in primary cutaneous lymphomas
Authors: Scheu Alexander , Schnabl Saskia Maria , Steiner Daniel Patric , Fend Falko , Berneburg Mark , Yazdi Amir Sadegh
Published: February 2021

Background and Objectives

Primary cutaneous lymphomas (PCL) often strongly differ in clinical behavior and prognosis from systemic lymphomas of the same histopathologic type. The aim of the study was to investigate the distribution of PCL subtypes, the average time from disease manifestation to diagnosis, the importance of diagnostic procedures, the occurrence of secondary malignancies and the different treatment modalities.

Patients and Methods

Retrospective analysis of 152 patients with PCL examined at the Department of Dermatology of the University Hospital Tübingen from 2010–2012.

Results

105 patients with CTCL (69.1 %) and 47 patients with CBCL (30.9 %) were included. The average time from disease manifestation to diagnosis was four years. The most common diagnosed lymphoma was mycosis fungoides (MF) (47.4 %). First‐line therapies here include phototherapy only (psoralen‐UV‐A [PUVA], n = 48; UVB 311 nm, n = 7) or combination therapies primarily phototherapy with systemic retinoids (n = 18). Most frequent second‐line therapy was interferon (INF)‐α plus PUVA (n = 15). The outcome was favorable (45.2 % remission, 28.6 % stable disease, 22.6 % progressive disease). Malignant comorbidities were observed more frequently compared to a healthy control group.

Conclusions

The diagnosis of lymphoma often takes several years. The value of staging procedures is still low and the treatment modalities for MF in earlier stages are mainly based on phototherapy.
Pluripotent stem cells in the research for extraembryonic cell differentiation
Authors: Toyooka Yayoi
Published: February 2021

Mouse embryonic stem cells (mESCs) are pluripotent stem cell populations derived from the preimplantation embryo and are used to study the differentiation of many types of somatic and germ cells in developing embryos. They are also used to study cell lineages of extraembryonic tissues, such as the trophectoderm (TE) and the primitive endoderm (PrE). mESC cultures are suitable systems for reproducing cellular and molecular events occurring during the differentiation of these cell types, such as changes in gene expression patterns, signaling events, and genome rearrangements although the consistency between the results obtained using mESCs and those of in vivo studies on embryos should be carefully taken into account. Since TE and PrE cells can be induced from mESCs in vitro, mESC cultures are useful systems to study differentiation of these cell lineages during development, if used appropriately. In addition, human pluripotent stem cells (hPSCs), such as human embryonic stem cells (hESCs) and human‐induced pluripotent stem cells (hiPSCs), are capable of generating extraembryonic lineages in vitro and are promising tools to study the differentiation of these lineages in the human embryo.
Evaluation of left ventricular functions by speckle‐tracking echocardiography in coarctation patients
Authors: Demircan Tülay , Kizilca Özgür , Yilmaz Nuh , Zihni Cüneyt , Kir Mustafa , Ünal Nurettin
Published: February 2021

Background/Aim

Two‐dimensional speckle‐tracking echocardiography (2D‐STE) is a novel method that allows the assessment of regional myocardial function. The aim of our study was to use 2D‐STE to assess left ventricular deformation in patients with coarctation of the aorta (CoA).

Methods

In this prospective study, patients with CoA (n = 42) and healthy controls (n = 39) were recruited. Children with CoA who visited the outpatient clinic between 2013 and 2014 were included. The data were compared with those obtained from the sex‐ and age‐matched controls.

Results

The mean age of the patients was 5.8 ± 4.5 years. Global longitudinal strain based on all three apical views and total global strain values did not appear to be different between the patient and the control groups (P = .59, P = .51, P = .15, P = .38). Hypertension was detected in 14 (33.3%) patients with CoA. There were significant differences between the global longitudinal strain values of the normotensive CoA subgroup and the hypertensive CoA subgroup (P < .05).

Conclusions

In our study, we found that 2D‐STE total strain analysis of patients with CoA was not different from comparative healthy controls. However, we determined that 2D‐STE parameters were lower in the hypertensive CoA subgroup compared to the normotensive CoA subgroup.
Characteristics of pediatric maxillofacial fractures in Kuwait: A single‐center retrospective study
Authors: AlAli Ahmad M. , Ibrahim Hussein H. H. , Algharib Abdullah , Alsaad Fahad , Rajab Bashar
Published: February 2021

Background

Pediatric maxillofacial fractures always present a challenge due to the unique nature of the facial skeleton anatomy and development. The aim of this study was to investigate the incidence, etiology, site of fracture, and management modalities of pediatric maxillofacial fractures in Kuwait.

Methods

A retrospective cross‐sectional study was conducted. The records of all pediatric patients who were diagnosed with maxillofacial fractures and admitted to one of the major hospitals in Kuwait between January 2007 and March 2020 were reviewed.

Results

A total of 186 patients aged between 0 and 13 years old were included. An average of 13 patients was seen each year between 2007 and 2020. The leading cause of the pediatric maxillofacial trauma was road traffic accidents (RTA) that accounted for 38.2% of the patients followed by 22% falls from height (FFH). Male patients were more affected than females, with a ratio of 2.3:1. More than half of the children had mid‐face fractures, of which 57% were in multiple sites. Conservative management was the main approach for 52.2% of the patients.

Conclusions

Pediatric maxillofacial fractures were mainly attributed to road traffic accidents in Kuwait. Mid‐face bone fractures were reported more than mandibular fractures and were mostly managed conservatively.
The ups and downs of alkyl‐carbamates in epilepsy therapy: How does cenobamate differ?
Authors: Löscher Wolfgang , Sills Graeme J. , White H. Steve
Published: February 2021

Since 1955, several alkyl‐carbamates have been developed for the treatment of anxiety and epilepsy, including meprobamate, flupirtine, felbamate, retigabine, carisbamate, and cenobamate. They have each enjoyed varying levels of success as antiseizure drugs; however, they have all been plagued by the emergence of serious and sometimes life‐threatening adverse events. In this review, we compare and contrast their predominant molecular mechanisms of action, their antiseizure profile, and where possible, their clinical efficacy. The preclinical, clinical, and mechanistic profile of the prototypical γ‐aminobutyric acidergic (GABAergic) modulator phenobarbital is included for comparison. Like phenobarbital, all of the clinically approved alkyl‐carbamates share an ability to enhance inhibitory neurotransmission through modulation of the GABAA receptor, although the specific mechanism of interaction differs among the different drugs discussed. In addition, several alkyl‐carbamates have been shown to interact with voltage‐gated ion channels. Flupirtine and retigabine share an ability to activate K+ currents mediated by KCNQ (Kv7) K+ channels, and felbamate, carisbamate, and cenobamate have been shown to block Na+ channels. In contrast to other alkyl‐carbamates, cenobamate seems to be unique in its ability to preferentially attenuate the persistent rather than transient Na+ current. Results from recent randomized controlled clinical trials with cenobamate suggest that this newest antiseizure alkyl‐carbamate possesses a degree of efficacy not witnessed since felbamate was approved in 1993. Given that ceno‐bamate's mechanistic profile is unique among the alkyl‐carbamates, it is not clear whether this impressive efficacy reflects an as yet undescribed mechanism of action or whether it possesses a unique synergy between its actions at the GABAA receptor and on persistent Na+ currents. The high efficacy of cenobamate is, however, tempered by the risk of serious rash and low tolerability at higher doses, meaning that further safety studies and clinical experience are needed to determine the true clinical value of cenobamate.
Long‐term chemogenetic suppression of seizures in a multifocal rat model of temporal lobe epilepsy
Authors: Goossens Marie‐Gabrielle , Boon Paul , Wadman Wytse , Van den Haute Chris , Baekelandt Veerle , Verstraete Alain G. , Vonck Kristl , Larsen Lars E. , Sprengers Mathieu , Carrette Evelien , Desloovere Jana , Meurs Alfred , Delbeke Jean , Vanhove Christian , Raedt Robrecht
Published: February 2021

Objective

One third of epilepsy patients do not become seizure‐free using conventional medication. Therefore, there is a need for alternative treatments. Preclinical research using designer receptors exclusively activated by designer drugs (DREADDs) has demonstrated initial success in suppressing epileptic activity. Here, we evaluated whether long‐term chemogenetic seizure suppression could be obtained in the intraperitoneal kainic acid rat model of temporal lobe epilepsy, when DREADDs were selectively expressed in excitatory hippocampal neurons.

Methods

Epileptic male Sprague Dawley rats received unilateral hippocampal injections of adeno‐associated viral vector encoding the inhibitory DREADD hM4D(Gi), preceded by a cell‐specific promotor targeting excitatory neurons. The effect of clozapine‐mediated DREADD activation on dentate gyrus evoked potentials and spontaneous electrographic seizures was evaluated. Animals were systemically treated with single (.1 mg/kg/24 h) or repeated (.1 mg/kg/6 h) injections of clozapine. In addition, long‐term continuous release of clozapine and olanzapine (2.8 mg/kg/7 days) using implantable minipumps was evaluated. All treatments were administered during the chronic epileptic phase and between 1.5 and 13.5 months after viral transduction.

Results

In the DREADD group, dentate gyrus evoked potentials were inhibited after clozapine treatment. Only in DREADD‐expressing animals, clozapine reduced seizure frequency during the first 6 h postinjection. When administered repeatedly, seizures were suppressed during the entire day. Long‐term treatment with clozapine and olanzapine both resulted in significant seizure‐suppressing effects for multiple days. Histological analysis revealed DREADD expression in both hippocampi and some cortical regions. However, lesions were also detected at the site of vector injection.

Significance

This study shows that inhibition of the hippocampus using chemogenetics results in potent seizure‐suppressing effects in the intraperitoneal kainic acid rat model, even 1 year after viral transduction. Despite a need for further optimization, chemogenetic neuromodulation represents a promising treatment prospect for temporal lobe epilepsy.
The HSP90 inhibitor RGRN‐305 exhibits strong immunomodulatory effects in human keratinocytes
Authors: Hansen Rikke S , Thuesen Katrine K. H. , Bregnhøj Anne , Moldovan Liviu I. , Kristensen Lasse S. , Grek Christina L. , Ghatnekar Gautam S. , Iversen Lars , Johansen Claus
Published: February 2021

Keratinocytes are the key cellular target for IL‐17A‐mediated effects in psoriasis and HSP90 is important for IL‐17A‐mediated signalling. RGRN‐305 is a novel HSP90 inhibitor reported to reduce psoriatic phenotypes in preclinical animal models. The aim of this study was to investigate the effect of RGRN‐305 on a psoriasis‐like inflammatory response in human keratinocytes in vitro. Using RT‐qPCR, we demonstrated a significantly increased expression of the HSP90 isoforms HSP90AB1, HSP90B1 and TRAP1 in lesional compared with non‐lesional psoriatic skin. In a psoriasis‐like setting where keratinocytes were stimulated with TNFα and/or IL‐17A, we analysed the mRNA expression using the NanoString nCounter technology and demonstrated that the HSP90 inhibitor RGRN‐305 significantly reduced the IL‐17A‐ and TNFα‐induced gene expression of a number of proinflammatory genes, including the psoriasis‐associated genes CCL20, NFKBIZ, IL36G and IL23A. In agreement with the mRNA data, the protein level of CCL20, IκBζ and IL‐36γ were inhibited by RGRN‐305 as demonstrated by western blotting and ELISA. Interestingly, when keratinocytes were stimulated with a TLR3 agonist, RGRN‐305 also demonstrated potent immunomodulatory effects, significantly inhibiting poly(I:C)‐induced expression of the proinflammatory genes TNFα, IL1B, IL6 and IL23A. Taken together, our data support a role for HSP90 not only in the pathogenesis of psoriasis, but also in broader immune responses. Therefore, HSP90 provides an attractive target for the treatment of psoriasis and other diseases where the innate immune system plays an important role.
Efficacy of PARP inhibition combined with EZH2 inhibition depends on BRCA mutation status and microenvironment in breast cancer
Authors: Chen Mei‐Kuang
Published: February 2021

The efficacy of the combination of a PARP inhibitor (PARPi) and an EZH2 inhibitor has been investigated in breast cancer cells with either BRCA1 mutation or BRCA2 mutation. However, earlier studies focused on the efficacy of this combination against BRCA‐mutated but not BRCA‐proficient breast cancer. Yang et al. observed that PARP1 depletion combined with EZH2 depletion via PRC2 depletion did not affect the growth of BRCA1/2 wild‐type breast cancer cells in vitro. Moreover, Yang et al. reported that this combination stimulated synthetic viability of BRCA1/2‐proficient breast cancer cells in vivo by regulating the tumor microenvironment to induce angiogenesis and differentiation of M2‐type macrophages. The findings of Yang et al. provided evidence that both in vitro and animal models should be employed in the studies of PARPi combination therapies in order to involve the alteration of the tumor microenvironment in these investigations. These studies of PARP inhibition combined with EZH2 inhibition in breast cancer showed that this combination may benefit breast cancer patients carrying BRCA1‐mutated tumor, but the combination may also enhance recurrence of BRCA2‐mutated tumor and may even promote BRCA‐proficient cancer cell survival. Therefore, BRCA1 mutation status should be used to select breast cancer patients for PARPi and EZH2 inhibitor combination treatment in clinical trials in the future.
Aberrant phase separation and cancer
Authors: Taniue Kenzui , Akimitsu Nobuyoshi
Published: February 2021

Eukaryotic cells are intracellularly divided into numerous compartments or organelles, which coordinate specific molecules and biological reactions. Membrane‐bound organelles are physically separated by lipid bilayers from the surrounding environment. Biomolecular condensates, also referred to membraneless organelles, are micron‐scale cellular compartments that lack membranous enclosures but function to concentrate proteins and RNA molecules, and these are involved in diverse processes. Liquid–liquid phase separation (LLPS) driven by multivalent weak macromolecular interactions is a critical principle for the formation of biomolecular condensates, and a multitude of combinations among multivalent interactions may drive liquid–liquid phase transition (LLPT). Dysregulation of LLPS and LLPT leads to aberrant condensate and amyloid formation, which causes many human diseases, including neurodegeneration and cancer. Here, we describe recent findings regarding abnormal forms of biomolecular condensates and aggregation via aberrant LLPS and LLPT of cancer‐related proteins in cancer development driven by mutation and fusion of genes. Moreover, we discuss the regulatory mechanisms by which aberrant LLPS and LLPT occur in cancer and the drug candidates targeting these mechanisms. Further understanding of the molecular events regulating how biomolecular condensates and aggregation form in cancer tissue is critical for the development of therapeutic strategies against tumorigenesis.
Differential lysine‐mediated allosteric regulation of plant dihydrodipicolinate synthase isoforms
Authors: Hall Cody J. , Lee Mihwa , Boarder Matthew P. , Mangion Alexandra M. , Gendall Anthony R. , Panjikar Santosh , Perugini Matthew A. , Soares da Costa Tatiana P.
Published: February 2021

Lysine biosynthesis in plants occurs via the diaminopimelate pathway. The first committed and rate‐limiting step of this pathway is catalysed by dihydrodipicolinate synthase (DHDPS), which is allosterically regulated by the end product,l‐lysine (lysine). Given that lysine is a common nutritionally limiting amino acid in cereal crops, there has been much interest in probing the regulation of DHDPS. Interestingly, knockouts inArabidopsis thalianaof each isoform (AtDHDPS1 and AtDHDPS2) result in different phenotypes, despite the enzymes sharing > 85% protein sequence identity. Accordingly, in this study, we compared the catalytic activity, lysine‐mediated inhibition and structures of bothA. thalianaDHDPS isoforms. We found that although the recombinantly produced enzymes have similar kinetic properties, AtDHDPS1 is 10‐fold more sensitive to lysine. We subsequently used X‐ray crystallography to probe for structural differences between the apo‐ and lysine‐bound isoforms that could account for the differential allosteric inhibition. Despite no significant changes in the overall structures of the active or allosteric sites, we noted differences in the rotamer conformation of a key allosteric site residue (Trp116) and proposed that this could result in differences in lysine dissociation. Microscale thermophoresis studies supported our hypothesis, with AtDHDPS1 having a ~ 6‐fold tighter lysine dissociation constant compared to AtDHDPS2, which agrees with the lower half minimal inhibitory concentration for lysine observed. Thus, we highlight that subtle differences in protein structures, which could not have been predicted from the primary sequences, can have profound effects on the allostery of a key enzyme involved in lysine biosynthesis in plants.

Databases

Structures described are available in the Protein Data Bank under the accession numbers6VVHand6VVI.
Was historical cisco Coregonus artedi yield consistent with contemporary recruitment and abundance in Lake Superior?
Authors: Rook Benjamin J. , Hansen Michael J. , Goldsworthy Cory A. , Ray Bradley A. , Gorman Owen T. , Yule Daniel L. , Bronte Charles R.
Published: February 2021

Historically, cisco Coregonus artedi Lesueur was the predominant prey fish and target of commercial fisheries throughout Lake Superior, but most spawning stocks collapsed by the mid‐1900s. Stocks partially recovered by the early 1990s, but contemporary abundance is considered to be below historical levels and driven by intermittent recruitment. Stochastic, age‐structured simulation models were used to determine whether historical (pre‐1955) cisco yield in Lake Superior was consistent with contemporary (1992–2015) abundance, life‐history characteristics and recruitment dynamics. When compared to contemporary stocks, the findings suggest historical stocks had: (1) similar recruits per spawner at low spawning stock sizes; (2) lower rates of compensatory density dependence; (3) similar or lower recruitment variation depending on the area and (4) higher median adult and age‐1 density. These findings are consistent with the hypothesis that eutrophication during the historical period supported greater recruitment and adult abundance and that re‐oligotrophication during the contemporary period may be limiting full recovery.
Urbanisation and eutrophication as drivers of morphological and physiological divergence among riverine fish populations
Authors: Côte Jessica , Morisseau Océane , Pilisi Camille , Veyssière Charlotte , Perrault Annie , Jezequel Céline , Loot Géraldine , Blanchet Simon , Jean Séverine , Jacquin Lisa
Published: February 2021

Freshwater ecosystems are highly impacted by human activities, but the effects of human‐induced perturbations on fish phenotypic divergence remain poorly understood, especially in riverine systems.

In this study, we tested the effects of urbanisation and eutrophication on several morphological and physiological traits in 17 gudgeon populations of Gobio occitaniae from South of France.

We first demonstrated that eutrophication gradient was associated with changes in morphology and energy reserves, while urbanisation was associated with changes in body condition. More specifically, fish from highly eutrophic sites had deeper bodies and larger jaws, and a higher lipid content in their muscles.

Urban fish had a higher body condition compared to their rural counterparts. The phenotypic divergence (Pst) among sites was significantly higher than the neutral genetic differentiation (Fst), suggesting that these morphological and physiological differences cannot be explained by neutral genetic drift alone.

This study thus suggests that eutrophication and urbanisation are major drivers of phenotypic divergence in riverine fish populations, and calls for further experimental studies investigating the ecological and evolutionary effects of human activities on riverine fish populations.
Heatwave‐induced synchrony within forage fish portfolio disrupts energy flow to top pelagic predators
Authors: Arimitsu Mayumi L. , Piatt John F. , Hatch Scott , Suryan Robert M. , Batten Sonia , Bishop Mary Anne , Campbell Rob W. , Coletti Heather , Cushing Dan , Gorman Kristen , Hopcroft Russell R. , Kuletz Kathy J. , Marsteller Caitlin , McKinstry Caitlin , McGowan David , Moran John , Pegau Scott , Schaefer Anne , Schoen Sarah , Straley Jan , von Biela Vanessa R.
Published: February 2021

During the Pacific marine heatwave of 2014–2016, abundance and quality of several key forage fish species in the Gulf of Alaska were simultaneously reduced throughout the system. Capelin (Mallotus catervarius), sand lance (Ammodytes personatus), and herring (Clupea pallasii) populations were at historically low levels, and within this community abrupt declines in portfolio effects identify trophic instability at the onset of the heatwave. Although compensatory changes in age structure, size, growth or energy content of forage fish were observed to varying degrees among all these forage fish, none were able to fully mitigate adverse impacts of the heatwave, which likely included both top‐down and bottom‐up forcing. Notably, changes to the demographic structure of forage fish suggested size‐selective removals typical of top‐down regulation. At the same time, changes in zooplankton communities may have driven bottom‐up regulation as copepod community structure shifted toward smaller, warm water species, and euphausiid biomass was reduced owing to the loss of cold‐water species. Mediated by these impacts on the forage fish community, an unprecedented disruption of the normal pelagic food web was signaled by higher trophic level disruptions during 2015–2016, when seabirds, marine mammals, and groundfish experienced shifts in distribution, mass mortalities, and reproductive failures. Unlike decadal‐scale variability underlying ecosystem regime shifts, the heatwave appeared to temporarily overwhelm the ability of the forage fish community to buffer against changes imposed by warm water anomalies, thereby eliminating any ecological advantages that may have accrued from having a suite of coexisting forage species with differing life‐history compensations.
Analysis of Spatial Networks From Bipartite Projections Using the R Backbone Package
Authors: Neal Zachary P. , Domagalski Rachel , Sagan Bruce
Published: February 2021

Bipartite projections have become a common way to measure spatial networks. They are now used in many subfields of geography, and are among the most common ways to measure the world city network, where intercity links are inferred from firm co‐location patterns. Bipartite projections are attractive because a network can be indirectly inferred from readily available data. However, spatial bipartite projections are difficult to analyze because the links in these networks are weighted, and larger weights do not necessarily indicate stronger or more important connections. Methods for extracting the backbone of bipartite projections offer a solution by using statistical models for identifying the links that have statistically significant weights. In this article, we introduce the open‐source backbone R package, which implements several backbone models, and demonstrate its key features by using it to measure a world city network.
Variations in ion transportation and accumulation in alfalfa plants under NaCl and Na2HCO3 stresses with different pH levels
Authors: Wang Xiaoshan , Liu Longyang , Wang Bingsheng , Dingxuan Qiyue , Zhou Guisheng
Published: February 2021

For revealing the effects of NaCl and NaHCO3 stress at different pH levels on the absorption and accumulation of main ions in roots, stems and leaves, alfalfa (Medicago sativa L.) plants were cultivated in a nutrient solution system. After NaCl and Na2HCO3 imposition, the contents of main ions in roots, stems, leaves and xylem bleeding sap were determined. Under NaCl and Na2HCO3 stresses with the same Na+ concentration, Na2HCO3 stress showed severer inhibitory effects on alfalfa growth in contrast to NaCl stress at different pH levels. Under NaCl stresses at different pH levels, alfalfa plants showed much lower Na+ accumulation and Na+ delivery rate in root bleeding sap than that under NaHCO3 stress. The plants of NaHCO3 stress showed a severer inhibition in K+ accumulation, lower K+ delivery rate, but higher Na+/K+ ratios than the plants of NaCl stress. NaHCO3 stress increased Ca2+ and Mg2+ accumulation in alfalfa roots, decreased Ca2+ and Mg2+ delivery rates and increased leaf Na+/Ca2+ ratio and Na+/Mg2+ ratio. Both NaCl and NaHCO3 stresses decreased the contents of Fe3+ and Mn2+ in roots, but increased the contents of Cu2+ in roots, stems and leaves, the content of Mn2+ in stems and leaf Zn2+ content in alfalfa plants. However, the contents of Fe3+ and Mn2+ in roots and stem Mn2+ content in the NaHCO3 treatments were much lower than those in the NaCl treatments. In conclusion, NaHCO3 stress produced severer injury and induced severer Na+ toxicity to alfalfa plants than NaCl stress. The effects of NaHCO3 stress and NaCl stress on the absorption and accumulation of trophic ions were different. Under NaCl stress, the increased pH did not alter Na+ absorption and accumulation in plants, but altered the distribution of some nutrient ions in roots, stems and leaves.
Arachnoiditis, a complication of epidural blood patch for the treatment of low‐pressure headache: A case report and systematic review
Authors: Villani Linda A. , Digre Kathleen B. , Cortez Melissa M. , Bokat Christina , Rassner Ulrich A. , Ozudogru Seniha N.
Published: February 2021

Objective

To report a case of arachnoiditis as a complication of epidural blood patch procedures and to systematically review the diagnostic workup, clinical outcomes, and treatment modalities reported in the literature.

Background

Epidural blood patching is an effective treatment for low‐pressure headache secondary to spontaneous cerebrospinal fluid leak or iatrogenic post‐dural puncture. Spontaneous intracranial hypotension is believed to be a rare headache disorder, but recently has been diagnosed at higher frequencies, making it an important differential diagnosis for intractable headaches. Arachnoiditis has surfaced as a rare complication of epidural blood patching. Symptom presentation does not always correlate with evidence of meningeal enhancement on imaging. Optimal methods for treatment remain largely unknown.

Methods

Databases Embase and PubMed were searched for all published studies on arachnoiditis post‐epidural blood patch using a combination of the following medical subject headings and keywords: arachnoiditis, arachnoid inflammation, adverse event, and epidural blood patch. All original English‐language articles that described arachnoid and/or meningeal inflammation in conjunction with epidural blood patch procedures were included for analysis. Title and abstract screening, data extraction, and risk of bias assessment were conducted independently and in duplicate by two reviewers.

Results

Seven other cases of arachnoiditis post‐blood patch placement have been documented, most of which were diagnosed via magnetic resonance imaging. Six of these were a result of a spinal‐epidural anesthesia for labor and delivery. Common symptoms reported were headache, back and radicular pain, paresthesia, and motor weakness. There are currently no proven consensus‐based treatment recommendations available. While intravenous methylprednisolone followed by oral prednisone taper was found to be effective in the case presented, the benefit of other multi‐modal therapies was unclear.

Conclusions

Headache specialists who treat postural headache should be aware of arachnoiditis as a potentially severe complication of epidural blood patch. The case presented is the first of its kind to report arachnoiditis as a complication of high‐volume blood patch for the treatment of spontaneous intracranial hypotension. More studies are required to determine suitable treatment options for post‐epidural blood patch arachnoiditis.
Differences in emotional reactions of Greek, Hungarian, and British users of English when watching television in English
Authors: Dewaele Jean‐Marc , Lorette Pernelle , Rolland Louise , Mavrou Irini
Published: February 2021

We investigated differences in self‐reported Emotional Reactions (ER) of first (L1) and foreign (LX) language users of English when watching television in English and identified the predictors. Participants were 271 British citizens, 282 Greek, and 271 Hungarians living in their home country. English LX users had significantly lower values for ER compared to L1 users. Frequency of watching television in English and Trait Emotional Intelligence were the strongest predictors of ER among LX users. No significant predictors emerged for L1 users. Significant differences emerged between the Greeks and Hungarians despite having similar levels of proficiency. This suggests that the implicit assumption in previous research that any group of LX users with the same L1 and LX represent all LX users in the world is incorrect.
Exploring the meanings and grammatical functions of idioms in teaching Chinese as a second language
Authors: Wang Shan , Luo Huiting
Published: February 2021

Idioms are an important part of Teaching Chinese as a Second Language (TCSL), but current research on the meanings and grammatical functions of idioms is still quite weak. This study selected commonly used idioms in TCSL, extracted sentences containing these idioms from large‐scale modern Chinese corpora, and manually annotated the meaning and grammatical functions of each idiom in these sentences. It then analyzed the characteristics of the idioms in TCSL and revealed the importance of meanings and grammatical functions in idiom teaching. This study further examined the problems of the idioms in textbooks and learner's dictionaries, proposed methods and principles for setting example sentences, and introduced how to carry out idiom teaching. This research not only provides theoretical and practical references for Chinese language teachers and learners, but also helps to promote the development of textbook editing, dictionary compilation, and idiom teaching.
Modelling perceived service quality and turnover intentions in gender‐segregated environments
Authors: Olya Hossein , Taheri Babak , Farmaki Anna , Joseph Gannon Martin
Published: February 2021

This study extends current understanding of how gender shapes value co‐creation, perceived service quality and turnover intention within health and fitness clubs. Survey responses were collected from 485 fitness club customers in Iran. Partial least squares structural equation modelling (PLS‐SEM) was deployed to demonstrate the effects of predictor variables while fuzzy‐set qualitative comparative analysis (fsQCA) was used to identify combinations of value co‐creation behaviours capable of predicting model outcomes. Necessary condition analysis (NCA) was also employed to identify the value co‐creation factors required to achieve low turnover intentions and high service quality perceptions. Results reveal the moderating role of gender in shaping the complex combinations of value co‐creation factors leading to low turnover and high perceived quality; fsQCA findings demonstrate how this differs between male and female consumers. NCA findings suggest that fitness club managers should foster an interactive environment through advocacy programmes, promoting responsible behaviours andwboosting tolerance, to encourage both male and female customers to participate in co‐creation processes. This is the first empirical study to apply complexity theory to explore whether service quality perceptions and turnover intentions vary across gender via structural and configurational modelling.
Efficacy and safety of intravesical instillation of KRP‐116D (50% dimethyl sulfoxide solution) for interstitial cystitis/bladder pain syndrome in Japanese patients: A multicenter, randomized, double‐blind, placebo‐controlled, clinical study
Authors: Yoshimura Naoki , Homma Yukio , Tomoe Hikaru , Otsuka Atsushi , Kitta Takeya , Masumori Naoya , Akiyama Yoshiyuki , Niimi Aya , Mitsui Takahiko , Nanri Masaharu , Namima Takashige , Takei Mineo , Yamaguchi Akito , Sekiguchi Yuki , Kajiwara Mitsuru , Kobayashi Shinya , Ameda Kaname , Ohashi Yozo , Sakamoto Sadaaki , Muraki Osamu , Shishido Toshihide , Kageyama Shinji , Kokura Koji , Okazoe Homare , Yamanishi Tomonori , Watanabe Toyohiko , Uno Takashi , Ohinata Akira , Ueda Tomohiro
Published: February 2021

Objective

To evaluate the efficacy and safety of intravesical KRP‐116D, 50% dimethyl sulfoxide solution compared with placebo, in interstitial cystitis/bladder pain syndrome patients.

Methods

Japanese interstitial cystitis/bladder pain syndrome patients with an O’Leary‐Sant Interstitial Cystitis Symptom Index score of ≥9, who exhibited the bladder‐centric phenotype of interstitial cystitis/bladder pain syndrome diagnosed by cystoscopy and bladder‐derived pain, were enrolled. Patients were allocated to receive either KRP‐116D (n = 49) or placebo (n = 47). The study drug was intravesically administered every 2 weeks for 12 weeks.

Results

For the primary endpoint, the change in the mean O’Leary‐Sant Interstitial Cystitis Symptom Index score from baseline to week 12 was −5.2 in the KRP‐116D group and −3.4 in the placebo group. The estimated difference between the KRP‐116D and placebo groups was −1.8 (95% confidence interval −3.3, −0.3; P = 0.0188). Statistically significant improvements for KRP‐116D were also observed in the secondary endpoints including O’Leary‐Sant Interstitial Cystitis Problem Index score, micturition episodes/24 h, voided volume/micturition, maximum voided volume/micturition, numerical rating scale score for bladder pain, and global response assessment score. The adverse drug reactions were mild to moderate, and manageable.

Conclusions

This first randomized, double‐blind, placebo‐controlled trial shows that KRP‐116D improves symptoms, voiding parameters, and global response assessment, compared with placebo, and has a well‐tolerated safety profile in interstitial cystitis/bladder pain syndrome patients with the bladder‐centric phenotype.
Prognostic significance of tertiary Gleason pattern in the contemporary era of Gleason grade grouping: A narrative review
Authors: Taguchi Satoru , Morikawa Teppei , Shibahara Junji , Fukuhara Hiroshi
Published: February 2021

Since the Gleason score was developed in 1966 as a histological classification for prostate cancer, it has been widely used in clinical practice and has evolved over time. The concept of a “tertiary Gleason pattern” (also known as a minor Gleason pattern) was first proposed in 2000, and has been used in clinical practice since the 2005 International Society of Urological Pathology conference. The prognostic significance of a tertiary Gleason pattern has been widely validated in various settings of prostate cancer, whereas its definition has yet to be fully established. Currently, a provisional definition of tertiary Gleason pattern is “<5% Gleason pattern 4 or 5 in radical prostatectomy specimens.” In contrast, “Gleason grade grouping” was proposed in 2013 and came into use in clinical practice in 2016 according to the 2014 International Society of Urological Pathology conference. Although the prognostic significance of Gleason grade grouping has already been widely confirmed, it does not incorporate the concept of tertiary Gleason pattern. Recently, the 2019 International Society of Urological Pathology conference discussed how to handle tertiary Gleason pattern in the current Gleason scoring system, but no consensus was reached on the issue. This review summarizes the evidence on the prognostic significance of tertiary Gleason pattern and discusses how to deal with it in the context of the contemporary Gleason grade grouping. It also refers to reporting of the percentage of Gleason patterns 4 and 5, as well as quantitative Gleason score models incorporating tertiary Gleason pattern.
La transition verte: analyser la croissance de l'emploi vert
Authors: SOFRONIOU Nick , ANDERSON Pauline
Published: February 2021

Les auteurs estiment le nombre des emplois verts en Écosse et analysent son évolution dans le temps en s'appuyant sur les données de l'Enquête sur la main‐d'œuvre du Royaume‐Uni (2011‐2014) et en croisant deux systèmes de classification professionnelle (CITP‐08 et O*NET). Leur cadre méthodologique est transposable à n'importe quelle région. Ils montrent qu'il vaut mieux retenir une définition large des emplois verts, plutôt qu'une définition étroite, pour mesurer correctement l'impact de la transition verte sur l'emploi en général. Ils concluent par ailleurs qu'il faudrait s'intéresser davantage à la qualité des emplois verts et au caractère inclusif de la croissance de l'emploi vert.