bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of direct‐acting antiviral agents on liver function in patients with chronic hepatitis C virus infection
Authors: Johnson Philip J. , Berhane Sarah , Walker Alex J. , Gordon Fiona H. , Ryder Steven D , McPherson Stuart , Sreedharan Aravamuthan , Ustianowski Andrew A. , Agarwal Kosh , Mutimer David , Kumada Takeshi , Toyoda Hidenori , Irving William L. ,   HCV Research UK
Published: September 2020

Whilst the benefit of direct‐acting antiviral agents (DAAs) in achieving sustained virological response (SVR) is now well‐accepted, their impact on liver function, particularly in relation to achievement of SVR, has not been well documented. We studied 2394 patients with chronic HCV infection, 1276 receiving DAAs and 1118 interferon‐based therapy. Liver function was assessed by the albumin‐bilirubin (ALBI) score or grade. Overall survival according to SVR status and baseline ALBI grade was examined. We also studied time to first decompensation according to ALBI grade, as well as longitudinal changes in ALBI score over time according to SVR. Among the patients receiving DAAs, 89% achieved SVR (Japan = 99%, UK = 78%). Amongst the decompensated patients in the UK cohort, three distinct risk groups according to ALBI grade at baseline were observed. The UK patients receiving DAAs, who had predominantly decompensated disease, showed clear evidence of improvement of liver function detectable within 2 years of the start of treatment, especially in those achieving SVR. These early changes in liver function were very similar to those observed in the first 2‐3 years after interferon‐based therapy. DAAs improve liver function especially in those with decompensated disease who achieve SVR. Experience with interferon‐based therapy suggests that failure to achieve SVR is associated with long‐term decline in liver function and, in contrast, patients who do achieve SVR can expect long‐term disease improvement and subsequent stabilization of liver function. Our initial analysis suggests that those receiving DAAs are likely, in the long term, to follow a similar course.
Hepatitis C and HIV combined screening in primary care: A cluster randomized trial
Authors: Martínez‐Sanz Javier , Vivancos María Jesús , Sánchez‐Conde Matilde , Gómez‐Ayerbe Cristina , Polo Lidia , Labrador Cristina , González Patricia , Mesa Alba , Muriel Alfonso , Chamorro Clotilde , de la Fuente Yolanda , Pérez Elías Pilar , Uranga Almudena , Herrero Margarita , Ares Sara , Barea Rafael , Moreno Santiago , Pérez‐Elías María Jesús
Published: September 2020

Hepatitis C virus (HCV) and HIV are major causes of worldwide disease. We aimed to evaluate the effect of a combined screening programme, which included a risk‐assessment questionnaire and rapid tests for point‐of‐care diagnosis, on screening and new diagnosis rates. This prospective, cluster randomized study was carried out in primary care. The intervention arm included a 4‐hour educational programme, the use of a risk‐assessment questionnaire and rapid tests. In the control centres, only the educational intervention was provided. The main variables compared were the screening coverage and the number and rate of new HCV and HIV diagnoses. Of a total of 7991 participants, 4670 (58.5%) and 2894 (36.2%) presented a risk questionnaire for HIV or HCV, respectively. The younger participants, men and those from Latin America and Eastern Europe, showed the greatest risk of presenting with a positive questionnaire. The overall screening coverage was higher within the intervention arm (OR 17.7; 95% CI 16.2‐19.5; P < .001). Only two HIV‐positives were identified compared to one in control centres. The rate of HCV diagnoses was higher among intervention centres, with 37 versus seven positive tests (OR 5.2; 95% CI 2.3‐11.6; P < .001). Of them, 10 were new diagnoses and 27 had been previously diagnosed, although not linked to care. In conclusion, a simple operational programme can lead to an increase in HCV and HIV screening rates, compared to an exclusively educational programme. The selection of at‐risk patients with a self‐questionnaire and the use of rapid tests significantly increased the diagnostic rate of HCV infection.
Planar and single‐photon emission computed tomography imaging in dogs with thyroid tumors: 68 cases
Authors: van den Berg Marit F. , Daminet Sylvie , Stock Emmelie , Vandermeulen Eva , Scheemaeker Stephanie , Campos Miguel , Kooistra Hans S. , Galac Sara , Duchateau Luc , Peremans Kathelijne
Published: September 2020

Background

Information on scintigraphy findings in dogs with thyroid neoplasia is scarce. The use of single‐photon emission computed tomography (SPECT) could improve detection of metastatic disease.

Hypothesis/Objectives

To describe planar and SPECT imaging findings in dogs with thyroid tumors, and to compare SPECT and thoracic radiography for metastasis detection.

Animals

Sixty‐eight dogs with thyroid neoplasia.

Methods

Retrospective study, search of medical records for dogs with thyroid neoplasia (2008‐2018).

Results

Thyroid scintigraphy was available from 68 dogs, of which 6 presented after surgical resection. Radionuclide uptake was increased in 56% of dogs, decreased in 24%, and comparable to that of the salivary glands in 13%. The remainder had multiple masses with variable uptake. A homogeneous uptake pattern was present in 16% and a heterogeneous uptake pattern in 73%. In 11% (all dogs with multiple masses), various uptake patterns were present. Thyroid tumors were well delineated in 55%. There was a significant association between hormone status and uptake pattern (P= .009), with a heterogeneous uptake pattern in the majority of euthyroid dogs, and hormone status and tumor circumscription (P= .003), with well‐circumscribed margins in the majority of hypothyroid and hyperthyroid dogs. Thoracic SPECT imaging was available in 39 dogs and identified metastatic lesions in 15 dogs. Thoracic radiographs were performed in 14 of these dogs, and detected metastases in 3 dogs.

Conclusions and Clinical Importance

SPECT imaging is a viable imaging technique to screen for thoracic metastasis and wider use of SPECT imaging is recommended in dogs with thyroid neoplasia.
Habitat type and island identity as drivers of community assembly in an archipelago
Authors: Chiarucci Alessandro , Buldrini Fabrizio , Cervellini Marco , Guarino Riccardo , Caccianiga Marco , Foggi Bruno , Viciani Daniele , Lazzaro Lorenzo , Casella Laura , Angelini Pierangela , Cerabolini Bruno Enrico Leone , Pasta Salvatore , Enea Mirko , Zannini Piero
Published: September 2020

Aim

Ecoinformatics offer new opportunity to test islands as biogeographic and ecological models. In this paper we predicted three hypotheses: (1) plot‐based data issuing from vegetation surveys can be used to predict Island Species‐Area Relationships (ISARs) or island similarity; (2) the habitat area is an independent predictor of species richness patterns within island; (3) species richness and composition are more dependent on habitat type than island identity in land‐bridge islands.

Area

Tuscan Archipelago, Italy.

Methods

We assembled a database of all the vegetation plots available for the archipelago. For the first hypothesis we calculated ISARs, using Arrhenius model, and Beta Diversity, using Jaccard dissimilarity, on both published floras and cumulative plot data. For the second hypothesis, we modelled Habitat Species‐Area Relationships (HSARs), using Arrhenius model. For the third hypothesis, we used additive partitioning of species richness, NMDS and PERMANOVA.

Results

Island Species‐Area Relationships based on plot data mirrored those on published floras, but absolute values of c and z parameters were different. Beta diversity based on plot data resembled those of published floras, but was higher. Species richness was significantly related to the habitat area. The total species richness of the archipelago was linked to large scale drivers, such as island identity, while plot species composition was driven by both habitat type and island identity.

Conclusions

Data assembled issuing from vegetation surveys are useful to describe biogeographic patterns. Species richness in the archipelago is driven by spatial factors such as the amount of habitats and the differences among islands, while the species composition of local assemblages is largely driven by habitat filters rather than by island identity, as expected in land‐bridge islands.
The response of productivity and its sensitivity to changes in precipitation: A meta‐analysis of field manipulation experiments
Authors: Zhang Jiayang , Li Junyong , Xiao Rui , Zhang Jiajia , Wang Dong , Miao Renhui , Song Hongquan , Liu Yinzhan , Yang Zhongling , Liu Mengzhou
Published: September 2020

Questions

Changes in precipitation can influence grassland productivity and its sensitivity to precipitation variation, but general patterns remain elusive.

Methods

Using data from 59 studies of experimental precipitation manipulations in grasslands, we tested the effect of increases and decreases in precipitation on above‐ground net primary productivity (ANPP), below‐ground net primary productivity (BNPP), forb and grass productivity, and their sensitivity to changes in precipitation.

Results

Our results demonstrated that: (a) ANPP sensitivity to increases in precipitation was 87.3% greater than to decreases in precipitation, whereas there was no difference in the sensitivity of BNPP to increases and decreases in precipitation; (b) the sensitivity of grasses was 315.5% higher to decreases in precipitation than to increases in precipitation, but there was no difference in the sensitivity of forbs to increases and decreases in precipitation; (c) the sensitivity of ANPP to increases and decreases in precipitation was 620.8% and 91.7% higher than that of BNPP, respectively; (d) the sensitivity of grasses to precipitation decreases was 157% higher than that of forbs, but there was no difference in the sensitivity of grasses and forbs to increases in precipitation; and (e) the sensitivity of ANPP to increases in precipitation and BNPP to both increases and decreases in precipitation reduced with increasing mean annual precipitation (MAP), and the reduced magnitude in BNPP sensitivity was higher to precipitation increases than to precipitation decreases. In contrast, neither grass nor forb sensitivity varied with changes in MAP.

Conclusions

Our study suggests that grassland productivity and its sensitivity to changes in precipitation not only depend on the magnitude of precipitation but also on the direction of precipitation change. These findings are important for the management of grasslands under future precipitation change scenarios.
HCV cirrhotic patients treated with direct‐acting antivirals: Detection of tubular dysfunction and resolution after viral clearance
Authors: Biliotti Elisa , Palazzo Donatella , Tinti Francesca , D'Alessandro Maria Domenica , Esvan Rozenn , Labriola Raffaella , Cappoli Andrea , Umbro Ilaria , Volpicelli Lorenzo , Bachetoni Alessandra , Villa Erica , Mitterhofer Anna Paola , Rucci Paola , Taliani Gloria
Published: September 2020

Background/Aims

Hepatitis C virus (HCV) has been identified in tubular epithelial cells of infected patients; however, the presence of tubular dysfunction, which is a risk factor for chronic kidney disease (CKD), has never been examined in vivo. The present prospective longitudinal study aimed to estimate the prevalence of tubular dysfunction alone or with glomerular damage and its evolution after HCV clearance in cirrhotic patients.

Methods

One hundred and thirty‐five consecutive Child‐Pugh A cirrhotic patients were evaluated before antiviral treatment and 6 months after the end of therapy. Tubular dysfunction was evaluated by urinary alpha1‐microglobulin to creatinine ratio (α1‐MCR), and glomerular damage was assessed by urinary albumin to creatinine ratio (ACR).

Results

Almost all the patients (93.3%) showed a normal or mildly decreased e‐GFR (KDIGO‐G1/G2‐categories). Tubular dysfunction was found in 23.7% (32/135) of patients, co‐occurring with glomerular damage in 37.5% (12/32) of cases, while glomerular damage was found in 16.3% (22/135) of patients. In multiple logistic regression, glomerular damage and the concomitant presence of diabetes and hypertension were the only predictors significantly associated with tubular dysfunction. After HCV clearance, patients experienced a significant reduction of α1‐MCR levels (21.0 vs 10.5 μg/mg, P = .009) and tubular dysfunction resolved in 57.1% of subjects.

Conclusions

Tubular dysfunction is an unrecognized feature of HCV‐related kidney disease in cirrhotic patients and its presence should be primarily investigated in subjects with glomerular damage, diabetes and hypertension, despite normal e‐GFR. Tubular dysfunction resolves in the majority of cases after HCV clearance; however, it may persist after antiviral treatment and further studies should evaluate its long‐term impact on kidney function.
Non‐selective beta‐blockers increase overall and liver mortality in alcoholic cirrhosis with MELD ≥ 12 over 5 years of follow‐up
Authors: Calès Paul , Bertrais Sandrine , Boursier Jérôme , Fouchard Isabelle , Oberti Frédéric ,   SNIFF 16 group
Published: September 2020

Background & Aims

Non‐cardioselective beta‐blocker (NSBB) effects on mortality in cirrhosis are controversial. We evaluated the impact of NSBBs on mortality according to liver severity and mortality cause.

Methods

Two hundred and fifty‐eight patients with alcoholic cirrhosis were included in a retroprospective cohort: 129 NSBB‐treated and 129 controls. The NSBB group had the following significant baseline differences: higher MELD, more frequent previous gastrointestinal bleeding, large oesophageal varices (OV) and lower heart rate. Propranolol dose was 160 mg/d in 81% of NSBB patients.

Results

(i) Liver function: during 5.3 ± 2.6 years of follow‐up, MELD progression was higher in NSBB patients: 1 (−1‐4) than in controls: 0 (−1‐1) (P = .017). (ii) Overall survival: no significant differences were observed between NSBBs and controls (Kaplan‐Meier curves: P = .291). In multivariate Cox analysis, baseline MELD interacted with NSBB (P = .011). Thus, the NSBB hazard ratio (HR) was 0.99 (0.50‐1.98) in MELD < 12 vs 3.17 (1.19‐8.42) in MELD ≥ 12. (iii) Liver survival: NSBB decreased liver survival (Kaplan‐Meier: P = .031). In multivariate Cox analysis, baseline MELD interacted with NSBB (P < .001). The NSBB HR was 0.81 (0.30‐2.19) in MELD < 12 vs 6.23 (1.94‐20.0) in MELD ≥ 12. In competing risk multivariate analysis for liver mortality, the MELD‐NSBB interaction was significant (P < .001): the NSBB HR was 1.02 (0.36‐2.91) in MELD < 12 vs 9.24 (3.18‐26.9) in MELD ≥ 12. 4) Non‐liver survival: contrastingly, non‐liver survival was increased by NSBBs, especially in MELD ≥ 12 (competing Kaplan‐Meier: P = .044). These results were confirmed in propensity risk score (PRS)‐matched patients.

Conclusion

In alcoholic cirrhosis with rather high propranolol doses, overall and liver survival are significantly aggravated when MELD is ≥12.
Oxygen and carbon stable isotope composition of the weathering Mg‐carbonates formed on the surface of the LEW 85320 ordinary chondrite: Revisited
Authors: El‐Shenawy Mohammed I. , Niles Paul B. , Ming Doug W. , Socki Rick , Righter Kevin
Published: September 2020

New δ13C and δ18O values were measured to constrain the formation mechanisms of two previously identified generations (Antarctica and Houston) of terrestrial weathering carbonates, nesquehonite, which formed on the surface of the Lewis Cliff 85320 ordinary chondrite. These two nesquehonite generations exhibit a characteristic carbon and oxygen isotopic trend which starts with a linear δ13C‐δ18O covariation followed by a continuous increase in δ18O with little to no change in δ13C. Based on the newly developed nesquehonite‐water oxygen isotope thermometry and the measured δ18O value of melted ice from Antarctica, the formation temperature of the Antarctic nesquehonite generation was estimated to be −1.9 ± 3 °C. Houston nesquehonite generation was most likely formed from an evaporative residue of the melted Antarctic ice at 30 ± 4 °C. Modeling the isotopic trend of the two generations suggests that evaporation created large δ18O variations in the nesquehonite while carbon isotopes were stabilized by exchange between the parent liquid and atmospheric CO2. Thus, we suggest that carbonates formed by terrestrial weathering in Antarctica should possess a wide spread in δ18O values and a narrow range in δ13C values under dry and cold conditions. Finally, the observed wide spread of δ18O in Martian carbonates (e.g., Allan Hills 84001 and Nakhla) can be explained by evaporation near 0 °C and may have formed by a similar mechanism to that of the nesquehonite in the LEW 85320. Meanwhile, the wide spread of δ13C suggests that two carbon reservoirs with distinct isotope compositions on Mars (e.g., the atmospheric carbon and magmatic carbon) may be actively participating in the formation process.
Rapid homoploid hybrid speciation in British gardens: The origin of Oxford ragwort (Senecio squalidus)
Authors: Nevado Bruno , Harris Stephen A. , Beaumont Mark A. , Hiscock Simon J.
Published: September 2020

Hybridisation can lead to homoploid hybrid speciation, i.e., the origin of new species without change in chromosome number between parents and offspring. Central to homoploid hybrid speciation is the role of hybridisation in the establishment of reproductive isolation between the hybrid and the parental species in the early stages of speciation, when typically all species occur at least partly in sympatry. In this work we analyse genome‐wide polymorphism data obtained by transcriptome sequencing of the British hybrid species Oxford ragwort (Senecio squalidus,Asteraceae), its two Italian parental species (S. aethnensisandS. chrysanthemifolius)and their naturally occurring hybrids on Mt Etna (Italy). We show that Oxford ragwort most likely originated from de novo hybridisation between its two Italian parental species whilst they were in cultivation in British gardens at the turn of the 18th century. Reproductive isolation between the new hybrid species and its parental species probably resulted from inheritance of genetic incompatibilities between the two parental species and subsequent ecological segregation – both of which have been shown in previous studies. Our results imply thatS. squalidusmeets the most stringent criteria set forth to identify homoploid hybrid speciation, and call attention to the creative role of hybridisation in responding to novel environmental conditions.
Monitoring the ecological status of rivers with diatom eDNA metabarcoding: A comparison of taxonomic markers and analytical approaches for the inference of a molecular diatom index
Authors: Apothéloz‐Perret‐Gentil Laure , Bouchez Agnès , Cordier Tristan , Cordonier Arielle , Guéguen Julie , Rimet Frederic , Vasselon Valentin , Pawlowski Jan
Published: September 2020

Recently, several studies demonstrated the usefulness of diatom eDNA metabarcoding as an alternative to assess the ecological quality of rivers and streams. However, the choice of the taxonomic marker as well as the methodology for data analysis differ between these studies, hampering the comparison of their results and effectiveness. The aim of this study was to compare two taxonomic markers commonly used in diatom metabarcoding and three distinct analytical approaches to infer a molecular diatom index. We used the values of classical morphological diatom index as a benchmark for this comparison. We amplified and sequenced both a fragment of the rbcL gene and the V4 region of the 18S rRNA gene for 112 epilithic samples from Swiss and French rivers. We inferred index values using three analytical approaches: by computing it directly from taxonomically assigned sequences, by calibrating de novo the ecovalues of all metabarcodes, and by using a supervised machine learning algorithm to train predictive models. In general, the values of index obtained using the two “taxonomy‐free” approaches, encompassing molecular assignment and machine learning, were closer correlated to the values of the morphological index than the values based on taxonomically assigned sequences. The correlations of the three analytical approaches were higher in the case of rbcL compared to the 18S marker, highlighting the importance of the reference database which is more complete for the rbcL marker. Our study confirms the effectiveness of diatom metabarcoding as an operational tool for rivers ecological quality assessment and shows that the analytical approaches by‐passing the taxonomic assignments are particularly efficient when reference databases are incomplete.
Westward range expansion from middle latitudes explains the Mississippi River discontinuity in a forest herb of eastern North America
Authors: Prior Carly J. , Layman Nathan C. , Koski Matthew H. , Galloway Laura F. , Busch Jeremiah W.
Published: September 2020

It is often expected that temperate plants have expanded their geographical ranges northward from primarily southern refugia. Evidence for this hypothesis is mixed in eastern North American species, and there is increasing support for colonization from middle latitudes. We studied genome‐wide patterns of variation in RADseq loci to test hypotheses concerning range expansion in a North American forest herb (Campanula americana). First, spatial patterns of genetic differentiation were determined. Then phylogenetic relationships and divergence times were estimated. Spatial signatures of genetic drift were also studied to identify the directionality of recent range expansion and its geographical origins. Finally, spatially explicit scenarios for the spread of plants across the landscape were compared, using variation in the population mutation parameter and Tajima's D. We found strong longitudinal subdivision, with populations clustering into groups west and east of the Mississippi River. While the southeastern region was probably part of a diverse Pleistocene refugium, there is little evidence that range expansion involved founders from these southern locales. Instead, declines in genetic diversity and the loss of rare alleles support a westward colonization wave from a middle latitude refugium near the southern Appalachian Mountains, with subsequent expansion from a Pleistocene staging ground in the Mississippi River Valley (0.51–1.27 million years ago). These analyses implicate stepping stone colonization from middle latitudes as an important mechanism of species range expansion in eastern North America. This study further demonstrates the utility of population genetics as a tool to infer the routes travelled by organisms during geographical range expansion.
FLI1 and ERG protein degradation is regulated via Cathepsin B lysosomal pathway in human dermal microvascular endothelial cells
Authors: Mazzotta Celestina , Marden Grace , Farina Alessandra , Bujor Andreea , Trojanowski Marcin A. , Trojanowska Maria
Published: September 2020

Objectives

Friend leukemia integration 1 and erythroblast transformation‐specific, important regulators of endothelial cell homeostasis, are reduced in microvascular endothelial cells in scleroderma patients, and their deficiency has been implicated in disease pathogenesis. The goal of this study was to identify the mechanisms involved in the protein turnover of friend leukemia integration 1 and erythroblast transformation‐specific in microvascular endothelial cells.

Methods

The effects of lysosome and proteosome inhibitors on friend leukemia integration 1 and erythroblast transformation‐specific levels were assessed by Western blotting and capillary morphogenesis. The effect of scleroderma and control sera on the levels of friend leukemia integration 1 and erythroblast transformation‐specific was examined.

Results

The reduction in the protein levels of friend leukemia integration 1 and erythroblast transformation‐specific in response to interferon α or Poly:(IC) was reversed by blocking either lysosomal (leupeptin and Cathepsin B inhibitor) or proteosomal degradation (MG132). MG132, leupeptin or CTSB‐(i) also counteracted the anti‐angiogenic effects of Poly:(IC) or interferon α. Scleroderma sera reduced protein levels of friend leukemia integration 1 and erythroblast transformation‐specific in comparison to control sera. Treatment with CTSB(i) increased the levels of friend leukemia integration 1 and erythroblast transformation‐specific in a majority of serum‐treated samples.

Conclusions

Inhibition of cathepsin B was effective in reversing the reduction of friend leukemia integration 1 and erythroblast transformation‐specific protein levels after treatment with interferon α or scleroderma sera, suggesting that targeting cathepsin B may have a beneficial effect in SSc vascular disease.
Transcriptional regulation of the Nε‐fructoselysine metabolism in Escherichia coli by global and substrate‐specific cues
Authors: Graf von Armansperg Benedikt , Koller Franziska , Gericke Nicola , Hellwig Michael , Jagtap Pravin Kumar Ankush , Heermann Ralf , Hennig Janosch , Henle Thomas , Lassak Jürgen
Published: September 2020

Thermally processed food is an important part of the human diet. Heat‐treatment, however, promotes the formation of so‐called Amadori rearrangement products, such as fructoselysine. The gut microbiota including Escherichia coli can utilize these compounds as a nutrient source. While the degradation route for fructoselysine is well described, regulation of the corresponding pathway genes frlABCD remained poorly understood. Here, we used bioinformatics combined with molecular and biochemical analyses and show that fructoselysine metabolism in E. coli is tightly controlled at the transcriptional level. The global regulator CRP (CAP) as well as the alternative sigma factor σ32 (RpoH) contribute to promoter activation at high cAMP‐levels and inside warm‐blooded hosts, respectively. In addition, we identified and characterized a transcriptional regulator FrlR, encoded adjacent to frlABCD, as fructoselysine‐6‐phosphate specific repressor. Our study provides profound evidence that the interplay of global and substrate‐specific regulation is a perfect adaptation strategy to efficiently utilize unusual substrates within the human gut environment.
Deciphering the Che2 chemosensory pathway and the roles of individual Che2 proteins from Pseudomonas aeruginosa
Authors: Orillard Emilie , Watts Kylie J.
Published: September 2020

Pseudomonas aeruginosa is an opportunistic pathogen that senses and responds to its environment via four chemosensory systems. Oxygen activates the Che2 chemosensory system by binding to the PAS‐heme domain of the Aer2 receptor. Ostensibly, the output of Che2 occurs via its response regulator CheY2, but controversy persists over CheY2’s exact role. In this study, we show that CheY2 does not interact with the flagellar motor and that the Che2 system does not transfer phosphoryl groups to the chemotaxis (Che) system. We show that CheY2 instead provides feedback control of Aer2 adaptation. In the presence of O2, Aer2 signaling increases the autophosphorylation of the histidine kinase CheA2, followed by CheY2‐mediated dephosphorylation. CheY2 does not stably retain phosphate and may not signal the output of the Che2 system. Rather, CheY2 activity enhances the direct interaction of CheY2 with the adaptation protein CheD (a role often facilitated by CheC, which P. aeruginosa lacks). In the absence of O2, Aer2 does not signal, and CheY2/CheD interactions attenuate. This frees CheD to augment CheR2‐mediated methylation of Aer2, which enhances Aer2 signaling. CheD does not interact with CheR2, but most likely interacts with Aer2 via conserved CheD‐binding motifs to make Aer2 a better methylation substrate.
Impact of biofilm production by Candida species and antifungal therapy on mortality of patients with candidemia
Authors: Lee Chen‐Hsiang , Chen Yi‐Chun , Chen I‐Ling , Chen Fang‐Ju , Chien Chun‐Chih
Published: September 2020

Background and Objectives

Few studies have investigated the clinical outcomes of patients with candidemia caused by Candida species with different levels of biofilm formation. We aimed to investigate the impact of antifungal therapy on the outcome of candidemia caused by Candida species that were categorised as low biofilm formers (LBFs), moderate biofilm formers (MBFs), and high biofilm formers (HBFs).

Methods

Adults with candidemia caused by LBF and HBF/MBF Candida species that were susceptible to fluconazole and caspofungin were included to investigate the impact of treatment with fluconazole vs an echinocandin on 30‐day crude mortality.

Results

In total, 215 patients with candidemia received fluconazole and 116 patients received an echinocandin. In multivariate analysis, Pittsburgh bacteremia score ≥ 4 (adjusted odds ratio [AOR] =2.42; 95% confidence interval [CI], 1.32‐4.41), malignancy (AOR = 3.45; 95% CI, 1.83‐6.51), not removing the central venous catheter within 48 hours of a positive blood culture (AOR = 4.69; 95% CI, 2.61‐8.45), and treatment with fluconazole for candidemia due to HBF/MBF Candida spp. (AOR = 2.23; 95% CI, 1.22‐4.06) were independent factors associated with 30‐day mortality. Of the 165 patients infected by HBF/MBF Candida isolates, those who received azole therapy had a significantly higher sepsis‐related mortality rate than those who received echinocandin therapy (44.9% [49/109] vs 26.8% [15/56], P = .03).

Conclusions

There was a trend of an independent association between fluconazole treatment and poor outcomes in the patients infected by HBF/MBF Candida strains.
Neurogeriatric approach to delirium/dementia in a multi‐faculty university hospital
Authors: Sakakibara Ryuji , Katsuragawa Shuichi , Iimura Ayako , Ogata Tsuyoshi , Terayama Keiichiro , Doi Hirokazu , Suzuki Keiko , Tateno Fuyuki , Aiba Yosuke , Sato Megumi
Published: September 2020

Objective

Delirium/dementia (collectively called cognitive spectrum disorder [CSD]) is a major issue in hospital wards. However, few reports are available on the incidence of CSD on multi‐faculty wards or on the factors contributing to it. The aim of this study was to address these issues by a neurogeriatric team (neurologists, psychiatrists, specialist nurses, and link nurses from all wards).

Patients and Methods

This was a retrospective study with a 12‐month recruiting period, a prospective follow‐up period of 3.0 ± 2.5 weeks, and ≥1×/week visits. We diagnosed acute‐onset delirium by the Confusion Assessment Method and analyzed underlying conditions. We also diagnosed premorbid dementia by neurocognitive examination and neuroimaging following published criteria.

Results

Our subjects were 723 CSD from 15 faculties, accounting for 6.5% of admissions, 393 men and 330 women, mean age 81 years. CSD was prevalent in cardiology/cardiac surgery (CAR), orthopedic surgery (OP), and neurology/neurosurgery (N), with dementia alone in ophthalmology and a combination of delirium/dementia in the other faculties. Premorbid dementia were diagnosed with Alzheimer's disease (AD), white matter disease, dementia with Lewy bodies (DLB), or some combination of these. Delirium was accompanied by worsening of gait difficulty. The ratio of brain (N) versus extra‐brain was 105 (14.5%):618 (85.5%). Severe CSD was common in DLB than AD but without statistical significance.

Conclusion

Total 6.5% of hospital admissions showed CSD, with CAR, OP, and N being prevalent. The ratio of brain versus extra‐brain was 14.5%:85.5%. Severe CSD was more prevalent in DLB patients than in AD patients, but without statistical significance.
A novel multi‐exon deletion in the dysferlin gene of a limb‐girdle muscular dystrophy type 2B Filipino patient
Authors: Porto Kristine Joyce L. , Mitsui Jun , Ishiura Hiroyuki , Kubota Akatsuki , Luspian Kathleen Jaye L. , Eduardo Emmanuel , Damian Ludwig , Toda Tatsushi , Tsuji Shoji
Published: September 2020

We present a 34‐year‐old woman, from Philippines, diagnosed limb‐girdle muscular dystrophy type 2B with compound heterozygous nonsense mutation W1478* and novel deletion of exons 43‐46 of the dysferlin gene. These loss‐of‐function mutations do not seem to be predictive of a severer clinical course. We report the first identification of microhomologous region of 2 bp (TG) identical sequences surrounding the breakpoint junction. Detailed analysis of the deleted allele should be pursued in order to better understand the underlying mechanism of genomic rearrangements of the dysferlin gene.
Recurrent severe and long‐lasting cerebellar ataxia attacks in adult‐onset neuronal intranuclear inclusion disease
Authors: Osakada Yosuke , Deguchi Kentaro , Deguchi Shoko , Higaki Fumiyo , Oda Wakako , Yoshida Mari , Ohta Yasuyuki , Yamashita Toru , Abe Koji
Published: September 2020

Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disease that is characterized by eosinophilic hyaline intranuclear inclusions. NIID presents highly variable clinical manifestations such as dementia, ataxia, convulsion, neuropathy, and autonomic dysfunction. A 60‐year‐old woman developed recurrent severe cerebellar ataxia (SARA score: 30/40 points). She was diagnosed with adult‐onset NIID by a characteristic brain diffusion‐weighed imaging hyperintensity lesion in subcortical white matter and intranuclear inclusion bodies in a skin biopsy. Her ataxia was more severe and lasted longer (additional 19 days) than a previous case, although she showed remarkable improvement.
Lotus japonicus Nuclear Factor YA1, a nodule emergence stage‐specific regulator of auxin signalling
Authors: Shrestha Arina , Zhong Sihui , Therrien Jasmine , Huebert Terry , Sato Shusei , Mun Terry , Andersen Stig U. , Stougaard Jens , Lepage Agnes , Niebel Andreas , Ross Loretta , Szczyglowski Krzysztof
Published: September 2020

Organogenesis of legume root nodules begins with the nodulation factor‐dependent stimulation of compatible root cells to initiate divisions, signifying an early nodule primordium formation event. This is followed by cellular differentiation, including cell expansion and vascular bundle formation, and we previously showed that Lotus japonicus NF‐YA1 is essential for this process, presumably by regulating three members of the SHORT INTERNODES/STYLISH (STY) transcription factor gene family.

In this study, we used combined genetics, genomics and cell biology approaches to characterize the role of STY genes during root nodule formation and to test a hypothesis that they mediate nodule development by stimulating auxin signalling.

We show here that L. japonicus STYs are required for nodule emergence. This is attributed to the NF‐YA1‐dependent regulatory cascade, comprising STY genes and their downstream targets, YUCCA1 and YUCCA11, involved in a local auxin biosynthesis at the post‐initial cell division stage. An analogous NF‐YA1/STY regulatory module seems to operate in Medicago truncatula in association with the indeterminate nodule patterning.

Our data define L. japonicus and M. truncatula NF‐YA1 genes as important nodule emergence stage‐specific regulators of auxin signalling while indicating that the inductive stage and subsequent formation of early nodule primordia are mediated through an independent mechanism(s).
CERBERUS is critical for stabilization of VAPYRIN during rhizobial infection in Lotus japonicus
Authors: Liu Miaoxia , Jia Ning , Li Xiaolin , Liu Ruijun , Xie Qi , Murray Jeremy D. , Downie J. Allan , Xie Fang
Published: September 2020

CERBERUS (also known as LIN) and VAPYRIN (VPY) are essential for infection of legumes by rhizobia and arbuscular mycorrhizal fungi (AMF). Medicago truncatula LIN (MtLIN) was reported to interact with MtVPY, but the significance of this interaction is unclear and the function of VPY in Lotus japonicus has not been studied.

We demonstrate that CERBERUS has auto‐ubiquitination activity in vitro and is localized within distinct motile puncta in L. japonicus root hairs and in Nicotiana benthamiana leaves. CERBERUS colocalized with the trans‐Golgi network/early endosome markers.

In L. japonicus, two VPY orthologs (LjVPY1 and LjVPY2) were identified. CERBERUS interacted with and colocalized with both LjVPY1 and LjVPY2. Co‐expression of CERBERUS with LjVPY1 or LjVPY2 in N. benthamiana led to increased protein levels of LjVPY1 and LjVPY2, which accumulated as mobile punctate bodies in the cytoplasm. Conversely, LjVPY2 protein levels decreased in cerberus roots after rhizobial inoculation. Mutant analysis indicates that LjVPY1 and LjVPY2 are required for rhizobial infection and colonization by AMF.

Our data suggest that CERBERUS stabilizes LjVPY1 and LjVPY2 within the trans‐Golgi network/early endosome, where they might function to regulate endocytic trafficking and/or the formation or recycling of signaling complexes during rhizobial and AMF symbiosis.
CircCDK8 regulates osteogenic differentiation and apoptosis of PDLSCs by inducing ER stress/autophagy during hypoxia
Authors: Zheng Jingjing , Zhu Ximei , He Yani , Hou Siyu , Liu Ting , Zhi Keqian , Hou Tiezhou , Gao Ling
Published: September 2020

Mounting evidence indicates that circular RNAs (circRNAs) have essential roles in several diseases, including periodontitis. Periodontal ligament stem cells (PDLSCs) exhibit potential for treating periodontitis accompanied by hypoxia. However, it is unclear how circRNA affects the osteogenesis of PDLSCs under hypoxia. In this study, a novel circRNA, hsa_circ_0003489, was found located at the gene for cyclin‐dependent kinase 8 (CDK8) and referred to as circCDK8. The expression levels of circCDK8 and hypoxia‐inducible factor‐1α were significantly increased in periodontitis tissues, and the expression of circCDK8 was further confirmed in a hypoxia model using cobalt chloride (CoCl2). Interestingly, the results showed that the expression levels of osteoblast markers (RUNX2, ALP, OCN, and COL1A1) were increased in CoCl2‐treated PDLSCs at 6 and 12 h, but decreased at 24, 48, and 72 h. On the basis of bioinformatics and functional experiments, CoCl2 also induced endoplasmic reticulum stress, autophagy, and apoptosis of PDLSCs; the inhibition of autophagy promoted the osteogenic differentiation of CoCl2‐treated PDLSCs. Furthermore, circCDK8 overexpression induced autophagy and apoptosis through mTOR signaling, and circCDK8 silencing reversed the inhibitory effects of CoCl2 on osteogenic differentiation of PDLSCs. In conclusion, our results indicate that circCDK8 represses the osteogenic differentiation of PDLSCs by triggering autophagy activation in a hypoxic microenvironment. CircCDK8 could be a new therapeutic target of periodontitis.
Changes in DNA methylation accompany changes in gene expression during chondrocyte hypertrophic differentiation in vitro
Authors: Singh Purva , Lessard Samantha G. , Mukherjee Piali , Rourke Brennan , Otero Miguel
Published: September 2020

During osteoarthritis (OA), articular chondrocytes undergo phenotypic changes that resemble developmental patterns characteristic of growth plate chondrocytes. These phenotypic alterations lead to a hypertrophy‐like phenotype characterized by altered production of extracellular matrix constituents and increased collagenase activity, which, in turn, results in cartilage destruction in OA disease. Recent studies have shown that the phenotypic instability and dysregulated gene expression in OA are associated with changes in DNA methylation patterns. Subsequent efforts have aimed to identify changes in DNA methylation with functional impact in OA disease, to potentially uncover therapeutic targets. Here, we paired an in vitro 3D/pellet culture system that mimics chondrocyte hypertrophy with RNA sequencing (RNA‐Seq) and enhanced reduced representation of bisulfite sequencing (ERRBS) to identify transcriptomic and epigenomic changes in murine primary articular chondrocytes undergoing hypertrophy‐like differentiation. We identified hypertrophy‐associated changes in DNA methylation patterns in vitro. Integration of RNA‐Seq and ERRBS datasets identified associations between changes in methylation and gene expression. Our integrative analyses showed that hypertrophic differentiation of articular chondrocytes is accompanied by transcriptomic and epigenomic changes in vitro. We believe that our integrative approaches have the potential to uncover new targets for therapeutic intervention.
Host–parasite dynamics set the ecological theatre for the evolution of state‐ and context‐dependent dispersal in hosts
Authors: Deshpande Jhelam N. , Kaltz Oliver , Fronhofer Emanuel A.
Published: September 2020

While host–parasite interactions are ubiquitous, the large‐scale consequences of parasite infections are mainly driven by the spatial context. One trait of pivotal importance for the eco‐evolutionary dynamics of such metapopulations is the spatial behaviour of hosts, that is, their dispersal. It is well established that dispersal is not a random process, rather dispersal is informed and may depend on internal and external factors. In host–parasite metapopulations, dispersal may be a function of a host's infection state, but also of the local context, such as host density or parasite prevalence. Using a dynamical host–parasite metapopulation model of a parasite that reduces host fecundity (sterilizing parasite), we explore whether host dispersal evolves to be state‐ and context‐dependent and what shapes the evolutionarily stable dispersal reaction norms have. We show that state‐dependent dispersal readily evolves in the sense that hosts disperse more when infected, except when infected hosts pay significantly higher dispersal costs. This dispersal bias evolves due to kin selection, which is consistent with previous studies. Most importantly, we show that prevalence‐dependent dispersal evolves, especially when virulence is high and epidemiological dynamics have predictable signatures. The observed evolutionary outcome, a negatively prevalence‐dependent dispersal reaction norm for susceptible hosts at high virulence, seems counter‐intuitive at first. However, our results can be readily explained by the emergent epidemiological dynamics, especially their spatial and temporal correlation patterns. Finally, we show that context‐dependency in dispersal may rely on both, prevalence, and host density cues. Our work provides new insights into the evolution of complex dispersal phenotypes in host–parasite metapopulations as well as on feedbacks with epidemiological dynamics.
Polyamines in the virulence of bacterial pathogens of respiratory tract
Authors: Banerji Rajashri , Kanojiya Poonam , Patil Amrita , Saroj Sunil D.
Published: September 2020

Polyamines are positively charged hydrocarbons that are essential for the growth and cellular maintenance in prokaryotes and eukaryotes. Polyamines have been demonstrated to play a role in bacterial pathogenicity and biofilm formation. However, the role of extracellular polyamines as a signaling molecule in the regulation of virulence is not investigated in detail. The bacterial pathogens residing in the respiratory tract remain asymptomatic for an extended period; however, the factors that lead to symptomatic behavior are poorly understood. Further investigation to understand the relation between the host‐secreted factors and virulence of pathogenic bacteria in the respiratory tract may provide insights into the pathogenesis of respiratory tract infections. Polyamines produced within the bacterial cell are generally sequestered. Therefore, the pool of extracellular polyamines formed by secretion of the commensals and the host may be one of the signaling molecules that might contribute toward the alterations in the expression of virulence factors in bacterial pathogens. Besides, convergent mechanisms of polyamine biosynthesis do exist across the border of species and genus level. Also, several novel polyamine transporters in the host and bacteria remain yet to be identified. The review focuses on the role of polyamines in the expression of virulence phenotypes and biofilm formation of the respiratory tract pathogens.
MutS HOMOLOG1 mediates fertility reversion from cytoplasmic male sterile Brassica juncea in response to environment
Authors: Zhao Na , Li Zhangping , Zhang Lili , Yang Xiaodong , Mackenzie Sally A. , Hu Zhongyuan , Zhang Mingfang , Yang Jinghua
Published: September 2020

Spontaneous fertility reversion has been documented in cytoplasmic male sterile (CMS) plants of several species, influenced in frequency by nuclear genetic background. In this study, we found that MutS HOMOLOG1 (MSH1) mediates fertility reversion via substoichiometric shifting (SSS) of the CMS‐associated mitochondrial Open Reading Frame 220 (ORF220), a process that may be regulated by pollination signalling in Brassica juncea. We show that plants adjust their growth and development in response to unsuccessful pollination. Measurable decrease in MSH1 transcript levels and evidence of ORF220 SSS under non‐pollination conditions suggest that this nuclear‐mitochondrial interplay influences fertility reversion in CMS plants in response to physiological signals. Suppression of MSH1 expression induced higher frequency SSS in CMS plants than occurs normally. Transcriptional analysis of floral buds under pollination and non‐pollination conditions, and the response of MSH1 expression to different sugars, supports the hypothesis that carbon flux is involved in the pollination signalling of fertility reversion in CMS plants. Our findings suggest that facultative gynodioecy as a reproductive strategy may incorporate environmentally responsive genes like MSH1 as an “on–off” switch for sterility–fertility transition under ecological conditions of reproductive isolation.
Dog bite injuries in a tertiary care children's hospital: A seven‐year review
Authors: Zangari Andrea , Cerigioni Elisabetta , Nino Fabiano , Guidi Roberto , Gulia Caterina , Piergentili Roberto , Ilari Michele , Mazzoni Nadia , Cobellis Giovanni
Published: September 2020

Background

Dog bites are a major cause of traumatic injury in children. The aim of this study was to determine the experience, management, and outcome of dog bite injuries in our department.

Methods

We retrospectively reviewed the clinical records for 127 patients (mean age 7.15 ± 4.24 years, range 1 to 17 years; 68 males) affected by dog‐related injuries, from 2012 to 2018. Characteristics of patients and dogs, type and severity of injuries, circumstances of the accidents, treatment and outcome were analyzed.

Results

Of 141 wounds, 73 (51.8%) affected the head and neck, 62 (44%) the limbs, and six (4.2%) affected the trunk. According to the Mcheik classification, 107 lesions (75.9%) were stage 1, 26 (18.4%) stage 2, and eight (5.7%) stage 3. Seventy‐eight percent of the cases involved known dogs. The breed of the dog was recorded in 62/127 cases (48.8%) and the most common were mongrels (23/62, 37.1%). Seventy‐five percent of the attacks occurred during spring and summer. All patients underwent antibiotic prophylaxis and immediate surgical repair. Wound infection was observed in two patients. Three unsightly scars required rectification, with good cosmetic results in all cases.

Conclusions

Our results are consistent with previous data showing that the typical dog‐related injury occurs from a known dog, during spring and summer, and in younger boys, who are frequently exposed to head and neck wounds. Our experience showed the feasibility and safety of primary repair and antibiotic prophylaxis in all patients, with very low incidence of infection and good cosmetic results.