bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment and outcome of autoimmune hepatitis: Audit of 28 UK centres
Authors: Gordon Victoria , Adhikary Ratul , Appleby Victoria , Das Debasish , Day James , Delahooke Toby , Dixon Selena , Elphick David , Hardie Claire , Heneghan Michael A. , Hoeroldt Barbara , Hooper Patricia , Hutchinson John , Jones Rebecca , Khan Faisal , Aithal Guruprasad P. , Metcalf Jane , Nkhoma Alick , Pelitari Stavroula , Prince Martin , Prosser Annell , Sathyanarayana Vinay , Saksena Sushma , Vani Deven , Yeoman Andrew , Abouda George , Nelson Andrew , Gleeson Dermot ,   UK Multi‐Centre AIH Audit Group
Published: March 2022

Background

With few data regarding treatment and outcome of patients with AIH outside of large centres we present such a study of patients with AIH in 28 UK hospitals of varying size and facilities.

Methods

Patients with AIH were identified in 14 University and 14 District General hospitals; incident cases during 2007–2015 and prevalent cases, presenting 2000–2015. Treatment and outcomes were analysed.

Results

In 1267 patients with AIH, followed up for 3.8 (0–15) years, 5‐ and 10‐year death/transplant rates were 7.1 ± 0.8% and 10.1 ± 1.3% (all‐cause) and 4.0 ± 0.6% and 5.9 ± 1% (liver related) respectively. Baseline parameters independently associated with death/transplantation for all causes were: older age, vascular/respiratory co‐morbidity, cirrhosis, decompensation, platelet count, attending transplant centre and for liver related: the last four of these and peak bilirubin. All‐cause and liver‐related death/transplantation was independently associated with: non‐treatment with corticosteroids, non‐treatment with a steroid‐sparing agent (SSA), non‐treatment of asymptomatic or non‐cirrhotic patients and initial dose of Prednisolone >35 mg/0.5 mg/kg/day (all‐cause only), but not with type of steroid (Prednisolone vs. Budesonide) or steroid duration beyond 12 months. Subsequent all‐cause and liver‐death/transplant rates showed independent associations with smaller percentage fall in serum ALT after 1 and 3 months, but not with failure to normalise levels over 12 months.

Conclusions

We observed higher death/transplant rates in patients with AIH who were untreated with steroids (including asymptomatic or non‐cirrhotic subgroups), those receiving higher Prednisolone doses and those who did not receive an SSA. Similar death/transplant rates were seen in those receiving Prednisolone or Budesonide, those continuing steroids after 12 months and patients attaining normal ALT within 12 months versus not.
Myelin‐oligodendrocyte glycoprotein antibody‐associated optic neuritis following SARS‐CoV‐2 pneumonia: A case report
Authors: Mitarnun Witoon , Naksanguan Theerawat , Laoharattanahirun Nutchaya , Roekrat Patarasaya , Kimavaha Suphakarn , Kajornrith Warut
Published: March 2022

We report a case of a 60‐year‐old man with optic neuritis following severe acute respiratory syndrome coronavirus 2 pneumonia. He tested positive for serum myelin‐oligodendrocyte glycoprotein IgG antibody and was treated with intravenous methylprednisolone (1 g/d) for 5 days followed by oral prednisolone taper. Six weeks after treatment, his symptoms resolved.
Using molecular data to test the generic placement of a new and unusual ginger species from the Philippines
Authors: Docot Rudolph Valentino A. , Mazo Kean Roe F. , Mendez Noe P. , Poulsen Axel Dalberg
Published: March 2022

A collection of a ginger from Zamboanga Peninsula, Philippines, superficially resembles Hornstedtia but is very different from all other known Philippine species especially by the elongate rachis and absence of sterile bracts. Furthermore, it does not match any other species elsewhere. In order to ascertain its generic placement, phylogenetic analyses using ITS and trnK/matK regions were conducted revealing a close relationship with H. tomentosa from Borneo, Java and Sumatra. The mystery species, H. tomentosa and the type of Hornstedtia are placed within a highly supported clade. Morphologically, it is similar to H. tomentosa having an elongate rachis with red bracts and yellow flowers but differs by the swollen and white mucro to the fertile bract, presence of a bracteole and the petaloid labellum. As a result, Hornstedtia albomucronata, is described as a new species here, and illustrations and information on its distribution, habitat, phenology and provisional IUCN conservation status are provided. An updated key to the nine Hornstedtia species in the Philippines is included.
Effects of reverse headgear therapy on mandibular trabecular structure: A fractal analysis study
Authors: Arslan Semiha , Korkmaz Yasemin Nur , Buyuk S. Kutalmış , Tekin Berat
Published: March 2022

Objectives

The aim of this study was to assess the effects of reverse headgear (RHG) treatment combined with rapid maxillary expansion (RME) on the trabecular structure of the mandibula using fractal dimension (FD) analysis.

Methods

Forty‐four individuals with skeletal Class III malocclusion were selected from the archives and divided into two groups as patients who underwent treatment with RME + RHG (RHG‐G, 22 patients) and untreated control group (C‐G, 22 patients). The before (T0) and after (T1) treatment lateral cephalometric and panoramic radiographs were collected in the RHG‐G and in the control group, radiographs obtained with similar time intervals were grouped as T0 and T1. Cephalometric and FD analysis was conducted on T0 and T1 lateral cephalometric and panoramic radiographs. The intragroup comparison of cephalometric and FD data was performed using paired t test and Wilcoxon Signed Ranks test, while independent t test and Mann‐Whitney U test were used for intergroup comparison.

Results

C‐G had higher FD values in the right mandibular corpus and left mandibular ramus values at T0 (P < .05). The only significant difference in the intragroup comparisons was detected in the FD values of the right mandibular corpus in the C‐G (P < .05). No significant differences were found in the FD between the groups in any of the areas measured (P > .05).

Conclusions

RME + RHG therapy did not cause any significant trabecular changes in the mandibula when compared to the control group.
Craniofacial characteristics in Van der Woude syndrome
Authors: Estévez‐Arroyo Blanca , Gómez‐Mendo Ignacio , Romero‐Maroto Martín , Solano‐Reina Enrique , Iglesias‐Linares Alejandro
Published: March 2022

Aim

To describe the particular craniofacial characteristics of Van der Woude syndrome(VWS) patients compared to patients with a non‐syndromic cleft (CG1) and to a malocclusive healthy population (CG2).

Material and methods

Retrospective case‐control study. A sample of 110 matched‐patients was recruited (VWS (n = 7), CG1 (n = 49), CG2 (n = 49)). Subsequently, 37 radiometric variables were analysed and the dental‐skeletal ages were determined. The intra/inter‐observer method errors were quantified. Descriptive statistics were computed, and different inferential analysis tests were used depending on the normality of the data (Chi‐square test, Fisher's exact test, paired Student's T‐test, Mann–Whitney U test) (p‐value < 0.05). Pairwise comparisons were corrected by Bonferroni's criteria.

Results

VW‐patients presented specific craniofacial characteristics and morphology. A marked tendency to the vertical growth pattern was found in VW‐patients compared to CG1‐CG2 (p < 0.001); at the sagittal level, skeletal class II caused by mandibular retrognathism, with a greatly increased ANB angle compared to CG1 (p = 0.042). Dental analysis showed that the lower incisor was more retruded and retroclined (p < 0.05 in all cases) and the interincisal angulation was increased (p < 0.001 (CG2)). At the profile level, an open nasolabial angle (p = 0.040; CG1) and a more protruding lower lip with respect to the Sn‐Pg plane (p = 0.040 (CG1); p = 0.044 (CG2)) were observed.

Conclusions

VW‐patients present particular characteristics in the facial skeletal structures. There is a critical necessity to increase the evidence regarding specific clinical features and orofacial pathology of rare diseases such as VWS, which will help to these minorities to gain access in the future to a better quality of care with precise treatment and diagnostic necessities.
Fiscal competition and state pension reforms
Authors: Hoang Trang
Published: March 2022

Fiscal competition literature emphasizes the need to consider fiscal implications of the flow of labor and capital across jurisdictional boundaries. This open‐economy consideration raises issues for the analysis of fiscal policies, ranging from taxation and expenditure policies to the structure of intergovernmental relations and interjurisdictional competition. Using data on state population movement and pension reforms (2002−2015), this study examines whether the adoption of pension reforms was motivated by state government competition for the mobile tax base. The findings suggest that interstate migration has an influence on states’ enactment of pension reform, and the effect differs by state population density.
Growth and Biochemical Responses of Green and Red Perilla Supplementally Subjected to UV‐A and Deep‐blue LED Lights
Authors: Nguyen Loan T. K. , Oh Myung‐Min
Published: March 2022

This study investigated the effects of UV‐A and UV‐A‐closed visible light (deep‐blue [DB]) on the growth and bioactive compound accumulation of green and red perilla. Four‐week‐old seedlings were cultivated in an environment control room under visible light with red, blue and white LEDs for 4 weeks and then were continuously grown under supplemental UV‐A (365 nm and 385 nm) and DB (415 nm and 430 nm) lights for 7 days. UV‐A and DB treatments did not enhance the growth characteristics of green perilla compared with the control; while these treatments enhanced the growth parameters of red perilla, and the values were highest in DB 415 nm. The photosynthesis rate of both cultivars showed similar trends as the growth results of each cultivar. The electron transport rate and maximum quantum yield of both cultivars were reduced under UV‐A 365 nm, while these values were maintained in DB treatments. In both cultivars, total phenolic, antioxidant capacity, rosmarinic and caffeic acids and perillaldehyde levels were enhanced in DB treatments, whereas UV‐A 365 nm and DB 415 nm increased the total anthocyanin content. Overall, supplemental DB 415 nm and 430 nm was suitable for improving the growth and biochemical accumulation of both perilla cultivars.
Intrusions of sediment laden rivers into density stratified water columns could be an unrecognized source of mixing in many lakes and coastal oceans
Authors: Lu George , Wells Mathew , van Strygen Ian , Hecky Robert. E.
Published: March 2022

When a sediment laden river flows into a stratified water body, the water mass can either intrude as an overflow, interflow or underflow, depending upon the density contrast. Different modes of sediment driven convection occur in each case. For the case of overflows, convective sedimentation occurs beneath the plume, whereby sediment rich plumes rapidly transport fine materials to depth. If underflow of dense sediment laden waters initially occurs, then after sediment has been deposited, the light interstitial material can subsequently loft and potentially mixes the entire water column. For an interflow, both lofting and sediment driven convection can occur above and below the pycnocline. All of these different regimes can be described in terms of two dimensionless parameters: namely RS = ΔρS/ΔρC and RA = ΔρA/ΔρC, where ΔρA is the density contrast between the upper layer and the river inflow (due to just salinity or temperature differences), ΔρC is the density contrast due to sediment between river and upper‐layer, and ΔρS is the density contrast between upper and lower layers (due to just salinity or temperature differences). Laboratory experiments were used to describe the vigour of convection in terms of these dimensionless parameters, which then allows behaviour of various inflows to be predicted. In most cases the convective velocities observed were an order of magnitude faster than Stokes settling velocities. These observations are also applied to predict how a turbidity current could lead to lofting and possible overturn of the stratification of Lake Kivu, a large meromictic lake between Rwanda and the Democratic Republic of the Congo.
Cytarabine‐induced TNFα promotes the expansion and suppressive functions of myeloid‐derived suppressor cells in acute myeloid leukaemia
Authors: Bai Hua , Peng Yuhui , Li Yi , Duan Juanjuan , Fu Wenli , Liang Xinming , Yu Wenfeng , Zhang Qifang
Published: March 2022

Acute myeloid leukaemia (AML) is very common haematopoietic malignancies with poor prognosis. Chemotherapy is still a mainstay therapy for AML patients. AML microenvironment plays critical roles in therapy response. However, the role of chemotherapy in AML microenvironment is poorly understood. In this study, we report that cytarabine (AraC)‐triggered TNFα from AML cells expanded myeloid‐derived suppressor cells (MDSCs) and enhanced MDSC functions and survival through activating IL‐6/STAT3 and NFκB pathways. Blockade of TNFα in conditioned medium‐derived AraC‐treated AML cells (AraC_CM) impaired MDSC expansion and functions, reduced IL‐6 secretion and the level of activated STAT3. Inhibiting IL6 or STAT3 abrogated AraC_CM‐mediated MDSC suppressive function. Additionally, inhibiting TNFα also impaired AraC_CM‐mediated NFκB activation. Blocking NFκB activation reduced MDSC viability induced by AraC_CM. Together, these results provided a role of AraC‐induced TNFα in MDSC expansion and functions and suggest that targeting TNFα may benefit AML patients to current anticancer strategies by blocking MDSC‐mediated immunosuppression.
A cofinancing model for disability insurance and local government employers
Authors: Hagen Johannes , Malmberg Hannes
Published: March 2022

Employer cofinancing in disability insurance (DI) systems aims to reduce the inflow to DI by making employers internalise their DI costs. We evaluate a cofinancing system for the local government sector in Sweden inspired by the literature on yardstick competition. In the system, local governments are responsible for the DI of their employees, while being compensated by the central government for their expected DI payments. The arrangement essentially eliminates the large fiscal externalities associated with DI. Also, the arrangement can be implemented within current administrative setups, and the design credibly ensures that no extra costs are imposed on the local government sector in the aggregate. Drawing on Swedish employer‐employee matched data, we show that the net transfers implied by the scheme are quite large as a share of DI payments, but sufficiently small as a share of tax payments to not be onerous, and that they only marginally increase regional inequality.
Análise Histórico-Crítica da Construção de Discursos nos Diagnósticos Psiquiátricos de Mulheres no Manicômio Judiciário de Alagoas
Authors: Silva Laura Fernandes da , Santos Hugo Leonardo Rodrigues
Published: March 2022

Este trabalho analisa os discursos e práticas operacionalizados no manicômio judiciário de Alagoas direcionados às mulheres que passaram pela instituição entre os anos de 1979 a 1983 e 2011 a 2016. A partir de metodologia empírica, baseada na análise de conteúdo dos laudos psiquiátricos das referidas mulheres, digitalizados nos arquivos da própria unidade, o estudo objetivou verificar se fatores externos à psiquiatria, aspectos sociais e morais, por exemplo, influenciaram na construção dos diagnósticos, intensificando o histórico silenciamento e o processo de normalização dos corpos femininos. A pesquisa partiu da hipótese de que os papéis de gênero, raça e classe, interseccionados, exercem impacto relevante na construção dos exames, reforçando os estereótipos atribuídos às mulheres consideradas loucas e criminosas. As informações referentes aos dois períodos foram analisadas diacronicamente, o que permitiu perceber se houve descontinuidades ou manutenção de antigos paradigmas no tratamento direcionado às pacientes ao longo do tempo. As conclusões da pesquisa foram no sentido de que, em ambos os períodos, os saberes jurídico-psiquiátricos foram utilizados como instrumentos de controle social e segregação de mulheres que não se adequavam às expectativas sociais. Tal constatação ficou mais evidente nos documentos referentes ao primeiro período estudado, mas também foi notada, ainda que em menor grau, em muitos documentos relativos aos anos de 2011 a 2016. Nesse último período foram identificados alguns encaminhamentos de mulheres para Centros de Atenção Psicossocial – CAPS, o que pode ser considerado como um tímido, porém importante reflexo da reforma psiquiátrica na realidade manicomial judiciária em Alagoas.
Autorregulação e Reserva de Jurisdição no Combate às Fake News
Authors: Arrabal Alejandro Knaesel , Beduschi Leonardo , Sousa Alexa Schmitt de
Published: March 2022

O presente artigo propõe o cotejo sobre a eficácia dos modelos de autorregulação e reserva de jurisdição no combate às Fake News. O estudo explora as técnicas processuais e decisórias à disposição dos juristas deste novo século, bem como os marcos regulatórios brasileiros responsáveis pela jurisgênese dos bens tutelados, especialmente o Marco Civil da Internet, a Lei Geral de Proteção de Dados e as inovações anunciadas pelo Projeto de Lei n.º 2.630/2020, além de ponderar sobre a aplicação prática das disposições do Código de Processo Civil para a inibição e remoção tempestiva das Fake News da rede mundial de computadores. Realizado por meio de revisão bibliográfica e análise jurisprudencial, o estudo indica que, para além da combinação dos modelos de autorregulação e reserva de jurisdição no combate às Fake News, é preciso atentar que a tutela jurisdicional revela efeitos com potencial protetivo muito maior do que o estrito ressarcimento, na medida que apresenta condições processuais cautelares para à inibição e/ou à remoção do ato ilícito.
Uma Nova Cara Para a Política? Considerações sobre Deepfakes e Democracia
Authors: Mulholland Caitlin , De Oliveira Samuel Rodrigues
Published: March 2022

Deepfakes – mídias audiovisuais hiper-realistas, manipuladas digitalmente mediante técnicas de inteligência artificial – são um fenômeno recente e, por isso, carecedor de debate. O objetivo deste artigo é investigar a influência que deepfakes exercem (ou podem exercer) no debate público e, consequentemente, no processo político como um todo. Para tanto, em um primeiro momento, realizamos uma construção teórica acerca da mediatização da política, da influência de fofocas e escândalos no processo democrático, e da polarização da “esfera pública conectada”, analisando como esses fenômenos corroboram aquilo que se denomina crise da democracia representativa. Em seguida, apresentamos e discutimos com maior detalhamento as chamadas deepfakes, explorando a sua relação com o fenômeno da desinformação, como elas se inserem no contexto do debate político na dita “era da informação” e como afetam (ou podem afetar) esse momento do processo democrático. Concluímos que, embora sejam um fenômeno relativamente novo e merecedor de atenção, as deepfakes, ao menos no que se refere ao processo político, não fazem muito além de aprofundar determinados problemas já existentes em nossa sociedade.
Don’t Shoot the Message: Regulating Disinformation Beyond Content
Authors: Iglesias Keller Clara
Published: March 2022

This paper approaches regulatory strategies against disinformation with two main goals: (i) exploring the policies recently implemented in different legal contexts to provide insight into both the risks they pose to free speech and their potential to address the rationales that motivated them, and (ii) to do so by bridging policy debates and recent social and communications studies findings on disinformation. An interdisciplinary theoretical framework informs both the paper’s scope (anchored on understandings of regulatory strategies and of disinformation) and the analysis of the legitimate motivations for states to establish statutory regulation that aims at disinformation. Departing from this analysis, I suggest an organisation of recently implemented and proposed policies into three groups based on their regulatory target: content, data, and structure. Combining the analysis of these three types of policies with the theoretical framework, I will argue that, in the realm of statutory regulation, state action is better off targeted at data or structure, as aiming at content represents disproportional risks to freedom of expression. Furthermore, content targeted regulation shows little potential to address the structural transformations on the public sphere of communications that, among other factors, influence current practices of production and spread of disinformation.
Sweep Effects on Fan–Intake Aerodynamics at High Angle of Attack
Authors: Mohankumar Ben , Hall Cesare A. , Wilson Mark J.
Published: March 2022

Sweep in a transonic fan is conventionally used to reduce design point losses by inclining the passage shock relative to the incoming flow. However, future low pressure ratio fans operate to lower Mach numbers meaning the role of sweep at cruise is diminished. Instead, sweep might be repurposed to improve the performance of critical high Mach number off-design conditions such as high angle of attack (AOA). In this article, we use unsteady computational fluid dynamics to compare two transonic low pressure ratio fans, one radially stacked and one highly swept, coupled to a short intake design, at the high AOA flight condition. The AOA considered is 35 deg, which is sufficient to separate the intake bottom lip. The midspan of the swept fan was shifted upstream to add positive sweep to the outer span. Based on previous design experience, it was hypothesized that the swept fan would reduce transonic losses when operating at high AOA. However, it was found that the swept fan increased the rotor loss by 24% relative to the radial fan. Loss was increased through two key mechanisms. (i) Rotor choking: flow is redistributed around the intake separation and enters the rotor midspan with high Mach numbers. Sweeping the fan upstream reduced the effective intake length, which increased the inlet relative Mach number and amplified choking losses. (ii): Rotor-separation interaction (RSI): the rotor tip experiences low mass flow inside the separation, which increases the pressure rise across the casing to a point where the casing boundary layer separates. The swept fan diffused the casing streamtube, causing the casing separation to increase in size and persist in the passage for longer. High RSI loss indicated that the swept fan was operating closer to the rotating stall point.
A Detailed Loss Analysis Methodology for Centrifugal Compressors
Authors: Zhang Luying , Kritioti Loukia , Wang Peng , Zhang Jiangnan , Zangeneh Mehrdad
Published: March 2022

A deep understanding of loss mechanisms inside a turbomachine is crucial for the design and analysis work. By quantifying the various losses generated from different flow mechanisms, a targeted optimization can be carried out on the blading design. In this paper, an evaluation method for computational fluid dynamics (CFD) simulations has been developed to quantify the loss generation based on entropy production in the flow field. A breakdown of losses caused by different mechanisms (such as skin friction, secondary flow, tip clearance vortex, and shock waves) is achieved by separating the flow field into different zones. Each zone is defined by the flow physics rather than by geometrical locations or empirical correlations, which makes the method a more general approach and applicable to different machine types. The method has been applied to both subsonic and transonic centrifugal compressors, where internal flow is complex due to the Coriolis acceleration and the curvature effect. An evaluation of loss decomposition is obtained at various operational conditions. The impact of design modification is also assessed by applying the same analysis to an optimized design.
Two subspecies of the snail mite Riccardoella (Proriccardoella) reaumuri Fain & van Goethem, 1986 (Acari, Prostigmata, Ereynetidae) from Japan
Authors: Waki Tsukasa , Motochin Risho , Asami Takahiro , Shimano Satoshi
Published: March 2022

Riccardoella (Proriccardoella) reaumuri Fain & van Goethem, 1986 has been reported in terrestrial mollusks in France and the Japanese Archipelago. The purpose of this study was to describe two new subspecies of this mite species from Japan based on their morphological characters. Mites were sampled from terrestrial mollusks at 13 locations in Japan from Oct. 16, 2016 to Nov. 13, 2020. The sampled mites and specimens deposited in museum were also used for morphological observations. As a result of principal component analysis (PCA) and cluster analysis based on morphology of dorsal setae on idiosoma and solenidia on palptarsus and tarsus I and II, mite specimens from France and Japan were divided into three groups: Group 1 (mites sampled in France), Group 2 (Okinawajima Is.) and Group 3 (the area from Kyushu Is. to Hokkaido Is.). The solenidia shapes also differed between the groups. We propose that the mites of each of the three groups should be defined as subspecies based on these morphological differences. Our phylogenetic tree of the two subspecies based on amino acid sequences of the mitochondrial cytochrome c oxidase subunit 1 (CO1) confirmed that these Japanese mites are members of the genus, family Ereynetidae.
Recent additions to the plant-inhabiting mite fauna of three European countries (Acari: Acariformes: Tydeoidea, Stigmaeidae)
Authors: Ripka Géza , Király Gergely , Szabó Árpád , Kaźmierski Andrzej
Published: March 2022

Date-locality-host records for 15 mite species of 4 families are presented for Hungary, Germany and Austria. These data include two new records for Europe, viz. Tydeus kabutarahangensis Khanjani et Ueckermann, 2003 and Tydeus meshkinensis André, Ueckermann et Rahmani, 2010, two new records for Hungary: Tydeus kabutarahangensis and Tydeus meshkinensis, two for Austria: Tydeus lindquisti (Marshall, 1970) and Tydeus meshkinensis, and one for Germany: Lorryia teresae Carmona, 1970. Details on habitats and plant associations are also provided.
Anthocyanin-Rich Blackcurrant Extract Preserves Gastrointestinal Barrier Permeability and Reduces Enterocyte Damage but Has No Effect on Microbial Translocation and Inflammation After Exertional Heat Stress
Authors: Lee Ben J. , Flood Tessa R. , Hiles Ania M. , Walker Ella F. , Wheeler Lucy E.V. , Ashdown Kimberly M. , Willems Mark E.T. , Costello Rianne , Greisler Luke D. , Romano Phebe A. , Hill Garrett W. , Kuennen Matthew R.
Published: March 2022

This study investigated the effects of 7 days of 600 mg/day anthocyanin-rich blackcurrant extract intake on small intestinal permeability, enterocyte damage, microbial translocation, and inflammation following exertional heat stress. Twelve recreationally active men (maximal aerobic capacity = 55.6 ± 6.0 ml·kg−1·min−1) ran (70% VO2max) for 60 min in an environmental chamber (34 °C, 40% relative humidity) on two occasions (placebo/blackcurrant, randomized double-blind crossover). Permeability was assessed from a 4-hr urinary excretion of lactulose and rhamnose and expressed as a ratio of lactulose/rhamnose. Venous blood samples were taken at rest and 20, 60, and 240 min after exercise to measure enterocyte damage (intestinal fatty acid-binding protein); microbial translocation (soluble CD14, lipopolysaccharide-binding protein); and interleukins 6, interleukins 10, and interleukins 1 receptor antagonist. Exercise increased rectal temperature (by ∼2.8 °C) and heart rate (by ∼123 beats/min) in each condition. Blackcurrant supplementation led to a ∼12% reduction in lactulose/rhamnose ratio (p < .0034) and enterocyte damage (∼40% reduction in intestinal fatty acid-binding protein area under the curve; p < .0001) relative to placebo. No between-condition differences were observed immediately after exercise for lipopolysaccharide-binding protein (mean, 95% confidence interval [CI]; +80%, 95% CI [+61%, +99%]); soluble CD14 (+37%, 95% CI [+22%, +51%]); interleukins 6 (+494%, 95% CI [+394%, +690%]); interleukins 10 (+288%, 95% CI [+105%, +470%]); or interleukins 1 receptor antagonist (+47%, 95% CI [+13%, +80%]; all time main effects). No between-condition differences for these markers were observed after 60 or 240 min of recovery. Blackcurrant extract preserves the GI barrier; however, at subclinical levels, this had no effect on microbial translocation and downstream inflammatory processes.
Monoclonal Antibodies Targeting Surface-Exposed Epitopes of Candida albicans Cell Wall Proteins Confer
In Vivo
Protection in an Infection Model
Authors: Palliyil Soumya , Mawer Mark , Alawfi Sami A. , Fogg Lily , Tan Tyng H. , De Cesare Giuseppe Buda , Walker Louise A. , MacCallum Donna M. , Porter Andrew J. , Munro Carol A.
Published: March 2022

Monoclonal antibody (mAb)-based immunotherapies targeting systemic and deep-seated fungal infections are still in their early stages of development, with no licensed antifungal mAbs currently being available for patients at risk. The cell wall glycoproteins of
Candida albicans
are of particular interest as potential targets for therapeutic antibody generation due to their extracellular location and key involvement in fungal pathogenesis.
An Intrinsically Disordered Peptide Tag that Confers an Unusual Solubility to Aggregation-Prone Proteins
Authors: Jo Byung Hoon
Published: March 2022

Production of recombinant proteins in
Escherichia coli
still suffers from the insolubility problem. Conventional solubility enhancers with large sizes, represented by maltose-binding protein (MBP), have remained the first-choice tags; however, the success of the soluble expression of tagged proteins is largely unpredictable.
Heterologous Expression and Biochemical Analysis Reveal a Schizokinen-Based Siderophore Pathway in
Leptolyngbya
(Cyanobacteria)
Authors: Wang Suqin , Pearson Leanne A. , Mazmouz Rabia , Liu Tianzhe , Neilan Brett A.
Published: March 2022

Iron availability limits the growth of many microorganisms, particularly those residing in high nutrient–low chlorophyll aquatic environments. Therefore, characterizing iron acquisition pathways in phytoplankton is essential for understanding nutrient cycling in our oceans.
Mechanical Forces Govern Interactions of Host Cells with Intracellular Bacterial Pathogens
Authors: Bastounis Effie E. , Radhakrishnan Prathima , Prinz Christopher K. , Theriot Julie A.
Published: March 2022

To combat infectious diseases, it is important to understand how host cells interact with bacterial pathogens. Signals conveyed from pathogen to host, and vice versa, may be either chemical or mechanical.
Complete Genome Sequence of Stenotrophomonas maltophilia Podophage Ptah
Authors: Berg Amelia , Tate Nathaniel , Clark James , Le Tram , Burrowes Ben , Liu Mei
Published: March 2022

Stenotrophomonas maltophilia
is an opportunistic pathogen demonstrating increasing drug resistance. Here, the genome of the T7-like
S. maltophilia
podophage Ptah is described. Its 42,593-bp genome is closely related to previously reported T7-like
S. maltophilia
podophages, including phage Ponderosa.
Correlation of Immunogenicity and Reactogenicity of BNT162b2 and CoronaVac SARS-CoV-2 Vaccines
Authors: Zhang Ruiqi , Leung Ka-Yi , Liu Danlei , Fan Yujing , Lu Lu , Chan Pui-Chun , To Kelvin Kai-Wang , Chen Honglin , Yuen Kwok-Yung , Chan Kwok-Hung , Hung Ivan Fan-Ngai
Published: March 2022

Effective vaccines against SARS-CoV-2 are vital tools for containing the COVID-19 pandemic by increasing population immunity. While currently available vaccines can elicit antibody response against SARS-CoV-2 with high efficacy, the associated side effects may cause vaccine hesitancy.
Integrated Omics Approaches Revealed the Osmotic Stress-Responsive Genes and Microbiota in Gill of Marine Medaka
Authors: Lai Keng Po , Zhu Peng , Boncan Delbert Almerick T. , Yang Lu , Leung Cherry Chi Tim , Ho Jeff Cheuk Hin , Lin Xiao , Chan Ting Fung , Kong Richard Yuen Chong , Tse William Ka Fai
Published: March 2022

This is the first study using the transcriptome and 16S rRNA gene sequencing to report the hypotonic responsive genes in gill cells and the compositions of gill microbiota in marine medaka. The overlapped glycosaminoglycan- and chitin-related pathways suggest host-bacterium interaction in fish gill during osmotic stress.
Internal Transcription Terminators Control Stoichiometry of ABC Transporters in Cellulolytic Clostridia
Authors: Wu Shasha , You Mengcheng , Wang Na , Ren Zhenxing , Xu Chenggang
Published: March 2022

Operons encoding protein complexes or metabolic pathways usually require fine-tuned gene expression ratios to create and maintain the appropriate stoichiometry for biological functions. In this study, a strategy for controlling differential expression of genes in an operon was proposed by utilizing ABC importers from
Ruminiclostridium cellulolyticum
.
Specific Detection of SARS-CoV-2 Variants B.1.1.7 (Alpha) and B.1.617.2 (Delta) Using a One-Step Quantitative PCR Assay
Authors: Erster Oran , Mendelson Ella , Kabat Areej , Levy Virginia , Mannasse Batya , Assraf Hadar , Azar Roberto , Ali Yaniv , Bucris Efrat , Bar-Ilan Dana , Mor Orna , Elul Michal , Mandelboim Michal , Sofer Danit , Fleishon Shay , Zuckerman Neta S. , Bar-Or Itay
Published: March 2022

The new assays described herein enable rapid, straightforward, and cost-effective detection of severe acute respiratory syndrome coronavirus 2 (SC-2) with immediate classification of the examined sample as Alpha, Delta, non-Alpha, or non-Delta variant. This is highly important for two main reasons: (i) it provides the scientific and medical community with a novel diagnostic tool to rapidly detect and classify any SC-2 sample of interest as Alpha, Delta, or none and can be applied to both clinical and environmental samples, and (ii) it demonstrates how to respond to the emergence of new variants of concern by developing a variant-specific assay.
Contribution of NOTCH1 genetic variants to bicuspid aortic valve and other congenital lesions
Authors: Debiec Radoslaw Marek , Hamby Stephen E , Jones Peter D , Safwan Kassem , Sosin Michael , Hetherington Simon Lee , Sprigings David , Sharman David , Lee Kelvin , Salahshouri Pegah , Wheeldon Nigel , Chukwuemeka Andrew , Boutziouka Vasiliki , Elamin Mohamed , Coolman Sue , Asiani Manish , Kharodia Shireen , Skinner Gregory J , Samani Nilesh J , Webb Tom R , Bolger Aidan P
Published: March 2022

Introduction

Bicuspid aortic valve (BAV) affects 1% of the general population. NOTCH1 was the first gene associated with BAV. The proportion of familial and sporadic BAV disease attributed to NOTCH1 mutations has not been estimated.

Aim

The aim of our study was to provide an estimate of familial and sporadic BAV disease attributable to NOTCH1 mutations.

Methods

The population of our study consisted of participants of the University of Leicester Bicuspid aoRtic vAlVe gEnetic research—8 pedigrees with multiple affected family members and 381 sporadic patients. All subjects underwent NOTCH1 sequencing. A systematic literature search was performed in the NCBI PubMed database to identify publications reporting NOTCH1 sequencing in context of congenital heart disease.

Results

NOTCH1 sequencing in 36 subjects from 8 pedigrees identified one variant c.873C>G/p.Tyr291* meeting the American College of Medical Genetics and Genomics criteria for pathogenicity. No pathogenic or likely pathogenic NOTCH1 variants were identified in 381 sporadic patients. Literature review identified 64 relevant publication reporting NOTCH1 sequencing in 528 pedigrees and 9449 sporadic subjects. After excluding families with syndromic disease pathogenic and likely pathogenic NOTCH1 variants were detected in 9/435 (2.1%; 95% CI: 0.7% to 3.4%) of pedigrees and between 0.05% (95% CI: 0.005% to 0.10%) and 0.08% (95% CI: 0.02% to 0.13%) of sporadic patients. Incomplete penetrance of definitely pathogenic NOTCH1 mutations was observed in almost half of reported pedigrees.

Conclusions

Pathogenic and likely pathogenic NOTCH1 genetic variants explain 2% of familial and <0.1% of sporadic BAV disease and are more likely to associate with tetralogy of Fallot and hypoplastic left heart.
ZEB1 transcription factor promotes immune escape in melanoma
Authors: Plaschka Maud , Benboubker Valentin , Grimont Maxime , Berthet Justine , Tonon Laurie , Lopez Jonathan , Le-Bouar Myrtille , Balme Brigitte , Tondeur Garance , de la Fouchardière Arnaud , Larue Lionel , Puisieux Alain , Grinberg-Bleyer Yenkel , Bendriss-Vermare Nathalie , Dubois Bertrand , Caux Christophe , Dalle Stéphane , Caramel Julie
Published: March 2022

Background

The efficacy of immunotherapies in metastatic melanoma depends on a robust T cell infiltration. Oncogenic alterations of tumor cells have been associated to T cell exclusion. Identifying novel cancer cell-intrinsic non-genetic mechanisms of immune escape, the targeting of which would reinstate T cell recruitment, would allow to restore the response to anti-programmed cell death protein 1 (PD-1) antibody therapy. The epithelial-to-mesenchymal transition (EMT)-inducing transcription factor ZEB1 is a major regulator of melanoma cell plasticity, driving resistance to mitogen-activated protein kinase (MAPK) targeted therapies. We thus wondered whether ZEB1 signaling in melanoma cells may promote immune evasion and resistance to immunotherapy.

Methods

We evaluated the putative correlation between ZEB1 expression in melanoma cells and the composition of the immune infiltrate in a cohort of 60 human melanoma samples by combining transcriptomic (RNA-sequencing) and seven-color spatial multi-immunofluorescence analyses. Algorithm-based spatial reconstitution of tumors allowed the quantification of CD8+, CD4+T cells number and their activation state (PD-1, Ki67). ZEB1 gain-of-function or loss-of-function approaches were then implemented in syngeneic melanoma mouse models, followed by monitoring of tumor growth, quantification of immune cell populations frequency and function by flow cytometry, cytokines secretion by multiplex analyses. Chromatin-immunoprecipitation was used to demonstrate the direct binding of this transcription factor on the promoters of cytokine-encoding genes. Finally, the sensitivity to anti-PD-1 antibody therapy upon ZEB1 gain-of-function or loss-of-function was evaluated.

Results

Combined spatial and transcriptomic analyses of the immune infiltrates in human melanoma samples demonstrated that ZEB1 expression in melanoma cells is associated with decreased CD8+T cell infiltration, independently of β-catenin pathway activation. ZEB1 ectopic expression in melanoma cells impairs CD8+T cell recruitment in syngeneic mouse models, resulting in tumor immune evasion and resistance to immune checkpoint blockade. Mechanistically, we demonstrate that ZEB1 directly represses the secretion of T cell-attracting chemokines, including CXCL10. Finally,Zeb1knock-out, by promoting CD8+T cell infiltration, synergizes with anti-PD-1 antibody therapy in promoting tumor regression.

Conclusions

We identify the ZEB1 transcription factor as a key determinant of melanoma immune escape, highlighting a previously unknown therapeutic target to increase efficacy of immunotherapy in melanoma.

Trial registration number

NCT02828202.
Oncolytic peptide LTX-315 induces anti-pancreatic cancer immunity by targeting the ATP11B-PD-L1 axis
Authors: Tang Tianyu , Huang Xing , Zhang Gang , Lu Minghao , Hong Zhengtao , Wang Meng , Huang Junming , Zhi Xiao , Liang Tingbo
Published: March 2022

Background

LTX-315 is an oncolytic peptide deriving from bovine lactoferrin, with the ability to induce cancer immunogenic cell death. However, the mechanism used by LTX-315 to trigger the antitumor immune response is still poorly understood. The expression of programmed cell death ligand 1 (PD-L1) largely determines the efficacy and effectiveness of cancer immunotherapies targeting this specific immune checkpoint. This study aimed to demonstrate the potential effect and mechanism of LTX-315 in PD-L1 inhibition-induced anti-pancreatic cancer immunity.

Methods

Both immunodeficient and immunocompetent mouse models were used to evaluate the therapeutic efficacy of monotherapy and combination therapy. Flow cytometry and immunohistochemistry were used to assess the immune microenvironment. Multiomic analysis was used to identify the potential target and down-streaming signaling pathway. Both in-house tissue microarray and open accessed The Cancer Genome Atlas data sets were used to evaluate the clinical relevance in pancreatic cancer prognosis.

Results

LTX-315 treatment inhibited PD-L1 expression and enhanced lymphocyte infiltration in pancreatic tumors. ATP11B was identified as a potential target of LTX-315 and a critical regulator in maintaining PD-L1 expression in pancreatic cancer cells. As regards the mechanism, ATP11B interacted with PD-L1 in a CKLF-like MARVEL transmembrane domain containing 6 (CMTM6)-dependent manner. The depletion of ATP11B promoted CMTM6-mediated lysosomal degradation of PD-L1, thus reactivating the immune microenvironment and inducing an antitumor immune response. The significant correlation among ATP11B, CMTM6, and PD-L1 was confirmed in clinical samples of pancreatic cancer.

Conclusions

LTX-315 was first identified as a peptide drug inducing PD-L1 downregulation via ATP11B. Therefore, LTX-315, or the development of ATP11B-targeting drugs, might improve the efficacy of cancer immunotherapy.
Exploring the safety, effect on the tumor microenvironment, and efficacy of itacitinib in combination with epacadostat or parsaclisib in advanced solid tumors: a phase I study
Authors: Naing Aung , Powderly John D , Nemunaitis John J , Luke Jason J , Mansfield Aaron S , Messersmith Wells A , Sahebjam Solmaz , LoRusso Patricia M , Garrido-Laguna Ignacio , Leopold Lance , Geschwindt Ryan , Ding Kai , Smith Michael , Berlin Jordan D
Published: March 2022

Background

This phase I multicenter study was designed to evaluate the safety, tolerability, efficacy, and translational effects on the tumor microenvironment of itacitinib (Janus-associated kinase 1 (JAK1) inhibitor) in combination with epacadostat (indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor) or parsaclisib (phosphatidylinositol 3-kinase δ (PI3Kδ) inhibitor).

Methods

Patients with advanced or metastatic solid tumors were enrolled and received itacitinib (100–400 mg once a day) plus epacadostat (50–300 mg two times per day; group A), or itacitinib (100–400 mg once a day) plus parsaclisib or parsaclisib monotherapy (0.3–10 mg once a day; group B).

Results

A total of 142 patients were enrolled in the study. The maximum tolerated dose was not reached for either the combination of itacitinib plus epacadostat (n=47) or itacitinib plus parsaclisib (n=90). One dose-limiting toxicity of serious, grade 3 aseptic meningitis was reported in a patient receiving itacitinib 300 mg once a day plus parsaclisib 10 mg once a day, which resolved when the study drugs were withdrawn. The most common treatment-related adverse events among patients treated with itacitinib plus epacadostat included fatigue, nausea, pyrexia, and vomiting, and for patients treated with itacitinib plus parsaclisib were fatigue, pyrexia, and diarrhea. In the itacitinib plus epacadostat group, no patient had an objective response. Among patients receiving itacitinib 100 mg once a day plus parsaclisib 0.3 mg once a day, three achieved partial response for an objective response rate (95% CI) of 7.1% (1.50 to 19.48). Treatment with itacitinib plus epacadostat demonstrated some increase in tumor CD8+T cell infiltration and minor changes in six plasma proteins, whereas treatment with itacitinib plus high-dose parsaclisib resulted in downregulation of 20 plasma proteins mostly involved in immune cell function, with no observed change in intratumoral CD8+T cell infiltration.

Conclusion

Adverse events with JAK1 inhibition combined with either IDO1 or PI3Kδ inhibition were manageable, but the combinations demonstrated limited clinical activity or enhancement of immune activation in the tumor microenvironment.

Trial registration number

NCT02559492.
Translational randomized phase II trial of cabozantinib in combination with nivolumab in advanced, recurrent, or metastatic endometrial cancer
Authors: Lheureux Stephanie , Matei Daniela E , Konstantinopoulos Panagiotis A , Wang Ben X , Gadalla Ramy , Block Matthew S , Jewell Andrea , Gaillard Stephanie L , McHale Michael , McCourt Carolyn , Temkin Sarah , Girda Eugenia , Backes Floor J , Werner Theresa L , Duska Linda , Kehoe Siobhan , Colombo Ilaria , Wang Lisa , Li Xuan , Wildman Rachel , Soleimani Shirin , Lien Scott , Wright John , Pugh Trevor , Ohashi Pamela S , Brooks David G , Fleming Gini F
Published: March 2022

Background

Combining immunotherapy and antiangiogenic agents is a promising treatment strategy in endometrial cancer. To date, no biomarkers for response have been identified and data on post-immunotherapy progression are lacking. We explored the combination of a checkpoint inhibitor (nivolumab) and an antiangiogenic agent (cabozantinib) in immunotherapy-naïve endometrial cancer and in patients whose disease progressed on previous immunotherapy with baseline biopsy for immune profiling.

Patients and methods

In this phase II trial (ClinicalTrials.govNCT03367741, registered December 11, 2017), women with recurrent endometrial cancer were randomized 2:1 to nivolumab with cabozantinib (Arm A) or nivolumab alone (Arm B). The primary endpoint was Response Evaluation Criteria in Solid Tumors-defined progression-free survival (PFS). Patients with carcinosarcoma or prior immune checkpoint inhibitor received combination treatment (Arm C). Baseline biopsy and serial peripheral blood mononuclear cell (PBMC) samples were analyzed and associations between patient outcome and immune data from cytometry by time of flight (CyTOF) and PBMCs were explored.

Results

Median PFS was 5.3 (90% CI 3.5 to 9.2) months in Arm A (n=36) and 1.9 (90% CI 1.6 to 3.4) months in Arm B (n=18) (HR=0.59, 90% CI 0.35 to 0.98; log-rank p=0.09, meeting the prespecified statistical significance criteria). The most common treatment-related adverse events in Arm A were diarrhea (50%) and elevated liver enzymes (aspartate aminotransferase 47%, alanine aminotransferase 42%). In-depth baseline CyTOF analysis across treatment arms (n=40) identified 35 immune-cell subsets. Among immunotherapy-pretreated patients in Arm C, non-progressors had significantly higher proportions of activated tissue-resident (CD103+CD69+) ɣδ T cells than progressors (adjusted p=0.009).

Conclusions

Adding cabozantinib to nivolumab significantly improved outcomes in heavily pretreated endometrial cancer. A subgroup of immunotherapy-pretreated patients identified by baseline immune profile and potentially benefiting from combination with antiangiogenics requires further investigation.
L∞-algebras in Freedman–Townsend model and Batalin–Vilkovisky formalism
Authors: Dai Jialiang
Published: March 2022

We present an [Formula: see text]-algebra description of the Freedman–Townsend tensor gauge theory with an emphasis on the Maurer–Cartan homotopy action form using cyclic inner product. It is explicitly shown that the gauge variations, the conservation law and the dynamics of the theory are all incorporated in the underlying [Formula: see text]-products. Also, following the more convenient method for reducible gauge theory, we propose the Batalin–Vilkovisky formalism of Freedman–Townsend model within the framework of [Formula: see text]-algebras.