bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional genomics atlas of synovial fibroblasts defining rheumatoid arthritis heritability
Authors: Ge Xiangyu , Frank-Bertoncelj Mojca , Klein Kerstin , McGovern Amanda , Kuret Tadeja , Houtman Miranda , Burja Blaž , Micheroli Raphael , Shi Chenfu , Marks Miriam , Filer Andrew , Buckley Christopher D. , Orozco Gisela , Distler Oliver , Morris Andrew P. , Martin Paul , Eyre Stephen , Ospelt Caroline 
Published: August 2021

AbstractBackgroundGenome-wide association studies have reported more than 100 risk loci for rheumatoid arthritis (RA). These loci are shown to be enriched in immune cell-specific enhancers, but the analysis so far has excluded stromal cells, such as synovial fibroblasts (FLS), despite their crucial involvement in the pathogenesis of RA. Here we integrate DNA architecture, 3D chromatin interactions, DNA accessibility, and gene expression in FLS, B cells, and T cells with genetic fine mapping of RA loci.ResultsWe identify putative causal variants, enhancers, genes, and cell types for 30–60% of RA loci and demonstrate that FLS account for up to 24% of RA heritability. TNF stimulation of FLS alters the organization of topologically associating domains, chromatin state, and the expression of putative causal genes such as TNFAIP3 and IFNAR1. Several putative causal genes constitute RA-relevant functional networks in FLS with roles in cellular proliferation and activation. Finally, we demonstrate that risk variants can have joint-specific effects on target gene expression in RA FLS, which may contribute to the development of the characteristic pattern of joint involvement in RA.ConclusionOverall, our research provides the first direct evidence for a causal role of FLS in the genetic susceptibility for RA accounting for up to a quarter of RA heritability.
Microarray-based analysis of renal complement components reveals a therapeutic target for lupus nephritis
Authors: Liu Tao , Yang Mingyue , Xia Ying , Jiang Chuan , Li Chenxu , Jiang Zhenyu , Wang Xiaosong 
Published: August 2021

Abstract
Background
Screening abnormal pathways and complement components in the kidneys of patients with lupus nephritis (LN) and NZB/W mice may help to identify complement-related therapeutic targets for LN.

Methods
KEGG and GO enrichment assays were used to analyze kidney microarray data of LN patients and NZB/W mice. Immunohistochemistry and immunofluorescence assays were used to measure renal expression of complement-related proteins and TGFβ1. Cytokines were measured using RT-qPCR and ELISA.

Results
We screened the renal pathogenic pathways present in LN patients and NZB/W mice and selected the complement activation pathway for further study. The results indicated greater renal expression of C1qa, C1qb, C3, C3aR1, and C5aR1 at the mRNA and protein levels. C3 appeared to be a key factor in LN and the renal signaling downstream of C1 was inhibited. There were significant correlations between the expression of TGFβ1 and C3. Analysis of primary cell cultures indicated that TGFβ1 promoted the expression of C3 and that a TGFβ1 antagonist decreased the levels of C3 and C3aR. TGFβ1 inhibition significantly inhibited the deposition of complement-related factors in the kidneys of NZB/W mice.

Conclusions
At the onset of LN, there are significant increases in the renal levels of C3 and other complement pathway-related factors in patients with LN and NZB/W mice. C3 may lead to albuminuria and participate in the pathogenesis of LN. TGFβ1 promotes C3 synthesis, and TGFβ1 inhibition may block the progression of LN by inhibiting the synthesis of C3 and other complement components.
Screening, assessment and management of perioperative malnutrition: a survey of UK practice
Authors: Matthews L. S. , Wootton S. A. , Davies S. J. , Levett D. Z. H. 
Published: August 2021

Abstract
Background
Perioperative malnutrition is common and is associated with increased mortality, complications and healthcare costs. Patients having surgery for cancer and gastro-intestinal disease are at particular risk. It is a modifiable pre-operative risk factor and perioperative clinicians are well placed to identify those at risk and instigate interventions shown to improve outcome. Thus, we conducted a survey of Perioperative Medicine Leads with the aim of assessing the current provision of nutritional screening and intervention pathways in the UK.

Methods
Perioperative Medicine Leads registered with the Royal College of Anaesthetists were asked to complete an online survey exploring current practice in screening, assessment and management of malnutrition in the perioperative period. The survey included a mixture of open and closed questions, graded response questions and options for free text. Where a response was not received, departments were phoned directly and e-mails sent to non-responders.

Results
We received 121 completed questionnaires from 167 Perioperative Medicine Leads (response rate of 72.5%). Seventy respondents (57.9%) reported using the Malnutrition Universal Screening Tool to screen patients; however, only 61 (50.4%) referred patients at nutritional risk onto a dietitian. Sixty (49.6%) lacked confidence in local ability to identify and manage malnutrition perioperatively, with 28 (23.1%) reporting having a structured pathway for managing malnourished patients. One hundred eleven respondents (91.7%) agreed that malnutrition impacts on quality of life after surgery and 105 (86.8%) felt adopting a standard protocol would improve outcomes for patients. Those reporting a lack of confidence in dealing with malnutrition perioperatively cited a lack of organisational support, patients being seen too close to surgery and lack of clarity around responsibility as key reasons for difficulties in managing this group of patients.

Conclusions
Malnutrition in the perioperative period is a modifiable risk factor which is common and results in increased morbidity for patients and increased cost to healthcare systems. This survey highlights areas of practice where perioperative clinicians can improve the assessment and management of patients at nutritional risk prior to elective surgery.
Characterization of Non–Small-Cell Lung Cancers With MET Exon 14 Skipping Alterations Detected in Tissue or Liquid: Clinicogenomics and Real-World Treatment Patterns
Authors: Lee Jessica K. , Madison Russell , Classon Anthony , Gjoerup Ole , Rosenzweig Mark , Frampton Garrett M. , Alexander Brian M. , Oxnard Geoffrey R. , Venstrom Jeffrey M. , Awad Mark M. , Schrock Alexa B. 
Published: August 2021

PURPOSEMET exon 14 ( METex14) skipping alterations are oncogenic drivers in non–small-cell lung cancer (NSCLC). We present a comprehensive overview of METex14 samples from 1,592 patients with NSCLC, associated clinicogenomic characteristics, potential mechanisms of acquired resistance, treatment patterns, and outcomes to MET inhibitors.METHODSHybrid capture–based comprehensive genomic profiling (CGP) was performed on samples from 69,219 patients with NSCLC. For treatment patterns and outcomes analysis, patients with advanced METex14-altered NSCLC were selected from the Flatiron Health-Foundation Medicine clinicogenomic database, a nationwide deidentified electronic health record–derived database linked to Foundation Medicine CGP for patients treated between January 2011 and March 2020.RESULTSA total of 1,592 patients with NSCLC (2.3%) were identified with 1,599 METex14 alterations spanning multiple functional sites (1,458 of 60,244 tissue samples and 134 of 8,975 liquid samples). Low tumor mutational burden and high programmed death ligand 1 expression were enriched in METex14-altered samples. MDM2, CDK4, and MET coamplifications and TP53 mutations were present in 34%, 19%, 11%, and 42% of tissue samples, respectively. Comparing tissue and liquid cohorts, coalteration frequency and acquired resistance mechanisms, including multiple MET mutations, EGFR, ERBB2, KRAS, and PI3K pathway alterations, were generally similar. Positive percent agreement with the tissue was 100% for METex14 pairs collected within 1 year (n = 7). Treatment patterns showed increasing adoption of MET inhibitors in METex14-altered NSCLC after receipt of CGP results; the real-world response rate to MET inhibitors was 45%, and time to treatment discontinuation was 4.4 months.CONCLUSIONDiverse METex14 alterations were present in 2%-3% of NSCLC cases. Tissue and liquid comparisons showed high concordance and similar coalteration profiles. Characterizing common co-occurring alterations and immunotherapy biomarkers, including those present before or acquired after treatment, may be critical for predicting responses to MET inhibitors and informing rational combination strategies.
LLF580, an FGF21 Analog, Reduces Triglycerides and Hepatic Fat in Obese Adults With Modest Hypertriglyceridemia
Authors: Rader Daniel J , Maratos-Flier Eleftheria , Nguyen Amanda , Hom Doug , Ferriere Michael , Li Yifang , Kompa Jill , Martic Miljen , Hinder Markus , Basson Craig T , Yowe David , Diener John , Goldfine Allison B ,   CLLF580X2102 Study Team, Bajaj Archna , Escalon Maricer , Fein Melanie , Hunt Allen , Kankam Martin K , Koren Michael , Rader Daniel J , Wilson Jessica 
Published: August 2021

Abstract

Purpose
To evaluate the safety and potential efficacy of LLF580, a genetically engineered variant of human fibroblast growth factor-21, for triglyceride lowering, weight loss, and hepatic fat reduction.

Methods
A multicenter, double-blind, parallel design trial in obese, mildly hypertriglyceridemic adults randomized (1:1) to LLF580 300 mg or placebo subcutaneously every 4 weeks for 3 doses.

Results
Of 64 randomized study participants, 61 (mean ± SD: age 45 ± 11 years, 49% male, 80/15/5% Caucasian/African American/other, body mass index 36.1 ± 3.8 kg/m2) received LLF580 (n = 30) or placebo (n = 31) at 7 research sites in the United States. LLF580 lowered serum triglycerides by 54% (least square mean placebo adjusted change from baseline), total cholesterol 7%, low-density lipoprotein cholesterol 12%, and increased high-density lipoprotein cholesterol 36% compared with placebo (all P &lt; 0.001) over 12 weeks. Substantial reduction of liver fat of 52% over placebo (P &lt; 0.001) was also demonstrated in the setting of improved liver function tests including alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase, the composite enhanced liver fibrosis score, and N-terminal type III collagen propeptide (all P &lt; 0.05). Insulin and C-peptide levels and insulin resistance by homeostatic model assessment for insulin resistance were all lower, and adiponectin higher with LLF580 treatment compared with placebo, whereas fasting glucose and glycated hemoglobin were unchanged. Reductions in biomarkers of bone formation without differences in markers of bone resorption were observed. LLF580 was generally safe and well tolerated, except for higher incidence of generally mild to moderate gastrointestinal adverse effects.

Conclusions
In obese, mildly hypertriglyceridemic adults, LLF580 was generally safe and demonstrated beneficial effects on serum lipids, liver fat, and biomarkers of liver injury, suggesting it may be effective for treatment of select metabolic disorders including hypertriglyceridemia and nonalcoholic fatty liver disease. Assessments of longer term safety and efficacy are warranted.

ClinicalTrials.gov Identifier
NCT03466203
LH Induces De Novo Cholesterol Biosynthesis via SREBP Activation in Granulosa Cells During Ovulation in Female Mice
Authors: Nakanishi Tomoya , Tanaka Risa , Tonai Shingo , Lee Joo Yeon , Yamaoka Manami , Kawai Tomoko , Okamoto Asako , Shimada Masayuki , Yamashita Yasuhisa 
Published: August 2021

Abstract
In the liver, the sterol response element binding protein (SREBP) and the SREBP cleavage-activated protein (SCAP) complex upregulate cholesterol biosynthesis by gene induction of de novo cholesterol synthetic enzymes (Hmgcr, Cyp51, and Dhcr7). Insulin induced gene 1 (INSIG1) negatively regulates cholesterol biosynthesis by the inhibition of de novo cholesterol biosynthetic gene expression. In the ovary, cholesterol is de novo synthesized; however, the roles of SREBP and its regulators (SCAP and INSIG1) are not well understood. In this study, when immature mice were treated with gonadotropins (eCG followed by hCG), eCG induced and hCG maintained the expression of SREBP-1a, -2, and SCAP granulosa cells, whereas INSIG1 expression was dramatically downregulated after hCG injection. Downregulation of INSIG1 led to generate the SREBPs active form and translocate the SREBPs active form to nuclei. Inhibition of generation of the SREBPs active form by fatostatin or Scap siRNA in both in vivo and in vitro significantly decreased the expressions of de novo cholesterol biosynthetic enzymes, cholesterol accumulation, and progesterone (P4) production compared with the control group. Fatostatin treatment inhibited the ovulation and increased the formation of abnormal corpus luteum which trapped the matured oocyte in the corpus luteum; however, the phenomenon was abolished by P4 administration. The results showed that decreasing INSIG1 level after hCG stimulation activated SREBP-induced de novo cholesterol biosynthesis in granulosa cells of preovulatory follicles, which is essential for P4 production and the rupture of matured oocyte during ovulation process.
On the “Spiritual” in Aesthetic Experience; or, The “Nonfactual in Facticity”
Authors: de Vries Hent 
Published: August 2021

AbstractThis article revisits the original meaning of “spiritual” as distinct from “intellectual” experience in Theodor W. Adorno’s late work. It does so through the implicitly Hegelian motifs in Wassily Kandinsky’s manifesto “On the Spiritual in Art,” a text that Adorno engages in passing in his Aesthetic Theory and that was, in turn, deeply influenced by the thought of Kandinsky’s nephew Alexandre Kojève, who also wrote an essay on his uncle’s paintings. This genealogy of motifs is of more than mere historical and anecdotal significance. At stake is nothing less than an accurate understanding of “spiritual experience [geistige Erfahrung]” as a more than merely theoretical matrix for what Adorno, in Negative Dialectics and the lecture courses, calls his materials studies. Rather than indicating largely esoteric or theosophical elements in Kandinsky’s influence on modernist aesthetic discourse, “spiritual experience,” in part read through the eyes of Kojève and, via him, Vladimir Soloviev, is thereby distinguished from what Adorno sees as an irrepressible tendency toward “spiritualization” in contemporary culture and the philosophy that reflects on it. Instead, it reveals a dimension of depth that the reception of Critical Theory has all too often ignored or disparaged.
Transforming growth factor β3 deficiency promotes defective lipid metabolism and fibrosis in murine kidney
Authors: Escasany Elia , Lanzón Borja , García-Carrasco Almudena , Izquierdo-Lahuerta Adriana , Torres Lucía , Corrales Patricia , Rodríguez Rodríguez Ana Elena , Luis-Lima Sergio , Martínez Álvarez Concepción , Javier Ruperez Francisco , Ros Manuel , Porrini Esteban , Rydén Mikael , Medina-Gómez Gema 
Published: August 2021

ABSTRACT
Glomerulosclerosis and tubulointerstitial fibrosis are pathological features of chronic kidney disease. Transforming growth factor β (TGFβ) is a key player in the development of fibrosis. However, of the three known TGFβ isoforms, only TGFβ1 has an established role in fibrosis, and the pathophysiological relevance of TGFβ2 and TGFβ3 is unknown. Because Tgfb3 deficiency in mice results in early postnatal lethality, we analyzed the kidney phenotype of heterozygous Tgfb3-knockout mice (Tgfb3+/−) and compared it with that of matched wild-type mice. Four-month-old Tgfb3+/− mice exhibited incipient renal fibrosis with epithelial–mesenchymal transition, in addition to glomerular basement membrane thickening and podocyte foot process effacement associated with albuminuria. Also evident was insulin resistance and oxidative stress at the renal level, together with aberrant renal lipid metabolism and mitochondrial function. Omics analysis revealed toxic species, such as diacylglycerides and ceramides, and dysregulated mitochondrial metabolism in Tgfb3+/− mice. Kidneys of Tgfb3+/− mice showed morphological alterations of mitochondria and overactivation of non-canonical MAPK ERK1/2 and JNK cascades. Our study indicates that renal TGFβ3 might have antifibrotic and renoprotective properties, opposing or counteracting the activity of TGFβ1.
This article has an associated First Person interview with the first author of the paper.
Electrocommunication signals indicate motivation to compete during dyadic interactions of an electric fish
Authors: Raab Till , Bayezit Sercan , Erdle Saskia , Benda Jan 
Published: August 2021

ABSTRACTAnimals across species compete for limited resources. Whereas in some species competition behavior is solely based on the individual's own abilities, other species assess their opponents to facilitate these interactions. Using cues and communication signals, contestants gather information about their opponent, adjust their behavior accordingly, and can thereby avoid high costs of escalating fights. We tracked electrocommunication signals known as ‘rises’ and agonistic behaviors of the gymnotiform electric fish Apteronotus leptorhynchus in staged competition experiments. A larger body size relative to the opponent was the sole significant predictor for winners. Sex and the frequency of the continuously emitted electric field only mildly influenced competition outcome. In males, correlations of body size and winning were stronger than in females and, especially when losing against females, communication and agonistic interactions were enhanced, suggesting that males are more motivated to compete. Fish that lost competitions emitted the majority of rises, but their quantity depended on the competitors’ relative size and sex. The emission of a rise could be costly since it provoked ritualized biting or chase behaviors by the other fish. Despite winners being accurately predictable based on the number of rises after the initial 25 min, losers continued to emit rises. The number of rises emitted by losers and the duration of chase behaviors depended in similar ways on physical attributes of contestants. Detailed evaluation of these correlations suggests that A. leptorhynchus adjusts its competition behavior according to mutual assessment, where rises could signal a loser's motivation to continue assessment through ritualized fighting.
Inguinoscrotal hernias containing stomach: risk of emergency presentation
Authors: Heylen J , Campioni-Norman D , Lowcock D , Varatharajan L , Kostalas M , Irukulla M , Ratnasingham K 
Published: August 2021

Introduction Inguinoscrotal hernias are the commonest form of abdominal wall hernia, but for them to contain stomach is extremely rare. The management of these hernias can be very challenging owing to their acute nature of presentation and distortion of anatomy. Our aim was to systematically review the literature for all reported cases of inguinoscrotal hernias containing stomach. In turn we analysed patient demographics, site of hernia, presentation and treatment. Outcomes were reviewed where available. Method We conducted a systematic search of the PUBMED, Embase and Medline databases with a combination of keywords: Hernia AND (inguin* OR scrot*) AND (gastric OR gastro*). An author's own case has also been included. Results There were 20 case reports included in the review, plus the author’s own case. They ranged in publication date from 1942 to 2020. Mean age at presentation was 71 years (range 49 to 87). All cases were male. In total, 62% (n = 13) of cases presented with combined symptoms of abdominal pain and vomiting, 48% (n = 10) presented with gastric outlet obstruction (GOO) and 48% (n = 10) presented with gastric perforation. All successfully treated cases with gastric perforation required a midline laparotomy approach, whereas 56% (n = 5) of patients in the GOO group were successfully treated conservatively. There were three deaths reported in this review, all in the gastric perforation group. Conclusion Stomach as a content of inguinoscrotal hernias is extremely rare. These hernias predominantly present acutely in the form of GOO or gastric perforation. All patients with gastric perforation will require a midline laparotomy. Patients with GOO can be successfully managed either surgically or in selective cases with conservative management.
Graphene-coupled silica microtoroid for optical polarization controlling and electro-optic modulation
Authors: Fan Huibo , Yin Qiming , Lu Cong , Fan Hongwei 
Published: August 2021

Whispering gallery (WG) microcavities have been applied for a variety of optoelectronic devices due to their extraordinary characteristics of high quality factor (

Q

) and small mode volume, crucial to accurately tune the quality factor for realizing the high-speed optical modulation and short pulse laser. In this paper, we propose and theoretically analyze a hybrid, graphene-coupled silica microtoroid device and realize optical polarization control and electro-optic modulation due to the polarization-dependent absorption of graphene on the different cavity WG modes. By changing the gap distance between graphene and the microtoroid, the influence of graphene absorption on the different polarization modes is diverse due to the different electric field distributions of modes in the microtoroid, therefore demonstrating the different resonant wavelength shifts and quality factor variations. The transmission depth variation of the second-order transverse electric mode upon changing the gap distance between graphene and microtoroid is 4.5 dB more than that of the second-order transverse magnetic mode, verifying that the polarization control is because of the polarization-dependent absorption of graphene. Furthermore, by applying the voltage on the graphene flakes, electro-optic modulation with a high contrast of 21.7 dB is demonstrated based on this hybrid graphene-coupled silica microtoroid.
Compact and broadband mode demultiplexer using a subwavelength grating engineered MMI coupler
Authors: Zhang Liang , Xiao Jinbiao 
Published: August 2021

A compact and broadband mode demultiplexer (DEMUX) using a subwavelength grating (SWG) engineered multimode interference (MMI) coupler is proposed and analyzed in detail. To effectively separate the input

T
E

0

and

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1

modes, the input port is formed by cascading two tapers, connected by a silicon wire, in a single SWG MMI coupler. Moreover, by partially tailoring the grating duty cycle of the SWGs, an extra phase shifter is directly integrated in the MMI coupler, parallel to the input port for adjusting the phase in mode conversion. The input

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mode can pass through the first taper and the silicon wire while being cut off and evolve into SWGs in the second taper, so that it is hardly affected by the extra phase shifter and directly mapped into the output port via MMI. On the contrary, the input

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1

mode is cut off in the first taper and evolves through the sidewall of the first taper into two

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-like components in the SWG region. Then an extra

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/

2

phase shift between them is generated by the phase shifter. Finally, they are combined into the output

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mode via MMI. By carefully choosing the structural parameters, the proposed

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/

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mode DEMUX shows a broad bandwidth of 350 nm from 1520 to 1870 nm for insertion loss

<

1.0

d
B

and cross talk

<

−

10

d
B

and achieves a low insertion loss of 0.37 dB/0.40 dB and cross talk of

−

18.50

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B

/

−

17.00

d
B

for

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input at 1550 nm, within a short device length of only 18.6 µm. In addition, the device also shows a good fabrication tolerance to the deviations of structure parameters.