bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mapping the cellular response to electron transport chain inhibitors reveals selective signaling networks triggered by mitochondrial perturbation
Authors: van der Stel Wanda , Yang Huan , Vrijenhoek Nanette G. , Schimming Johannes P. , Callegaro Giulia , Carta Giada , Darici Salihanur , Delp Johannes , Forsby Anna , White Andrew , le Dévédec Sylvia , Leist Marcel , Jennings Paul , Beltman Joost B. , van de Water Bob , Danen Erik H. J. 
Published: October 2021

AbstractMitochondrial perturbation is a key event in chemical-induced organ toxicities that is incompletely understood. Here, we studied how electron transport chain (ETC) complex I, II, or III (CI, CII and CIII) inhibitors affect mitochondrial functionality, stress response activation, and cell viability using a combination of high-content imaging and TempO-Seq in HepG2 hepatocyte cells. CI and CIII inhibitors perturbed mitochondrial membrane potential (MMP) and mitochondrial and cellular ATP levels in a concentration- and time-dependent fashion and, under conditions preventing a switch to glycolysis attenuated cell viability, whereas CII inhibitors had no effect. TempO-Seq analysis of changes in mRNA expression pointed to a shared cellular response to CI and CIII inhibition. First, to define specific ETC inhibition responses, a gene set responsive toward ETC inhibition (and not to genotoxic, oxidative, or endoplasmic reticulum stress) was identified using targeted TempO-Seq in HepG2. Silencing of one of these genes, NOS3, exacerbated the impact of CI and CIII inhibitors on cell viability, indicating its functional implication in cellular responses to mitochondrial stress. Then by monitoring dynamic responses to ETC inhibition using a HepG2 GFP reporter panel for different classes of stress response pathways and applying pathway and gene network analysis to TempO-Seq data, we looked for downstream cellular events of ETC inhibition and identified the amino acid response (AAR) as being triggered in HepG2 by ETC inhibition. Throughin silicoapproaches we provide evidence indicating that a similar AAR is associated with exposure to mitochondrial toxicants in primary human hepatocytes. Altogether, we (i) unravel quantitative, time- and concentration-resolved cellular responses to mitochondrial perturbation, (ii) identify a gene set associated with adaptation to exposure to active ETC inhibitors, and (iii) show that ER stress and an AAR accompany ETC inhibition in HepG2 and primary hepatocytes.
Deformations of higher-page analogues of $$\partial {{\bar{\partial }}}$$-manifolds
Authors: Popovici Dan , Stelzig Jonas , Ugarte Luis 
Published: October 2021

AbstractWe extend the notion of small essential deformations of Calabi–Yau complex structures from the case of the Iwasawa manifold, for which they were introduced recently by the first-named author, to the general case of page-1-$$\partial {{\bar{\partial }}}$$

∂

∂

¯

-manifolds that were jointly introduced very recently by all three authors. We go on to obtain an analogue of the unobstructedness theorem of Bogomolov, Tian and Todorov for Calabi–Yau page-1-$$\partial {{\bar{\partial }}}$$

∂

∂

¯

-manifolds. As applications of this discussion, we study the small deformations of certain Nakamura solvmanifolds and reinterpret the cases of the Iwasawa manifold and its 5-dimensional analogue from this standpoint.
Combined transarterial iodized oil injection and computed tomography-guided thermal ablation for hepatocellular carcinoma: utility of the iodized oil retention pattern
Authors: Tan Jie , Mathy René Michael , Chang De-Hua , Tang Tian , Zhang Zi-Shu , Xiao Yu-Dong 
Published: October 2021

Abstract
Purpose
To investigate whether the iodized oil (Lipiodol, Guerbet Group, Villepinte, France) retention pattern influences the treatment efficacy of combined transarterial Lipiodol injection (TLI) and thermal ablation in patients with hepatocellular carcinoma (HCC).

Methods
Data of 198 patients (280 HCC lesions), who underwent TLI plus computed tomography (CT)-guided thermal ablation at three separate medical institutions between June 2014 and September 2020, were reviewed and analyzed. The Lipiodol retention pattern was classified as complete or incomplete based on non-enhanced CT at the time of ablation. The primary outcome was local recurrence-free survival (LRFS) for lesions; the secondary outcome was overall survival (OS) for patients. Propensity score matching (PSM) was performed using a caliper width of 0.1 between the two groups. Differences in LRFS and OS between the two groups were compared using the log-rank test.

Results
A total of 133 lesions exhibited a complete Lipiodol retention pattern, while 147 exhibited an incomplete pattern. After PSM analysis of baseline characteristics of the lesions, 121 pairs of lesions were matched. LRFS was significantly longer for lesions exhibiting complete retention than for those exhibiting incomplete retention (P = 0.030). After PSM analysis of patient baseline characteristics, 74 pairs of patients were matched. There was no significant difference in OS between the two groups (P = 0.456).

Conclusion
Lipiodol retention patterns may influence the treatment efficacy of combined TLI and thermal ablation for HCC lesions. However, a survival benefit for the Lipiodol retention pattern among HCC patients was not observed and needs further confirmation.
Regulation of STAT3 and its role in cardioprotection by conditioning: focus on non-genomic roles targeting mitochondrial function
Authors: Comità Stefano , Femmino Saveria , Thairi Cecilia , Alloatti Giuseppe , Boengler Kerstin , Pagliaro Pasquale , Penna Claudia 
Published: October 2021

AbstractIschemia–reperfusion injury (IRI) is one of the biggest challenges for cardiovascular researchers given the huge death toll caused by myocardial ischemic disease. Cardioprotective conditioning strategies, namely pre- and post-conditioning maneuvers, represent the most important strategies for stimulating pro-survival pathways essential to preserve cardiac health. Conditioning maneuvers have proved to be fundamental for the knowledge of the molecular basis of both IRI and cardioprotection. Among this evidence, the importance of signal transducer and activator of transcription 3 (STAT3) emerged. STAT3 is not only a transcription factor but also exhibits non-genomic pro-survival functions preserving mitochondrial function from IRI. Indeed, STAT3 is emerging as an influencer of mitochondrial function to explain the cardioprotection phenomena. Studying cardioprotection, STAT3 proved to be crucial as an element of the survivor activating factor enhancement (SAFE) pathway, which converges on mitochondria and influences their function by cross-talking with other cardioprotective pathways. Clearly there are still some functional properties of STAT3 to be discovered. Therefore, in this review, we highlight the evidence that places STAT3 as a promoter of the metabolic network. In particular, we focus on the possible interactions of STAT3 with processes aimed at maintaining mitochondrial functions, including the regulation of the electron transport chain, the production of reactive oxygen species, the homeostasis of Ca2+and the inhibition of opening of mitochondrial permeability transition pore. Then we consider the role of STAT3 and the parallels between STA3/STAT5 in cardioprotection by conditioning, giving emphasis to the human heart and confounders.
Neuroendocrine neoplasms of the pancreas: diagnosis and pitfalls
Authors: Konukiewitz Björn , Jesinghaus Moritz , Kasajima Atsuko , Klöppel Günter 
Published: October 2021

AbstractCommon to neuroendocrine neoplasms of the pancreas is their expression of synaptophysin, chromogranin A, and/or INSM1. They differ, however, in their histological differentiation and molecular profile. Three groups can be distinguished: well-differentiated neuroendocrine neoplasms (neuroendocrine tumors), poorly differentiated neuroendocrine neoplasms (neuroendocrine carcinomas), and mixed neuroendocrine-non-neuroendocrine neoplasms. However, the expression of synaptophysin and, to a lesser extent, also chromogranin A is not restricted to the neuroendocrine neoplasms, but may also be in a subset of non-neuroendocrine epithelial and non-epithelial neoplasms. This review provides the essential criteria for the diagnosis of pancreatic neuroendocrine neoplasms including diagnostic clues for the distinction of high-grade neuroendocrine tumors from neuroendocrine carcinomas and an algorithm avoiding diagnostic pitfalls in the delineation of non-neuroendocrine neoplasms with neuroendocrine features from pancreatic neuroendocrine neoplasms.
Vitamin D in Gambian children with discordant tuberculosis (TB) infection status despite matched TB exposure: a case control study
Authors: Stockdale Lisa , Sambou Basil , Sissoko Muhamed , Egere Uzochukwu , Sillah Abdou K. , Kampmann Beate , Basu Roy Robin 
Published: October 2021

AbstractUsing a matched case control design conducted at MRC Gambia in 2015, we measured vitamin D levels in pairs of asymptomatic children with discordant tuberculin skin test status despite the same sleeping proximity to the same adult TB index case. Median ages of groups (infected; 10.0 years, uninfected 8.8 years) were not significantly different (p = 0.13). Mean vitamin D levels were 2.05 ng/mL (95% CI − 0.288 to 4.38) higher in 24 highly TB-exposed uninfected children compared with 24 matched highly TB-exposed infected children (p = 0.08). The findings warrant further investigation in larger studies to understand the implications and significance. Conclusion: Vitamin D levels were higher in TB-uninfected children compared with TB-infected despite equal high exposure to a TB case.

What is Known:• Paediatrics TB represents one of the leading causes of child death globally.• Current literature shows an inconsistent relationship between vitamin D deficiency and increased risk of TB disease however a large Phase 3 trial of vitamin D supplementation in (largely vitamin D deficient) Mongolian children did not find any association with TB infection rates.

What is New:• This study adds to the literature in a vitamin D sufficient paediatric population whereby children with equal exposure to a household TB case with no evidence of TB infection have higher levels of vitamin D compared with matched children with TB infection.
Onchocerciasis drug development: from preclinical models to humans
Authors: Ngwewondo Adela , Scandale Ivan , Specht Sabine 
Published: October 2021

Abstract
Twenty diseases are recognized as neglected tropical diseases (NTDs) by World Health Assembly resolutions, including human filarial diseases. The end of NTDs is embedded within the Sustainable Development Goals for 2030, under target 3.3. Onchocerciasis afflicts approximately 20.9 million people worldwide with > 90% of those infected residing in Africa. Control programs have made tremendous efforts in the management of onchocerciasis by mass drug administration and aerial larviciding; however, disease elimination is not yet achieved. In the new WHO roadmap, it is recognized that new drugs or drug regimens that kill or permanently sterilize adult filarial worms would significantly improve elimination timelines and accelerate the achievement of the program goal of disease elimination. Drug development is, however, handicapped by high attrition rates, and many promising molecules fail in preclinical development or in subsequent toxicological, safety and efficacy testing; thus, research and development (R&D) costs are, in aggregate, very high. Drug discovery and development for NTDs is largely driven by unmet medical needs put forward by the global health community; the area is underfunded and since no high return on investment is possible, there is no dedicated drug development pipeline for human filariasis. Repurposing existing drugs is one approach to filling the drug development pipeline for human filariasis. The high cost and slow pace of discovery and development of new drugs has led to the repurposing of “old” drugs, as this is more cost-effective and allows development timelines to be shortened. However, even if a drug is marketed for a human or veterinary indication, the safety margin and dosing regimen will need to be re-evaluated to determine the risk in humans. Drug repurposing is a promising approach to enlarging the pool of active molecules in the drug development pipeline. Another consideration when providing new treatment options is the use of combinations, which is not addressed in this review. We here summarize recent advances in the late preclinical or early clinical stage in the search for a potent macrofilaricide, including drugs against the nematode and against its endosymbiont, Wolbachia pipientis.
Plasticity in induced resistance to sequential attack by multiple herbivores in Brassica nigra
Authors: de Bobadilla Maite Fernández , Van Wiechen Roel , Gort Gerrit , Poelman Erik H. 
Published: October 2021

AbstractIn nature, plants interact with multiple insect herbivores that may arrive simultaneously or sequentially. There is extensive knowledge on how plants defend themselves against single or dual attack. However, we lack information on how plants defend against the attack of multiple herbivores that arrive sequentially. In this study, we investigated whether Brassica nigra L. plants are able to defend themselves against caterpillars of the late-arriving herbivore Plutella xylostella L., when plants had been previously exposed to sequential attack by four other herbivores (P. xylostella, Athalia rosae, Myzus persicae and Brevicoryne brassicae). We manipulated the order of arrival and the history of attack by four herbivores to investigate which patterns in sequential herbivory determine resistance against the fifth attacker. We recorded that history of sequential herbivore attack differentially affected the capability of B. nigra plants to defend themselves against caterpillars of P. xylostella. Caterpillars gained less weight on plants attacked by a sequence of four episodes of attack by P. xylostella compared to performance on plants that were not previously damaged by herbivores. The number of times the plant was attacked by herbivores of the same feeding guild, the identity of the first attacker, the identity and the guild of the last attacker as well as the order of attackers within the sequence of multiple herbivores influenced the growth of the subsequent herbivory. In conclusion, this study shows that history of sequential attack is an important factor determining plant resistance to herbivores.
Immune function differs among tropical environments but is not downregulated during reproduction in three year-round breeding equatorial lark populations
Authors: Ndithia Henry K. , Matson Kevin D. , Muchai Muchane , Tieleman B. Irene 
Published: October 2021

AbstractSeasonal variation in immune function can be attributed to life history trade-offs, and to variation in environmental conditions. However, because phenological stages and environmental conditions co-vary in temperate and arctic zones, their separate contributions have not been determined. We compared immune function and body mass of incubating (female only), chick-feeding (female and male), and non-breeding (female and male) red-capped larksCalandrella cinereabreeding year-round in three tropical equatorial (Kenya) environments with distinct climates. We measured four immune indices: haptoglobin, nitric oxide, agglutination, and lysis. To confirm that variation in immune function between breeding (i.e., incubating or chick-feeding) and non-breeding was not confounded by environmental conditions, we tested if rainfall, average minimum temperature (Tmin), and average maximum temperature (Tmax) differed during sampling times among the three breeding statuses per location.TminandTmaxdiffered between chick-feeding and non-breeding, suggesting that birds utilized environmental conditions differently in different locations for reproduction. Immune indices did not differ between incubating, chick-feeding and non-breeding birds in all three locations. There were two exceptions: nitric oxide was higher during incubation in cool and wet South Kinangop, and it was higher during chick-feeding in the cool and dry North Kinangop compared to non-breeding birds in these locations. For nitric oxide, agglutination, and lysis, we found among-location differences within breeding stage. In equatorial tropical birds, variation in immune function seems to be better explained by among-location climate-induced environmental conditions than by breeding status. Our findings raise questions about how within-location environmental variation relates to and affects immune function.
Thrombosis associated with ventriculoatrial shunts
Authors: Wu Dengjun , Guan Zhengyan , Xiao Limin , Li Donghai 
Published: October 2021

AbstractVentriculoatrial shunts are the most common second-line procedure for cases in which ventriculoperitoneal shunts are unsuitable. Shunting-associated thrombosis is a potentially life-threatening complication after ventriculoatrial shunt insertion. The overall prevalence of this complication is still controversial because of substantial differences in the numbers found in studies using clinical data and in those analyzing postmortem findings. The etiology of thrombosis may be multifactorial, including shunt catheter itself, contents of cerebrospinal fluid, shunt infection, and genetic disorder. The clinical presentation can vary widely, ranging from asymptomatic to a life-threatening condition. Timely recognition of thromboembolic lesions is critical for treatment. However, early diagnosis and management is still challenging because of a relatively long asymptomatic latency and lack of clear guideline recommendations. The purpose of this review is to provide an overview of ventriculoatrial shunt thrombosis, especially to focus on its etiopathogenesis, diagnosis, treatment, and prevention.
Dexmedetomidine attenuates haemorrhage-induced thalamic pain by inhibiting the TLR4/NF-κB/ERK1/2 pathway in mice
Authors: Huang Tianfeng , Li Yong , Hu Wenqing , Yu Dapeng , Gao Ju , Yang Fan , Xu Yingying , Wang Zehua , Zong Liang 
Published: October 2021

Abstract
Background
Thalamic pain, a neuropathic pain syndrome, frequently occurs after stroke. This research aimed to investigate the effect of dexmedetomidine (DEX) on thalamic pain.

Methods
The cellular localization of the TLR4 protein was determined by immunostaining. The expression of Iba1, GFAP and protein associated with the TLR4/NF-κB/ERK1/2 pathway was measured by Western blotting. Continuous pain hypersensitivity was evaluated by behavioural tests. The results were analysed by one-way ANOVA, two-way ANOVA and Tukey’s post hoc test.

Results
The results demonstrated that DEX obviously alleviated thalamic pain induced by haemorrhage on the ipsilateral side and delayed the development of pain hypersensitivity. Furthermore, the expression levels of Iba1, GFAP and proteins associated with the TLR4/NF-κB/ERK1/2 signalling pathway were greatly increased in mice with thalamic pain, but these effects were reversed by DEX.

Conclusion
Our findings suggest that DEX alleviates the inflammatory response during thalamic pain through the TLR4/NF-κB/ERK1/2 signalling pathway and might be a potential therapeutic agent for thalamic pain.
Let’s Connect to Keep the Distance: How SMEs Leverage Information and Communication Technologies to Address the COVID-19 Crisis
Authors: Wendt Charlotte , Adam Martin , Benlian Alexander , Kraus Sascha 
Published: October 2021

AbstractCOVID-19 caused significant challenges for small and medium-sized enterprises (SMEs) in the event industry. To address these challenges, many SMEs leveraged information and communication technologies (ICTs), with some even emerging strengthened from the crisis. Drawing on the technology-organization-environment framework and technology-affordances-and-constraints theory, we investigate the adoption of ICTs as a crisis response strategy in 10 SMEs in the German business event (e.g., corporate events, conferences) industry. Our findings reveal that ICT adoption not only depends on rational decisions based on organizational, environmental, and technological characteristics, but also on these dimensions’ interrelationship and the specific ICTs’ affordances and constraints. Introducing readily available ICTs (e.g., video-conferencing) has significant potential in addressing physical distancing in the short and medium term, while more sophisticated ICTs (e.g., virtual reality) are more likely to gain importance in the long term. Thus, we expand our understanding of organizational technology adoption and ICT-enabled crisis response strategies in SMEs.
The Mediating Effects of Alexithymia, Intolerance of Uncertainty, and Anxiety on the Relationship Between Sensory Processing Differences and Restricted and Repetitive Behaviours in Autistic Adults
Authors: Moore Heather L. , Brice Samuel , Powell Lauren , Ingham Barry , Freeston Mark , Parr Jeremy R. , Rodgers Jacqui 
Published: October 2021

AbstractDistress caused by sensory processing differences for autistic individuals may be reduced by repetitive behaviours (RRB), including repetitive motor (RMB) and insistence on sameness (ISB) behaviours. Intolerance of uncertainty (IU) and anxiety mediate the relationship between sensory processing and RRB in autistic children. We replicated this model in autistic adults, extending it to include alexithymia. Serial mediation, using data from 426 autistic adults, identified significant direct effects from sensory processing to RMB and ISB, and indirect effects through alexithymia-IU-anxiety for RMB, and IU alone, and alexithymia-IU for ISB. Different mechanisms may underpin RMB and ISB. Alexithymia alongside, IU and anxiety, should be considered when understanding the relationship between sensory processing and RRB, and when offering interventions to support autistic people.
Proof Complexity of Modal Resolution
Authors: Sigley Sarah , Beyersdorff Olaf 
Published: October 2021

AbstractWe investigate the proof complexity of modal resolution systems developed by Nalon and Dixon (J Algorithms 62(3–4):117–134, 2007) and Nalon et al. (in: Automated reasoning with analytic Tableaux and related methods—24th international conference, (TABLEAUX’15), pp 185–200, 2015), which form the basis of modal theorem proving (Nalon et al., in: Proceedings of the twenty-sixth international joint conference on artificial intelligence (IJCAI’17), pp 4919–4923, 2017). We complement these calculi by a new tighter variant and show that proofs can be efficiently translated between all these variants, meaning that the calculi are equivalent from a proof complexity perspective. We then develop the first lower bound technique for modal resolution using Prover–Delayer games, which can be used to establish “genuine” modal lower bounds for size of dag-like modal resolution proofs. We illustrate the technique by devising a new modal pigeonhole principle, which we demonstrate to require exponential-size proofs in modal resolution. Finally, we compare modal resolution to the modal Frege systems of Hrubeš (Ann Pure Appl Log 157(2–3):194–205, 2009) and obtain a “genuinely” modal separation.