bluuebunny/crossref_metadata_2025 huggingface dataset:
Prefix Imputation of Orphan Events in Event Stream Processing
Authors: Zaman Rashid , Hassani Marwan , Van Dongen Boudewijn F.
Published: October 2021

In the context of process mining, event logs consist of process instances called cases. Conformance checking is a process mining task that inspects whether a log file is conformant with an existing process model. This inspection is additionally quantifying the conformance in an explainable manner. Online conformance checking processes streaming event logs by having precise insights into the running cases and timely mitigating non-conformance, if any. State-of-the-art online conformance checking approaches bound the memory by either delimiting storage of the events per case or limiting the number of cases to a specific window width. The former technique still requires unbounded memory as the number of cases to store is unlimited, while the latter technique forgets running, not yet concluded, cases to conform to the limited window width. Consequently, the processing system may later encounter events that represent some intermediate activity as per the process model and for which the relevant case has been forgotten, to be referred to as orphan events. The naïve approach to cope with an orphan event is to either neglect its relevant case for conformance checking or treat it as an altogether new case. However, this might result in misleading process insights, for instance, overestimated non-conformance. In order to bound memory yet effectively incorporate the orphan events into processing, we propose an imputation of missing-prefix approach for such orphan events. Our approach utilizes the existing process model for imputing the missing prefix. Furthermore, we leverage the case storage management to increase the accuracy of the prefix prediction. We propose a systematic forgetting mechanism that distinguishes and forgets the cases that can be reliably regenerated as prefix upon receipt of their future orphan event. We evaluate the efficacy of our proposed approach through multiple experiments with synthetic and three real event logs while simulating a streaming setting. Our approach achieves considerably higher realistic conformance statistics than the state of the art while requiring the same storage.
Prey Foraging Behavior After Predator Introduction Is Driven by Resource Knowledge and Exploratory Tendency
Authors: Bracis Chloe , Wirsing Aaron J.
Published: October 2021

Predator reintroductions are often used as a means of restoring the ecosystem services that these species can provide. The ecosystem consequences of predator reintroduction depend on how prey species respond. Yet, to date, we lack a general framework for predicting these responses. To address this knowledge gap, we modeled the impacts of predator reintroduction on foragers as a function of predator characteristics (habitat domain; i.e., area threatened) and prey characteristics (knowledge of alternative habitat and exploratory tendency). Foraging prey had the capacity to both remember and return to good habitat and to remember and avoid predators. In general, we found that forager search time increased and consumption decreased after predator introduction. However, predator habitat domain played a key role in determining how much prey habitat use changed following reintroduction, and the forager's knowledge of alternative habitats and exploratory inclinations affected what types of habitat shifts occurred. Namely, habitat shifts and consumption sacrifices by prey were extreme in some cases, particularly when they were pushed far from their starting locations by broad-domain predators, whereas informed foragers spent less time searching and displayed smaller reductions to consumption than their naïve counterparts following predator exposure. More exploratory foragers exhibited larger habitat shifts, thereby sacrificing consumption but reducing encounters by relocating to refugia, whereas less exploratory foragers managed risk in place and consequently suffered increased encounters while consuming more resources. By implication, reintroductions of predators with broad habitat domains are especially likely to impose foraging and movements costs on prey, but forager spatial memory state can mitigate these effects, as informed foragers can better access alternate habitat and avoid predators with smaller reductions in consumption.
Chemosensory Gene Expression for Two Closely Relative Species Rhodnius robustus and R. prolixus (Hemiptera, Reduviidade, Triatominae) Vectors of Chagas Disease
Authors: Marchant Axelle , Mougel Florence , Jacquin-Joly Emmanuelle , Almeida Carlos E. , Blanchet Denis , Bérenger Jean-Michel , da Rosa João A. , Harry Myriam
Published: October 2021

Two closely related species, Rhodnius prolixus and Rhodnius robustus, are the vectors of Trypanosoma cruzi, which is the causative agent of Chagas disease, but clearly exhibit clear-cut differences in their ecological behavior. R. prolixus is considered as a domiciliated species, whereas R. robustus only sporadically visits human houses in Amazonia. We performed a chemosensory gene expression study via RNA-sequencing (RNA-seq) for the two species and also included a laboratory introgressed R. robustus strain. We built an assembled transcriptome for each sample and for both sexes and compiled all in a reference transcriptome for a differential gene expression study. Because the genes specifically expressed in one condition and not expressed in another may also reflect differences in the adaptation of organisms, a comparative study of the presence/absence of transcripts was also performed for the chemosensory transcripts, namely chemosensory proteins (CSPs), odorant-binding proteins (OBPs), odorant receptors (ORs), gustatory receptors (GRs), and ionotropic receptors (IRs), as well as takeout (TO) transcripts because TO proteins have been proposed to be associated with chemosensory perception in both olfactory and taste systems. In this study, 12 novel TO transcripts from the R. prolixus genome were annotated. Among the 199 transcripts, out of interest, annotated in this study, 93% were conserved between R. prolixus and the sylvatic R. robustus. Moreover, 10 transcripts out of interest were specifically expressed in one sex and absent in another. Three chemosensory transcripts were found to be expressed only in the reared R. prolixus (CSP19, OBP9, and OR89) and only one in sylvatic R. robustus (OR22). A large set of transcripts were found to be differentially expressed (DE) between males and females (1,630), with a majority of them (83%) overexpressed in males. Between environmental conditions, 8,596 transcripts were DE, with most (67%) overexpressed in the sylvatic R. robustus samples, including 17 chemosensory transcripts (4 CSPs, 1 OBP, 5 ORs, 1 GR, 4 IR, and 2 TO), but 4 genes (OBP19, OR13, OR40, and OR79) were overexpressed in the reared samples.
Case Report: Novel Compound-Heterozygous Variants of SKIV2L Gene that Cause Trichohepatoenteric Syndrome 2
Authors: Zhang Qiao , Qian Xia , Zhou Jianli , Han Lin , Zhou Shaoming , Wang Zhaoxia
Published: October 2021

Background: Trichohepatoenteric syndrome (THES) is a rare disease that mainly causes intractable diarrhea. It is classified into THES1 and THES2, which are associated with the tetratricopeptide repeat domain 37 (TTC37) gene and Ski2-like RNA helicase (SKIV2L) gene, respectively. THES is not very prevalent in China or worldwide, but new cases have increasingly been reported.

Methods and Results: Here, we report the clinical and genetic information of a 1.5-month-old girl who was admitted to our hospital due to diarrhea and failure to thrive. Whole-exome sequencing (WES) revealed novel compound-heterozygous variants of the SKIV2L gene, c.3602_3609delAGCGCCTG (p.Q1201Rfs*2), and c.1990A > G (p.T664A) as the causative factors, which were confirmed via Sanger sequencing. Upon continuous feeding with an amino-acid formula through a gastric tube and parenteral nutrition, the patient resumed thriving and her stool frequency decreased.

Conclusion: We report a girl carrying novel variants of the SKIV2L gene that cause THES2, thereby providing valuable information on the diagnosis of THES2 and expanding the spectrum of disease-causing SKIV2L mutations.
Stamp2 Protects From Maladaptive Structural Remodeling and Systolic Dysfunction in Post-Ischemic Hearts by Attenuating Neutrophil Activation
Authors: Mollenhauer Martin , Bokredenghel Senai , Geißen Simon , Klinke Anna , Morstadt Tobias , Torun Merve , Strauch Sabrina , Schumacher Wibke , Maass Martina , Konradi Jürgen , Peters Vera B. M. , Berghausen Eva , Vantler Marius , Rosenkranz Stephan , Mehrkens Dennis , Braumann Simon , Nettersheim Felix , Hof Alexander , Simsekyilmaz Sakine , Winkels Holger , Rudolph Volker , Baldus Stephan , Adam Matti , Freyhaus Henrik ten
Published: October 2021

The six-transmembrane protein of prostate 2 (Stamp2) acts as an anti-inflammatory protein in macrophages by protecting from overt inflammatory signaling and Stamp2 deficiency accelerates atherosclerosis in mice. Herein, we describe an unexpected role of Stamp2 in polymorphonuclear neutrophils (PMN) and characterize Stamp2’s protective effects in myocardial ischemic injury. In a murine model of ischemia and reperfusion (I/R), echocardiography and histological analyses revealed a pronounced impairment of cardiac function in hearts of Stamp2-deficient- (Stamp2-/-) mice as compared to wild-type (WT) animals. This difference was driven by aggravated cardiac fibrosis, as augmented fibroblast-to-myofibroblast transdifferentiation was observed which was mediated by activation of the redox-sensitive p38 mitogen-activated protein kinase (p38 MAPK). Furthermore, we observed increased production of reactive oxygen species (ROS) in Stamp2-/- hearts after I/R, which is the likely cause for p38 MAPK activation. Although myocardial macrophage numbers were not affected by Stamp2 deficiency after I/R, augmented myocardial infiltration by polymorphonuclear neutrophils (PMN) was observed, which coincided with enhanced myeloperoxidase (MPO) plasma levels. Primary PMN isolated from Stamp2-/- animals exhibited a proinflammatory phenotype characterized by enhanced nuclear factor (NF)-κB activity and MPO secretion. To prove the critical role of PMN for the observed phenotype after I/R, antibody-mediated PMN depletion was performed in Stamp2-/- mice which reduced deterioration of LV function and adverse structural remodeling to WT levels. These data indicate a novel role of Stamp2 as an anti-inflammatory regulator of PMN and fibroblast-to-myofibroblast transdifferentiation in myocardial I/R injury.
The Immune System and the Antiviral Responses in Chinese Giant Salamander, Andrias davidianus
Authors: Jiang Nan , Fan Yuding , Zhou Yong , Meng Yan , Liu Wenzhi , Li Yiqun , Xue Mingyang , Robert Jacques , Zeng Lingbing
Published: October 2021

The Chinese giant salamander, belonging to an ancient amphibian lineage, is the largest amphibian existing in the world, and is also an important animal for artificial cultivation in China. However, some aspects of the innate and adaptive immune system of the Chinese giant salamander are still unknown. The Chinese giant salamander iridovirus (GSIV), a member of the Ranavirus genus (familyIridoviridae), is a prominent pathogen causing high mortality and severe economic losses in Chinese giant salamander aquaculture. As a serious threat to amphibians worldwide, the etiology of ranaviruses has been mainly studied in model organisms, such as theAmbystoma tigrinumandXenopus. Nevertheless, the immunity to ranavirus in Chinese giant salamander is distinct from other amphibians and less known. We review the unique immune system and antiviral responses of the Chinese giant salamander, in order to establish effective management of virus disease in Chinese giant salamander artificial cultivation.
Oncolytic Viro-Immunotherapy: An Emerging Option in the Treatment of Gliomas
Authors: Zeng Jiayi , Li Xiangxue , Sander Max , Zhang Haipeng , Yan Guangmei , Lin Yuan
Published: October 2021

The prognosis of malignant gliomas remains poor, with median survival fewer than 20 months and a 5-year survival rate merely 5%. Their primary location in the central nervous system (CNS) and its immunosuppressive environment with little T cell infiltration has rendered cancer therapies mostly ineffective, and breakthrough therapies such as immune checkpoint inhibitors (ICIs) have shown limited benefit. However, tumor immunotherapy is developing rapidly and can help overcome these obstacles. But for now, malignant gliomas remain fatal with short survival and limited therapeutic options. Oncolytic virotherapy (OVT) is a unique antitumor immunotherapy wherein viruses selectively or preferentially kill tumor cells, replicate and spread through tumors while inducing antitumor immune responses. OVTs can also recondition the tumor microenvironment and improve the efficacy of other immunotherapies by escalating the infiltration of immune cells into tumors. Some OVTs can penetrate the blood-brain barrier (BBB) and possess tropism for the CNS, enabling intravenous delivery. Despite the therapeutic potential displayed by oncolytic viruses (OVs), optimizing OVT has proved challenging in clinical development, and marketing approvals for OVTs have been rare. In June 2021 however, as a genetically engineered OV based on herpes simplex virus-1 (G47Δ), teserpaturev got conditional and time-limited approval for the treatment of malignant gliomas in Japan. In this review, we summarize the current state of OVT, the synergistic effect of OVT in combination with other immunotherapies as well as the hurdles to successful clinical use. We also provide some suggestions to overcome the challenges in treating of gliomas.
Interleukin-4 Programmed Macrophages Suppress Colitis and Do Not Enhance Infectious-Colitis, Inflammation-Associated Colon Cancer or Airway Hypersensitivity
Authors: Callejas Blanca E. , Blyth Graham A. D. , Jendzjowsky Nicholas , Wang Arthur , Babbar Anshu , Koro Konstantin , Wilson Richard J. A. , Kelly Margaret M. , Cobo Eduardo R. , McKay Derek M.
Published: October 2021

The murine interleukin-4 treated macrophage (MIL4) exerts anti-inflammatory and pro-healing effects and has been shown to reduce the severity of chemical-induced colitis. Positing M(IL4) transfer as an anti-inflammatory therapy, the possibility of side-effects must be considered. Consequently, bone marrow-derived M(IL4)s were administered via intraperitoneal injection to mice concomitant with Citrobacter rodentium infection (infections colitis), azoxymethane/dextran sodium sulphate (AOM/DSS) treatment [a model of colorectal cancer (CRC)], or ovalbumin sensitization (airway inflammation). The impact of M(IL4) treatment on C. rodentium infectivity, colon histopathology, tumor number and size and tissue-specific inflammation was examined in these models. The anti-colitic effect of the M(IL4)s were confirmed in the di-nitrobenzene sulphonic acid model of colitis and the lumen-to-blood movement of 4kDa FITC-dextran and bacterial translocation to the spleen and liver was also improved by M(IL4) treatment. Analysis of the other models of disease, that represent comorbidities that can occur in human inflammatory bowel disease (IBD), revealed that M(IL4) treatment did not exaggerate the severity of any of the conditions. Rather, there was reduction in the size (but not number) of polyps in the colon of AOM/DSS-mice and reduced infectivity and inflammation in C. rodentium-infected mice in M(IL4)-treated mice. Thus, while any new therapy can have unforeseen side effects, our data confirm and extend the anti-colitic capacity of murine M(IL4)s and indicate that systemic delivery of one million M(IL4)s did not exaggerate disease in models of colonic or airways inflammation or colonic tumorigenesis.
LN Monocytes Limit DC-Poly I:C Induced Cytotoxic T Cell Response via IL-10 and Induction of Suppressor CD4 T Cells
Authors: Tewari Anita , Prabagar Miglena G. , Gibbings Sophie L. , Rawat Kavita , Jakubzick Claudia V.
Published: October 2021

Every immune response has accelerators and brakes. Depending on the pathogen or injury, monocytes can play either role, promoting or resolving immunity. Poly I:C, a potent TLR3 ligand, licenses cross-presenting dendritic cells (DC1) to accelerate a robust cytotoxic T cells response against a foreign antigen. Poly I:C thus has promise as an adjuvant in cancer immunotherapy and viral subunit vaccines. Like DC1s, monocytes are also abundant in the LNs. They may act as either immune accelerators or brakes, depending on the inflammatory mediator they encounter. However, little is known about their contribution to adaptive immunity in the context of antigen and Poly I:C. Using monocyte-deficient and chimeric mice, we demonstrate that LN monocytes indirectly dampen a Poly I:C induced antigen-specific cytotoxic T cell response, exerting a “braking” function. This effect is mediated by IL-10 production and induction of suppressor CD4+ T cells. In a metastatic melanoma model, we show that a triple-combination prophylactic treatment consisting of anti-IL-10, tumor peptides and Poly I:C works because removing IL-10 counteracts the monocytic brake, resulting in significantly fewer tumors compared to mice treated with tumor peptides and Poly I:C alone. Finally, in human LN tissue, we observed that monocytes (unlike DCs) express high levels of IL-10, suggesting that anti-IL-10 may be an important addition to treatments. Overall, our data demonstrates that LN monocytes regulate the induction of a robust DC1-mediated immune response. Neutralization of either IL-10 or monocytes can augment Poly I:C-based treatments and enhance T cell cytotoxicity.
Structure and Magnetization of Strontium Hexaferrite (SrFe12O19) Films Prepared by Pulsed Laser Deposition
Authors: Khojaste khoo M. , Kameli P.
Published: October 2021

M-type strontium hexaferrite (SrM) thin films show excellent magnetic properties and uniaxial magnetic anisotropy. We systematically investigated the magnetism of SrM films prepared by pulsed-laser deposition on different substrates [Al2O3 (11¯02), SrTiO3 (100), ZnO (0001), and LiNbO3 (0001)] at vacuum (10−4 Pa) and a substrate temperature of 800°C. Prepared films were annealed in air at a temperature of 1,000°C for 2 hours. This investigation determined the effect of annealing and different substrates on the morphology, strain, and hysteresis loops of the films. The prepared films were characterized using x-ray diffractometry, Raman spectroscopy, scanning electron microscopy, and superconducting quantum interference device (SQUID) magnetometry. X-ray diffraction analyses confirmed c-oriented growth along the out-of-plane direction in most films. We found that annealing causes enhanced crystallization in films and a significant increase in coercivity. The highest coercivity of ∼11 KOe was measured for the film deposited on the Al2O3 (11¯02) substrate.
A Retrospective Paired Comparison Between Untargeted Next Generation Sequencing and Conventional Microbiology Tests With Wisely Chosen Metagenomic Sequencing Positive Criteria
Authors: Qin Hanyu , Peng Jinmin , Liu Ling , Wu Jing , Pan Lingai , Huang Xiaobo , Huang Man , Qiu Haibo , Du Bin ,   The China Critical Care Clinical Trials Group (CCCCTG)
Published: October 2021

Objectives: To evaluate the performance of metagenomic next generation sequencing (mNGS) using adequate criteria for the detection of pathogens in lower respiratory tract (LRT) samples with a paired comparison to conventional microbiology tests (CMT).

Methods: One hundred sixty-seven patients were reviewed from four different intensive care units (ICUs) in mainland China during 2018 with both mNGS and CMT results of LRT samples available. The reads per million ratio (RPMsample/RPMnon−template−control ratio) and standardized strictly mapped reads number (SDSMRN) were the two criteria chosen for identifying positive pathogens reported from mNGS. A McNemar test was used for a paired comparison analysis between mNGS and CMT.

Results: One hundred forty-nine cases were counted into the final analysis. The RPMsample/RPMNTC ratio criterion performed better with a higher accuracy for bacteria, fungi, and virus than SDSMRN criterion [bacteria (RPMsample/RPMNTC ratio vs. SDSMRN), 65.1 vs. 55.7%; fungi, 75.8 vs. 71.1%; DNA virus, 86.3 vs. 74.5%; RNA virus, 90.9 vs. 81.8%]. The mNGS was also superior in bacteria detection only if an SDSMRN ≥3 was used as a positive criterion with a paired comparison to culture [SDSMRN positive, 92/149 (61.7%); culture positive, 54/149 (36.2%); p < 0.001]; however, it was outperformed with significantly more fungi and DNA virus identification when choosing both criteria for positive outliers [fungi (RPMsample/RPMNTC ratio vs. SDSMRN vs. culture), 23.5 vs. 29.5 vs. 8.7%, p < 0.001; DNA virus (RPMsample/RPMNTC ratio vs. SDSMRN vs. PCR), 14.1 vs. 20.8 vs. 11.8%, p < 0.05].

Conclusions: Metagenomic next generation sequencing may contribute to revealing the LRT infection etiology in hospitalized groups of potential fungal infections and in situations with less access to the multiplex PCR of LRT samples from the laboratory by choosing a wise criterion like the RPMsample/RPMNTC ratio.
High Mortality of HLH in ICU Regardless Etiology or Treatment
Authors: Bichon Amandine , Bourenne Jérémy , Allardet-Servent Jérôme , Papazian Laurent , Hraiech Sami , Guervilly Christophe , Pauly Vanessa , Kaplanski Gilles , Mokart Djamel , Gainnier Marc , Carvelli Julien
Published: October 2021

Background: Adult hemophagocytic lymphohistiocytosis (HLH) is highly lethal in the ICU. The diagnostic and therapeutic emergency that HLH represents is compounded by its unknown pathophysiological mechanisms. Here, we report on a large cohort of adult HLH in the ICU (ICU-HLH). We analyzed prognostic factors associated with mortality to define the diagnostic and therapeutic challenges in this specific population.

Methods: This retrospective study included adult patients diagnosed with HLH in four ICUs in Marseille, France between 2010 and 2020. Patients who fulfilled the HLH-2004 criteria (≥ 4/8) and/or had an HScore ≥ 169 were diagnosed with HLH. HLH was categorized into four groups according to etiology: sepsis-associated HLH, intracellular infection-associated HLH, malignancy-associated HLH, and idiopathic HLH.

Results: Two hundred and sixty patients were included: 121 sepsis-associated HLH (47%), 84 intracellular infection-associated HLH (32%), 28 malignancy-associated HLH (11%), and 27 idiopathic HLH (10%). The ICU mortality rate reached 57% (n = 147/260) without a statistical difference between etiological groups. Independent factors associated with mortality in multivariate analysis included age (OR (5 years) = 1.31 [1.16–1.48], p < 0.0001), SOFA score at ICU admission (OR = 1.37 [1.21–1.56], p < 0.0001), degradation of the SOFA score between ICU arrival and HLH diagnosis (Delta SOFA) (OR = 1.47 [1.28–1.70], p < 0.0001), the presence of bone-marrow hemophagocytosis (OR = 5.27 [1.11–24.97], p = 0.04), highly severe anemia (OR = 1.44 [1.09–1.91], p = 0.01), and hypofibrinogenemia (OR = 1.21 [1.04–1.41], p = 0.02).

Conclusions: In this large retrospective cohort study of critically ill patients, ICU-HLH in adults was associated with a 57% mortality rate, regardless of HLH etiology or specific treatment. Factors independently associated with prognosis included age, presence of hemophagocytosis in bone-marrow aspirates, organ failure at admission, and worsening organ failure during the ICU stay. Whether a rapid diagnosis and the efficacy of specific therapy improve outcome is yet to be prospectively investigated.
Graph-Based Approaches Significantly Improve the Recovery of Antibiotic Resistance Genes From Complex Metagenomic Datasets
Authors: Shafranskaya Daria , Chori Alexander , Korobeynikov Anton
Published: October 2021

The lack of control over the usage of antibiotics leads to propagation of the microbial strains that are resistant to many antimicrobial substances. This situation is an emerging threat to public health and therefore the development of approaches to infer the presence of resistant strains is a topic of high importance. The resistome construction of an isolate microbial species could be considered a solved task with many state-of-the-art tools available. However, when it comes to the analysis of the resistome of a microbial community (metagenome), then there exist many challenges that influence the accuracy and precision of the predictions. For example, the prediction sensitivity of the existing tools suffer from the fragmented metagenomic assemblies due to interspecies repeats: usually it is impossible to recover conservative parts of antibiotic resistance genes that belong to different species that occur due to e.g., horizontal gene transfer or residing on a plasmid. The recent advances in development of new graph-based methods open a way to recover gene sequences of interest directly from the assembly graph without relying on cumbersome and incomplete metagenomic assembly. We present GraphAMR—a novel computational pipeline for recovery and identification of antibiotic resistance genes from fragmented metagenomic assemblies. The pipeline involves the alignment of profile hidden Markov models of target genes directly to the assembly graph of a metagenome with further dereplication and annotation of the results using state-of-the art tools. We show significant improvement of the quality of the results obtained (both in terms of accuracy and completeness) as compared to the analysis of an output of ordinary metagenomic assembly as well as different read mapping approaches. The pipeline is freely available from https://github.com/ablab/graphamr.
Compartment Niche Shapes the Assembly and Network of Cannabis sativa-Associated Microbiome
Authors: Wei Guangfei , Ning Kang , Zhang Guozhuang , Yu Haibin , Yang Shuming , Dai Fei , Dong Linlin , Chen Shilin
Published: October 2021

Interactions between plants and microbes may promote the growth of plants and regulate the production of secondary metabolites. Hemp (Cannabis sativa) is an annual herb and an important commercial crop. However, the assembly and network of hemp-associated microbiomes inhabiting in soil and plant compartments have not been comprehensively understood. This work investigated the assembly and network of bacterial and fungal communities living in soils (bulk and rhizosphere) and plant compartments (root, stem, leaf, and flower) of four hemp ecotypes cultivated in the same habitat. Microbiome assembly was predominantly shaped by compartment niche. Microbial alpha diversity was the highest in soil, continually decreased from root to flower. Core bacterial generaPseudomonas,Bacillus,Rhizobium,Planococcus, andSphingomonaswere mostly enriched in aerial endosphere niches;Clitopilus,Plectosphaerella, andMortierellawere enriched in belowground endosphere. Microbial network complexity and connectivity decreased from root to flower. According to source tracking analysis, hemp microbiota primarily originated from soil and were subsequently filtered in different plant compartments. This work provides details on hemp-associated microbiome along the soil–plant continuum and a comprehensive understanding of the origin and transmission mode of endophytes in hemp.
Low Specific Phosphorus Uptake Affinity of Epilithon in Three Oligo- to Mesotrophic Post-mining Lakes
Authors: Konopáčová Eliška , Nedoma Jiří , Čapková Kateřina , Čapek Petr , Znachor Petr , Pouzar Miloslav , Říha Milan , Řeháková Klára
Published: October 2021

Epilithon contributes to phosphorus (P) cycling in lakes, but its P uptake traits have been rarely studied. We measured the chemical composition of epilithon and its inorganic P uptake kinetics using isotope 33P in three deep oligo- to mesotrophic post-mining lakes in April, July, and October 2019. Over the sampling period, epilithon biomass doubled, while the P content in biomass dropped to 60% of the April values, and the seasonal changes in P content expressed per epilithon area were only marginal and statistically not significant. High epilithic C:P molar ratios (677 on average) suggested strong P deficiency in all investigated lakes. Regarding the kinetic parameters of phosphorus uptake, maximum uptake velocity (Vmax, seasonal range 1.9–129 mg P g OM–1 h–1) decreased by an order of magnitude from April to October, while half-saturation constant (KS, seasonal range 3.9–135 mg P L–1) did not show any consistent temporal trend. Values of epilithic specific P uptake affinity (SPUAE, seasonal range 0.08–3.1 L g OM–1 h–1) decreased from spring to autumn and were two to four orders of magnitude lower than the corresponding values for seston (SPUAsest), which showed an opposite trend. Considering our results, we suggest a possible mechanism underlying a stable coexistence of planktonic and epilithic microorganisms, with plankton prospering mostly in summer and autumn and epilithon in winter and spring season. Additionally, a phenomenon of reversible abiotic P adsorption on epilithon was observed.
In-Depth Analysis of the Role of the Acinetobactin Cluster in the Virulence of Acinetobacter baumannii
Authors: Conde-Pérez Kelly , Vázquez-Ucha Juan C. , Álvarez-Fraga Laura , Ageitos Lucía , Rumbo-Feal Soraya , Martínez-Guitián Marta , Trigo-Tasende Noelia , Rodríguez Jaime , Bou Germán , Jiménez Carlos , Beceiro Alejandro , Poza Margarita
Published: October 2021

Acinetobacter baumannii is a multidrug-resistant pathogen that represents a serious threat to global health. A. baumannii possesses a wide range of virulence factors that contribute to the bacterial pathogenicity. Among them, the siderophore acinetobactin is one of the most important, being essential for the development of the infection. In this study we performed an in-depth analysis of the acinetobactin cluster in the strain A. baumannii ATCC 17978. For this purpose, nineteen individual isogenic mutant strains were generated, and further phenotypical analysis were performed. Individual mutants lacking the biosynthetic genes entA, basG, basC, basD, and basB showed a significant loss in virulence, due to the disruption in the acinetobactin production. Similarly, the gene bauA, coding for the acinetobactin receptor, was also found to be crucial for the bacterial pathogenesis. In addition, the analysis of the ΔbasJ/ΔfbsB double mutant strain demonstrated the high level of genetic redundancy between siderophores where the role of specific genes of the acinetobactin cluster can be fulfilled by their fimsbactin redundant genes. Overall, this study highlights the essential role of entA, basG, basC, basD, basB and bauA in the pathogenicity of A. baumannii and provides potential therapeutic targets for the design of new antivirulence agents against this microorganism.
Exploring the Bidirectional Associations Between Short or Long Sleep Duration and Lower Cognitive Function: A 7-Year Cohort Study in China
Authors: Hua Jianian , Zhuang Sheng , Shen Yueping , Tang Xiang , Sun Hongpeng , Fang Qi
Published: October 2021

Background: Sleep duration is linked to cognitive function, but whether short or prolonged sleep duration results from impaired cognition or vice versa has been controversial in previous studies. We aimed to investigate the bidirectional association between sleep duration and cognitive function in older Chinese participants.

Methods: Data were obtained from a nationally representative study conducted in China. A total of 7984 participants aged 45 years or older were assessed at baseline between June 2011 and March 2012 (Wave 1), 2013 (Wave 2), 2015 (Wave 3), and 2018 (Wave 4). Nocturnal sleep duration was evaluated using interviews. Cognitive function was examined via assessments of global cognition, including episodic memory, visuospatial construction, calculation, orientation and attention capacity. Latent growth models and cross-lagged models were used to assess the bidirectional association between sleep duration and cognitive function.

Results: Among the 7,984 participants who were followed in the four waves of the study, the baseline mean (SD) age was 64.7 (8.4) years, 3862 (48.4%) were male, and 6453 (80.7%) lived in rural areas. Latent growth models showed that both sleep duration and global cognition worsened over time. Cross-lagged models indicated that short or long sleep duration in the previous wave was associated with lower global cognition in the subsequent wave (standardized β = −0.066; 95% CI: −0.073, −0.059; P < 0.001; Wave 1 to 2) and that lower global cognition in the previous wave was associated with short or long sleep duration in the subsequent wave (standardized β = −0.106; 95% CI: −0.116, −0.096; P < 0.001; Wave 1 to 2).

Conclusion: There was a bidirectional association between sleep duration and cognitive function, with lower cognitive function having a stronger association with long or short sleep duration than the reverse relationship. Global cognition was likely the major driver in these reciprocal associations.
Cre-Dependent Anterograde Transsynaptic Labeling and Functional Imaging in Zebrafish Using VSV With Reduced Cytotoxicity
Authors: Kler Stanislav , Ma Manxiu , Narayan Sujatha , Ahrens Misha B. , Pan Y. Albert
Published: October 2021

The small size and translucency of larval zebrafish (Danio rerio) have made it a unique experimental system to investigate whole-brain neural circuit structure and function. Still, the connectivity patterns between most neuronal types remain mostly unknown. This gap in knowledge underscores the critical need for effective neural circuit mapping tools, especially ones that can integrate structural and functional analyses. To address this, we previously developed a vesicular stomatitis virus (VSV) based approach called Tracer with Restricted Anterograde Spread (TRAS). TRAS utilizes lentivirus to complement replication-incompetent VSV (VSVΔG) to allow restricted (monosynaptic) anterograde labeling from projection neurons to their target cells in the brain. Here, we report the second generation of TRAS (TRAS-M51R), which utilizes a mutant variant of VSVΔG [VSV(M51R)ΔG] with reduced cytotoxicity. Within the primary visual pathway, we found that TRAS-M51R significantly improved long-term viability of transsynaptic labeling (compared to TRAS) while maintaining anterograde spread activity. By using Cre-expressing VSV(M51R)ΔG, TRAS-M51R could selectively label excitatory (vglut2a positive) and inhibitory (gad1b positive) retinorecipient neurons. We further show that these labeled excitatory and inhibitory retinorecipient neurons retained neuronal excitability upon visual stimulation at 5–8 days post fertilization (2–5 days post-infection). Together, these findings show that TRAS-M51R is suitable for neural circuit studies that integrate structural connectivity, cell-type identity, and neurophysiology.
TCAD Modeling of Resistive-Switching of HfO2 Memristors: Efficient Device-Circuit Co-Design for Neuromorphic Systems
Authors: Zeumault Andre , Alam Shamiul , Wood Zack , Weiss Ryan J. , Aziz Ahmedullah , Rose Garrett S.
Published: October 2021

In neuromorphic computing, memristors (or “memory resistors”) have been primarily studied as key elements in artificial synapse implementations, where the memristor provides a variable weight with intrinsic long-term memory capabilities, based on its modifiable resistive-switching characteristics. Here, we demonstrate an efficient methodology for simulating resistive-switching of HfO2 memristors within Synopsys TCAD Sentaurus—a well established, versatile framework for electronic device simulation, visualization and modeling. Kinetic Monte Carlo is used to model the temporal dynamics of filament formation and rupture wherein additional band-to-trap electronic transitions are included to account for polaronic effects due to strong electron-lattice coupling in HfO2. The conductive filament is modeled as oxygen vacancies which behave as electron traps as opposed to ionized donors, consistent with recent experimental data showing p-type conductivity in HfOx films having high oxygen vacancy concentrations and ab-initio calculations showing the increased thermodynamic stability of neutral and charged oxygen vacancies under conditions of electron injection. Pulsed IV characteristics are obtained by inputting the dynamic state of the system—which consists of oxygen ions, unoccupied oxygen vacancies, and occupied oxygen vacancies at various positions—into Synopsis TCAD Sentaurus for quasi-static simulations. This allows direct visualization of filament electrostatics as well as the implementation of a nonlocal, trap-assisted-tunneling model to estimate current-voltage characteristics during switching. The model utilizes effective masses and work functions of the top and bottom electrodes as additional parameters influencing filament dynamics. Together, this approach can be used to provide valuable device- and circuit-level insight, such as forming voltage, resistance levels and success rates of programming operations, as we demonstrate.
An in vivo Calcium Imaging Approach for the Identification of Cell-Type Specific Patterns in the Developing Cortex
Authors: Che Alicia , De Marco García Natalia V.
Published: October 2021

Neuronal activity profoundly shapes the maturation of developing neurons. However, technical limitations have hampered the ability to capture the progression of activity patterns in genetically defined neuronal populations. This task is particularly daunting given the substantial diversity of pyramidal cells and interneurons in the neocortex. A hallmark in the development of this neuronal diversity is the participation in network activity that regulates circuit assembly. Here, we describe detailed methodology on imaging neuronal cohorts longitudinally throughout postnatal stages in the mouse somatosensory cortex. To capture neuronal activity, we expressed the genetically encoded calcium sensor GCaMP6s in three distinct interneuron populations, the 5HT3aR-expressing layer 1 (L1) interneurons, SST interneurons, and VIP interneurons. We performed cranial window surgeries as early as postnatal day (P) 5 and imaged the same cohort of neurons in un-anesthetized mice from P6 to P36. This Longitudinal two-photon imaging preparation allows the activity of single neurons to be tracked throughout development as well as plasticity induced by sensory experience and learning, opening up avenues of research to answer fundamental questions in neural development in vivo.
Effect of Severity of Liver Cirrhosis on Surgical Outcomes of Hepatocellular Carcinoma After Liver Resection and Microwave Coagulation
Authors: Li Jiang , Tao Hai-su , Li Jian , Wang Wen-qiang , Sheng Wei-wei , Huang Zhi-yong , Zhang Er-lei
Published: October 2021

Background

Liver resection (LR) and percutaneous microwave coagulation therapy (PMCT) are both considered as radical treatments for small hepatocellular carcinoma (HCC). However, it is still unclear whether to select LR or PMCT in HCC patients with different degrees of liver cirrhosis. The purpose of this study was to compare the efficacy of LR and PMCT in the treatment of solitary and small HCC accompanied with different degrees of liver cirrhosis.

Methods

In this study, 230 patients with solitary HCC lesions ≤ 3 cm and Child-Pugh A liver function were retrospectively reviewed. Among these patients, 122 patients underwent LR, and 108 received PMCT. The short- and long-term outcomes were compared between these two procedures. Severity of liver cirrhosis was evaluated by using clinical scoring system (CSS) as previously published. Subgroup analysis based on CSS was performed to evaluate the effect of severity of liver cirrhosis on surgical outcomes after LR and PMCT.

Results

There was no mortality within 90 days in both groups. Major complications were significantly more frequent in the LR group than in the PMCT group (18.8% vs. 4.6%, p<0.001). However, LR provided better surgical outcomes than PMCT. The 5-year overall survival (OS) rates for the LR and PMCT groups were 65.2% and 42%, respectively (p=0.006), and the corresponding disease-free survival (DFS) rates were 51.7% and 31.5%, respectively (p=0.004). Nevertheless, subgroup analysis showed that PMCT provided long-term outcomes that were similar to LR and lower surgical complications in HCC patients with CSS score≥4.

Conclusions

LR may provide better OS and DFS rates than PMCT for patients with solitary HCC lesions ≤ 3 cm and Child-Pugh A liver function irrespective of liver cirrhosis. PMCT should be viewed as the optimal treatment for solitary and small HCC with severe cirrhosis.
Efficacy and Safety of Fruquintinib Plus PD-1 Inhibitors Versus Regorafenib Plus PD-1 Inhibitors in Refractory Microsatellite Stable Metastatic Colorectal Cancer
Authors: Sun Liying , Huang Shenglan , Li Dan , Mao Ye , Wang Yurou , Wu Jianbing
Published: October 2021

Background

Microsatellite stability (MSS) or mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) is resistant to immune checkpoint inhibitors. Studies have shown that antiangiogenic drugs combined with programmed death receptor-1 (PD-1) inhibitors can improve immunosuppression. The purpose of this study was to compare the efficacy of fruquintinib combined with PD-1 inhibitor (FP) and regorafenib combined with PD-1 inhibitor (RP) in the treatment of advanced mCRC with MSS or pMMR.

Materials and Methods

We retrospectively collected advanced MSS or pMMR mCRC patient data from The Second Affiliated Hospital of Nanchang, China, from June 2019 to March 2021. Then, we analyzed and compared the efficacy and safety of FP and RP.

Results

A total of 51 patients who met the criteria were divided into FP (n = 28) and RP groups (n = 23). The overall response rate of the FP and RP groups was 7.1% and 8.7% and the disease control rate was 89.3% and 56.5%, respectively. The median progression-free survival (PFS) time was higher in the FP group than in the RP group (6.4 vs. 3.9 months, respectively; P = 0.0209). Patients with no liver metastasis, KRAS wild type, and left colon tumor may benefit from FP. Eight patients (15.7%) had grade 3 toxicity related to treatment. Cox multivariate regression analysis showed that the treatment method was an independent risk factor for median PFS time.

Conclusion

Our study indicates that FP could improve PFS time of patients with advanced mCRC compared with RP.
The Effect of 10 Most Common Nonurological Primary Cancers on Survival in Men With Secondary Prostate Cancer
Authors: Wenzel Mike , Nocera Luigi , Würnschimmel Christoph , Collà Ruvolo Claudia , Tian Zhe , Saad Fred , Briganti Alberto , Tilki Derya , Graefen Markus , Becker Andreas , Roos Frederik C. , Chun Felix K. H. , Karakiewicz Pierre I.
Published: October 2021

Background

This study aims to test the effect of the 10 most common nonurological primary cancers (skin, rectal, colon, lymphoma, leukemia, pancreas, stomach, esophagus, liver, lung) on overall mortality (OM) after secondary prostate cancer (PCa).

Material and Methods

Within the Surveillance, Epidemiology, and End Results (SEER) database, patients with 10 most common primary cancers and concomitant secondary PCa (diagnosed 2004–2016) were identified and were matched in 1:4 fashion (age, year at diagnosis, race/ethnicity, treatment type, TNM stage) with primary PCa controls. OM was compared between secondary and primary PCa patients and was stratified according to primary cancer type, as well as according to time interval between primary cancer vs. secondary PCa diagnoses.

Results

We identified 24,848 secondary PCa patients (skin, n = 3,871; rectal, n = 798; colon, n = 3,665; lymphoma, n = 2,583; leukemia, n = 1,102; pancreatic, n = 118; stomach, n = 361; esophagus, n = 219; liver, n = 160; lung, n = 1,328) vs. 531,732 primary PCa patients. Secondary PCa characteristics were less favorable than those of primary PCa patients (PSA and grade), and smaller proportions of secondary PCa patients received active treatment. After 1:4 matching, all secondary PCa exhibited worse OM than primary PCa patients. Finally, subgroup analyses showed that the survival disadvantage of secondary PCa patients decreased with longer time interval since primary cancer diagnosis and subsequent secondary PCa.

Conclusion

Patients with secondary PCa are diagnosed with less favorable PSA and grade. Even after matching for PCa characteristics, secondary PCa patients still exhibit worse survival. However, the survival disadvantage is attenuated, when secondary PCa diagnosis is made after longer time interval, since primary cancer diagnosis.
Habitat Imaging-Based 18F-FDG PET/CT Radiomics for the Preoperative Discrimination of Non-small Cell Lung Cancer and Benign Inflammatory Diseases
Authors: Chen Ling , Liu Kanfeng , Zhao Xin , Shen Hui , Zhao Kui , Zhu Wentao
Published: October 2021

Purpose

To propose and evaluate habitat imaging-based 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) radiomics for preoperatively discriminating non-small cell lung cancer (NSCLC) and benign inflammatory diseases (BIDs).

Methods

Three hundred seventeen 18F-FDG PET/CT scans were acquired from patients who underwent aspiration biopsy or surgical resection. All volumes of interest (VOIs) were semiautomatically segmented. Each VOI was separated into variant subregions, namely, habitat imaging, based on our adapted clustering-based habitat generation method. Radiomics features were extracted from these subregions. Three feature selection methods and six classifiers were applied to construct the habitat imaging-based radiomics models for fivefold cross-validation. The radiomics models whose features extracted by conventional habitat-based methods and nonhabitat method were also constructed. For comparison, the performances were evaluated in the validation set in terms of the area under the receiver operating characteristic curve (AUC). Pairwise t-test was applied to test the significant improvement between the adapted habitat-based method and the conventional methods.

Results

A total of 1,858 radiomics features were extracted. After feature selection, habitat imaging-based 18F-FDG PET/CT radiomics models were constructed. The AUC of the adapted clustering-based habitat radiomics was 0.7270 ± 0.0147, which showed significantly improved discrimination performance compared to the conventional methods (p <.001). Furthermore, the combination of features extracted by our adaptive habitat imaging-based method and non-habitat method showed the best performance than the other combinations.

Conclusion

Habitat imaging-based 18F-FDG PET/CT radiomics shows potential as a biomarker for discriminating NSCLC and BIDs, which indicates that the microenvironmental variations in NSCLC and BID can be captured by PET/CT.
Case Report: Autologous Bone Marrow Derived Intrathecal Stem Cell Transplant for Autistic Children - A Report of Four Cases and Literature Review
Authors: Kobinia Georg S. , Zaknun John J. , Pabinger Christof , Laky Brenda
Published: October 2021

Despite steadily growing numbers of children diagnosed with autism spectrum disorders (ASD), causative treatment is unavailable. Recently, biological cell therapies involving pluripotent cells have raised hopes towards sustained beneficial outcome. We herein report data of four children diagnosed with ASD, who were treated with autologous, bone marrow (BM)-derived, intrathecally and simultaneously intravenously applied, point-of-care stem cell transplant (SCT). The three boys and one girl received the diagnosis at ages between 2–4 years. The decision to perform the procedure was preceded by limited beneficiary impact of conventional symptom-based, psychological and pharmacological interventions. At ages of 4–14 years the children received their SCT, no immediate or late adverse events were reported. Disappearance of symptoms were observed by the parents during the following year and consequently improved Autism Treatment Evaluation Checklist (ATEC) scores were reported. The SCT procedure, in trained hands, can be a safe and promising treatment option in children with ASD, responding in a non-satisfactory manner to conventional treatments. It is postulated that SCT may, among others, assert its positive effect by counteracting a cerebral inflammatory autoimmune process which in turn supports the responsiveness to behavioral and pharmacological interventions. Our results in this small group are encouraging, but certainly need further investigation in larger cohorts.