bluuebunny/crossref_metadata_2025 huggingface dataset:
The Mechanosensory Role of Osteocytes and Implications for Bone Health and Disease States
Authors: Choi Jung Un Ally , Kijas Amanda W. , Lauko Jan , Rowan Alan E.
Published: February 2022

Bone homeostasis is a dynamic equilibrium between bone-forming osteoblasts and bone-resorbing osteoclasts. This process is primarily controlled by the most abundant and mechanosensitive bone cells, osteocytes, that reside individually, within chambers of porous hydroxyapatite bone matrix. Recent studies have unveiled additional functional roles for osteocytes in directly contributing to local matrix regulation as well as systemic roles through endocrine functions by communicating with distant organs such as the kidney. Osteocyte function is governed largely by both biochemical signaling and the mechanical stimuli exerted on bone. Mechanical stimulation is required to maintain bone health whilst aging and reduced level of loading are known to result in bone loss. To date, both in vivo and in vitro approaches have been established to answer important questions such as the effect of mechanical stimuli, the mechanosensors involved, and the mechanosensitive signaling pathways in osteocytes. However, our understanding of osteocyte mechanotransduction has been limited due to the technical challenges of working with these cells since they are individually embedded within the hard hydroxyapatite bone matrix. This review highlights the current knowledge of the osteocyte functional role in maintaining bone health and the key regulatory pathways of these mechanosensitive cells. Finally, we elaborate on the current therapeutic opportunities offered by existing treatments and the potential for targeting osteocyte-directed signaling.
Neural Epidermal Growth Factor-Like Like Protein 2 Is Expressed in Human Oligodendroglial Cell Types
Authors: Shaker Mohammed R. , Kahtan Amna , Prasad Renuka , Lee Ju-Hyun , Pietrogrande Giovanni , Leeson Hannah C. , Sun Woong , Wolvetang Ernst J. , Slonchak Andrii
Published: February 2022

Neural epidermal growth factor-like like 2 (NELL2) is a cytoplasmic and secreted glycosylated protein with six epidermal growth factor-like domains. In animal models, NELL2 is predominantly expressed in neural tissues where it regulates neuronal differentiation, polarization, and axon guidance, but little is known about the role of NELL2 in human brain development. In this study, we show that rostral neural stem cells (rNSC) derived from human-induced pluripotent stem cell (hiPSC) exhibit particularly strongNELL2expression and that NELL2 protein is enriched at the apical side of neural rosettes in hiPSC-derived brain organoids. Following differentiation of human rostral NSC into neurons, NELL2 remains robustly expressed but changes its subcellular localization from >20 small cytoplasmic foci in NSC to one–five large peri-nuclear puncta per neuron. Unexpectedly, we discovered that in human brain organoids, NELL2 is readily detectable in the oligodendroglia and that the number of NELL2 puncta increases as oligodendrocytes mature. Artificial intelligence-based machine learning further predicts a strong association of NELL2 with multiple human white matter diseases, suggesting that NELL2 may possess yet unexplored roles in regulating oligodendrogenesis and/or myelination during human cortical development and maturation.
Extracellular Matrix in Aging Aorta
Authors: Mammoto Akiko , Matus Kienna , Mammoto Tadanori
Published: February 2022

The aging population is booming all over the world and arterial aging causes various age-associated pathologies such as cardiovascular diseases (CVDs). The aorta is the largest elastic artery, and transforms pulsatile flow generated by the left ventricle into steady flow to maintain circulation in distal tissues and organs. Age-associated structural and functional changes in the aortic wall such as dilation, tortuousness, stiffening and losing elasticity hamper stable peripheral circulation, lead to tissue and organ dysfunctions in aged people. The extracellular matrix (ECM) is a three-dimensional network of macromolecules produced by resident cells. The composition and organization of key ECM components determine the structure-function relationships of the aorta and therefore maintaining their homeostasis is critical for a healthy performance. Age-associated remodeling of the ECM structural components, including fragmentation of elastic fibers and excessive deposition and crosslinking of collagens, is a hallmark of aging and leads to functional stiffening of the aorta. In this mini review, we discuss age-associated alterations of the ECM in the aortic wall and shed light on how understanding the mechanisms of aortic aging can lead to the development of efficient strategy for aortic pathologies and CVDs.
Long Non-Coding RNA PNKY Modulates the Development of Choroidal Neovascularization
Authors: Shi Lianjun , Han Xue , Liu Chang , Li Xiumiao , Lu Shuting , Jiang Qin , Yao Jin
Published: February 2022

Long non-coding RNAs (lncRNAs) have been widely implicated in human diseases. Our aim was to explore the regulatory role of changes in the expression levels of PNKY and its linked signaling networks in mediating stress-induced choroidal neovascularization. PNKY expression levels were reduced in mice by laser and exposure of endothelial cell to hypoxic stress. PNKY silencing exacerbated the formation of CNV in a laser-induced CNV model and an ex vivo model, while overexpression inhibited CNV development. Silencing or overexpression of PNKY altered the viability, proliferation, migration, and tube-forming capacity of endothelial cells in vitro. Mechanistically, through the lncRNA–RNA binding protein–miRNA interaction analysis involving loss of function and gain-of-function experiments, we found that lncRNA PNKY inhibited the binding of miR124 to PTBP1 and maintained the homeostasis of choroidal vascular function by promoting Bcl-2 like protein 11 (BIM), and its dysfunction led to exacerbation of CNV lesion. Therefore, this study suggests that the lncPNKY/PTBP1–miR-124 axis is involved in regulating the development of CNV, providing a potential therapeutic target for the treatment of CNV.
Transcriptional Control of Axon Guidance at Midline Structures
Authors: Herrera Eloísa , Escalante Augusto
Published: February 2022

The development of the nervous system is a time-ordered and multi-stepped process that includes neurogenesis and neuronal specification, axonal navigation, and circuits assembly. During axonal navigation, the growth cone, a dynamic structure located at the tip of the axon, senses environmental signals that guide axons towards their final targets. The expression of a specific repertoire of receptors on the cell surface of the growth cone together with the activation of a set of intracellular transducing molecules, outlines the response of each axon to specific guidance cues. This collection of axon guidance molecules is defined by the transcriptome of the cell which, in turn, depends on transcriptional and epigenetic regulators that modify the structure and DNA accessibility to determine what genes will be expressed to elicit specific axonal behaviors. Studies focused on understanding how axons navigate intermediate targets, such as the floor plate of vertebrates or the mammalian optic chiasm, have largely contributed to our knowledge of how neurons wire together during development. In fact, investigations on axon navigation at these midline structures led to the identification of many of the currently known families of proteins that act as guidance cues and their corresponding receptors. Although the transcription factors and the regulatory mechanisms that control the expression of these molecules are not well understood, important advances have been made in recent years in this regard. Here we provide an updated overview on the current knowledge about the transcriptional control of axon guidance and the selection of trajectories at midline structures.
Platinum Nanocatalysts Supported on Defective Hollow Carbon Spheres: Oxygen Reduction Reaction Durability Studies
Authors: Mashindi Victor , Mente Pumza , Phaahlamohlaka Tumelo N. , Mpofu Nobuhle , Makgae Ofentse A. , Moreno Beatriz D. , Barrett Dean H. , Forbes Roy P. , Levecque Pieter B. , Ozoemena Kenneth I. , Coville Neil J.
Published: February 2022

The durability and long-term applicability of catalysts are critical parameters for the commercialization and adoption of fuel cells. Even though a few studies have been conducted on hollow carbon spheres (HCSs) as supports for Pt in oxygen reduction reactions (ORR) catalysis, in-depth durability studies have not been conducted thus far. In this study, Pt/HCSs and Pt/nitrogen-doped HCSs (Pt/NHCSs) were prepared using a reflux deposition technique. Small Pt particles were formed with deposition on the outside of the shell and inside the pores of the shell. The new catalysts demonstrated high activity (>380 μA cm−2 and 240 mA g−1) surpassing the commercial Pt/C by more than 10%. The catalysts demonstrated excellent durability compared to a commercial Pt/C in load cycling, experiencing less than 50% changes in the mass-specific activity (MA) and surface area-specific activity (SA). In stop-start durability cycling, the new materials demonstrated high stability with more than 50% retention of electrochemical active surface areas (ECSAs). The results can be rationalised by the high BET surface areas coupled with an array of meso and micropores that led to Pt confinement. Further, pair distribution function (PDF) analysis of the catalysts confirmed that the nitrogen and oxygen functional groups, as well as the shell curvature/roughness provided defects and nucleation sites for the deposition of the small Pt nanoparticles. The balance between graphitic and diamond-like carbon was critical for the electronic conductivity and to provide strong Pt-support anchoring.
The Application of Small Molecules to the Control of Typical Species Associated With Oral Infectious Diseases
Authors: Yang Sirui , Lyu Xiaoying , Zhang Jin , Shui Yusen , Yang Ran , Xu Xin
Published: February 2022

Oral microbial dysbiosis is the major causative factor for common oral infectious diseases including dental caries and periodontal diseases. Interventions that can lessen the microbial virulence and reconstitute microbial ecology have drawn increasing attention in the development of novel therapeutics for oral diseases. Antimicrobial small molecules are a series of natural or synthetic bioactive compounds that have shown inhibitory effect on oral microbiota associated with oral infectious diseases. Novel small molecules, which can either selectively inhibit keystone microbes that drive dysbiosis of oral microbiota or inhibit the key virulence of the microbial community without necessarily killing the microbes, are promising for the ecological management of oral diseases. Here we discussed the research progress in the development of antimicrobial small molecules and delivery systems, with a particular focus on their antimicrobial activity against typical species associated with oral infectious diseases and the underlying mechanisms.
Pseudomonas aeruginosa Affects Airway Epithelial Response and Barrier Function During Rhinovirus Infection
Authors: Endres Adrian , Hügel Christian , Boland Helena , Hogardt Michael , Schubert Ralf , Jonigk Danny , Braubach Peter , Rohde Gernot , Bellinghausen Carla
Published: February 2022

Cystic fibrosis (CF) lung disease is aggravated by recurrent and ultimately chronic bacterial infections. One of the key pathogens in adult CF lung disease is P. aeruginosa (PA). In addition to bacteria, respiratory viral infections are suggested to trigger pulmonary exacerbations in CF. To date, little is known on how chronic infections with PA influence susceptibility and response to viral infection. We investigated the interactions between PA, human rhinovirus (HRV) and the airway epithelium in a model of chronic PA infection using differentiated primary bronchial epithelial cells (pBECs) and clinical PA isolates obtained from the respiratory sample of a CF patient. Cells were repeatedly infected with either a mucoid or a non-mucoid PA isolate for 16 days to simulate chronic infection, and subsequently co-infected with HRV. Key cytokines and viral RNA were quantified by cytometric bead array, ELISA and qPCR. Proteolytic degradation of IL-6 was analyzed by Western Blots. Barrier function was assessed by permeability tests and transepithelial electric resistance measurements. Virus infection stimulated the production of inflammatory and antiviral mediators, including interleukin (IL)-6, CXCL-8, tumor necrosis factor (TNF)-α, and type I/III interferons. Co-infection with a non-mucoid PA isolate increased IL-1β protein concentrations (28.88 pg/ml vs. 6.10 pg/ml), but in contrast drastically diminished levels of IL-6 protein (53.17 pg/ml vs. 2301.33 pg/ml) compared to virus infection alone. Conditioned medium obtained from co-infections with a non-mucoid PA isolate and HRV was able to rapidly degrade recombinant IL-6 in a serine protease-dependent manner, whereas medium from individual infections or co-infections with a mucoid isolate had no such effect. After co-infection with HRV and the non-mucoid PA isolate, we detected lower mRNA levels of Forkhead box J1 (FOXJ1) and Cilia Apical Structure Protein (SNTN), markers of epithelial cell differentiation to ciliated cells. Moreover, epithelial permeability was increased and barrier function compromised compared to single infections. These data show that PA infection can influence the response of bronchial epithelial cells to viral infection. Altered innate immune responses and compromised epithelial barrier function may contribute to an aggravated course of viral infection in PA-infected airways.
AQUA Mutant Protein Quantification of Endomyocardial Biopsy-Sized Samples From a Patient With Hypertrophic Cardiomyopathy
Authors: Becker Edgar , Francino Antonio , Pich Andreas , Perrot Andreas , Kraft Theresia , Radocaj Ante
Published: February 2022

In genetic diseases like hypertrophic cardiomyopathy, reliable quantification of the expression level of mutant protein can play an important role in disease research, diagnosis, treatment and prognosis. For heterozygous β-myosin heavy chain (β-MyHC) mutations it has been shown that disease severity is related to the fraction of mutant protein in the myocardium. Yet, heart tissue from patients with genetically characterized diseases is scarce. Here we asked, if even in the case of small endomyocardial biopsies, single quantifications produce reliable results. Myocardial samples were taken from four different regions of an explanted heart of a patient with hypertrophic cardiomyopathy carrying point mutation p.Gly716Arg in β-MyHC. From both, large samples (15 mg) and small, endomyocardial biopsy-sized samples (≤ 1 mg) myosin was extracted and enzymatically digested to yield a specific peptide of interest that allowed to distinguish mutant and wild-type β-MyHC. Absolute quantification by mass spectrometry (AQUA) of the peptide of interest was performed repeatedly for both sample sizes to determine the fraction of mutant β-MyHC. Fractions of mutant β-MyHC (32% on average) showed only small differences between the four cardiac regions and for large and small samples. The standard deviations were smaller than five percentage points for all cardiac regions. The two quantification methods (large and small sample size) produce results with comparable accuracy and precision. Consequently, with our method even small endomyocardial biopsies allow reliable protein quantification for potential diagnostic purposes.
Predictive Value of Echocardiographic Strain for Myocardial Fibrosis and Adverse Outcomes in Autoimmune Diseases
Authors: Jia Fuwei , Li Xiao , Zhang Dingding , Jiang Shu , Yin Jie , Feng Xiaojin , Zhu Yanlin , Liu Yingxian , Zhu Yuanyuan , Lai Jinzhi , Yang Huaxia , Fang Ligang , Chen Wei , Wang Yining
Published: February 2022

Background

Myocardial fibrosis is an important pathophysiologic mechanism of cardiac involvement that leads to increased mortality in patients with autoimmune diseases (AIDs). The aim of this study was to evaluate the association between myocardial strain from speckle-tracking echocardiography (STE) and fibrosis on cardiovascular magnetic resonance (CMR) and to further explore their prognostic implications in patients with AIDs.

Methods

We prospectively included 102 AIDs patients with clinically suspected cardiac involvement and 102 age- and sex-matched healthy individuals. Patients underwent CMR for evaluation of myocardial fibrosis by late gadolinium enhancement (LGE) and T1 mapping. A semiquantitative evaluation based on the extent of LGE was used to calculate the total (tLGEs) and segmental (sLGEs) LGE score. Global longitudinal strain (GLS) was evaluated by STE in all subjects. All patients were regularly followed up every 6 months. The primary endpoint was the composite incidence of all-cause death and cardiovascular hospitalization.

Results

Compared to healthy controls, AIDs patients had impaired GLS (−17.9 ± 5.1% vs. −21.2 ± 2.5%, p < 0.001). LGE was detected in 70% of patients. Patients with LGE presented worse GLS (−17.1 ± 5.3% vs. −19.6 ± 4.1%, p = 0.018) than those without LGE. On multivariate logistic analysis, GLS ≥ −15% was an independent predictor of LGE presence (OR = 4.98, 95%CI 1.35–18.33, p = 0.016). Moreover, a marked and stepwise impairment of segmental longitudinal strain (−19.3 ± 6.6 vs. −14.9 ± 6.5 vs. −8.9 ± 6.3, p < 0.001) was observed as sLGEs increased. During a median follow-up time of 25 months, 6 patients died, and 14 patients were hospitalized for cardiovascular reasons. Both GLS ≥ −15% (HR 3.56, 95%CI 1.28–9.86, p = 0.015) and tLGEs ≥ 6 (HR 4.13, 95%CI 1.43–11.92, p = 0.009) were independently associated with the primary endpoint.

Conclusions

In AIDs patients, impaired myocardial strain on STE could reflect the presence and extent of myocardial fibrosis and provide incremental prognostic value in addition to LGE in the prediction of adverse outcomes.
Predictors of Near-Infrared Spectroscopy-Detected Lipid-Rich Plaques by Optical Coherence Tomography-Defined Morphological Features in Patients With Acute Coronary Syndrome
Authors: Usui Eisuke , Yonetsu Taishi , Ohmori Mari , Kanno Yoshinori , Nakao Masahiko , Niida Takayuki , Matsuda Yuji , Matsuda Junji , Umemoto Tomoyuki , Misawa Toru , Hada Masahiro , Hoshino Masahiro , Kanaji Yoshihisa , Sugiyama Tomoyo , Kakuta Tsunekazu , Sasano Tetsuo
Published: February 2022

Background

Near-infrared spectroscopy (NIRS) provides the localization of lipid-rich components in coronary plaques. However, morphological features in NIRS-detected lipid-rich plaques (LRP) are unclear.

Methods

A total of 140 de novo culprit lesions in 140 patients with the acute coronary syndrome (ACS) who underwent NIRS and optical coherence tomography (OCT) examinations for the culprit lesions at the time of percutaneous coronary interventions were investigated. We defined a NIRS-LRP as a lesion with a maximum lipid core burden index of 4 mm [LCBI4mm] > 500 in the culprit plaque. Clinical demographics, angiographic, and OCT findings were compared between the patients with NIRS-LRP (n = 54) vs. those without NIRS-LRP (n = 86). Uni- and multivariable logistic regression analyses were performed to examine the independent OCT morphological predictors for NIRS-LRP.

Results

Clinical demographics showed no significant differences between the two groups. The angiographic minimum lumen diameter was smaller in the NIRS-LRP group than in the non- NIRS-LRP group. In OCT analysis, the minimum flow area was smaller; lipid angle, lipid length, the prevalence of thin-cap fibroatheroma, and cholesterol crystals were greater in the NIRS-LRP group than in the non-NIRS-LRP group. Plaque rupture and thrombi were more frequent in the NIRS-LRP group, albeit not significant. In a multivariable logistic regression analysis, presence of thin-cap fibroatheroma [odds ratio (OR): 2.56; 95% CI: 1.12 to 5.84; p = 0.03] and cholesterol crystals (OR: 2.90; 95% CI: 1.20 to 6.99; p = 0.02) were independently predictive of NIRS-LRP.

Conclusions

In ACS culprit lesions, OCT-detected thin-cap fibroatheroma and cholesterol crystals rather than plaque rupture and thrombi were closely associated with a great lipid-core burden.
A Meta Analysis of Factors Affecting Teaching and Student Learning in Higher Education
Authors: Chaudhary Priya , Singh Reetesh K.
Published: February 2022

The objective of this study was to conduct a meta analysis of studies conducted in the past on effective teaching and its impact on student learning outcomes. Meta analysis is a powerful tool for synthesizing previous research and empirically validating theoretical frameworks. For this purpose, the dynamic model of educational effectiveness was used as a guiding framework to select and organize 132 studies examining the impact of teaching factors on student learning outcomes. The teaching factors of dynamic model were found to be moderately associated with learning outcomes. Various moderators like level of education and type of study were also identified. The study has various theoretical, methodological and practical implications. The study points out that when it comes to teaching, imposing non-essential and superfluous dichotomies between different teaching approaches might be impractical. The findings of this meta analysis may also provide implications for practitioners and policymakers especially in the domain of faculty development and education programs. It can give existing or prospective teachers an opportunity to practice and rehearse these factors in classroom, reflect on them and receive feedback on how their practice can be improved.
“Lost All Hope in Government”: Learned Helplessness of Professionals Working in Specialised Education Settings in England During COVID-19
Authors: Mahmud Arif , Castro-Kemp Susana
Published: February 2022

COVID-19 has had substantial impact on children’s educational experiences, with schools and educators facing numerous challenges in adapting to the new reality of distance learning and/or social distancing. However, previous literature mostly focuses on the experiences of families [including families of children with special educational needs and disabilities (SEND)] and those of teachers, predominantly working in mainstream settings. This article aims to gauge the perspectives of educators working in specialised education settings that serve children with SEND in England on how they experienced working in those settings during the pandemic, including in during lockdown. A mixed (qualitative and quantitative) online survey was responded to by 93 educators. Responses denote emotionally charged views and a sense of learned helplessness. Most special schools were unable to implement social distancing measures in full or provide adequate protective equipment. The main challenges the respondents mentioned included lack of guidance from Governmental authorities, staff shortages, work overload, challenging relationship with parents and issues in meeting children’s complex needs. Professionals working for less than 3 years in a special school were more likely to say they would change jobs if they could, when compared to professionals with more years of experience. No effects of demographic characteristics were found in relation to professionals’ ratings of their own wellbeing during lockdown. Findings are discussed in light of the concept of learned helplessness and suggest that there is a need to reform provision in special schools in England to foster its sustainability and positive outcomes for children.
Thyroid Status During Pregnancy in Women With Polycystic Ovary Syndrome and the Effect of Metformin
Authors: Trouva Anastasia , Alvarsson Michael , Calissendorff Jan , Åsvold Bjørn Olav , Vanky Eszter , Hirschberg Angelica Lindén
Published: February 2022

Objective

Polycystic ovary syndrome (PCOS) and hypothyroidism are related conditions, and both are associated with adverse pregnancy outcomes. Knowledge is lacking about the complex interaction between thyroid status and PCOS during pregnancy. We investigated the thyroid status and its association with pregnancy complications in PCOS, and in relation to metformin treatment.

Design

Post-hoc analyses of two randomized, double-blind, placebo-controlled trials.

Methods

288 pregnant women with PCOS were randomized to treatment with metformin or placebo from first trimester to delivery. We measured serum levels of thyroid stimulating hormone (TSH) and free thyroxine (fT4) at gestational week (gw) 5-12, 19, 32 and 36 and related to metformin treatment and pregnancy complications. Thyroid peroxidase antibodies (TPO-ab) were analyzed at inclusion and at gw 36.

Results

The overall prevalence of subclinical and overt hypothyroidism was 1.5% and 0%, respectively. The TSH level was not affected by metformin, whereas fT4 was significantly higher in the metformin group with less decrease throughout pregnancy compared to placebo, p<0.001. A lower decrease in fT4 during pregnancy correlated to less weight gain (r= -0.17, p=0.020) and tended to be associated with reduced odds ratio for gestational diabetes (OR 0.85 per 1 pmol/L, 95% CI 0.71;1.02).

Conclusions

In women with PCOS, metformin treatment during pregnancy was associated with less decrease in fT4 compared to placebo, while it did not affect TSH. A smaller decrease in fT4 correlated to less weight gain and tended to be associated with a lower risk of gestational diabetes.

Clinical Trial Registration

ClinicalTrials.gov, identifier NCT00159536 (The PregMet study); identifier NCT03259919 (The pilot study).
Mini Review: Effect of GLP-1 Receptor Agonists and SGLT-2 Inhibitors on the Growth Hormone/IGF Axis
Authors: Cignarelli Angelo , Genchi Valentina Annamaria , Le Grazie Giulia , Caruso Irene , Marrano Nicola , Biondi Giuseppina , D’Oria Rossella , Sorice Gian Pio , Natalicchio Annalisa , Perrini Sebastio , Laviola Luigi , Giorgino Francesco
Published: February 2022

Accumulating evidence supports the early use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium glucose transporter-2 inhibitors (SGLT-2is) for the treatment of type 2 diabetes. Indeed, these compounds exert numerous pleiotropic actions that favorably affect metabolism and diabetes comorbidities, showing an additional effect beyond glucose control. Although a substantial amount of knowledge has been generated regarding the mechanism of action of both drug classes, much remains to be understood. Growth hormone (GH) is an important driver for multiple endocrine responses involving changes in glucose and lipid metabolism, and affects several tissues and organs (e.g., bone, heart). It acts directly on several target tissues, including skeletal muscle and bone, but several effects are mediated indirectly by circulating (liver-derived) or locally produced IGF-1. In consideration of the multiple metabolic and cardiovascular effects seen in subjects treated with GLP-1RAs and SGLT-2is (e.g., reduction of hyperglycemia, weight loss, free/fat mass and bone remodeling, anti-atherosclerosis, natriuresis), it is reasonable to speculate that GH and IGF-1 may play a about a relevant role in this context. This narrative mini-review aims to describe the involvement of the GH/IGF-1/IGF-1R axis in either mediating or responding to the effects of each of the two drug classes.
What Peace Means for Deforestation: An Analysis of Local Deforestation Dynamics in Times of Conflict and Peace in Colombia
Authors: Ganzenmüller Raphael , Sylvester Janelle M. , Castro-Nunez Augusto
Published: February 2022

Using Colombia as a case study, this analysis provides insights on deforestation dynamics in times of conflict and peace and the different factors driving these dynamics. We performed time series clustering of yearly deforestation data (2001–2018) from 708 out of 1,122 mainland Colombian municipalities (accounting for 98% of the total deforestation areas in Colombia) and produced regression models using a gradient tree boosting framework (XGBoost) to identify drivers that explain varying, local-level deforestation dynamics. Municipalities were characterized by seven categories of deforestation dynamics, with the Amazon region being largely represented by only four categories and the Andes region displaying all categories of deforestation dynamics. Notably, six of the seven representative categories exhibit substantial increases in deforestation in the years following the peace agreement. The regression analysis revealed that coca cultivation area, number of cattle, and municipality area are the top three drivers of deforestation dynamics at national, regional, and category levels. However, the importance of the different variables varied according to the different spatial dimensions. Results provide further understanding on how the drivers of deforestation change not only at a regional scale, as assumed by much of the current literature about drivers of deforestation, but also at a lower scale of analysis (intraregional and intradepartmental variation in the case of Colombia). Insights from this study can be used to understand deforestation dynamics in other countries experiencing times of conflict and peace and will support decision-makers in creating programs that align actions for peacebuilding, climate change mitigation, and biodiversity conservation more effectively.
Changes in Soil Chemistry After 17 Years in Urban and Rural Forest Patches
Authors: Yesilonis Ian , Giorgio Vincent , Hu Yinhong , Pouyat Richard , Szlavecz Katalin
Published: February 2022

Cycling of carbon (C), nitrogen (N), calcium (Ca), phosphorus (P), and sulfur (S) is an important ecosystem service that forest soils provide. Humans influence these biogeochemical processes through the deposition of atmospheric pollutants and site disturbances. One way to study these potential anthropogenic trajectories is through long-term monitoring in association with human-caused environmental gradients such as urban-rural gradients. The objective of this study was to characterize changes in surface soil chemistry of urban, suburban and rural forest patches in the Baltimore Metropolitan area. Soil composite samples (0–10 cm) were analyzed for macro- and micronutrients, pH, and C. A total of 12 sites in forest patches dominated by white oak (Quercus alba) and tulip poplar (Liriodendron tulipifera) were established in 2001, and resampled in 2018. We hypothesized that after almost two decades (1) concentrations of N, Ca, and P, as well as soil pH would be higher, especially in urban forest patches due to local deposition; (2) S levels would be lower due to decreased regional atmospheric deposition and; (3) total soil C would increase overall, but the rate of increase would be higher in the urban end of the gradient due to increased NPP. Overall, means of Ca concentration, pH, and C:N ratios significantly changed from 2001 to 2018. Calcium increased by 35% from 622 to 844 mg kg–1, pH increased from 4.1 to 4.5, and C:N ratios decreased from 17.8 to 16.7. Along the gradient, Ca, N, P, and S were statistically significant with Ca concentration higher in the urban sites; S and N higher in the suburban sites; and P lower in the urban sites. Confounding factors, such as different geologic parent material may have affected these results. However, despite the unique site conditions, patterns of surface soil chemistry in space and time implies that local and regional factors jointly affect soil development in these forest patches. The increase in pH and Ca is especially notable because other long-term studies demonstrated changes in the opposite direction.
Totoro: Identifying Active Reactions During the Transient State for Metabolic Perturbations
Authors: Galvão Ferrarini Mariana , Ziska Irene , Andrade Ricardo , Julien-Laferrière Alice , Duchemin Louis , César Roberto Marcondes , Mary Arnaud , Vinga Susana , Sagot Marie-France
Published: February 2022

Motivation: The increasing availability of metabolomic data and their analysis are improving the understanding of cellular mechanisms and how biological systems respond to different perturbations. Currently, there is a need for novel computational methods that facilitate the analysis and integration of increasing volume of available data.

Results: In this paper, we present Totoro a new constraint-based approach that integrates quantitative non-targeted metabolomic data of two different metabolic states into genome-wide metabolic models and predicts reactions that were most likely active during the transient state. We applied Totoro to real data of three different growth experiments (pulses of glucose, pyruvate, succinate) from Escherichia coli and we were able to predict known active pathways and gather new insights on the different metabolisms related to each substrate. We used both the E. coli core and the iJO1366 models to demonstrate that our approach is applicable to both smaller and larger networks.

Availability:Totoro is an open source method (available at https://gitlab.inria.fr/erable/totoro) suitable for any organism with an available metabolic model. It is implemented in C++ and depends on IBM CPLEX which is freely available for academic purposes.
Carabin Deficiency Aggravates Hepatic Ischemia-Reperfusion Injury Through Promoting Neutrophil Trafficking via Ras and Calcineurin Signaling
Authors: Ni Xuhao , Wu Xiao , Zhu Xiao-Xu , Li Jian-Hui , Yin Xiao-Yu , Lu Ling
Published: February 2022

Neutrophil infiltration plays an important role in the initial phase of hepatic ischemia and reperfusion injury (HIRI). Despite many different key molecules that have been reported to meditate neutrophil trafficking in HIRI, the mechanism of this process has not been fully elucidated. In this study, we found that Carabin deficiency in myeloid cells (LysMCre : Carabinfl/fl) aggravated IRI-induced hepatic injury and apoptosis through increasing the infiltration of CD11b+Ly6G+neutrophils. ImmGen Datasets further revealed that Carabin was expressed in bone marrow neutrophils (GM.BM) but was significantly downregulated in thio-induced peripheral neutrophils (GN.Thio.PC), which was consistently verified by comparing GM.BM and liver-infiltrating neutrophils induced by IRI. Mechanistically, up-regulation of Carabin in GM.BMin vitroreduced the expression levels of P-selectin, E-selectin, and αvβ3 integrin through inhibiting Ras-ERK and Calcineurin-NFAT signaling. Furthermore, blocking P-selectin, E-selectin, and αvβ3 integrin in LysMCre : Carabinfl/fl mice decreased the frequency and number of CD11b+Ly6G+neutrophils and reversed hepatic ischemia−reperfusion damage. In conclusion, our results provide a new understanding of Carabin, such that it is expressed and functions not only in adaptive immune cells (T and B cells) but also in innate immune cells (neutrophils), contributing to the migration of neutrophils. These findings provide novel and promising therapeutic targets for the prevention of HIRI during liver transplantation or hepatic surgery.
Mechanism and Disease Association With a Ubiquitin Conjugating E2 Enzyme: UBE2L3
Authors: Zhang Xiaoxia , Huo Chengdong , Liu Yating , Su Ruiliang , Zhao Yang , Li Yumin
Published: February 2022

Ubiquitin conjugating enzyme E2 is an important component of the post-translational protein ubiquitination pathway, which mediates the transfer of activated ubiquitin to substrate proteins. UBE2L3, also called UBcH7, is one of many E2 ubiquitin conjugating enzymes that participate in the ubiquitination of many substrate proteins and regulate many signaling pathways, such as the NF-κB, GSK3β/p65, and DSB repair pathways. Studies on UBE2L3 have found that it has an abnormal expression in many diseases, mainly immune diseases, tumors and Parkinson’s disease. It can also promote the occurrence and development of these diseases. Resultantly, UBE2L3 may become an important target for some diseases. Herein, we review the structure of UBE2L3, and its mechanism in diseases, as well as diseases related to UBE2L3 and discuss the related challenges.
CAR T Cell Therapy in Primary Brain Tumors: Current Investigations and the Future
Authors: Lin Ya-Jui , Mashouf Leila A. , Lim Michael
Published: February 2022

Chimeric antigen receptor T cells (CAR T cells) are engineered cells expressing a chimeric antigen receptor (CAR) against a specific tumor antigen (TA) that allows for the identification and elimination of cancer cells. The remarkable clinical effect seen with CAR T cell therapies against hematological malignancies have attracted interest in developing such therapies for solid tumors, including brain tumors. Glioblastoma (GBM) is the most common primary brain tumor in adults and is associated with poor prognosis due to its highly aggressive nature. Pediatric brain cancers are similarly aggressive and thus are a major cause of pediatric cancer-related death. CAR T cell therapy represents a promising avenue for therapy against these malignancies. Several specific TAs, such as EGFR/EGFRvIII, IL13Rα2, B7-H3, and HER2, have been targeted in preclinical studies and clinical trials. Unfortunately, CAR T cells against brain tumors have showed limited efficacy due to TA heterogeneity, difficulty trafficking from blood to tumor sites, and the immunosuppressive tumor microenvironment. Here, we review current CAR T cell approaches in treating cancers, with particular focus on brain cancers. We also describe a novel technique of focused ultrasound controlling the activation of engineered CAR T cells to achieve the safer cell therapies. Finally, we summarize the development of combinational strategies to improve the efficacy and overcome historical limitations of CAR T cell therapy.
Pediatric Prediction Model for Low Immunoglobulin G Level Based on Serum Globulin and Illness Status
Authors: Suratannon Narissara , Tantithummawong Phimphika , Hurst Cameron Paul , Chongpison Yuda , Wongpiyabovorn Jongkonnee , van Hagen P. Martin , Dik Willem A. , Chatchatee Pantipa
Published: February 2022

Hypogammaglobulinemia is a condition that requires prompt diagnosis and treatment. Unfortunately, serum immunoglobulin (Ig) measurements are not widely accessible in numerous developing countries. Serum globulin is potentially the best candidate for screening of low IgG level (IgGLo) due to its high availability, low cost, and rapid turnover time. However, multiple factors may influence the probability of prediction. Our study aimed to establish a simple prediction model using serum globulin to predict the likelihood of IgGLo in children. For retrospective data of patients who were suspected of having IgGLo, both serum IgG and globulin were simultaneously collected and measured. Potential factors interfering with serum globulin and IgG levels were investigated for their impact using bivariate binary logistic regression. A multivariate binary logistic regression was used to generate a formula and score to predict IgGLo. We obtained 953 samples from 143 pediatric patients. A strong positive correlation between serum globulin and IgG levels was observed (r=0.83, p < 0.001). A screening test model using serum globulin and illness status was constructed to predict IgGLo. The formula for predicting IgGLo was generated as follows; Predicted score = (2 x globulin (g/dl)) – illness condition score (well=0, sick=1). When the score was <4, the patient has the probability of having IgGLo with a sensitivity of 0.78 (0.71, 0.84), a specificity of 0.71 (0.68, 0.74), PPV of 0.34 (0.29, 0.40) and NPV of 0.94 (0.92, 0.96). This formula will be useful as rapid and inexpensive screening tool for early IgGLo detection, particularly in countries/locations where serum IgG measurement is inaccessible.
Neo-Splicetopes in Tumor Therapy: A Lost Case?
Authors: Kloetzel Peter M.
Published: February 2022

Proteasome generates spliced peptides by ligating two distant cleavage products in a reverse proteolysis reaction. The observation that CD8+ T cells recognizing a spliced peptide induced T cell rejection in a melanoma patient following adoptive T cell transfer (ATT), raised some hopes with regard to the general therapeutic and immune relevance of spliced peptides. Concomitantly, the identification of spliced peptides was also the start of a controversy with respect to their frequency, abundancy and their therapeutic applicability. Here I review some of the recent evidence favoring or disfavoring an immune relevance of splicetopes and discuss from a theoretical point of view the potential usefulness of tumor specific splicetopes and why against all odds it still may seem worth trying to identify such tumor and patient-specific neosplicetopes for application in ATT.
Strength Analysis and Optimization of Alkali Activated Slag Backfills Through Response Surface Methodology
Authors: Dai Xinghang , Ren Lei , Gu Xiaozhong , Yilmaz Erol , Fang Kun , Jiang Haiqiang
Published: February 2022

The significant difference in water-to-binder ratio, activator type and concentration between alkali-activated slag (AAS) paste/mortar/concrete and AAS-based cemented paste backfill (AAS-CPB) means that previous results related to the properties and mix optimization of AAS materials cannot be directly translated to AAS-CPB. This study statistically identifies the effect of key influential variables such as silicate modulus, slag fineness and activator concentration on 3- and 28 day unconfined compressive strength (UCS) of AAS-CPB by central composite design (CCD) established in response surface methodology (RSM). In this study, the prominence of independent variables and their relations are investigated by using ANOVA (analysis of variance) having a significant level of 0.05. ANOVA results certify that there is a strong link between the level of variable contribution on UCS performance of AAS-CPB and curing age. Obviously, silicate modulus and activator concentration are the most major variables influencing UCS at 3 and 28 days, respectively. Increased fineness of slag and higher pH of pore solution enhance 3 day UCS, but restrain the further hydration of unreacted slag and subsequent the gain in strength at advanced curing ages. The combination of independent variables of silicate modulus (0.295), slag fineness (12630.2), activator concentration (0.45) gives the optimum responses.
A Patient With Failed Liver Transplantation After the Use of PD-1 Blockade Combined With Lenvaxen
Authors: Yin Jun , Wen Meng , Cheng Jun , Hu Lifen , Yang Li , Chang Xiao , Zhou Zhongsong , Li Hongbin , Liu Yan , Li Jiabin
Published: February 2022

Hepatocellular carcinoma (HCC) is a common malignant tumor with high extent of invasiveness. Its invasion process is closely related to complex tumor microenvironment and microvascular characteristics. Recently, immune combined targeted therapy has been applied to patients, combination therapy program with better effect needs to be explored. Atezolizumab combined Bevacizumab regimen in phase III clinical trial IMbrave150 was approved by U.S. Federal Drug Administration (FDA) for HCC treatment. This program is mostly used for liver malignant tumors have failed other treatments. Patients in terminal stage, overall curative has an unsatisfactory effect, survival time of patients is limited. Therefore, seeking best plan for combined treatment to improve patient's life quality and survival rate are still one of the most important clinical difficulties. This report describes a 37-year-old male who suffered from HCC repeatedly relapsed after hepatectomy. The patient received transcatheter arterial chemoembolization (TACE), microwave ablation (MWA), targeted therapy, and other combined treatments, all showed poor treatment effects. He received liver transplantation (LT) after receiving PD-1 blockade combined targeted therapy, eventually died due to severe immune rejection. It's first case of an allogeneic liver transplantation patient who received PD-1 blockade and Lenvaxen combined therapy. PD-1 blockade treatment and clinical observations of this case were summarized.
Lymphatic Vessel Invasion in Routine Pathology Reports of Papillary Thyroid Cancer
Authors: Chiapponi Costanza , Alakus Hakan , Schmidt Matthias , Faust Michael , Bruns Christiane J. , Büttner Reinhard , Eich Marie-Lisa , Schultheis Anne M.
Published: February 2022

Purpose

It is not mandatory to report lymphatic vessel invasion in pathology reports of papillary thyroid cancer (PTC) according to the current Union for International Cancer Control (UICC) TNM (tumor, nodes, and metastases) classification. However, there is some evidence for its correlation with lymph node metastasis (LNM) and prognosis. The aim of this study was to explore the clinical implication of lymphatic vessel invasion documentation of PTC because pathology reports play a pivotal role in postsurgical clinical decision-making in endocrine tumor boards.

Methods

Patients undergoing postoperative radioiodine treatment for PTC at the University Hospital of Cologne, Germany between December 2015 and March 2020 were identified. Pathology reports were screened for documentation of lymphatic vessel invasion. Demographics and clinicopathologic data of patients documented, including lymphatic vessel invasion and lymph nodal involvement were analyzed.

Results

A total of 578 patients were identified and included. Lymphatic vessel invasion was reported in pathology reports of 366 (63.3%) and omitted in 112 (36.7%) patients. Positive lymphatic vessel invasion (L1) was diagnosed in 67 (18.3%) of 366 patients and was documented as absent (L0) in 299 (81.7%) patients. Lymph nodal (N) status was positive (N+) in 126 (45.6%) and negative (N0) in 150 (54.3%) of these patients. In 54 (80.6%) L1 cases N+ status and in 137 (65.6%) L0 cases N0 status was diagnosed. In 13 (19.4%) cases with L1 status, there were no LNMs (L1 N0). In total, 72 (34.4%) patients had LNM despite L0 status (L0 N+). The sensitivity and specificity of LVI reporting for LNM were 0.42 and 0.91, respectively.

Conclusion

In routine pathology reports of PTC used for indication to postoperative radioiodine treatment by a German endocrine tumor board, lymphatic vessel invasion was found to be reported inconsistently and mostly as L0. L1 diagnoses, however, reliably correlated with reported LNM and might, thus, be relevant for clinical decision-making. For this reason, we advocate for standardized pathologic reassessment of lymphatic vessel invasion, in particular for cases where lymph nodes are not included in the pathologic specimen and if L0 is documented.
Use of Electronic Auscultation in Full Personal Protective Equipment to Detect Ventilation Status in Selective Lung Ventilation: A Randomized Controlled Trial
Authors: Wei Tzu-Jung , Hsiung Ping-Yan , Liu Jen-Hao , Lin Tzu-Chun , Kuo Fang-Tzu , Wu Chun-Yu
Published: February 2022

Chest auscultation is the first procedure performed to detect endotracheal tube malpositioning but conventional stethoscopes do not conform to the personal protective equipment (PPE) protocol during the COVID-19 pandemic. This double-blinded randomized controlled trial evaluated the feasibility of using ear-contactless electronic stethoscope to identify endobronchial blocker established selective lung ventilation, simulating endobronchial intubation during thoracic surgery with full PPE. Conventional and electronic auscultation was performed without and with full PPE, respectively, of 50 patients with selective lung ventilation. The rates of correct ventilation status detection were 86 and 88% in the conventional and electronic auscultation groups (p = 1.00). Electronic auscultation revealed a positive predictive value of 87% (95% CI 77 to 93%), and a negative predictive value of 91% (95% CI 58 to 99%), comparable to the results for conventional auscultation. For detection of the true unilateral lung ventilation, the F1 score and the phi were 0.904 and 0.654, respectively for conventional auscultation; were 0.919 and 0.706, respectively for electronic auscultation. Furthermore, the user experience questionnaire revealed that the majority of participant anesthesiologists (90.5%) rated the audio quality of electronic lung sounds as comparable or superior to that of conventional acoustic lung sounds. In conclusion, electronic auscultation assessments of ventilation status as examined during thoracic surgery in full PPE were comparable in accuracy to corresponding conventional auscultation assessments made without PPE. Users reported satisfactory experience with the electronic stethoscope.