bluuebunny/crossref_metadata_2025 huggingface dataset:
Mouse intestinal tuft cells express advillin but not villin
Authors: Esmaeilniakooshkghazi Amin , George Sudeep P. , Biswas Ritwika , Khurana Seema
Published: June 2020

Tuft (or brush) cells are solitary chemosensory cells scattered throughout the epithelia of the respiratory and alimentary tract. The actin-binding protein villin (Vil1) is used as a marker of tuft cells and the villin promoter is frequently used to drive expression of the Cre recombinase in tuft cells. While there is widespread agreement about the expression of villin in tuft cells there are several disagreements related to tuft cell lineage commitment and function. We now show that many of these inconsistencies could be resolved by our surprising finding that intestinal tuft cells, in fact, do not express villin protein. Furthermore, we show that a related actin-binding protein, advillin which shares 75% homology with villin, has a tuft cell restricted expression in the gastrointestinal epithelium. Our study identifies advillin as a marker of tuft cells and provides a mechanism for driving gene expression in tuft cells but not in other epithelial cells of the gastrointestinal tract. Our findings fundamentally change the way we identify and study intestinal tuft cells.
Clarifying relationships between cranial form and function in tapirs, with implications for the dietary ecology of early hominins
Authors: DeSantis Larisa R. G. , Sharp Alana C. , Schubert Blaine W. , Colbert Matthew W. , Wallace Steven C. , Grine Frederick E.
Published: June 2020

Paleontologists and paleoanthropologists have long debated relationships between cranial morphology and diet in a broad diversity of organisms. While the presence of larger temporalis muscle attachment area (via the presence of sagittal crests) in carnivorans is correlated with durophagy (i.e. hard-object feeding), many primates with similar morphologies consume an array of tough and hard foods—complicating dietary inferences of early hominins. We posit that tapirs, large herbivorous mammals showing variable sagittal crest development across species, are ideal models for examining correlations between textural properties of food and sagittal crest morphology. Here, we integrate dietary data, dental microwear texture analysis, and finite element analysis to clarify the functional significance of the sagittal crest in tapirs. Most notably, pronounced sagittal crests are negatively correlated with hard-object feeding in extant, and several extinct, tapirs and can actually increase stress and strain energy. Collectively, these data suggest that musculature associated with pronounced sagittal crests—and accompanied increases in muscle volume—assists with the processing of tough food items in tapirs and may yield similar benefits in other mammals including early hominins.
Temperate insects with narrow seasonal activity periods can be as vulnerable to climate change as tropical insect species
Authors: Johansson Frank , Orizaola Germán , Nilsson-Örtman Viktor
Published: June 2020

The magnitude and ecological impact of climate change varies with latitude. Several recent models have shown that tropical ectotherms face the greatest risk from warming because they currently experience temperatures much closer to their physiological optimum than temperate taxa. Even a small increase in temperature may thus result in steep fitness declines in tropical species but increased fitness in temperate species. This prediction, however, is based on a model that does not account for latitudinal differences in activity periods. Temperate species in particular may often experience considerably higher temperatures than expected during the active season. Here, we integrate data on insect warming tolerance and temperature-dependent development to re-evaluate latitudinal trends in thermal safety margins after accounting for latitudinal trends in insect seasonal activity. Our analyses suggest that temperate and tropical species differ far less in thermal safety margins than commonly assumed, and add to the recent number of studies suggesting that tropical and temperate species might face similar levels of threat from climate change.
Inhibition of PI3K by copanlisib exerts potent antitumor effects on Merkel cell carcinoma cell lines and mouse xenografts
Authors: Fang Bin , Kannan Aarthi , Zhao Stephanie , Nguyen Quy H. , Ejadi Samuel , Yamamoto Maki , Camilo Barreto J. , Zhao Haibo , Gao Ling
Published: June 2020

Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer with steadily increasing incidence and poor prognosis. Despite recent success with immunotherapy, 50% of patients still succumb to their diseases. To date, there is no Food and Drug Administration-approved targeted therapy for advanced MCC. Aberrant activation of phosphatidylinositide-3-kinase (PI3K)/AKT/mTOR pathway is frequently detected in MCC, making it an attractive therapeutic target. We previously found PI3K pathway activation in human MCC cell lines and tumors and demonstrated complete clinical response in a Stage IV MCC patient treated with PI3K inhibitor idelalisib. Here, we found that both PI3K-α and -δ isoforms are abundantly expressed in our MCC cell lines and clinical samples; we therefore examined antitumor efficacy across a panel of five PI3K inhibitors with distinctive isoform-specificities, including idelalisib (PI3K-δ), copanlisib (PI3K-α/δ), duvelisib (PI3K-γ/δ), alpelisib (PI3K-α), and AZD8186 (PI3K-β/δ). Of these, copanlisib exerts the most potent antitumor effects, markedly inhibiting cell proliferation, survival, and tumor growth by suppressing PI3K/mTOR/Akt activities in mouse models generated from MCC cell xenografts and patient-derived tumor xenografts. These results provide compelling preclinical evidence for application of copanlisib in advanced MCC with aberrant PI3K activation for which immunotherapy is insufficient, or patients who are unsuitable for immunotherapy.
Lentiviral mediated RPE65 gene transfer in healthy hiPSCs-derived retinal pigment epithelial cells markedly increased RPE65 mRNA, but modestly protein level
Authors: Udry Florian , Decembrini Sarah , Gamm David M. , Déglon Nicole , Kostic Corinne , Arsenijevic Yvan
Published: June 2020

The retinal pigment epithelium (RPE) is a monolayer of cobblestone-like epithelial cells that accomplishes critical functions for the retina. Several protocols have been published to differentiate pluripotent stem cells into RPE cells suitable for disease modelling and therapy development. In our study, the RPE identity of human induced pluripotent stem cell (hiPSC)-derived RPE (iRPE) was extensively characterized, and then used to test a lentiviral-mediated RPE65 gene augmentation therapy. A dose study of the lentiviral vector revealed a dose-dependent effect of the vector on RPE65 mRNA levels. A marked increase of the RPE65 mRNA was also observed in the iRPE (100-fold) as well as in an experimental set with RPE derived from another hiPSC source and from foetal human RPE. Although iRPE displayed features close to bona fide RPE, no or a modest increase of the RPE65 protein level was observed depending on the protein detection method. Similar results were observed with the two other cell lines. The mechanism of RPE65 protein regulation remains to be elucidated, but the current work suggests that high vector expression will not produce an excess of the normal RPE65 protein level.
Change in basilar artery length and bending according to aging and vertebral artery dominance: A longitudinal study
Authors: Ngo Minh Tri , Kwak Hyo Sung , Chung Gyung Ho
Published: June 2020

This study aimed to investigate the basilar artery (BA) geometric changes in a longitudinal study. 154 subjects with normal vertebrobasilar arterial systems on magnetic resonance angiography were assigned into two groups: 1) non-dominant vertebral artery (VA) and 2) VA dominance. We defined the dominant VA as either that the VA is 3 millimeters larger in diameter or the VA is connected to BA in a more straight angle. BA imaging was segmented to obtain BA bending length (BABL) and BA length (BAL). A mixed model ANOVA was conducted to investigate the impact of aging and VA dominance on the change of BABL and BAL after 123.6 ± 16.2 months. There was a significant main effect of VA dominance on the change of BABL after about 10 years, F (1,152) = 39.78, p < 0.01. On the other hand, there was a significant main effect of aging on the change of BAL during the same period of time, F (1,152) = 6.64, p = 0.01. Most subjects had an opposite directional relationship between the dominant VA and BA bending (71.3%; p < 0.01). Our study supported the hypothesis that the bending of the BA depends on the dominance of the VA, whereas the increased length of the BA depends on aging.
Magnetic and Photoluminescent Sensors Based on Metal-Organic Frameworks Built up from 2-aminoisonicotinate
Authors: García-Valdivia Antonio A. , Pérez-Yáñez Sonia , García Jose A. , Fernández Belén , Cepeda Javier , Rodríguez-Diéguez Antonio
Published: June 2020

In this work, three isostructural metal-organic frameworks based on first row transition metal ions and 2-aminoisonicotinate (2ain) ligands, namely, {[M(μ-2ain)2]·DMF}n [MII = Co (1), Ni (2), Zn (3)], are evaluated for their sensing capacity of various solvents and metal ions by monitoring the modulation of their magnetic and photoluminescence properties. The crystal structure consists of an open diamond-like topological 3D framework that leaves huge voids, which allows crystallizing two-fold interpenetrated architecture that still retains large porosity. Magnetic measurements performed on 1 reveal the occurrence of field-induced spin-glass behaviour characterized by a frequency-independent relaxation. Solvent-exchange experiments lead successfully to the replacement of lattice molecules by DMSO and MeOH, which, on its part, show dominating SIM behaviour with low blocking temperatures but substantially high energy barriers for the reversal of the magnetization. Photoluminescence studied at variable temperature on compound 3 show its capacity to provide bright blue emission under UV excitation, which proceeds through a ligand-centred charge transfer mechanism as confirmed by time-dependent DFT calculations. Turn-off and/or shift of the emission is observed for suspensions of 3 in different solvents and aqueous solutions containing metal ions.
The Haemodynamic Response to Endotracheal Intubation at Different Time of Fentanyl Given During Induction: A Randomised Controlled Trial
Authors: Teong Cheng Yeon , Huang Chien-Chung , Sun Fang-Ju
Published: June 2020

Endotracheal intubation elicits huge spectrum of stress responses which are hazardous in high-risk patients. Numerous drugs and techniques have been applied to attenuate the stress responses. In this double-blind study, one hundred and forty-five patients over 20 years old, ASA physical status I and II, undergoing elective surgeries requiring general anaesthesia with endotracheal intubation were included. Patients were randomly divided into three groups which fentanyl 2 mcg/kg was given at either 1, 2, 3 minutes before intubation. All groups received midazolam 0.05 mg/kg, lidocaine 0.5 mg/kg, propofol 2 mg/kg and rocuronium 1 mg/kg before intubation. Haemodynamic parameters were recorded for 10 minutes after induction. Two-level longitudinal hierarchical linear models were used for data interpretation and P < 0.05 was considered statistically significant. The study demonstrated significantly lower haemodynamic responses in the group who received fentanyl 2 minutes before intubation (P < 0.05). Confounding factors such as smoking, hypertension, diabetes mellitus and preoperative intravenous fluid supplement were analysed. In conclusion, fentanyl injection 2 minutes before intubation is recommended in order to obtain the most stable haemodynamic status.
Feasibility of the Energy Expenditure Prediction for Athletes and Non-Athletes from Ankle-Mounted Accelerometer and Heart Rate Monitor
Authors: Ho Chin-Shan , Chang Chun-Hao , Hsu Yi-Ju , Tu Yu-Tsai , Li Fang , Jhang Wei-Lun , Hsu Chih-Wen , Huang Chi-Chang
Published: June 2020

Due to the nature of micro-electromechanical systems, the vector magnitude (VM) activity of accelerometers varies depending on the wearing position and does not identify different levels of physical fitness. Without an appropriate energy expenditure (EE) estimation equation, bias can occur in the estimated values. We aimed to amend the EE estimation equation using heart rate reserve (HRR) parameters as the correction factor, which could be applied to athletes and non-athletes who primarily use ankle-mounted devices. Indirect calorimetry was used as the criterion measure with an accelerometer (ankle-mounted) equipped with a heart rate monitor to synchronously measure the EE of 120 healthy adults on a treadmill in four groups. Compared with ankle-mounted accelerometer outputs, when the traditional equation was modified using linear regression by combining VM with body weight and/or HRR parameters (modified models: Model A, without HRR; Model B, with HRR), both Model A (r: 0.931 to 0.972; ICC: 0.913 to 0.954) and Model B (r: 0.933 to 0.975; ICC: 0.930 to 0.959) showed the valid and reliable predictive ability for the four groups. With respect to the simplest and most reasonable mode, Model A seems to be a good choice for predicting EE when using an ankle-mounted device.
Postnatal loss of the insulin receptor in osteoprogenitor cells does not impart a metabolic phenotype
Authors: Fowlkes John L. , Clay Bunn R. , Kalaitzoglou Evangelia , Ray Phil , Popescu Iuliana , Thrailkill Kathryn M.
Published: June 2020

The relationship between osteoblast-specific insulin signaling, osteocalcin activation and gluco-metabolic homeostasis has proven to be complex and potentially inconsistent across animal-model systems and in humans. Moreover, the impact of postnatally acquired, osteoblast-specific insulin deficiency on the pancreas-to-skeleton-to-pancreas circuit has not been studied. To explore this relationship, we created a model of postnatal elimination of insulin signaling in osteoprogenitors. Osteoprogenitor-selective ablation of the insulin receptor was induced after ~10 weeks of age in IRl°x/lox/Osx-Cre+/− genotypic male and female mice (designated postnatal-OIRKO). At ~21 weeks of age, mice were then phenotypically and metabolically characterized. Postnatal-OIRKO mice demonstrated a significant reduction in circulating concentrations of undercarboxylated osteocalcin (ucOC), in both males and females compared with control littermates. However, no differences were observed between postnatal-OIRKO and control mice in: body composition (lean or fat mass); fasting serum insulin; HbA1c; glucose dynamics during glucose tolerance testing; or in pancreatic islet area or islet morphology, demonstrating that while ucOC is impacted by insulin signaling in osteoprogenitors, there appears to be little to no relationship between osteocalcin, or its derivative (ucOC), and glucose homeostasis in this model.
Single crystal structure, vibrational spectroscopy, gas sorption and antimicrobial properties of a new inorganic acidic diphosphates material (NH4)2Mg(H2P2O7)2•2H2O
Authors: Essehli Rachid , Sabri Souhir , El-Mellouhi Fedwa , Aïssa Brahim , Ben Yahia Hamdi , Altamash Tausif , Khraisheh Majeda , Amhamed Abdulkarem , El Bali Brahim
Published: June 2020

We report on the successful synthesis of diammonium magnesium dihydrogendiphosphate (V) dihydrate compound (NH4)2Mg(H2P2O7)2•2H2O using a wet chemical route. Single crystal X-ray diffraction analysis and micro Raman spectroscopy are employed to characterize the compound. We demonstrate, using a multidisciplinary approach, that this compound is ideal for carbon dioxide (CO2) capture in addition to other anthropogenic gasses. We show here -from both an experimental as well as from a density functional theory (DFT) calculations routes- the potential for adopting this compound into domestic air-conditioning units (ACUs). From these experiments, the resistance to bacterial growth is also investigated, which is critical for the adoption of this compound in ACUs. Our  compound exhibits a higher methane (CH4) sorptivity as compared to CO2 at 25 °C and 45 °C under pressures up to 50 bars. Furthermore, DFT electronic structure calculations are used to compute the main structural and electronic properties of the compound, taking into consideration the characteristics of the identified pores as a function of the progressive CO2 vs. CH4 loadings. Finally, the antibacterial assay reveals a strong antibacterial activity against the tested Gram-positive and Gram-negative bacteria, with a large zone of inhibition against the tested E. Coli, S. Aureus and K. Pneumonia.
Moringa Isothiocyanate-rich Seed Extract Delays the Onset of Diabetes in UC Davis Type-2 Diabetes Mellitus Rats
Authors: Waterman Carrie , Graham James L. , Arnold Charles D. , Stanhope Kimber L. , Tong Jason H. , Jaja-Chimedza Asha , Havel Peter J.
Published: June 2020

Moringa seeds have been used traditionally in the management of type 2 diabetes mellitus (T2DM) and contain potent bioactive isothiocyanates. This study evaluated the efficacy of an isothiocyanate-rich moringa seed extract in delaying the onset of T2DM in UC Davis T2DM rats, a well validated model which closely mimics T2DM in humans. Rats were separated into three groups; control, moringa seed extract at 0.4%, and a weight matched group. Rats were fed respective diets for 8 months, during which energy intake, body weight, the onset of diabetes circulating hormones, metabolites and markers of inflammation and liver function, and were monitored. The MS group had a significantly slower rate of diabetes onset p = 0.027), lower plasma glucose (p = 0.043), and lower HbA1c (p = 0.008) compared with CON animals. There were no significant differences in food intake and body weight between all groups. This study demonstrated MS can delay the onset of diabetes in the UC Davis T2DM rat model to a greater extent than moderate caloric restriction (by comparison to the WM group). The results support its documented traditional uses and a bioactive role of moringa isothiocyanates and suggest the potential efficacy for moringa supplementation for diabetes management in populations at risk for T2DM.
Comparison of clinical and pathological findings of patients undergoing elective colectomy for uncomplicated diverticulitis
Authors: Pesce Antonio , Barchitta Martina , Agodi Antonella , Salerno Monica , La Greca Gaetano , Magro Gaetano , Latteri Saverio , Puleo Stefano
Published: June 2020

Diverticular disease affects ∼5–10% people worldwide, yet the indications for elective colectomy in uncomplicated diverticulitis are unclear. As there is no strong scientific evidence regarding histology in diverticular disease, the primary outcome of the study was to analyze the degree of inflammation of colonic wall in patients that underwent elective colectomy for uncomplicated diverticulitis and to retrospectively assess the correlation between patient clinical history and pathological features of surgical specimens in order to find some predictive factors that may be strictly correlated with histology. An observational retrospective study was conducted. Patients undergoing elective colectomy for uncomplicated diverticulitis between January 2014 and January 2016 in an academic medical center were collected. The majority of patients (46.2%) had previously encountered one episode of acute diverticulitis prior to colectomy, while 21.5% and 10.8% had experienced two and three or more prior episodes respectively. Most patients had recurrent or chronic abdominal pain in the left iliac fossa (66.2%) for diverticular disease and a large proportion also experienced constipation (40.0%). Diverticulitis was identified pathologically as being “mild” in 44.6% patients and “severe” in 55.4% patients. The mean age was significantly lower in patients with severe diverticulitis (56.7 years) than in patients with mild diverticulitis (67.0 years). 71.9% of males had severe diverticulitis compared to 39.4% of females. Males have a 3.9 times higher risk of histological severe diverticulitis than females (OR = 3.932; 1.390–11.122; p = 0.008). Multivariate logistic regression analysis confirmed that age and gender were independent factors associated with histological diagnosis. Single-institution data and retrospective design were main limitations of this study. Age and gender are independent factors associated with severity inflammation index derived at histological analysis and they could be translated to clinical practice to better categorize patients with uncomplicated diverticulitis at the bedside.
Species-dependent protoplast enlargement involves different types of vacuole generation in bacteria
Authors: Takahashi Sawako , Mizuma Marin , Kami Satoshi , Nishida Hiromi
Published: June 2020

Vacuole generation occurs frequently during the enlargement of bacterial protoplasts and spheroplasts. Gram-positive Enterococcus faecalis protoplasts and gram-negative Lelliottia amnigena spheroplasts had large and small vacuoles inside the cytoplasm, respectively. Although no vacuoles were found at the early stage of cell enlargement, all enlarged cells used in the microinjection procedures had vacuoles. The plasma membrane of L. amnigena was more flexible than that of E. faecalis. In addition, E. faecalis protoplasts had unique discoidal structures as well as spherical structures in the cytoplasm. Our findings showed that the number of vacuoles increased as the L. amnigena plasma membrane expanded and that the size of vacuoles increased as the E. faecalis plasma membrane expanded, suggesting that bacterial cell enlargement involved vacuole generation. Thus, biosynthesis of the plasma and vacuolar membranes was synchronous with the bacterial cell enlargement. Differences in the plasma membrane flexibility might influence the different types of vacuole generation.
Fabrication and Piezoresistive/Piezoelectric Sensing Characteristics of Carbon Nanotube/PVA/Nano-ZnO Flexible Composite
Authors: Chen Shuaichao , Luo Jianlin , Wang Xiaoli , Li Qiuyi , Zhou Liucong , Liu Chao , Feng Chao
Published: June 2020

Flexible sensors with a high sensitivity and wide-frequency response are essential for structural health monitoring (SHM) while they are attached. Here, carbon nanotube (CNT) films doped with various PVA fractions (CNT/PVA) and ZnO nanowires (nano-ZnO) on zinc sheets were first fabricated by functionalized self-assembly and hydrothermal synthesis processes. A CNT/PVA/nano-ZnO flexible composite (CNT/PVA/ZnO) sandwiched with a zinc wafer was then prepared by the spin-coating method. The piezoresistive and/or piezoelectric capabilities of the CNT/PVA/ZnO composite were comprehensively investigated under cyclic bending and impact loading after it was firmly adhered to a substrate (polypropylene sheet or mortar plate). The results show that the piezoresistive sensitivity and linear stability of the CNT/PVA films doped with 20%, 50%, and 100% PVA during bending are 5.47%/mm, 11.082%/mm, and 11.95%/mm and 2.3%, 3.42%, and 4.78%, respectively. The piezoelectric sensitivity, linear stability, and response accuracy of the CNT/PVA/ZnO composite under impulse loading are 4.87 mV/lbf, 3.42%, and 1.496 ms, respectively. These merits support the use of CNT/PVA/ZnO as a piezoresistive and/or piezoelectric compound sensor to monitor the static/dynamic loads on concrete structures while it is attached.
Enhanced photon emission from a double-layer target at moderate laser intensities
Authors: Jirka Martin , Klimo Ondrej , Gu Yan-Jun , Weber Stefan
Published: June 2020

In this paper we study photon emission in the interaction of the laser beam with an under-dense target and the attached reflecting plasma mirror. Photons are emitted due to the inverse Compton scattering when accelerated electrons interact with a reflected part of the laser pulse. The enhancement of photon generation in this configuration lies in using the laser pulse with a steep rising edge. Such a laser pulse can be obtained by the preceding interaction of the incoming laser pulse with a thin solid-density foil. Using numerical simulations we study how such a laser pulse affects photon emission. As a result of employing a laser pulse with a steep rising edge, accelerated electrons can interact directly with the most intense part of the laser pulse that enhances photon emission. This approach increases the number of created photons and improves photon beam divergence.
Effects of different straw biochars on soil organic carbon, nitrogen, available phosphorus, and enzyme activity in paddy soil
Authors: Jing Yulin , Zhang Yuhu , Han Ihnsup , Wang Peng , Mei Qiwen , Huang Yunjie
Published: June 2020

Biochar is widely used as a soil amendment. Enzyme activity is an important factor that reflects soil metabolic activity, and is involved in biochemical processes such as organic matter decomposition and nutrient cycling in soils. However, the effects of biochar prepared for different straw materials on soil enzyme activity and soil nutrients are rarely studied. Through pot experiments, the effects of different straw (wheat, rice, maize) biochars (obtained by pyrolysis at 500 °C) on soil organic carbon, nitrogen, available phosphorus, and enzyme activity were studied in paddy soil. The results showed that the addition of biochar increased the soil organic carbon content, which gradually decreased with the extension of the rice growth period. The soil ammonium nitrogen content gradually decreased as the rice growth period continued; however, the soil nitrate nitrogen content first decreased and then increased over the rice growth period. Soil invertase, phosphatase, and urease activity first increased and then decreased, and the enzyme activity was the highest at the heading stage of rice. At this time, there were also significant correlations between enzyme activity and carbon, nitrogen, and phosphorus levels, except in the case of soil urease activity. The geometric mean of the investigated enzyme activities was the highest after amendment with rice straw biochar. These results indicate that the response of enzyme activity to biochar depends on the biochar feedstock and the rice growth stage.
The ratio of maximal handgrip force and maximal cycloergometry power as a diagnostic tool to screen for metabolic myopathies
Authors: Noury Jean-Baptiste , Zagnoli Fabien , Petit François , Le Maréchal Cédric , Marcorelles Pascale , Rannou Fabrice
Published: June 2020

Metabolic myopathies comprise a diverse group of inborn errors of intermediary metabolism affecting skeletal muscle, and often present clinically as an inability to perform normal exercise. Our aim was to use the maximal mechanical performances achieved during two functional tests, isometric handgrip test and cycloergometer, to identify metabolic myopathies among patients consulting for exercise-induced myalgia. Eighty-three patients with exercise-induced myalgia and intolerance were evaluated, with twenty-three of them having a metabolic myopathy (McArdle, n = 9; complete myoadenylate deaminase deficiency, n = 10; respiratory chain deficiency, n = 4) and sixty patients with non-metabolic myalgia. In all patients, maximal power (MP) was determined during a progressive exercise test on a cycloergometer and maximal voluntary contraction force (MVC) was assessed using a handgrip dynamometer. The ratio between percent-predicted values for MVC and MP was calculated for each subject (MVC%pred:MP%pred ratio). In patients with metabolic myopathy, the MVC%pred:MP%pred ratio was significantly higher compared to non-metabolic myalgia (1.54 ± 0.62 vs. 0.92 ± 0.25; p < 0.0001). ROC analysis of MVC%pred:MP%pred ratio showed AUC of 0.843 (0.758–0.927, 95% CI) for differentiating metabolic myopathies against non-metabolic myalgia. The optimum cutoff was taken as 1.30 (se = 69.6%, sp = 96.7%), with a corresponding diagnostic odd ratio of 66.3 (12.5–350.7, 95% CI). For a pretest probability of 15% in our tertiary reference center, the posttest probability for metabolic myopathy is 78.6% when MVC%pred:MP%pred ratio is above 1.3. In conclusion, the MVC%pred:MP%pred ratio is appropriate as a screening test to distinguish metabolic myopathies from non-metabolic myalgia.
Kyphoplasty Restores the Global Sagittal Balance of the Spine Independently from Pain Reduction
Authors: Pumberger Matthias , Schitz Florian , Bürger Justus , Schömig Friederike , Putzier Michael , Palmowski Yannick
Published: June 2020

Kyphoplasty is the standard surgical treatment of vertebral compression fractures. We aimed to clarify the influence of kyphoplasty on the sagittal profile as well as the relation between posture improvement and pain relief. For this purpose, we evaluated various radiological parameters of the sagittal profile on whole spine standing radiographs of 73 Patients with a single vertebral fracture treated by kyphoplasty. The key outcome was the postoperative change of the sagittal vertical axis (SVA). Additionally, clinical parameters including pain scores on visual analogue scale (VAS) and use of analgesics were obtained from medical records. Pre- and postoperative radiological as well as clinical parameters were compared. Additionally, the correlation between changes of SVA and changes of local kyphotic angle (LKA) or VAS was examined. The clinical parameters as well as various radiographic parameters (SVA, LKA, Gardner, Cobb) improved significantly postoperatively. The improvement of SVA correlated significantly with the correction of the LKA but not with postoperative pain relief. We conclude that kyphoplasty helps to restore the global sagittal balance of the spine after vertebral fractures. The correction of the sagittal profile seems to depend on the correction of the local kyphotic angle but does not correlate with postoperative pain relief.
Successful outcomes of endoscopic lithotripsy in completely bedridden patients with symptomatic urinary calculi
Authors: Waseda Yuma , Takazawa Ryoji , Kobayashi Masaki , Yoshida Satoshi , Uchida Yusuke , Kohno Yusuke , Tsujii Toshihiko
Published: June 2020

Due to the aging population, the number of completely bedridden individuals is expected to increase, and such individuals are at high risk of developing urinary calculi. This retrospective study included 32 consecutive bedridden patients, who had undergone endoscopic lithotripsy between 2010 and 2019, and aimed to identify the treatment outcomes of endoscopic lithotripsy for bedridden patients. A total of 45 endoscopic lithotripsies were performed to treat stones (median cumulative diameter, 24 mm). The stone-free rate (SFR) < 4 mm and complete SFR (0 mm) were achieved in 81% and 63% of patients, respectively. Postoperatively, 10 patients (22%) developed symptoms of systemic inflammatory response syndrome, and three patients (7%) had bloodstream infections. Except for one patient (3%) having a retained ureteral stent ultimately died from septic shock, drainage tube-free discharge was achieved in all patients. The 2-year cumulative incidence of stone-related events, and overall mortality rate, were 18% and 27%, respectively. Endoscopic lithotripsy is well tolerated and is associated with a high success rate, even with severe comorbidities and a relatively large stone burden. Physicians should consider performing endoscopic lithotripsy in bedridden patients with symptomatic urinary calculi regardless of their relatively short life expectancy and the remote risk of perioperative mortality.
Repeated dose multi-drug testing using a microfluidic chip-based coculture of human liver and kidney proximal tubules equivalents
Authors: Lin Ni , Zhou Xiaobing , Geng Xingchao , Drewell Christopher , Hübner Juliane , Li Zuogang , Zhang Yingli , Xue Ming , Marx Uwe , Li Bo
Published: June 2020

A microfluidic multi-organ chip emulates the tissue culture microenvironment, enables interconnection of organ equivalents and overcomes interspecies differences, making this technology a promising and powerful tool for preclinical drug screening. In this study, we established a microfluidic chip-based model that enabled non-contact cocultivation of liver spheroids and renal proximal tubule barriers in a connecting media circuit over 16 days. Meanwhile, a 14-day repeated-dose systemic administration of cyclosporine A (CsA) alone or in combination with rifampicin was performed. Toxicity profiles of the two different doses of CsA on different target organs could be discriminated and that concomitant treatment with rifampicin from day6 onwards decreased the CsA concentration and attenuated the toxicity compared with that after treatment with CsA for 14 consecutive days. The latter is manifested with the changes in cytotoxicity, cell viability and apoptosis, gene expression of metabolic enzymes and transporters, and noninvasive toxicity biomarkers. The on chip coculture of the liver and the proximal tubulus equivalents showed its potential as an effective and translational tool for repeated dose multi-drug toxicity screening in the preclinical stage of drug development.
Endothelial dysfunction in nonalcoholic steatohepatitis with low cardiac disease risk
Authors: Al-hamoudi Waleed , Alsadoon Amani , Hassanian Mazen , Alkhalidi Hisham , Abdo Ayman , Nour Mohamed , Halwani Rabih , Sanai Faisal , Alsharaabi Abdulsalam , Alswat Khalid , Hersi Ahmed , Albenmousa Ali , Alsaif Faisal
Published: June 2020

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. We prospectively evaluated endothelial function by assessing flow-mediated dilatation (FMD) of the brachial artery in patients with biopsy-proven NAFLD. This prospective study included 139 patients (50 healthy controls, 47 patients with steatosis and 42 patients with steatohepatitis), all of whom were nondiabetic. Patients with long-standing or uncontrolled hypertension, smokers, and morbidly obese patients were excluded. The medians (ranges) for vascular FMD in the steatohepatitis, steatosis, and control groups were 6% (0–37.5%), 10.8% (0–40%) and 13.6% (0–50%), respectively. The control group had a higher average FMD than the NAFLD group (15.13% vs 10.46%), and statistical significance was reached when the control and steatohepatitis groups were compared (13.6% vs 6%, p = 0.027). Average alanine aminotransferase was significantly higher in the steatohepatitis group than in the steatosis and control groups (54 (U/L) vs 31 (U/L), p = 0.008). Cholesterol levels were similar between all groups. In the multivariate analysis, FMD (OR = 0.85, p = 0.035) and high triglycerides (OR = 76.4, p = 0.009) were significant predictors of steatohepatitis. In the absence of major cardiac risk factors, we demonstrated better endothelial function in healthy controls, evidenced by a higher FMD of the brachial artery than that of patients with steatohepatitis.
The Phenomenon of Compensatory Cell Proliferation in Olfactory Epithelium in Fish Caused by Prolonged Exposure to Natural Odorants
Authors: Klimenkov Igor V. , Sudakov Nikolay P. , Pastukhov Mikhail V. , Kositsyn Nikolay S.
Published: June 2020

It was previously shown that activation of the processes of neurogenesis in the olfactory epithelium (OE) can be caused after intranasal administration of toxic or neurotrophic factors, after axon transection, or as a result of bulbectomy. Our study showed for the first time that a significant increase in olfactory cell renewal can also occur in animals due to periodic chemostimulation with natural odorants (amino acids and peptides) for 15 days. Using electron and laser confocal microscopy in fish (Paracottus knerii (Cottidae), Dybowski, 1874) from Lake Baikal, we showed that periodic stimulation of aquatic organisms with a water-soluble mixture of amino acids and peptides causes stress in OE, which leads to programmed death cells and compensatory intensification of their renewal. We estimated the level of reactive oxygen species, number of functionally active mitochondria, intensity of apoptosis processes, and mitosis activity of cells in the OE of fish in the control group and after periodic natural odorants exposure. This study showed that new stem cells are activated during enhanced odor stimulation and subsequent degenerative changes in the cells of the sensory apparatus. Those new activated stem cells are located in previously proliferatively inactive regions of OE that become involved in compensatory processes for the formation of new cells.
Pre-mRNA processing factor 3 enhances the progression of keratinocyte-derived cutaneous squamous cell carcinoma by regulating the JAK2/STAT3 pathway
Authors: Zuo Siyao , Li Xin , Bao Wanguo , Li Shanshan
Published: June 2020

The precise role of pre-mRNA processing factors (PRPs) in human tumorigenesis has not been yet explored. The object of the present study was to explore the effects of PRP3 in a common metastatic skin cancer, keratinocyte-derived cutaneous squamous cell carcinoma (cSCCs). RT-qPCR and western blotting were conducted to measure the expression levels of PRP3 in various cSCC cell lines and cSCC tissues. A benign epidermal keratinocyte cell line was transfected with a eukaryotic expression plasmid to overexpress PRP3. In addition, the endogenous expression level of PRP3 in cSCC cells was silenced using a short hairpin RNA method, and the role of PRP3 on cell proliferation and migration was examined by Cell Counting Kit-8, colony formation, wound healing assay and Transwell assays following knockdown in cSCC cells, and overexpression in keratinovcyte cells. Elevated levels of PRP3 mRNA and protein were noted in cSCC cell lines or cSCC tissues compared with actinic keratosis (AK) or benign epidermal keratinocyte cell line, respectively. Upregulation of PRP3 expression was found to be associated with poor clinical outcomes in patients with cSCCs. The upregulation of PRP3 promoted cell viability, metastasis and the activity of the JAK2/STAT3 pathway in epidermal keratinocyte cells. Interestingly, loss of PRP3 had no obvious impact on cell viability and migration in benign epidermal keratinocyte cells. Functionally, the inhibition of the JAK2/STAT3 pathway reversed the increased cell viability and migration of cSCC cells induced by PRP3. Taken together, the present observations indicated that PRP3 served as a tumor active factor in cSCCs by targeting the JAK2/STAT3 pathway. Moreover, it is implied that impeding the PRP3 activity may selectively constrain cancer cell growth and migration with limited effect on normal skin cells.
Sex and gender differences and biases in artificial intelligence for biomedicine and healthcare
Authors: Cirillo Davide , Catuara-Solarz Silvina , Morey Czuee , Guney Emre , Subirats Laia , Mellino Simona , Gigante Annalisa , Valencia Alfonso , Rementeria María José , Chadha Antonella Santuccione , Mavridis Nikolaos
Published: June 2020

Precision Medicine implies a deep understanding of inter-individual differences in health and disease that are due to genetic and environmental factors. To acquire such understanding there is a need for the implementation of different types of technologies based on artificial intelligence (AI) that enable the identification of biomedically relevant patterns, facilitating progress towards individually tailored preventative and therapeutic interventions. Despite the significant scientific advances achieved so far, most of the currently used biomedical AI technologies do not account for bias detection. Furthermore, the design of the majority of algorithms ignore the sex and gender dimension and its contribution to health and disease differences among individuals. Failure in accounting for these differences will generate sub-optimal results and produce mistakes as well as discriminatory outcomes. In this review we examine the current sex and gender gaps in a subset of biomedical technologies used in relation to Precision Medicine. In addition, we provide recommendations to optimize their utilization to improve the global health and disease landscape and decrease inequalities.
Lem2 and Lnp1 maintain the membrane boundary between the nuclear envelope and endoplasmic reticulum
Authors: Hirano Yasuhiro , Kinugasa Yasuha , Osakada Hiroko , Shindo Tomoko , Kubota Yoshino , Shibata Shinsuke , Haraguchi Tokuko , Hiraoka Yasushi
Published: June 2020

The nuclear envelope (NE) continues to the endoplasmic reticulum (ER). Proper partitioning of NE and ER is crucial for cellular activity, but the key factors maintaining the boundary between NE and ER remain to be elucidated. Here we show that the conserved membrane proteins Lem2 and Lnp1 cooperatively play a crucial role in maintaining the NE-ER membrane boundary in fission yeast Schizosaccharomyces pombe. Cells lacking both Lem2 and Lnp1 caused severe growth defects associated with aberrant expansion of the NE/ER membranes, abnormal leakage of nuclear proteins, and abnormal formation of vacuolar-like structures in the nucleus. Overexpression of the ER membrane protein Apq12 rescued the growth defect associated with membrane disorder caused by the loss of Lem2 and Lnp1. Genetic analysis showed that Apq12 had overlapping functions with Lnp1. We propose that a membrane protein network with Lem2 and Lnp1 acts as a critical factor to maintain the NE-ER boundary.
Mutually suppressive roles of KMT2A and KDM5C in behaviour, neuronal structure, and histone H3K4 methylation
Authors: Vallianatos Christina N. , Raines Brynne , Porter Robert S. , Bonefas Katherine M. , Wu Michael C. , Garay Patricia M. , Collette Katie M. , Seo Young Ah , Dou Yali , Keegan Catherine E. , Tronson Natalie C. , Iwase Shigeki
Published: June 2020

Histone H3 lysine 4 methylation (H3K4me) is extensively regulated by numerous writer and eraser enzymes in mammals. Nine H3K4me enzymes are associated with neurodevelopmental disorders to date, indicating their important roles in the brain. However, interplay among H3K4me enzymes during brain development remains largely unknown. Here, we show functional interactions of a writer-eraser duo, KMT2A and KDM5C, which are responsible for Wiedemann-Steiner Syndrome (WDSTS), and mental retardation X-linked syndromic Claes-Jensen type (MRXSCJ), respectively. Despite opposite enzymatic activities, the two mouse models deficient for either Kmt2a or Kdm5c shared reduced dendritic spines and increased aggression. Double mutation of Kmt2a and Kdm5c clearly reversed dendritic morphology, key behavioral traits including aggression, and partially corrected altered transcriptomes and H3K4me landscapes. Thus, our study uncovers common yet mutually suppressive aspects of the WDSTS and MRXSCJ models and provides a proof of principle for balancing a single writer-eraser pair to ameliorate their associated disorders.
Integrative omics analysis of the termite gut system adaptation to Miscanthus diet identifies lignocellulose degradation enzymes
Authors: Calusinska Magdalena , Marynowska Martyna , Bertucci Marie , Untereiner Boris , Klimek Dominika , Goux Xavier , Sillam-Dussès David , Gawron Piotr , Halder Rashi , Wilmes Paul , Ferrer Pau , Gerin Patrick , Roisin Yves , Delfosse Philippe
Published: June 2020

Miscanthus sp. biomass could satisfy future biorefinery value chains. However, its use is largely untapped due to high recalcitrance. The termite and its gut microbiome are considered the most efficient lignocellulose degrading system in nature. Here, we investigate at holobiont level the dynamic adaptation of Cortaritermes sp. to imposed Miscanthus diet, with a long-term objective of overcoming lignocellulose recalcitrance. We use an integrative omics approach combined with enzymatic characterisation of carbohydrate active enzymes from termite gut Fibrobacteres and Spirochaetae. Modified gene expression profiles of gut bacteria suggest a shift towards utilisation of cellulose and arabinoxylan, two main components of Miscanthus lignocellulose. Low identity of reconstructed microbial genomes to closely related species supports the hypothesis of a strong phylogenetic relationship between host and its gut microbiome. This study provides a framework for better understanding the complex lignocellulose degradation by the higher termite gut system and paves a road towards its future bioprospecting.
Mechanism of biomolecular recognition of trimethyllysine by the fluorinated aromatic cage of KDM5A PHD3 finger
Authors: Pieters Bas J. G. E. , Wuts Maud H. M. , Poater Jordi , Kumar Kiran , White Paul B. , Kamps Jos J. A. G. , Sherman Woody , Pruijn Ger J. M. , Paton Robert S. , Beuming Thijs , Bickelhaupt F. Matthias , Mecinović Jasmin
Published: June 2020

The understanding of biomolecular recognition of posttranslationally modified histone proteins is centrally important to the histone code hypothesis. Despite extensive binding and structural studies on the readout of histones, the molecular language by which posttranslational modifications on histone proteins are read remains poorly understood. Here we report physical-organic chemistry studies on the recognition of the positively charged trimethyllysine by the electron-rich aromatic cage containing PHD3 finger of KDM5A. The aromatic character of two tryptophan residues that solely constitute the aromatic cage of KDM5A was fine-tuned by the incorporation of fluorine substituents. Our thermodynamic analyses reveal that the wild-type and fluorinated KDM5A PHD3 fingers associate equally well with trimethyllysine. This work demonstrates that the biomolecular recognition of trimethyllysine by fluorinated aromatic cages is associated with weaker cation–π interactions that are compensated by the energetically more favourable trimethyllysine-mediated release of high-energy water molecules that occupy the aromatic cage.
A periodic dodecagonal supertiling by self-assembly of star-shaped molecules in the liquid crystalline state
Authors: Poppe Marco , Chen Changlong , Poppe Silvio , Liu Feng , Tschierske Carsten
Published: June 2020

Molecular tessellations are known in solid state systems and their formation is often induced or supported by a periodic surface lattice. Here we discover a complex tessellation on the 10 nm length scale, spontaneously formed in the highly dynamic liquid crystalline state. It is composed of overlapping dodecagonal supertiles combining prismatic cells with triangular and square cross sections. This complex honeycomb occurs between a triangular honeycomb at high and a square at low temperature, being opposite to the sequence expected for a thermal expansion of the side chains in the prismatic cells. Formation of the supertiles is supported by the segregation of alkyl chains with different length. The emergent behaviour of this complex soft matter structure is demonstrated, and intriguing connections between self-assembly on surfaces, in liquid crystals, and in block copolymers are drawn. Moreover, the tessellation represents a close approximant of the elusive columnar liquid quasicrystal with dodecagonal symmetry.
Nitrogen doping to atomically match reaction sites in microbial fuel cells
Authors: Wu Xiaoshuai , Qiao Yan , Guo Chunxian , Shi Zhuanzhuan , Li Chang Ming
Published: June 2020

Direct electron transfer at microbial anodes offers high energy conversion efficiency but relies on low concentrations of redox centers on bacterium membranes resulting in low power density. Here a heat-treatment is used to delicately tune nitrogen-doping for atomic matching with Flavin (a diffusive mediator) reaction sites resulting in strong adsorption and conversion of diffusive mediators to anchored redox centers. This impregnates highly concentrated fixed redox centers in the microbes-loaded biofilm electrode. This atomic matching enables short electron transfer pathways resulting in fast, direct electrochemistry as shown in Shewanella putrefaciens (S. putrefaciens) based microbial fuel cells (MFCs), showing a maximum power output higher than the conventional non-matched nitrogen-doped anode based MFCs by 21 times. This work sheds a light on diffusion mediation for fast direct electrochemistry, while holding promise for efficient and high power MFCs.