bluuebunny/crossref_metadata_2025 huggingface dataset:
Hemodynamic Assessment in Bicuspid Aortic Valve Disease and Aortic Dilation: New Insights From Voxel-By-Voxel Analysis of Reverse Flow, Stasis, and Energetics
Authors: Geeraert Patrick , Jamalidinan Fatemehsadat , Burns Fiona , Jarvis Kelly , Bristow Michael S. , Lydell Carmen , Hidalgo Tobon Silvia S. , de Celis Alonso Benito , Fedak Paul W. M. , White James A. , Garcia Julio
Published: January 2022

Objectives: Clinical management decisions surrounding ascending aorta (AAo) dilation in bicuspid aortic valve (BAV) disease benefit from personalized predictive tools. 4D-flow MRI may provide patient-specific markers reflective of BAV-associated aortopathy. This study aims to explore novel 4D-flow MRI parametric voxel-by-voxel forward flow, reverse flow, kinetic energy and stasis in BAV disease. We hypothesize that novel parametric voxel-by-voxel markers will be associated with aortic dilation and referral for surgery and can enhance our understanding of BAV hemodynamics beyond standard metrics.

Methods: A total of 96 subjects (73 BAV patients, 23 healthy controls) underwent MRI scan. Healthy controls had no known cardiovascular disease. Patients were clinically referred for AAo dilation assessment. Indexed diameters were obtained by dividing the aortic diameter by the patient’s body surface area. Patients were followed for the occurrence of aortic surgery. 4D-flow analysis was performed by a single observer in five regions: left ventricular outflow tract (LVOT), AAo, arch, proximal descending aorta (PDAo), and distal descending aorta (DDAo). In each region peak velocity, kinetic energy (KE), forward flow (FF), reverse flow (RF), and stasis were measured on a voxel-by-voxel basis. T-tests (or non-parametric equivalent) compared flow parameters between cohorts. Univariate and multivariate analyses explored associations between diameter and parametric voxel-by-voxel parameters.

Results: Compared to controls, BAV patients showed reduced stasis (p < 0.01) and increased RF and FF (p < 0.01) throughout the aorta, and KE remained similar. In the AAo, indexed diameter correlated with age (R = 0.326, p = 0.01), FF (R = −0.648, p < 0.001), RF (R = −0.441, p < 0.001), and stasis (R = −0.288, p < 0.05). In multivariate analysis, FF showed a significant inverse association with AAo indexed diameter, independent of age. During a median 179 ± 180 days of follow-up, 23 patients (32%) required aortic surgery. Compared to patients not requiring surgery, they showed increased KE and peak velocity in the proximal aorta (p < 0.01), accompanied by increased RF and reduced stasis throughout the entire aorta (p < 0.01).

Conclusion: Novel voxel-by-voxel reverse flow and stasis were altered in BAV patients and are associated with aortic dilation and surgical treatment.
Cutaneous Sensitivity Across Regions of the Foot Sole and Dorsum are Influenced by Foot Posture
Authors: Smith Simone G.V.S. , Yokich Maiya K. , Beaudette Shawn M. , Brown Stephen H. M. , Bent Leah R.
Published: January 2022

Understanding the processing of tactile information is crucial for the development of biofeedback interventions that target cutaneous mechanoreceptors. Mechanics of the skin have been shown to influence cutaneous tactile sensitivity. It has been established that foot skin mechanics are altered due to foot posture, but whether these changes affect cutaneous sensitivity are unknown. The purpose of this study was to investigate the potential effect of posture-mediated skin deformation about the ankle joint on perceptual measures of foot skin sensitivity. Participants (N = 20) underwent perceptual skin sensitivity testing on either the foot sole (N = 10) or dorsum (N = 10) with the foot positioned in maximal dorsiflexion/toe extension, maximal plantarflexion/toe flexion, and a neutral foot posture. Perceptual tests included touch sensitivity, stretch sensitivity, and spatial acuity. Regional differences in touch sensitivity were found across the foot sole (p < 0.001) and dorsum (p < 0.001). Touch sensitivity also significantly increased in postures where the skin was compressed (p = 0.001). Regional differences in spatial acuity were found on the foot sole (p = 0.002) but not dorsum (p = 0.666). Spatial acuity was not significantly altered by posture across the foot sole and dorsum, other than an increase in sensitivity at the medial arch in the dorsiflexion posture (p = 0.006). Posture*site interactions were found for stretch sensitivity on the foot sole and dorsum in both the transverse and longitudinal directions (p < 0.005). Stretch sensitivity increased in postures where the skin was pre-stretched on both the foot sole and dorsum. Changes in sensitivity across locations and postures were believed to occur due to concurrent changes in skin mechanics, such as skin hardness and thickness, which follows our previous findings. Future cutaneous biofeedback interventions should be applied with an awareness of these changes in skin sensitivity, to maximize their effectiveness for foot sole and dorsum input.
Comparative Functional Morphology of Human and Chimpanzee Feet Based on Three-Dimensional Finite Element Analysis
Authors: Ito Kohta , Nakamura Tomoya , Suzuki Ryo , Negishi Takuo , Oishi Motoharu , Nagura Takeo , Jinzaki Masahiro , Ogihara Naomichi
Published: January 2022

To comparatively investigate the morphological adaptation of the human foot for achieving robust and efficient bipedal locomotion, we develop three-dimensional finite element models of the human and chimpanzee feet. Foot bones and the outer surface of the foot are extracted from computer tomography images and meshed with tetrahedral elements. The ligaments and plantar fascia are represented by tension-only spring elements. The contacts between the bones and between the foot and ground are solved using frictionless and Coulomb friction contact algorithms, respectively. Physiologically realistic loading conditions of the feet during quiet bipedal standing are simulated. Our results indicate that the center of pressure (COP) is located more anteriorly in the human foot than in the chimpanzee foot, indicating a larger stability margin in bipedal posture in humans. Furthermore, the vertical free moment generated by the coupling motion of the calcaneus and tibia during axial loading is larger in the human foot, which can facilitate the compensation of the net yaw moment of the body around the COP during bipedal locomotion. Furthermore, the human foot can store elastic energy more effectively during axial loading for the effective generation of propulsive force in the late stance phase. This computational framework for a comparative investigation of the causal relationship among the morphology, kinematics, and kinetics of the foot may provide a better understanding regarding the functional significance of the morphological features of the human foot.
Bioengineered Zinc Oxide Nanoparticle-Loaded Hydrogel for Combinative Treatment of Spinal Cord Transection
Authors: Lin Sen , Zhao Hao-sen , Xu Chang , Zhou Zi-peng , Wang Da-hao , Chen Shu-rui , Mei Xi-fan
Published: January 2022

Spinal cord injury (SCI) is one of the most destructive diseases. The neuroinflammation microenvironment needs comprehensive mitigation of damages. Thus, regulation of local, microenvironment drugs could be a potential effective treatment. However, clinical studies on SCI with common treatment have reported it to cause systemic toxicity and side effects. Zinc oxide nanoparticles (ZnONPs) have been widely reported to have satisfying anti-inflammation function. Furthermore, green synthesis procedures can improve the capability and possible utilization of ZnONPs. However, the efficient administration and underlying mechanism of ZnONPs in SCI treatment remain unclear. Herein, an innovative approach was built by utilizing ZnONPs loaded in a skeletal muscle-derived adhesive hydrogel (ZnONPs-Gel). Different from the systemic application of ZnONPs, the local administration of ZnONPs-Gel offered the ZnONPs-loaded extracellular matrix with beneficial biocompatibility to the injured spinal cord, thereby promoting effective function recovery. Mechanistically, the ZnONPs-Gel treatment not only markedly reduced ROS production but also decreased apoptosis in the injured spinal cord. Therefore, the strategy based on local administration of the ZnONPs-Gel in the early stage of SCI may be an effective therapeutic treatment.
Immobilization of β-Galactosidase by Encapsulation of Enzyme-Conjugated Polymer Nanoparticles Inside Hydrogel Microparticles
Authors: Suvarli Narmin , Wenger Lukas , Serra Christophe , Perner-Nochta Iris , Hubbuch Jürgen , Wörner Michael
Published: January 2022

Increasing the shelf life of enzymes and making them reusable is a prominent topic in biotechnology. The encapsulation inside hydrogel microparticles (HMPs) can enhance the enzyme’s stability by preserving its native conformation and facilitating continuous biocatalytic processes and enzyme recovery. In this study, we present a method to immobilize β-galactosidase by, first, conjugating the enzyme onto the surface of polymer nanoparticles, and then encapsulating these enzyme-conjugated nanoparticles (ENPs) inside HMPs using microfluidic device paired with UV-LEDs. Polymer nanoparticles act as anchors for enzyme molecules, potentially preventing their leaching through the hydrogel network especially during swelling. The affinity binding (through streptavidin-biotin interaction) was used as an immobilization technique of β-galactosidase on the surface of polymer nanoparticles. The hydrogel microparticles of roughly 400 μm in size (swollen state) containing unbound enzyme and ENPs were produced. The effects of encapsulation and storage in different conditions were evaluated. It was discovered that the encapsulation in acrylamide (AcAm) microparticles caused an almost complete loss of enzymatic activity. Encapsulation in poly(ethylene glycol) (PEG)-diacrylate microparticles, on the other hand, showed a residual activity of 15–25%, presumably due to a protective effect of PEG during polymerization. One of the major factors that affected the enzyme activity was presence of photoinitiator exposed to UV-irradiation. Storage studies were carried out at room temperature, in the fridge and in the freezer throughout 1, 7 and 28 days. The polymer nanoparticles showcased excellent immobilization properties and preserved the activity of the conjugated enzyme at room temperature (115% residual activity after 28 days), while a slight decrease was observed for the unbound enzyme (94% after 28 days). Similar trends were observed for encapsulated ENPs and unbound enzyme. Nevertheless, storage at −26°C resulted in an almost complete loss of enzymatic activity for all samples.
Dual Inhibition of mTORC1/2 Reduces Migration of Cholangiocarcinoma Cells by Regulation of Matrixmetalloproteinases
Authors: Joechle Katharina , Jumaa Huda , Thriene Kerstin , Hellerbrand Claus , Kulemann Birte , Fichtner-Feigl Stefan , Lang Sven A. , Guenzle Jessica
Published: January 2022

Cholangiocarcinoma (CCA) is a rare but highly aggressive tumor entity for which systemic therapies only showed limited efficacy so far. As OSI-027—a dual kinase inhibitor targeting both mTOR complexes, mTORC1 and mTORC2 - showed improved anti-cancer effects, we sought to evaluate its impact on the migratory and metastatic capacity of CCA cells in vitro. We found that treatment with OSI-027 leads to reduced cell mobility and migration as well as a reduced surviving fraction in colony-forming ability. While neither cell viability nor proliferation rate was affected, OSI-027 decreased the expression of MMP2 and MMP9. Moreover, survival as well as anti-apoptotic signaling was impaired upon the use of OSI-027 as determined by AKT and MAPK blotting. Dual targeting of mTORC1/2 might therefore be a viable option for anti-neoplastic therapy in CCA.
Extracellular Vesicles Derived From Stem Cells in Intervertebral Disc Degeneration
Authors: Wu Xinjie , Sun Wei
Published: January 2022

Intervertebral disc degeneration (IVDD) is the leading cause of low back pain related to degradation of cartilaginous tissues, mainly resulting from oxidative stress, cell apoptosis, and extracellular matrix degradation. Extracellular vesicles (EVs) exist in all bodily fluids and can be produced by all types of cells. Stem cell-derived EVs (SC-EVs), which are the main paracrine components of stem cells, have gained significant attention in the field of regenerative medicine. Over the past years, accumulating evidence indicates the therapeutic and diagnostic potentials of EVs in IVDD. The main mechanisms involve the induction of regenerative phenotypes, apoptosis alleviation, and immune modulation. In addition, the efficiency of SC-EVs can be enhanced by choosing appropriate donor cells and cell phenotypes, optimizing cell culture conditions, or engineering EVs to deliver drugs and targeting molecules. Given the importance and novelty of SC-EVs, we give an overview of SC-EVs and discuss the roles of SC-EVs in IVDD.
Deconstructing Pancreatic Cancer Using Next Generation-Omic Technologies–From Discovery to Knowledge-Guided Platforms for Better Patient Management
Authors: Schreyer Daniel , Neoptolemos John P. , Barry Simon T. , Bailey Peter
Published: January 2022

Comprehensive molecular landscaping studies reveal a potentially brighter future for pancreatic ductal adenocarcinoma (PDAC) patients. Blood-borne biomarkers obtained from minimally invasive “liquid biopsies” are now being trialled for early disease detection and to track responses to therapy. Integrated genomic and transcriptomic studies using resectable tumour material have defined intrinsic patient subtypes and actionable genomic segments that promise a shift towards genome-guided patient management. Multimodal mapping of PDAC using spatially resolved single cell transcriptomics and imaging techniques has identified new potentially therapeutically actionable cellular targets and is providing new insights into PDAC tumour heterogeneity. Despite these rapid advances, defining biomarkers for patient selection remain limited. This review examines the current PDAC cancer biomarker ecosystem (identified in tumour and blood) and explores how advances in single cell sequencing and spatially resolved imaging modalities are being used to uncover new targets for therapeutic intervention and are transforming our understanding of this difficult to treat disease.
Short-Chain Fatty Acid Butyrate Induces Cilia Formation and Potentiates the Effects of HDAC6 Inhibitors in Cholangiocarcinoma Cells
Authors: Pant Kishor , Richard Seth , Gradilone Sergio A.
Published: January 2022

Cholangiocarcinoma (CCA) is a deadly form of liver cancer with limited therapeutic approaches. The pathogenesis of CCA involves the loss of primary cilia in cholangiocytes, an important organelle that regulates several key cellular functions including the regulation of cell polarity, growth, and differentiation, by a mechanism involving increased expression of deacetylases like HDAC6 and SIRT1. Therefore, cilia restoration may represent an alternative and novel therapeutic approach against CCA. Butyrate is produced by bacterial fermentation of fibers in the intestine and has been shown to inhibit SIRT1, showing antitumor effects on various cancers. Herein, we investigated the role of butyrate on CCA cell proliferation, migration, and EMT and evaluated the synergistic effects with specific HDAC6 inhibition. When CCA cells, including HuCCT1 and KMCH, were treated with butyrate, the cilia formation and acetylated-tubulin levels were increased, while no significant effects were observed in normal human cholangiocytes. Butyrate treatment also depicted reduced cell proliferation in HuCCT1 and KMCH cells, but on the other hand, it affected cell growth of the normal cholangiocytes only at high concentrations. In HuCCT1 cells, spheroid formation and cell migration were also halted by butyrate treatment. Furthermore, we found that butyrate augmented the previously described effects of HDAC6 inhibitors on CCA cell proliferation and migration by reducing the expression of CD44, cyclin D1, PCNA, Zeb1, and Vimentin. In summary, butyrate targets cancer cell growth and migration and enhances the anti-cancer effects of HDAC6 inhibitors in CCA cells, suggesting that butyrate may have therapeutic effects in CCA and other ciliopathies.
Modulating Room-Temperature Phosphorescence-To-Phosphorescence Mechanochromism by Halogen Exchange
Authors: Takewaki Yoshika , Ogawa Takuji , Tani Yosuke
Published: January 2022

Modulating the stimulus-responsiveness of a luminescent crystal is challenging owing to the complex interdependent nature of its controlling factors, such as molecular structure, molecular conformation, crystal packing, optical properties, and amorphization behavior. Herein, we demonstrate a halogen-exchange approach that disentangles this problem, thereby realizing the modulation of room-temperature phosphorescence-to-phosphorescence mechanochromism. Replacing the bromine atoms in a brominated thienyl diketone with chlorine atoms afforded isostructural crystals; i.e., molecules with different halogen atoms exhibited the same molecular conformation and crystal packing. Consequently, amorphization behavior toward mechanical stimulation was also the same, and the phosphorescence of amorphous states originated from the same conformer of each diketone. In contrast, the phosphorescence properties of each conformer were modulated differently, which is ascribable to heavy atom effects, resulting in the modulation of the mechanochromism. Thus, halogen exchange is a promising approach for modulating the stimulus-responsive photofunctions of crystals involving spin-forbidden processes.
Design of a Controlled-Release Delivery Composite of Antibacterial Agent Gatifloxacin by Spherical Silica Nanocarrier
Authors: Guo Xueping , Mo Wenjing , Zhang Dingyang , Wang Yurong , Cao Fang , Zhai Tianyun , Rao Wenhua , Guan Xiong , Xu Lei , Pan Xiaohong
Published: January 2022

In this study, a spherical silica nanoparticle was explored as a gatifloxacin carrier synthesized by the chemical precipitation method. It was found that there was no new chemical bond formation during the loading process between gatifloxacin and silica, which implies that the binding was driven by physical interaction. In addition, the drug loading and encapsulation efficiency could be improved by appropriately increasing nano-silica content in the loading process. Meanwhile, the release rate of gatifloxacin after loading nano-silica was also improved, suggesting the successful design of a controlled-release delivery composite. The silica nanocarrier could significantly improve the antibacterial performance of Escherichia coli by 2.1 times, which was higher than the pure gatifloxacin. The 24 h bacteriostatic rate was higher than that of a simple mixture of silica nanoparticles and gatifloxacin. Strong reactive oxygen species (ROS) in GAT-SiO2 NPs suggests that ROS might be associated with bactericidal activity. The synergy between the physicochemical effect and ROS production of this material is proposed as the mechanism of its antibacterial activity, which can also be confirmed by the cell membrane damage observed under electron microscopy and DNA damage experiments. Collectively, our finding indicates that nano-silica microspheres could serve as a promising carrier for the sustained release of gatifloxacin, thereby providing a new carrier design scheme for the improvement of the antibacterial effect.
Methods Used to Investigate the Plasmodium falciparum Digestive Vacuole
Authors: Edgar Rebecca C. S. , Counihan Natalie A. , McGowan Sheena , de Koning-Ward Tania F.
Published: January 2022

Plasmodium falciparum malaria remains a global health problem as parasites continue to develop resistance to all antimalarials in use. Infection causes clinical symptoms during the intra-erythrocytic stage of the lifecycle where the parasite infects and replicates within red blood cells (RBC). During this stage, P. falciparum digests the main constituent of the RBC, hemoglobin, in a specialized acidic compartment termed the digestive vacuole (DV), a process essential for survival. Many therapeutics in use target one or multiple aspects of the DV, with chloroquine and its derivatives, as well as artemisinin, having mechanisms of action within this organelle. In order to better understand how current therapeutics and those under development target DV processes, techniques used to investigate the DV are paramount. This review outlines the involvement of the DV in therapeutics currently in use and focuses on the range of techniques that are currently utilized to study this organelle including microscopy, biochemical analysis, genetic approaches and metabolomic studies. Importantly, continued development and application of these techniques will aid in our understanding of the DV and in the development of new therapeutics or therapeutic partners for the future.
Bio-Inspired Multimodal Imaging in Reduced Visibility
Authors: Lapray Pierre-Jean , Thomas Jean-Baptiste , Farup Ivar
Published: January 2022

The visual systems found in nature rely on capturing light under different modalities, in terms of spectral sensitivities and polarization sensitivities. Numerous imaging techniques are inspired by this variety, among which, the most famous is color imaging inspired by the trichromacy theory of the human visual system. We investigate the spectral and polarimetric properties of biological imaging systems that will lead to the best performance on scene imaging through haze, i.e., dehazing. We design a benchmark experiment based on modalities inspired by several visual systems, and adapt state-of-the-art image reconstruction algorithms to those modalities. We show the difference in performance of each studied systems and discuss it in front of our methodology and the statistical relevance of our data.
Clinical Characteristics of Cryoglobulinemia With Cardiac Involvement in a Single Center
Authors: He Kun , Zhang Yun , Wang Wei , Wang Yu , Sha Yue , Zeng Xuejun
Published: January 2022

Background: Cryoglobulinemia is a syndrome characterized by the presence of cryoglobulins (CGs) in serum, and cardiac involvement is a rare occurrence that can affect treatment and prognosis. This study aimed to explore the clinical characteristics of cryoglobulinemia with cardiac involvement.

Methods: 108 patients diagnosed with cryoglobulinemia who were admitted and treated in Peking Union Medical College Hospital (PUMCH) between June 1985 and June 2019 were enrolled in the present study. Clinical characteristics, therapy, and prognosis of patients with cardiac involvement were retrospectively analyzed.

Results: The cryoglobulinemia with cardiac involvement was found in 7 patients, thus reaching the incidence of 6.5%. Heart failure was the main cardiac manifestation found in these patients, all with the involvement of external cardiac organs. Laboratory examinations showed significant elevation of N-terminal brain natriuretic peptide precursor (NT-proBNP) and brain natriuretic peptide (BNP) with negative troponin (cTnI). Electrocardiogram (ECG) was generally normal or only showed low-flat and biphasic multi-lead T waves. Echocardiography was performed in 6 patients, all of whom showed enlargement of heart cavity. Five patients had reduced left ventricular myocardial contractible motion with decreased ejection fraction, 3 patients had pericardial effusion, and 1 patient had left ventricular hypertrophy or severe aortic insufficiency. Cardiac magnetic resonance imaging showed delayed myocardial enhancement in 2 patients. One patient underwent a myocardial biopsy, which showed perivasculitis. Condition in 6 patients who received active treatment targeting improved in the early stage. Three patients (3/7, 42.9%) died due to disease progression during follow-up period.

Conclusions: Cryoglobulinemia with cardiac involvement is a rare but serious condition that has relatively high risk of death. When patients with cryoglobulinemia without underlying heart disease experience heart failure, chest pain, or elevation of asymptomatic NT-proBNP and BNP, there is a high possibility of cardiac involvement, even if the electrocardiogram and troponin are negative. Further examinations such as echocardiography, cardiac magnetic resonance imaging, and myocardial biopsy examination could contribute to the diagnosis. Cardiac manifestations could be timely reversed after active targeted treatment. NT-proBNP and echocardiography could be used for the monitoring of disease efficacy.
Trpc6 Promotes Doxorubicin-Induced Cardiomyopathy in Male Mice With Pleiotropic Differences Between Males and Females
Authors: Norton Nadine , Bruno Katelyn A. , Di Florio Damian N. , Whelan Emily R. , Hill Anneliese R. , Morales-Lara Andrea Carolina , Mease Anna A. , Sousou John M. , Malavet Jose A. , Dorn Lauren E. , Salomon Gary R. , Macomb Logan P. , Khatib Sami , Anastasiadis Zacharias P. , Necela Brian M. , McGuire Molly M. , Giresi Presley G. , Kotha Archana , Beetler Danielle J. , Weil Raegan M. , Landolfo Carolyn K. , Fairweather DeLisa
Published: January 2022

Background: Doxorubicin is a widely used and effective chemotherapy, but the major limiting side effect is cardiomyopathy which in some patients leads to congestive heart failure. Genetic variants in TRPC6 have been associated with the development of doxorubicin-induced cardiotoxicity, suggesting that TRPC6 may be a therapeutic target for cardioprotection in cancer patients.

Methods: Assessment of Trpc6 deficiency to prevent doxorubicin-induced cardiac damage and function was conducted in male and female B6.129 and Trpc6 knock-out mice. Mice were treated with doxorubicin intraperitoneally every other day for a total of 6 injections (4 mg/kg/dose, cumulative dose 24 mg/kg). Cardiac damage was measured in heart sections by quantification of vacuolation and fibrosis, and in heart tissue by gene expression of Tnni3 and Myh7. Cardiac function was determined by echocardiography.

Results: When treated with doxorubicin, male Trpc6-deficient mice showed improvement in markers of cardiac damage with significantly reduced vacuolation, fibrosis and Myh7 expression and increased Tnni3 expression in the heart compared to wild-type controls. Similarly, male Trpc6-deficient mice treated with doxorubicin had improved LVEF, fractional shortening, cardiac output and stroke volume. Female mice were less susceptible to doxorubicin-induced cardiac damage and functional changes than males, but Trpc6-deficient females had improved vacuolation with doxorubicin treatment. Sex differences were observed in wild-type and Trpc6-deficient mice in body-weight and expression of Trpc1, Trpc3 and Rcan1 in response to doxorubicin.

Conclusions: Trpc6 promotes cardiac damage following treatment with doxorubicin resulting in cardiomyopathy in male mice. Female mice are less susceptible to cardiotoxicity with more robust ability to modulate other Trpc channels and Rcan1 expression.
RETRACTED: STK35 Gene Therapy Attenuates Endothelial Dysfunction and Improves Cardiac Function in Diabetes
Authors: Joladarashi Darukeshwara , Zhu Yanan , Willman Matthew , Nash Kevin , Cimini Maria , Thandavarayan Rajarajan Amirthalingam , Youker Keith A. , Song Xuehong , Ren Di , Li Ji , Kishore Raj , Krishnamurthy Prasanna , Wang Lianchun
Published: January 2022

Diabetic cardiomyopathy (DCM) is characterized by microvascular pathology and interstitial fibrosis that leads to progressive heart failure. The mechanisms underlying DCM pathogenesis remain obscure, and no effective treatments for the disease have been available. In the present study, we observed that STK35, a novel kinase, is decreased in the diabetic human heart. High glucose treatment, mimicking hyperglycemia in diabetes, downregulated STK35 expression in mouse cardiac endothelial cells (MCEC). Knockdown of STK35 attenuated MCEC proliferation, migration, and tube formation, whereas STK35 overexpression restored the high glucose-suppressed MCEC migration and tube formation. Angiogenesis gene PCR array analysis revealed that HG downregulated the expression of several angiogenic genes, and this suppression was fully restored by STK35 overexpression. Intravenous injection of AAV9-STK35 viral particles successfully overexpressed STK35 in diabetic mouse hearts, leading to increased vascular density, suppression of fibrosis in the heart, and amelioration of left ventricular function. Altogether, our results suggest that hyperglycemia downregulates endothelial STK35 expression, leading to microvascular dysfunction in diabetic hearts, representing a novel mechanism underlying DCM pathogenesis. Our study also emerges STK35 is a novel gene therapeutic target for preventing and treating DCM.
Characterization of Turbulent Flow Behind a Transcatheter Aortic Valve in Different Implantation Positions
Authors: Pietrasanta Leonardo , Zheng Shaokai , De Marinis Dario , Hasler David , Obrist Dominik
Published: January 2022

The development of turbulence after transcatheter aortic valve (TAV) implantation may have detrimental effects on the long-term performance and durability of the valves. The characterization of turbulent flow generated after TAV implantation can provide fundamental insights to enhance implantation techniques. A self-expandable TAV was tested in a pulse replicator and the three-dimensional flow field was extracted by means of tomographic particle image velocimetry. The valve was fixed inside a silicone phantom mimicking the aortic root and the flow field was studied for two different supra-annular axial positions at peak systole. Fluctuating velocities and turbulent kinetic energy were compared between the two implantations. Velocity spectra were derived at different spatial positions in the turbulent wakes to characterize the turbulent flow. The valve presented similar overall flow topology but approximately 8% higher turbulent intensity in the lower implantation. In this configuration, axial views of the valve revealed smaller opening area and more corrugated leaflets during systole, as well as more accentuated pinwheeling during diastole. The difference arose from a lower degree of expansion of the TAV's stent inside the aortic lumen. These results suggest that the degree of expansion of the TAV in-situ is related to the onset of turbulence and that a smaller and less regular opening area might introduce flow instabilities that could be detrimental for the long-term performance of the valve. The present study highlights how implantation mismatches may affect the structure and intensity of the turbulent flow in the aortic root.
Immunotherapeutic Strategies in Cancer and Atherosclerosis—Two Sides of the Same Coin
Authors: Nettersheim Felix Sebastian , Picard Felix Simon Ruben , Hoyer Friedrich Felix , Winkels Holger
Published: January 2022

The development and clinical approval of immunotherapies has revolutionized cancer therapy. Although the role of adaptive immunity in atherogenesis is now well-established and several immunomodulatory strategies have proven beneficial in preclinical studies, anti-atherosclerotic immunotherapies available for clinical application are not available. Considering that adaptive immune responses are critically involved in both carcinogenesis and atherogenesis, immunotherapeutic approaches for the treatment of cancer and atherosclerosis may exert undesirable but also desirable side effects on the other condition, respectively. For example, the high antineoplastic efficacy of immune checkpoint inhibitors, which enhance effector immune responses against tumor cells by blocking co-inhibitory molecules, was recently shown to be constrained by substantial proatherogenic properties. In this review, we outline the specific role of immune responses in the development of cancer and atherosclerosis. Furthermore, we delineate how current cancer immunotherapies affect atherogenesis and discuss whether anti-atherosclerotic immunotherapies may similarly have an impact on carcinogenesis.
Top-Down Machine Learning-Based Architecture for Cyberattacks Identification and Classification in IoT Communication Networks
Authors: Abu Al-Haija Qasem
Published: January 2022

With the prompt revolution and emergence of smart, self-reliant, and low-power devices, Internet of Things (IoT) has inconceivably expanded and impacted almost every real-life application. Nowadays, for example, machines and devices are now fully reliant on computer control and, instead, they have their own programmable interfaces, such as cars, unmanned aerial vehicles (UAVs), and medical devices. With this increased use of IoT, attack capabilities have increased in response, which became imperative that new methods for securing these systems be developed to detect attacks launched against IoT devices and gateways. These attacks are usually aimed at accessing, changing, or destroying sensitive information; extorting money from users; or interrupting normal business processes. In this research, we present new efficient and generic top-down architecture for intrusion detection, and classification in IoT networks using non-traditional machine learning is proposed in this article. The proposed architecture can be customized and used for intrusion detection/classification incorporating any IoT cyber-attack datasets, such as CICIDS Dataset, MQTT dataset, and others. Specifically, the proposed system is composed of three subsystems: feature engineering (FE) subsystem, feature learning (FL) subsystem, and detection and classification (DC) subsystem. All subsystems have been thoroughly described and analyzed in this article. Accordingly, the proposed architecture employs deep learning models to enable the detection of slightly mutated attacks of IoT networking with high detection/classification accuracy for the IoT traffic obtained from either real-time system or a pre-collected dataset. Since this work employs the system engineering (SE) techniques, the machine learning technology, the cybersecurity of IoT systems field, and the collective corporation of the three fields have successfully yielded a systematic engineered system that can be implemented with high-performance trajectories.
Using Machine Learning to Predict Mortality for COVID-19 Patients on Day 0 in the ICU
Authors: Jamshidi Elham , Asgary Amirhossein , Tavakoli Nader , Zali Alireza , Setareh Soroush , Esmaily Hadi , Jamaldini Seyed Hamid , Daaee Amir , Babajani Amirhesam , Sendani Kashi Mohammad Ali , Jamshidi Masoud , Jamal Rahi Sahand , Mansouri Nahal
Published: January 2022

Rationale: Given the expanding number of COVID-19 cases and the potential for new waves of infection, there is an urgent need for early prediction of the severity of the disease in intensive care unit (ICU) patients to optimize treatment strategies.

Objectives: Early prediction of mortality using machine learning based on typical laboratory results and clinical data registered on the day of ICU admission.

Methods: We retrospectively studied 797 patients diagnosed with COVID-19 in Iran and the United Kingdom (U.K.). To find parameters with the highest predictive values, Kolmogorov-Smirnov and Pearson chi-squared tests were used. Several machine learning algorithms, including Random Forest (RF), logistic regression, gradient boosting classifier, support vector machine classifier, and artificial neural network algorithms were utilized to build classification models. The impact of each marker on the RF model predictions was studied by implementing the local interpretable model-agnostic explanation technique (LIME-SP).

Results: Among 66 documented parameters, 15 factors with the highest predictive values were identified as follows: gender, age, blood urea nitrogen (BUN), creatinine, international normalized ratio (INR), albumin, mean corpuscular volume (MCV), white blood cell count, segmented neutrophil count, lymphocyte count, red cell distribution width (RDW), and mean cell hemoglobin (MCH) along with a history of neurological, cardiovascular, and respiratory disorders. Our RF model can predict patient outcomes with a sensitivity of 70% and a specificity of 75%. The performance of the models was confirmed by blindly testing the models in an external dataset.

Conclusions: Using two independent patient datasets, we designed a machine-learning-based model that could predict the risk of mortality from severe COVID-19 with high accuracy. The most decisive variables in our model were increased levels of BUN, lowered albumin levels, increased creatinine, INR, and RDW, along with gender and age. Considering the importance of early triage decisions, this model can be a useful tool in COVID-19 ICU decision-making.
Gamification in Everyday Classrooms: Observations From Schools in Hong Kong
Authors: Lam Paul , Tse Alan
Published: January 2022

Gamification refers to the use of game elements in non-game context to improve user experience and engagement (Deterding et al., 2011a). The potential of games to make learning more engaging has been widely noted by educators and researchers. Many of the applications and research studies in this area focused on non-customizable digital games that are designed for a specific group and a narrow range of subject content. In actual classrooms, however, non-customizable digital games may not be flexible enough to enable teachers to adapt gamification into practice. Hence, teachers sometimes use a mixed set of strategies to flexibly embed game-based mechanics into their teaching. How can different gamification tools be applied in classrooms? Based on classroom observations and teacher interviews from schools from primary to secondary level in Hong Kong, this paper explores the role of gamification in real practice. We frame the discussion based on the following approaches with ranging levels of flexibility: versatile gamification, gamification platform, and rigid gamification. Versatile gamification was seen as more feasible compared with the other two approaches. We also examine how game-based mechanics such as competition, rules, graphics, and achievements are used to enrich classroom interaction. It was found that gamification is already popular in the classroom. Follow up interviews with teachers suggested that game is a powerful way to engage students. Good practices in game-based lesson design and potentials for further development of gamification tools are discussed.
Effective Integration of Distance Courses Through Project-Based Learning
Authors: Malyuga Elena N. , Petrosyan Gayane O.
Published: January 2022

The paper aims to single out critical success factors contributing to efficient implementation of distance learning practices and to explain the role of project-based learning in ensuring effective teaching of profession-oriented foreign language in a distance format. The authors argue in favor of distance learning as a beneficial educational tool providing for the training of large groups of people regardless of the place of residence and placing a priority on students’ individual capacities. Study design included a preliminary survey of 150 respondents specializing in the natural sciences and the humanities identifying the key analysis criteria, a complex of experimental online lessons incorporating project-based teaching principles, and a summarizing questionnaire verifying respondents’ post-experiment outlooks. The methodology of empirical research was based on a systematic approach and deployed the methods of pedagogical observation, project-based teaching, sociological research, and statistical analysis using Neural Designer software for calculating questionnaire results. Analyzing the obtained results, the authors conclude that: 1) Students specializing in the humanities have a higher motivation to study related minor subjects; 2) interdisciplinary integration using the English language allows to achieve a cumulative effect for major and related minor subjects; 3) interdisciplinary integration based on the project method is an effective means of improving academic performance in major subjects; 4) interdisciplinary integration based on the project method makes it possible to acquaint students with the best practices in their chosen specialty; 5) project method allows to achieve related didactic goals—self-expression, independent continuous learning and the formation of professional competencies.
The Independent Association of TSH and Free Triiodothyronine Levels With Lymphocyte Counts Among COVID-19 Patients
Authors: Lui David Tak Wai , Lee Chi Ho , Chow Wing Sun , Lee Alan Chun Hong , Tam Anthony Raymond , Pang Polly , Ho Tip Yin , Cheung Chloe Yu Yan , Fong Carol Ho Yi , Law Chun Yiu , To Kelvin Kai Wang , Lam Ching Wan , Tan Kathryn Choon Beng , Woo Yu Cho , Hung Ivan Fan Ngai , Lam Karen Siu Ling
Published: January 2022

Background

Both lymphopenia and thyroid dysfunction are commonly observed among COVID-19 patients. Whether thyroid function independently correlates with lymphocyte counts (LYM) remains to be elucidated.

Methods

We included consecutive adults without known thyroid disorder admitted to Queen Mary Hospital for COVID-19 from July 2020 to April 2021 who had thyroid-stimulating hormone (TSH), free thyroxine (fT4), free triiodothyronine (fT3) and LYM measured on admission.

Results

A total of 541 patients were included. Median LYM was 1.22 x 109/L, with 36.0% of the cohort lymphopenic. 83 patients (15.4%) had abnormal thyroid function tests (TFTs), mostly non-thyroidal illness syndrome (NTIS). Patients with lymphopenia had lower TSH, fT4 and fT3 levels than those without. Multivariable stepwise linear regression analysis revealed that both TSH (standardized beta 0.160, p<0.001) and fT3 (standardized beta 0.094, p=0.023), but not fT4, remained independently correlated with LYM, in addition to age, SARS-CoV-2 viral load, C-reactive protein levels, coagulation profile, sodium levels and more severe clinical presentations. Among the 40 patients who had reassessment of TFTs and LYM after discharge, at a median of 9 days from admission, there were significant increases in TSH (p=0.031), fT3 (p<0.001) and LYM (p<0.001). Furthermore, patients who had both lymphopenia and NTIS were more likely to deteriorate compared to those who only had either one alone, and those without lymphopenia or NTIS (p for trend <0.001).

Conclusion

TSH and fT3 levels showed independent positive correlations with LYM among COVID-19 patients, supporting the interaction between the hypothalamic-pituitary-thyroid axis and immune system in COVID-19.
Clinical Characteristics of COVID-19 Patients in a Regional Population With Diabetes Mellitus: The ACCREDIT Study
Authors: Llanera Daniel Kevin , Wilmington Rebekah , Shoo Haika , Lisboa Paulo , Jarman Ian , Wong Stephanie , Nizza Jael , Sharma Dushyant , Kalathil Dhanya , Rajeev Surya , Williams Scott , Yadav Rahul , Qureshi Zubair , Narayanan Ram Prakash , Furlong Niall , Westall Sam , Nair Sunil
Published: January 2022

Objective

To identify clinical and biochemical characteristics associated with 7- & 30-day mortality and intensive care admission amongst diabetes patients admitted with COVID-19.

Research Design and Methods

We conducted a cohort study collecting data from medical notes of hospitalised people with diabetes and COVID-19 in 7 hospitals within the Mersey-Cheshire region from 1 January to 30 June 2020. We also explored the impact on inpatient diabetes team resources. Univariate and multivariate logistic regression analyses were performed and optimised by splitting the dataset into a training, test, and validation sets, developing a robust predictive model for the primary outcome.

Results

We analyzed data from 1004 diabetes patients (mean age 74.1 (± 12.6) years, predominantly men 60.7%). 45% belonged to the most deprived population quintile in the UK. Median BMI was 27.6 (IQR 23.9-32.4) kg/m2. The primary outcome (7-day mortality) occurred in 24%, increasing to 33% by day 30. Approximately one in ten patients required insulin infusion (9.8%). In univariate analyses, patients with type 2 diabetes had a higher risk of 7-day mortality [p < 0.05, OR 2.52 (1.06, 5.98)]. Patients requiring insulin infusion had a lower risk of death [p = 0.02, OR 0.5 (0.28, 0.9)]. CKD in younger patients (<70 years) had a greater risk of death [OR 2.74 (1.31-5.76)]. BMI, microvascular and macrovascular complications, HbA1c, and random non-fasting blood glucose on admission were not associated with mortality. On multivariate analysis, CRP and age remained associated with the primary outcome [OR 3.44 (2.17, 5.44)] allowing for a validated predictive model for death by day 7.

Conclusions

Higher CRP and advanced age were associated with and predictive of death by day 7. However, BMI, presence of diabetes complications, and glycaemic control were not. A high proportion of these patients required insulin infusion warranting increased input from the inpatient diabetes teams.
Weight and Glycemic Control Outcomes of Bariatric Surgery and Pharmacotherapy in Patients With Melanocortin-4 Receptor Deficiency
Authors: Fojas Esphie Grace Fodra , Radha Saradalekshmi Koramannil , Ali Tomader , Nadler Evan P. , Lessan Nader
Published: January 2022

Background

Melanocortin-4 receptor (MC4R) mutations are the most common of the rare monogenic forms of obesity. However, the efficacy of bariatric surgery (BS) and pharmacotherapy on weight and glycemic control in individuals with MC4R deficiency (MC4R-d) is not well-established. We investigated and compared the outcomes of BS and pharmacotherapy in patients with and without MC4R-d.

Methods

Pertinent details were derived from the electronic database among identified patients who had BS with MC4R-d (study group, SG) and wild-type controls (age- and sex-matched control group, CG). Short- and long-term outcomes were reported for the SG. Short-term outcomes were compared between the two groups.

Results

Seventy patients were screened for MC4R-d. The SG [six individuals (four females, two males); 18 (10–27) years old at BS; 50.3 (41.8–61.9) kg/m2 at BS, three patients with homozygous T162I mutations, two patients with heterozygous T162I mutations, and one patient with heterozygous I170V mutation] had a follow-up duration of up to 10 years. Weight loss, which varied depending on mutation type [17.99 (6.10–22.54) %] was stable for 6 months; heterogeneity of results was observed thereafter. BS was found superior to liraglutide on weight and glycemic control outcomes. At a median follow-up of 6 months, no significant difference was observed on weight loss (20.8% vs. 23.0%, p = 0.65) between the SG and the CG [eight individuals (four females, four males); 19.0 (17.8–36.8) years old at BS, 46.2 (42.0–48.3) kg/m2 at BS or phamacotherapeutic intervention]. Glycemic control in patients with MC4R-d and Type 2 diabetes improved post-BS.

Conclusion

Our data indicate efficacious short-term but varied long-term weight loss and glycemic control outcomes of BS on patients with MC4R-d, suggesting the importance of ongoing monitoring and complementary therapeutic interventions.
Intelligent Control on Urban Natural Gas Supply Using a Deep-Learning-Assisted Pipeline Dispatch Technique
Authors: Zhang Tao , Bai Hua , Sun Shuyu
Published: January 2022

Natural gas has been attracting increasing attentions all around the world as a relatively cleaner energy resource compared with coal and crude oil. Except for the direct consumption as fuel, electricity generation is now another environmentally-friendly utilization of natural gas, which makes it more favorable as the energy supply for urban areas. Pipeline transportation is the main approach connecting the natural gas production field and urban areas thanks to the safety and economic reasons. In this paper, an intelligent pipeline dispatch technique is proposed using deep learning methods to predict the change of energy supply to the urban areas as a consequence of compressor operations. Practical operation data is collected and prepared for the training and validation of deep learning models, and the accelerated predictions can help make controlling plans regarding compressor operations to meet the requirement in urban natural gas supply. The proposed deep neutral network is equipped with self-adaptability, which enables the general adaption on various temporal compressor conditions including failure and maintenance.