bluuebunny/crossref_metadata_2025_split huggingface dataset:
Non‐invasive Neuromodulation Using Ultrasound
Authors: Vasan Aditya , Friend James 
Published: April 2020

The discovery of light sensitive proteins led to the development of optogenetics and allowed the precise manipulation of neuronal and non‐neuronal cells. This technique uses particular wavelengths of light to manipulate both neuronal and non‐neuronal cells
[2,
5]. It has enabled the study of information processing in the brain and recent studies are looking into clinical translational applications of the technique
[1]. Despite the advantages offered by optegenetics, it has the drawback of being invasive as light does not penetrate skin past a few millimeters. It is not possible to target deep tissue within the body using this technique and this limits the application in the context of diseases such as Parkinson’s
[3] or heart malfunction
[4].We are developing devices that can non‐invasively manipulate cells using a technique termed “sonogenetics”. This technique uses a combination of engineering cells to be more sensitive to mechanical stimuli as well as developing ultrasound transducers capable of stimulating cells in freely moving, awake mice. We demonstrate the development of miniature transducers made from non‐hysteretic single crystal lithium niobate to be used for the development of sonogenetics. In addition, we o er mathematical insights to the mechanism of action of ultrasound on neurons. Our analysis of membrane deflection enables us to predict cellular activity based on the applied ultrasound stimulus. By extension, we use this analytical framework to inform the development of transducers and stimulation parameters for achieving non‐invasive stimulation of cells.Support or Funding InformationWM Keck FoundationNational Institute of HealthMembrane Deflection and Capacitance Change due to Ultrasounda–d) Membrane deflection due to an ultrasound stimulus, with parameters 7 MHz and 1 MPa pressure. The stimulus is provided for 10 ms, the resulting area change(e) and the capacitance (f) are then calculated from the input parameters. The value of capacitance generated in this model is then used in a Hodgkin‐Huxley neuron model to determine action potential generation.Figure 1a) LN transducer housed in a MMCX coaxial connector designed for long term behavioral studies in awake, freely‐moving mice. b) Device mounted on a mouse skull to be used for characterization using an automated hydrophone setup (c). d)Pressure profile over the transducer face with a 450 mV input results in up to 2 MPa pressures. e) Transducer attached to mouse skull for long term behavioral studies.Figure 2
SPARC: Wireless Fecobionics Device in dogs
Authors: Wang Yanmin , Gregersen Hans , Kassab Ghassan 
Published: April 2020

ObjectiveWe developed a novel wireless device (Fecobionics) for mapping colonic and anorectal neuromuscular function. Fecobionics measures pressures, cross‐sectional areas and bending of the device and transmits data wireless to a receiver unit outside the body (figure
1). This study evaluated the safety of the device in dogs relative to the predicate THD SensyProbe device for biofeedback. Furthermore, physiological data were obtained with Fecobionics.MethodsTwelve male Mongrel dogs with 25kg body weight were assigned into two groups: Fecobionics group and predicate control group (N=6 of each). Fecobionics and the predicate device were transanally inserted into rectum. Further, each group was divided into two sub‐groups: The acute group in which the animals were euthanized immediately after the evacuation of the device, and the chronic group in which the animals were terminated after 2 weeks. The animals were monitored daily. Tissue from different colon segments and anorectum were collected after the dogs were euthanized. HE staining and immunofluorescence staining were performed.ResultsAll procedures were performed successfully without complications. All chronic animals showed normal food intake and behavior after the procedure. Wireless transmission of Fecobionics data were without significant data loss or data error. Fecobionics studies demonstrated defecation pressures in the range 60–100cmH2O. The bending of the device, representative of the anorectal angle, was less than 30 degrees. The shape of the bag was obtained from the serial cross‐sectional area measurements. The shape of Fecobionics was cylindrical in rectum and changed to hourglass shape when it passed through the anal canal. No signs of inflammation were identified in the tissue sections examined histologically or immunohistochemically (macrophages and caspase‐3) in both Fecobionics and control groups.ConclusionsWireless Fecobionics is as safe as the predicate device, without inducing macro‐ or microscopic changes or inflammatory status of anorectal muscle. Novel physiological data were obtained. Dogs seems not to have an anorectal angle like humans, which makes defecatory efficacy more dependent on intrarectal pressure and anal sphincter relaxation compared to humans.Support or Funding InformationFundingNIH SPARC OT2OD025308The Fecobionics device (left), the wireless receiver (middle) and the data collection device (right).Figure 1
A 3D Printable model of pulmonary arteriovenous malformations
Authors: Olson Holly , Rochon Paul 
Published: April 2020

Pulmonary arteriovenous malformations (PAVMs) are vascular anomalies in which there is a direct connection between pulmonary arteries and veins, bypassing the lung capillary bed
(1). The most common cause of PAVMs are congenital, resulting from an autosomal dominant disorder, hereditary hemorrhagic telangiectasia (HHT), causing mutations in proteins important in the vascular signaling pathway
(2). Complications of untreated PAVM include stroke, hypoxemia, dyspnea, platypnea, infections, and anemia
(1,
3). Treatment of PAVMs is most commonly done so via endovascular embolization
(1). When HHT patients develop PAVMs and come to the IR clinic to obtain treatment, they are often anxious about their diagnosis and explaining the anatomy, pathology, and treatment of their disease can present challenges to the physician. The current method of patient education uses the patient’s 2D CT scans along with the physician’s narrative, which the patient may find difficult to follow because they are not trained in reading such medical datasets. We hypothesized that having a patient interact with a 3D‐printed model of PAVM would improve their understanding of the disease and anatomy involved, and decrease their anxiety regarding their diagnosis and treatment. To test this hypothesis, we first created a 3D model using the software 3D Slicer (
www.slicer.org) to segment CT scans from a single patient with multiple, untreated PAVMs. One PAVM was chosen to be segmented for its distinctive feeding artery exiting the pulmonary trunk into these fistula and distinctive vein exiting the fistula and entering the left atrium. The 3D model was then imported into Maya where it was sculpted, artistically adjusted, and enhanced to provide anatomically accurate representation of the chest anatomy applicable to this disease, to then be printed. This novel model of a disease has the potential to decrease patient anxiety prior to the treatment of their PAVM and improve their knowledge on the anatomy and pathology. The effects of HHT patient interaction with the model on the patient’s anxiety levels and understanding of the disease remains to be investigated.CT axial section of PAVM used for segmentationFigure 13D model produced in 3D SlicerFigure 2
Radiofrequency Renal Denervation (RF‐RDN) Ameliorates the Severity of Heart Failure with Preserved Ejection Fraction (HFpEF)
Authors: Hidalgo Hunter A. , Gao Juan , LaPenna Kyle , Haydel Amelia , Kapusta Daniel , Goodchild Traci , Lefer David 
Published: April 2020

BackgroundHeart failure with preserved ejection fraction (HFpEF) is a complex heterogeneous syndrome that results in significant morbidity, repeat hospitalizations, and excessive healthcare expenditures. At present, there are no FDA approved therapies for HFpEF patients. Subtypes of HFpEF have recently been characterized, defining these presentations using phenomapping methodologies. One subtype, termed obesity‐cardiometabolic HFpEF, demonstrates global sympathetic nervous system hyperactivity and metabolic disturbances. The role of the kidney in the pathophysiologic development of these disturbances is significant, suggesting that renal‐based therapies may prove beneficial in HFpEF. Renal denervation (RDN) has been shown to lower blood pressure in the setting of resistant hypertension.MethodsWe investigated obese ZSF‐1 rats (n = 8–10 rats/study group) that underwent either radio‐frequency renal denervation (RF‐RDN) or a sham RF‐RDN surgery. The rats were enrolled at 16 weeks of age and RF‐RDN or sham surgery was performed when the rats were 20 weeks of age followed by a 6 week observation period. We investigated a spectrum of clinically relevant parameters were assessed, including echocardiographic, radiotelemetry, exercise capacity, vascular function, cardiac fibrosis, and metabolic profiling (i.e. glucose tolerance, insulin sensitivity, serum lipids, and obesity).ResultsRats undergoing RF‐RDN treatment exhibited significant improvements in left ventricular (LV) diastolic function according to echocardiographic determination of E/E’ ratio (Figure
). RF‐RDN treatment resulted in a significant improvement in exercise capacity (Figure
). Radiotelemetry recordings shows a significant reduction in systolic blood pressure and a halt in the progression of hypertension (Figure
). Histological evaluation of the hearts revealed attenuation of cardiac fibrosis following RF‐RDN treatment. RF‐RDN therapy failed to exert beneficial effects in terms of obesity, diabetes, or dyslipidemia in the ZSF‐1 obese rat.ConclusionOur findings suggest that RF‐RDN may be a viable option for the treatment of HFpEF by lowering blood pressure, improving cardiac function, and increasing exercise capacity. These findings suggest that this treatment may improve the quality of life in the setting of clinical HFpEF.Support or Funding InformationNational Institutes of General Medical Sciences (NIGMS) COBRE grant no. P30GM106392 to Dr. KapustaA. Diastolic functional measure of E/E’ ratio six weeks after RF‐RDN or sham RF‐RDN surgery. B. Exercise capacity duration six weeks after RF‐RDN or sham RF‐RDN surgery. C. Weekly conscious systolic blood pressure recordings. (*p < 0.05; **p < 0.01)Figure 1
Characterizing mucus‐based biofilms in human Clostridium difficile infection
Authors: Engevik Melinda A. , Danhof Heather A. , Auchtung Jennifer , Endres Bradley T. , Bassères Eugénie T. , Garey Kevin T. , Britton Robert A. , Versalovic James 
Published: April 2020

BackgroundClostridium difficile infection (CDI) is a major nosocomial disease associated with antibiotic use throughout the globe. Limited therapies are available for the treatment of CDI. As a result, understanding the mechanisms of CDI and developing novel therapeutics is a high priority. C. difficile has been observed in the MUC2 mucus layer of mice and patients, indicating that C. difficile may establish a mucus‐related niche and interact with members of the mucus‐associated microbiome. We hypothesized that certain mucus‐associated microbes would promote C. difficile colonization and biofilm formation.Methods & ResultsTo address this hypothesis, we utilized a human centered approach. We found that C. difficile adhered to O‐glycan structures on human MUC2 using mucin‐producing cells lines and human colonoid monolayers. To identify other microbes residing with C. difficile in the mucus layer during infection, we seeded bioreactors with healthy human stool, added antibiotics and C. diffiicle to mirror patient infection. We then inserted human MUC2‐coated coverslips and examined the community structure. 16S rRNA sequencing revealed a unique biofilm profile with substantial co‐colonization with Fusobacterium. Chemotaxis assays revealed that motile C. diffiicle was chemoattracted to Fusobacterium nucleatum subspecies nucleatum, polymorphum, and animalis. We also observed that C. difficile co‐aggregated with all F. nucleatum subspecies; an effect that was mediated by the F. nucleatum adhesin RadD. Moreover, addition of F. nucleatum enhanced C. difficile biofilm formation as denoted by ruby red biofilm staining, crystal violet and SEM. These biofilms were more resistant to standard dispersion methods and the antibiotic vancomycin. Consistent with our biofilm findings, RNAseq data revealed significant changes in C. difficile surface adhesion and antimicrobial resistance genes following exposure to F. nucleatum metabolites. Finally, publicly available datasets and patient stool samples revealed that a subset of patients with C. difficile infection exhibited high levels of Fusobacterium OTUs. C. difficile and F. nucleatum were found to co‐localize by FISH in CDI positive adult stool and pediatric IBD stool, as well as in the mucus layer of CDI patients in surgical resections.ConclusionsTogether, these data demonstrate the unique role of mucus‐associated bacteria such as F. nucleatum in enhancing C. difficile mucus‐associated biofilms.Clostridium difficile adheres to human intestinal MUC2 (left) and aggregates with another mucus‐associated microbe Fusobacterium nucleatum in a RadD dependent manner (right).Figure 1
Genetic Knockout of 3‐Mercaptopyruvate Sulfurtransferase Increases Acute Myocardial Ischemia/Reperfusion Injury in Aged Mice
Authors: Xia Huijing , Li Zhen , Nagahara Noriyuki , Carnal Jean , Lefer David 
Published: April 2020

BackgroundHydrogen Sulfide (H2S) plays important roles in cardiovascular homeostasis. 3‐Mercaptopyruvate sulfurtransferase (3‐MST), one of the endogenous H2S producing enzymes, is abundant in the heart and localized primarily in mitochondria. We hypothesized that the H2S generated by 3‐MST is critical for cardiovascular homeostasis and plays an important role in cardioprotection.MethodMale global 3‐MST KO and wildtype (WT) mice at 12 and 23 weeks of age (n=10–15 per group) were utilized in these studies. Initial studies were performed to evaluate exercise capacity in the 3‐MST KO and WT mice. Subsequently, mice were subjected to 45 minutes of left coronary artery ligation (MI) followed by 24 hours of reperfusion (R). Myocardial infarct size was determined by Evan’s Blue + triphenyltetrazolium chloride (TTC) staining. Blood was collected at 4 hours of reperfusion for troponin‐I measurement.ResultsThe 3‐MST KO mice had significantly reduced exercise capacity compared to WT at both 12 weeks of age (Duration: 47.8 ± 7.6 vs. 70.7 ± 5.9 min; Distance: 848 ± 137 vs. 1261 ± 107 m, p < 0.05) and 23 weeks of age (Duration: 13.1 ± 1.1 vs. 31.9 ± 5.5 min; Distance: 224 ± 21 vs. 562 ± 100 m, p < 0.05), suggesting important roles of 3‐MST in cardiac and/or skeletal muscle mitochondrial function. Interestingly, following MI/R, 3‐MST KO mice at 12 weeks of age exhibited significantly reduced myocardial infarct size as well as plasma troponin‐I levels when compared to WT (Infarct /Area at Risk: 36.9 ± 3.4 % vs. 49.3 ± 3.6%, p < 0.01; Troponin‐I 10.9 ± 1.8 vs. 15.1 ± 0.9 ng/ml, p = 0.05). However, at 23 weeks of age, both myocardial infarct size (64.7 ± 3.2% vs. 57.6 ± 1.5%, p = 0.05) and plasma troponin‐I level (34.8 ± 2.1 vs. 28.7 ± 1.3 ng/ml, p < 0.05) were higher in 3‐MST KO mice compared to WT.ConclusionOur data demonstrate that 3‐MST plays a critical positive role in the physiological response to exercise. Furthermore, despite transient cardioprotective effects of 3‐MST deficiency at a young age, loss of 3‐MST significantly worsens MI/R injury in older animals. 3‐MST appears to play important roles in maintaining cardiac function. Further studies are underway to investigate the molecular mechanisms by which 3‐MST impacts mitochondrial function and cardiovascular homeostasis.Support or Funding InformationNIH/NHLBI R01 HL146098‐01Myocardial infarct size following MI/R in 3‐MST KO and WT mice.Figure 1
New Mechanistic Insights about the Enzyme Cytochrome c nitrite reductase (ccNiR) from studies of the wild type and its variants
Authors: Shahid Shahid , Pacheco A. Andrew 
Published: April 2020

Cytochrome c Nitrite Reductase (ccNiR) is a periplasmic, decaheme homodimeric enzyme that catalyzes the six‐electron reduction of nitrite to ammonia. Under standard assay conditions catalysis proceeds without detected intermediates, and it has been assumed that this is also true in vivo. However, in vitro we have found it possible to trap putative intermediates, or to release partially reduced nitrogen species such as nitric oxide, by controlling the electrochemical potential at which reduction takes place. This poster will present UV‐Vis spectropotentiometric titrations of the active site variants R103Q and H257Q, and steady‐state and stopped‐flow kinetic studies of ccNiR‐catalyzed reduction of nitrite to nitric oxide by the weak reductant N,N,N′,N′‐tetramethyl‐p‐phenylenediamine (TMPD). Wild type nitrite‐loaded ccNiR is reduced chemically or electrochemically at very high potentials (midpoint potential of 246 mV vs SHE) in a concerted 2‐electron process that forms an {FeNO}7 moiety at the active site. By contrast, the H257Q variant’s active site midpoint potential is downshifted to 125 mV vs SHE and is now a 1‐electron reduction to yield an {FeNO}6 moiety. The wild type catalyzes the reduction of nitrite to NO• by TMPD. H257Q does not appear to catalyze this reaction, which may be due to its lower active site midpoint potential or to the much slower turnover of the mutant; studies with more powerful reductants are now under way.Figure 1
High protein diet increases kidney macrophages and accelerates polycystic kidney disease
Authors: Huang Jifeng , Hsu Jung-Shan , Saigusa Takamitsu 
Published: April 2020

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease that leads to end stage renal disease. Interestingly, the disease severity is highly variable even among families with the same gene mutation, suggesting factors other than genetics may affect cystogenesis. One factor that accelerates cystogenesis in PKD rodent is a high protein diet that results in renal hypertrophy. However, the mechanism of how a high protein diet promotes cystogenesis is unknown. We have shown that renal hypertrophy triggered by unilateral nephrectomy increases kidney macrophages and accelerates cystogenesis in ADPKD mouse. Therefore, we hypothesize that a high protein diet fed in ADPKD mice leads to increased kidney macrophages and accelerates cyst growth similar to a unilateral nephrectomy model.MethodsWe used adult tamoxifen inducible Pkd1flox/flox mice with or without Cagg cre‐ER. These adult conditional Pkd1 knockout mice typically requires months to develop major kidney cysts. Three weeks after cre induction, mice were fed with either a high protein (HP: 60%), a normal protein (NP: 18%) or a low protein (LP: 6%) diet for a total of 1 and 6 weeks. Some mice were given a HP diet and treated either with liposomal clodronate (to deplete macrophage) or with PBS (IP twice a week) for a total of 6 weeks. All mice were sacrificed at the end of the experiment and kidneys were harvested for histology, cytokines and flow cytometry for kidney immune cell sorting.ResultsPkd1 mice fed a HP diet for 6 weeks resulted in increased number of kidney resident macrophage (CD11blo, F4/80 hi) and infiltrating macrophages (CD11bhi, F4/80lo) compared to kidneys from a NP or LP diet fed mice. A HP diet resulted in increased kidney pro‐inflammatory cytokines, chemokine and developed severe kidney cysts compared to a NP or LP diet group. Pkd1 mice treated with liposomal clodronate had fewer resident and infiltrating macrophages and smaller kidneys compared to control PBS treated group. Interestingly, mice fed a HP diet for 1 week already had larger kidneys compared to those fed a LP diet, but there were no differences in kidney chemokines or tubular injury marker.ConclusionsRenal hypertrophy triggered by a HP diet increases kidney macrophages, inflammatory cytokine production and promotes cyst growth in adult Pkd1 mice. The mechanism of how dietary protein initiates and accelerates cyst growth remains to be determined.Support or Funding InformationNIH/NIDDK K08 DK106465, R03 DK119717 PKD Foundation 232G19a
The Role of FAT10 in Alcoholic Hepatitis Pathogenesis
Authors: Jia Yue , French Sameul W. 
Published: April 2020

BackgroundMorphologic features of Alcoholic Hepatitis (AH) balloon cells forming Mallory‐Denk bodies and bile duct metaplasia are two morphologic features consistently being found in AH. Increased FAT10 expression may induce increasing mitotic non‐disjunction and chromosome instability leading to tumorigenesis. FAT10 expression is highly up‐regulated by pro‐inflammatory cytokines IFNγ and TNFα in all cell types and tissues.ObjectiveTo clarify the role of FAT10 in alcoholic hepatitis pathogenesis, we studied FAT10 expression in liver biopsy samples from patients with AH.MethodsWe use gene and protein array to detect the potential changes during alcoholic hepatitis pathogenesis. The potential target, FAT10, were tested at protein expression level by using western blot, immunofluorescent (IF) staining and quantitation. And FAT10 was also studied by using knockout animal models.ResultsThe results show that FAT10 is essential to maintain the function of liver cell protein quality control and Mallory‐Denk body (MDB) formation. This is consistent with the finding with fat10−/− mice which fail to form MDBs. FAT10 also signals a switch in the 26s proteasome’s proteases to cause the proteins accumulation, overexpression, and then forming MDBs. FAT10 overexpression in AH causes an extensive change in protein content in the liver leading to balloon degeneration and MDB aggregation formation, all of which is prevented in fat10−/− mice. The pathway that increases FAT10 expression includes TNFα, IFNγ, followed by NFκB and STAT3, which were all up‐regulated in AH. Using proteins expression quantitation by measuring the intensity of immunofluorescent (IF) staining, it showed the FAT10 protein expression was 4.5 fold increased in the AH livers but not in the NASH or control livers.DiscussionMilk thistle derivatives were used to treat FAT10 overexpression experimentally. Flavanone derivatives of milk thistle inhibit IFNγ/TNFα, NFκB and STAT3 then inhibits the expression of FAT10. NFκB is the key nodal hub of the IFNα/TNFα‐response genes. Silibinin derived from milk thistle is reported to be a powerful antioxidant and has anti‐carcinoma effects including against TNFα‐induced tumor growth. Studies on Silibinin or other milk thistle derivatives to treat AH confirms that overexpressed FAT10 with NFκB and TNFα are the major key nodal molecules in these networks.ConclusionOverexpressed FAT10 with over‐activated NFκB and TNFα are the major key nodal molecules in alcoholic hepatitis pathogenesis. These molecules might be potential therapeutic targets.