bluuebunny/crossref_metadata_2025 huggingface dataset:
Which Inner Ear Disorders Lie Behind a Selective Posterior Semicircular Canal Hypofunction on Video Head Impulse Test?
Authors: Castellucci Andrea , Piras Gianluca , Del Vecchio Valeria , Ferri Gian Gaetano , Ghidini Angelo , Brandolini Cristina
Published: December 2020

Objective:

To assess all different patterns of associated abnormalities on audiometry, bithermal caloric test (BCT) and cervical/ocular vestibular-evoked myogenic potentials (VEMPs) to air/bone-conduction in patients with selective posterior semicircular canal (PSC) hypofunction and to correlate them with underlying disorders.

Study Design:

Retrospective review.

Setting:

Tertiary referral center.

Patients:

51 patients (23 men, 28 women, mean age 57.5 yr) with isolated PSC deficit (one bilateral).

Interventions:

Correlation with instrumental data and underlying diagnoses.

Main Outcome Measures:

Video-oculographic findings, objective measurements on audiometry, BCT, VEMPs and video-head impulse test (vHIT).

Results:

Ongoing or previous acute vestibular loss (AVL) was diagnosed in 13 patients (25.5%, 3 inferior vestibular neuritis, 10 AVL with sudden sensorineural hearing loss [SSNHL]), Meniere's disease (MD) in 12 (23.5%), cerebellopontine angle (CPA) lesion in 9 (17.6%), various causes in 7 (13.7%), benign paroxysmal positional vertigo (BPPV) involving the non-ampullary arm of PSC in 5 cases (9.8%) whereas unknown pathology in 5 (9.8%). Involvement of at least one additional receptor besides PSC was seen in 89.8% of cases. Cochlear involvement was diagnosed in 74.5% with pure-tone average significantly greater in patients with AVL+SSNHL (p < 0.05). Overall involvement of labyrinthine receptors or afferents was highest in patients with AVL+SSNHL (p < 0.01), MD and CPA lesions (p < 0.05).

Conclusions:

Isolated loss of PSC function on vHIT is mostly accompanied by additional labyrinthine deficits that could only be identified through an accurate instrumental evaluation. Assessment of all receptors and afferents should be always pursued to identify the lesion site and better understand the underlying pathophysiological mechanisms.
Comparative Performance of Lateral Wall and Perimodiolar Cochlear Implant Arrays
Authors: Sturm Joshua J. , Patel Vir , Dibelius Greg , Kuhlmey Megan , Kim Ana H.
Published: December 2020

Objective:

The physical shape of cochlear implant (CI) arrays may impact hearing outcomes. The goal of this study was to compare post-operative speech and melody perception between patients with lateral wall (LW) and perimodiolar (PM) electrode arrays across a range of lengths and manufacturers.

Study Design:

Retrospective chart review.

Setting:

Tertiary Care Hospital.

Patients:

119 adult patients with post-lingual hearing loss who underwent cochlear implantation.

Main Outcome Measures:

A total of seven different electrodes were evaluated including 5 different LW electrodes (CI422 [Cochlear American], 1J [Advanced Bionics], Medium [Med El], Standard [Med El], Flex28 [Med El]) and 2 PM electrodes (Contour [Cochlear American], MidScala [Advanced Bionics]). Speech perception outcomes (n = 119 patients) were measured by Consonant-Nucleus-Consonant (CNC) scores collected 3, 6, 12 and 24 months after implantation. Melody perception outcomes (n = 35 CI patients and n = 6 normal hearing patients) were measured by Melodic Contour Identification (MCI).

Results:

CNC scores increased over time after implantation across all array designs. PM designs exhibited higher CNC scores compared to LW electrodes, particularly 6-months after implantation. Pre-operative pure tone averages did not correlate with post-operative CNC scores. PM arrays outperformed LW electrodes in terms of MCI scores.

Conclusions:

The physical shape of cochlear implant electrode arrays may impact hearing performance. Compared to LW designs, PM arrays appear to offer superior speech perception during the first 6 months after implantation, with performance equalizing between groups by 24 months. Compared to LW designs, PM arrays also appear to afford superior melody perception.
When to Refer a Hearing-impaired Patient for a Cochlear Implant Evaluation
Authors: Hunter Jacob B. , Tolisano Anthony M.
Published: December 2020

Objectives:

To explore the predictive value of utilizing routine audiometry to best determine cochlear implant (CI) candidacy using AzBio sentences.

Methods:

A retrospective chart review was performed between 2011 and 2018 for 206 adult patients who underwent CI evaluation assessed with AzBio sentences. Better hearing ear word recognition score (WRS) using Northwestern University-6 word lists presented at decibel hearing level from a standard audiogram was used to determine when best to refer a patient for CI evaluation. Predicted AzBio scores from multivariate regression models were calculated and compared with the actual CI candidacy to assess accuracy of the regression models.

Results:

Race, marital status, hearing aid type, better hearing ear WRS, and HL were all independently and significantly associated with AzBio testing in quiet on univariate analyses. Better hearing ear WRS and better hearing ear decibel hearing level predicted AzBio Quiet on multivariate regression analysis. For AzBio +10 dB signal-to-noise ratio (SNR), sex, and better hearing ear WRS each significantly predicted speech perception testing. Predicted CI candidacy was based on AzBio sentence testing of ≤60% for the ease of statistical analysis. Regression models for AzBio sentence testing in quiet and +10 dB SNR agreed with the actual testing most of the time (85.0 and 87.9%, respectively). A generalized linear model was built for both AzBio testing in quiet and +10 dB SNR.

Conclusion:

A WRS of <60% in the better hearing ear derived from a routine audiogram will identify 83.1% of CI candidates while appropriately excluding 63.8% of patients.
Biomechanical Analysis of Cervical Motion With a Pediatric Immobilization and Extrication Device
Authors: Hontoria Hernández María Isabel , Gordillo Martin Raquel , Juguera Rodriguez Laura , Serrano Martinez Francisco Javier , Alonso Ibañez Lourdes , Rico Berbegal Pablo , Horodyski MaryBeth , Pardo Ríos Manuel
Published: December 2020

Objective

To determine the motions produced during pediatric extrication when using a system of motion estriction and extrication.

Methods

Simulation-based biomechanical analysis study conducted with inertial sensors to measure motion produced in the cervical spine of a pediatric simulator during extrication from a vehicle.

Results

The mean of the movements was 3.5° (SD ±1.35°). The mean time was 4 minutes 1 second (SD, ±45.09 seconds). The mean rotation toward the right was 3.34° (SD ±3.52°) and toward the left 2.62° (SD ±2.26°). The mean for lateralization was 6.24° (SD ±3.20°) toward the right and 2.50° (DE ±2.76°) toward the left. The mean for flexion was 2.36° (SD ±2.10°) and for extension 4.21° (SD ±2.15°).

Conclusions

The device analyzed allows for the extrication of the pediatric patient with high levels of motion restriction of the spinal column with the Pediatric Immobilization and Extrication System.
Mesenchymal Stem/Stromal Cells Increase Cardiac miR-187-3p Expression in a Polymicrobial Animal Model of Sepsis
Authors: Ektesabi Amin M. , Mori Keisuke , Tsoporis James N. , Vaswani Chirag M. , Gupta Sahil , Walsh Chris , Varkouhi Amir K. , Mei Shirley H.J. , Stewart Duncan J. , Liles W. Conrad , Marshall John C. , Hu Pingzhao , Parker Thomas G. , dos Santos Claudia C.
Published: December 2020

Sepsis-induced myocardial dysfunction (MD) is an important pathophysiological feature of multiorgan failure caused by a dysregulated host response to infection. Patients with MD continue to be managed in intensive care units with limited understanding of the molecular mechanisms controlling disease pathogenesis. Emerging evidences support the use of mesenchymal stem/stromal cell (MSC) therapy for treating critically ill septic patients. Combining this with the known role that microRNAs (miRNAs) play in reversing sepsis-induced myocardial-dysfunction, this study sought to investigate how MSC administration alters miRNA expression in the heart. Mice were randomized to experimental polymicrobial sepsis induced by cecal ligation and puncture (CLP) or sham surgery, treated with either MSCs (2.5 × 105) or placebo (saline). Twenty-eight hours post-intervention, RNA was collected from whole hearts for transcriptomic and microRNA profiling. The top microRNAs differentially regulated in hearts by CLP and MSC administration were used to generate a putative mRNA-miRNA interaction network. Key genes, termed hub genes, within the network were then identified and further validated in vivo. Network analysis and RT-qPCR revealed that septic hearts treated with MSCs resulted in upregulation of five miRNAs, including miR-187, and decrease in three top hit putative hub genes (Itpkc, Lrrc59, and Tbl1xr1). Functionally, MSC administration decreased inflammatory and apoptotic pathways, while increasing cardiac-specific structural and functional, gene expression. Taken together, our data suggest that MSC administration regulates host-derived miRNAs production to protect cardiomyocytes from sepsis-induced MD.
Hypobaria Exposure Worsens Cardiac Function and Endothelial Injury in AN Animal Model of Polytrauma: Implications for Aeromedical Evacuation
Authors: Lopez Kerri , Suen Andrew , Yang Yang , Wang Sheng , Williams Brittney , Zhu Jing , Hu Jiang , Fiskum Gary , Cross Alan , Kozar Rosemary , Miller Catriona , Zou Lin , Chao Wei
Published: December 2020

Background:

Aeromedical evacuation can expose traumatically injured patients to low pressure (hypobaria) and hypoxia. Here, we sought to assess the impact of hypobaria on inflammation, organ injury, and mortality in a mouse model of polytrauma.

Methods:

Eight to 12-week-old male C57BL/6J mice were subjected to sham or polytrauma consisting of bowel ischemia by superior mesenteric artery occlusion, hindlimb muscle crush, and tibia fracture. Two hours after injury, animals were randomized to undergo either 6 h of hypobaria or sea-level, room air conditions. At 8 or 24 h after injury, transthoracic echocardiography was performed. Acute kidney injury (AKI) biomarkers were measured by qRT-PCR. Plasma cytokine and endothelial injury markers were determined by enzyme-linked immunosorbent assay.

Results:

Eight hours after traumatic injury, mice exhibited a marked increase in plasma IL-6 (57 pg/mL vs. 1,216 pg/mL), AKI with increased Ngal and Kim-1, and endothelial injury as evidenced by significantly increased plasma hyaluronic acid (96 ng/mL vs.199 ng/mL), thrombomodulin (23.2 ng/mL vs. 58.9 ng/mL), syndecan-1 (0.99 ng/mL vs. 4.34 ng/mL), and E-selectin (38.6 ng/mL vs. 62.7 ng/mL). The trauma mice also developed cardiac dysfunction with decreased cardiac output and stroke volume at 8 h postinjury. Hypobaric exposure after polytrauma led to decreased ejection fraction (81.0% vs. 74.2%, P < 0.01) and increased plasma hyaluronic acid (199 ng/mL vs. 260 ng/mL, P < 0.05), thrombomodulin (58.9 ng/mL vs. 75.4 ng/mL, P < 0.05), and syndecan-1 (4.34 ng/mL vs. 8.33 ng/mL, P < 0.001) at 8 h postinjury.

Conclusions:

Hypobaria exposure appeared to worsen cardiac dysfunction and endothelial injury following polytrauma and thus may represent a physiological “second hit” following traumatic injury.
Enisamium reduces influenza virus shedding and improves patient recovery by inhibiting viral RNA polymerase activity
Authors: Zubkova Tatiana G. , te Velthuis Aartjan J.W. , Shaw Megan , Mehle Andrew , Boltz David , Gmeinwieser Norbert , Stammer Holger , Milde Jens , Müller Lutz , Margitich Victor
Published: December 2020

Infections with respiratory viruses constitute a huge burden on our health and economy. Antivirals against some respiratory viruses are available, but further options are urgently needed. Enisamium iodide (laboratory code FAV00A, trade name Amizon®) is an antiviral marketed in countries of the Commonwealth of Independent States for the treatment of viral respiratory infections, but its clinical efficacy and mode of action are not well understood. Here, we investigated the efficacy of FAV00A in patients aged between 18-60 years with confirmed influenza and other viral respiratory infections. FAV00A treatment resulted in reduced influenza virus shedding (at day 3, 71.2% in FAV00A group tested negative versus 25.0% in placebo group, p < 0.0001), faster patient recovery (at day 14, 93.9% in FAV00A group had recovered versus 32.5 % in placebo group, p < 0.0001), and reduced disease symptoms compared to placebo (from 9.6 ± 0.7 to 4.6 ± 0.9 score points in FAV00A group versus 9.7 ± 1.1 to 5.6 ± 1.1 score points in placebo group, p < 0.0001). Using mass-spectrometry, and cell-based and cell-free viral RNA synthesis assays, we identified a hydroxylated metabolite of FAV00A, VR17-04. VR17-04 is capable of inhibiting influenza virus RNA synthesis and present in plasma of patients treated with FAV00A. VR-17-04 inhibits the activity of the influenza virus RNA polymerase more potently than its parent compound. Overall, these results suggest that FAV00A is metabolized in humans to an inhibitor of the influenza virus RNA polymerase that reduces viral shedding and improves patient recovery in influenza patients.

Clinical data are available on ClincalTrials.gov under NCT04682444.
Recombinant VEGF-C (Cys156Ser) protein restores mesenteric lymphatic drainage and improves gut immune surveillance in experimental liver cirrhosis
Authors: Juneja Pinky , Rahman Syed Nazrin Ruhina , Tripathi Dinesh M , Kaur Impreet , Rohilla Sumati , Gupta Abhishek , Rawal Preety , Baweja Sukriti , Rastogi Archana , Naidu VGM , Sarin Shiv K , Banerjee Subham , Kaur Savneet
Published: December 2020

Background and Aim

Lymphatic vessels (LVs) are crucial for maintaining abdominal fluid homeostasis and immunity. In liver cirrhosis, mesenteric LVs (mLVs) are dilated and dysfunctional. Given an established protective role of VEGF-C in LVs, we hypothesized that VEGF-C treatment could improve functions of mLVs in cirrhosis.

Method

In this study, we developed a nanoformulation comprising LV-specific growth-factor, recombinant human VEGF-C(Cys156Ser) protein(E-VEGF-C) and delivered it orally in rat models of liver cirrhosis to target mLVs. Nanoformulation without VEGF-C served as vehicle. Drainage of mLVs was analyzed using tracer dye. Portal and systemic physiological assessments and computed-tomography were performed to measure portal pressures and ascites. Gene expression of mesenteric lymphatic endothelial cells (LyECs) was studied. Immune cell subsets in mesenteric lymph nodes (MLNs) were quantified by flow-cytometry. Gut bacterial translocation to MLNs was examined using GFP-labelled bacteria.

Results

In cirrhotic rats, mLVs were dilated and leaky with impaired drainage. Treatment with E-VEGF-C induced proliferation of VEGFR3+ mLVs, reduced their diameter and improved functional drainage. Ascites and portal pressures were significantly reduced in E-VEGF-C treated rats compared to vehicle. At molecular level, E-VEGF-C treatment upregulated the expression of cell adhesion and permeability genes (VCAM1, VE-Cad) in LyECs. In MLNs of E-VEGF-C rats, there was an increased percentage of CD8+CD134+ T-cells and decreased CD25+Treg-cells. Bacterial translocation was also limited to MLNs only in E-VEGF-C treated rats with reduced levels of endotoxins in ascites in comparison to vehicle.

Conclusion

E-VEGF-C treatment ameliorates mesenteric lymph drainage, portal pressure, and strengthens cytotoxic immune responses in MLNs in experimental cirrhosis. It may thus serve as a promising therapy to manage ascites and portal pressure and reduce gut bacterial translocation in patients with cirrhosis.

Lay Summary

A human recombinant pro-lymphangiogenic growth factor, VEGF-C, was encapsulated in nanolipocarriers (E-VEGF-C) and orally delivered in rat models of decompensated liver cirrhosis to facilitate its gut lymphatic vessel uptake. E-VEGF-C administration significantly increased mesenteric lymphatic vessel proliferation and improved lymph drainage, attenuating abdominal ascites and portal pressures in the animal models. E-VEGF-C treatment limits bacterial translocation to MLNs only with reduced gut bacterial load and ascitic endotoxins. E-VEGF-C therapy holds the potential to manage ascites and portal pressure and reduce gut bacterial translocation in patients with decompensated cirrhosis.

Graphical Abstract
AIE-nanoparticle assisted ultra-deep microscopy in thein vivomouse brain under 1300-nm excitation
Authors: Li Dong-yu , Zhang He-qun , Streich Lina L. , Lu Ping , Wang Ling , Prevedel Robert , Qian Jun
Published: December 2020

Aggregation-induced emission nanoparticles serve as promising fluorescence probes for multi-photon excitation microscopy due to the large absorption cross-section at NIR-IIb region. Here we present organic AIE nanoparticles that feature high aborption cross-section under three-photon excitation. We show that these enable ultra-deep NIR-IIa excited three-photon imaging in the in-vivo mouse brain.
Aspen leaves as a “chemical landscape” for fungal endophyte diversity – Can nitrogen and herbivory shape the community composition in controlled conditions?
Authors: Witzell Johanna , Decker Vicki Huizu Guo , Agostinelli Marta , Tapia Carmen Romeralo , Cleary Michelle , Albrectsen Benedicte Riber
Published: December 2020

Abstract

The endophytic microbiome may influence the ecological performance of plants, including forest trees. Various abiotic and biotic factors may shape the endophyte communities directly but also indirectly, by modifying the quality of host plants as a substrate. We hypothesized that potentially antifungal or fungistatic condensed tannins (CTs) would determine the quality of aspen (Populus tremula) leaves as a substrate for endophytic fungi. By subjecting the plants to nitrogen fertilization (N) or herbivory (H; leaf beetles) we aimed to change the internal “chemical landscape”, especially the CT levels, in aspen leaves. We expected that this would lead to changes in the fungal community composition, in line with the predictions of heterogeneity-diversity relationship hypothesis. To test this we conducted a greenhouse study where aspen plants were subjected to N and H treatments, individually or in combination. The chemical status of the leaves was analysed using GC/MS (114 metabolites), LC/MS (11 phenolics) and UV-spectrometry (CTs) and the endophytic communities were characterized using culture-dependent sequencing. Nitrogen treatment, alone or in combination with herbivory had a suppressing effect on the concentration and within-treatment variation in the CT precursors, catechins, and resulted in similar trend also in CTs. Nitrogen increased the concentration of certain amino acids, and it also tended to increase most of the analysed sugars sugars. Herbivory had a negligible effect on chemical traits. In N-treated plants, the endophyte richness and abundance were higher than in plants exposed to H, but in general, the diversity of the culturable endophytes remaind stable despite the subtle changes in leaf chemistry.
Macromolecular tissue volume mapping of lateral geniculate nucleus subdivisions in living human brains
Authors: Oishi Hiroki , Takemura Hiromasa , Amano Kaoru
Published: December 2020

The human lateral geniculate nucleus (LGN) is composed mainly of the magnocellular and parvocellular subdivisions. The non-invasive identification of these subdivisions is, however, difficult due to the small size of the LGN. Here we propose a method to identify these subdivisions by combining two structural MR measures: high-resolution proton-density weighted images and macromolecular tissue volume maps. We collected MRI data from 15 healthy subjects and found that the spatial organization of these subdivisions identified by our method was consistent with post-mortem histological data. Furthermore, the stimulus selectivity in these regions measured by functional MRI was consistent with physiological studies. These results suggest that macromolecular tissue volume mapping is a promising approach to evaluating the tissue properties of LGN subdivisions in living humans. This method potentially will enable neuroscientific and clinical hypotheses about the human LGN to be tested.
The neutralization effect of Montelukast on SARS-CoV-2 is shown by multiscalein silicosimulations and combinedin vitrostudies
Authors: Durdagi Serdar , Avsar Timucin , Orhan Muge Didem , Serhatli Muge , Balcioglu Bertan Koray , Ozturk Hasan Umit , Kayabolen Alisan , Cetin Yuksel , Aydinlik Seyma , Bagci-Onder Tugba , Tekin Saban , Demirci Hasan , Guzel Mustafa , Akdemir Atilla , Calis Seyma , Oktay Lalehan , Tolu Ilayda , Butun Yasar Enes , Erdemoglu Ece , Olkan Alpsu , Tokay Nurettin , Işık Şeyma , Ozcan Aysenur , Acar Elif , Buyukkilic Sehriban , Yumak Yesim
Published: December 2020

Small molecule inhibitors have previously been investigated in different studies as possible therapeutics in the treatment of SARS-CoV-2. In the current drug repurposing study, we identified the leukotriene (D4) receptor antagonist Montelukast as a novel agent that simultaneously targets two important drug targets of SARS-CoV-2. We initially demonstrated the dual inhibition profile of Montelukast through multiscale molecular modeling studies. Next, we characterized its effect on both targets by differentin vitroexperiments including the Fluorescent Resonance Energy Transfer (FRET)-based main protease enzyme inhibition assay, surface plasmon resonance (SPR) spectroscopy, pseudovirus neutralization on HEK293T / hACE2, and virus neutralization assay using xCELLigence MP real time cell analyzer. Our integratedin silicoandin vitroresults confirmed the dual potential effect of the Montelukast both on virus entry into the host cell (Spike/ACE2) and on the main protease enzyme inhibition. The virus neutralization assay results showed that while no cytotoxicity of the Montelukast was observed at 12 μM concentration, the cell index time 50 (CIT50) value was delayed for 12 hours. Moreover, it was also shown that Favipiravir, a well-known antiviral used in COVID-19 therapy, should be used by 16-fold higher concentrations than Montelukast in order to have the same effect of Montelukast. The rapid use of new small molecules in the pandemic is very important today. Montelukast, whose pharmacokinetic and pharmacodynamic properties are very well characterized and has been widely used in the treatment of asthma since 1998, should urgently be completed in clinical phase studies and if its effect is proven in clinical phase studies, it should be used against COVID-19.
The mechanism of SARS-CoV-2 nucleocapsid protein recognition by the human 14-3-3 proteins
Authors: Tugaeva Kristina V. , Hawkins Dorothy E. D. P. , Smith Jake L. R. , Bayfield Oliver W. , Ker De-Sheng , Sysoev Andrey A. , Klychnikov Oleg I. , Antson Alfred A. , Sluchanko Nikolai N.
Published: December 2020

The coronavirus nucleocapsid protein (N) controls viral genome packaging and contains numerous phosphorylation sites located within unstructured regions. Binding of phosphorylated SARS-CoV N to the host 14-3-3 protein in the cytoplasm was reported to regulate nucleocytoplasmic N shuttling. All seven isoforms of the human 14-3-3 are abundantly present in tissues vulnerable to SARS-CoV-2, where N can constitute up to ~1% of expressed proteins during infection. Although the association between 14-3-3 and SARS-CoV-2 N proteins can represent one of the key host-pathogen interactions, its molecular mechanism and the specific critical phosphosites are unknown. Here, we show that phosphorylated SARS-CoV-2 N protein (pN) dimers, reconstituted via bacterial co-expression with protein kinase A, directly associate, in a phosphorylation-dependent manner, with the dimeric 14-3-3 protein, but not with its monomeric mutant. We demonstrate that pN is recognized by all seven human 14-3-3 isoforms with various efficiencies and deduce the apparent KDto selected isoforms, showing that these are in a low micromolar range. Serial truncations pinpointed a critical phosphorylation site to Ser197, which is conserved among related zoonotic coronaviruses and located within the functionally important, SR-rich region of N. The relatively tight 14-3-3/pN association can regulate nucleocytoplasmic shuttling and other functions of N via occlusion of the SR-rich region, while hijacking cellular pathways by 14-3-3 sequestration. As such, the assembly may represent a valuable target for therapeutic intervention.

Highlights

SARS-CoV-2 nucleocapsid protein (N) binds to all seven human 14-3-3 isoforms. This association with 14-3-3 strictly depends on phosphorylation of N. The two proteins interact in 2:2 stoichiometry and with the Kd in a μM range. Affinity of interaction depends on the specific 14-3-3 isoform. Conserved Ser197-phosphopeptide of N is critical for the interaction.
The chirality of the mitotic spindle provides a mechanical response to forces and depends on microtubule motors and augmin
Authors: Trupinić Monika , Kokanović Barbara , Ponjavić Ivana , Barišić Ivan , Šegvić Siniša , Ivec Arian , Tolić Iva M.
Published: December 2020

Forces produced by motor proteins and microtubule dynamics within the mitotic spindle are crucial for proper chromosome segregation. In addition to linear forces, rotational forces or torques are present in the spindle, reflected in the left-handed twisted shapes of microtubule bundles that make the spindle chiral. However, the biological role and molecular origins of spindle chirality are unknown. By developing methods for measuring spindle twist, we show that spindles are most chiral near the metaphase-to-anaphase transition. To assess the role of chirality in maintaining spindle robustness under force, we compressed the spindles along their axis. This resulted in stronger left-handed twist, suggesting that the twisted shape allows for a mechanical response to forces. Inhibition or depletion of motor proteins that perform chiral stepping, Eg5/kinesin-5, Kif18A/kinesin-8, MKLP1/kinesin-6, and dynein, decreased the left-handed twist or led to right-handed twist, implying that these motors regulate the twist by rotating microtubules within their antiparallel overlaps or at the spindle pole. Right-handed twist was also observed after the depletion of the microtubule nucleator augmin, indicating its contribution to the twist through the nucleation of antiparallel bridging microtubules. The uncovered switch from left-handed to right-handed twist reveals the existence of competing mechanisms that promote twisting in opposite directions. As round spindles were more twisted than elongated ones, we infer that bending and twisting moments are generated by similar molecular mechanisms and propose a physiological role for spindle chirality in allowing the spindle to absorb mechanical load.
Increased ketohexokinase-A governs fructose-induced podocyte hypertrophy by IL-6/STAT3 signaling activation
Authors: Zhou Jie , Zhang Dong-Mei , Yang Jie , Ding Hong , Li Tu-Shuai , Liu Zhi-Hong , Chen Li , Jiao Rui-Qing , Kong Ling-Dong
Published: December 2020

Glomerular hypertrophy is crucial for podocyte damage and proteinuria. Our previous study showed that fructose induced podocyte injury. However, the molecular mechanism underlying podocyte hypertrophy under fructose is unclear. We observed that fructose significantly initiated the hypertrophy in rat glomeruli and cultured differentiated human podocytes (HPCs). Consistently, it induced inflammatory response with the down-regulation of zinc-finger protein tristetraprolin (TTP) and the activation of interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) signaling in these animal and cell models. Subsequently, high-expression of miR-92a-3p and its target protein cyclin-dependent kinase inhibitor p57 (P57) down-regulation, representing the abnormal proliferation and apoptosis, were observedin vivoandin vitro. Moreover, fructose increased ketohexokinase-A (KHK-A) in rat glomeruli and HPCs. Animal-free recombinant human IL-6, maslinic acid andTTPsiRNA were used to manifest that fructose may decrease TTP to activate IL-6/STAT3 signaling in podocyte overproliferation and apoptosis, causing podocyte hypertrophy.KHK-AsiRNA transfection further demonstrated that the inactivation of IL-6/STAT3 to relieve podocyte hypertrophy mediated by inhibiting KHK-A to increase TTP may be a novel strategy for fructose-associated podocyte injury and proteinuria.

Graphic Abstract
Effect of Cholesterol on Membrane Partitioning Dynamics of Hepatitis A Virus-2B peptide
Authors: Sikdar Samapan , Banerjee Manidipa , Vemparala Satyavani
Published: December 2020

Understanding the viral peptide detection, partitioning and subsequent host membrane composition-based response is required for gaining insights into viral mechanism. Here, we probe the crucial role of presence of membrane lipid packing defects, depending on the membrane composition, in allowing the viral peptide belonging to C-terminal Hepatitis A Virus-2B (HAV-2B) to detect, attach and subsequently partition into the host cell membrane mimics. We conclusively show that the hydrophobic residues in the viral peptide detect the transiently present lipid packing defects, insert themselves into such defects, form anchor points and facilitate the partitioning of the peptide. We also show that the presence of cholesterol significantly alters such lipid packing defects, both in size and in number, thus mitigating the partitioning of the membrane active viral peptide into cholesterol-rich membranes. These results show differential ways in which presence and absence of cholesterol can alter the permeability of the host membranes to the membrane active viral peptide component of HAV-2B virus, via lipid packing defects, and can possibly be a part of general membrane detection mechanism for the viroporin class of viruses.
Precision mapping of the mouse brain metabolome
Authors: Pang Huanhuan , Li Jun-Liszt , Hu Xiao-Ling , Chen Fei , Gao Xiaofei , Zacharias Lauren G. , Cai Feng , DeBerardinis Ralph J. , Sun Wenzhi , Hu Zeping , Ge Woo-ping
Published: December 2020

Metabolism is physiologically fundamental to a biological system. Understanding brain metabolism is critical for our comprehensive knowledge of brain function in health and disease. Combining a microarray collection system with targeted metabolomics analysis, here we performed precision mapping of the metabolome in the mouse brain and created maps for 79 metabolites with a resolution of 0.125mm3per pixel (i.e., brain subregion). The metabolome atlas provides researchers with a useful resource to interpret the vulnerability of specific brain regions to various disease-relevant metabolic perturbations.
Priming of Myelin-Specific T Cells in the Absence of Dendritic Cells Results in Accelerated Development of Experimental Autoimmune Encephalomyelitis
Authors: Luu Thaiphi , Cheung Julie F. , Waldner Hanspeter
Published: December 2020

Experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS), is predominantly mediated by pro-inflammatory CD4+T cell responses to CNS antigens, including myelin proteolipid protein (PLP). Dendritic cells (DCs) are considered critical for inducing T cell responses against infectious agents, but the importance of DCs in priming self-reactive CD4+ T cells in autoimmune disease such as MS has been unclear.

To determine the requirement of DCs in PLP-specific CD4+T cell responses and EAE, we genetically deleted CD11c+DCs in PLP T cell receptor (TCR) transgenic SJL mice constitutively. DC deficiency did not impair the development, selection or the pathogenic function of PLP-specific CD4+T cells in these mice, and resulted in accelerated spontaneous EAE compared to DC sufficient controls. In addition, using a genetic approach to ablate DCs conditionally in SJL mice, we show that CD11c+DCs were dispensable for presenting exogenous or endogenous myelin antigen to PLP-specific T cells and for promoting pro-inflammatory T cell responses and severe EAE. Our findings demonstrate that constitutive or conditional ablation of CD11c+DCs diminished self-tolerance to PLP autoantigen. They further show that in the absence of DCs, non-DCs can efficiently present CNS myelin antigens such as PLP to self-reactive T cells, resulting in accelerated onset of spontaneous or induced EAE.
A computational model for investigating the evolution of colonic crypts during Lynch syndrome carcinogenesis
Authors: Haupt Saskia , Gleim Nils , Ahadova Aysel , Bläker Hendrik , von Knebel Doeberitz Magnus , Kloor Matthias , Heuveline Vincent
Published: December 2020

Lynch syndrome (LS), the most common inherited colorectal cancer (CRC) syndrome, increases the cancer risk in affected individuals. LS is caused by pathogenic germline variants in one of the DNA mismatch repair (MMR) genes, complete inactivation of which causes numerous mutations in affected cells. As CRC is believed to originate in colonic crypts, understanding the intra-crypt dynamics caused by mutational processes is essential for a complete picture of LS CRC and may have significant implications for cancer prevention.

We propose a computational model describing the evolution of colonic crypts during LS carcinogenesis. Extending existing modeling approaches for the non-Lynch scenario, we incorporated MMR deficiency and implemented recent experimental data demonstrating that somaticCTNNB1mutations are common drivers of LS-associated CRCs, if affecting both alleles of the gene. Further, we simulated the effect of different mutations on the entire crypt, distinguishing non-transforming and transforming mutations.

As an example, we analyzed the spread of mutations in the genesAPCandCTNNB1, which are frequently mutated in LS tumors, as well as of MMR deficiency itself. We quantified each mutation’s potential for monoclonal conversion and investigated the influence of the cell location and of stem cell dynamics on mutation spread.

Thein silicoexperiments underline the importance of stem cell dynamics for the overall crypt evolution. Further, simulating different mutational processes is essential in LS since mutations without survival advantages (the MMR deficiency-inducing second hit) play a key role. The effect of other mutations can be simulated with the proposed model. Our results provide first mathematical clues towards more effective surveillance protocols for LS carriers.
Come together: bioelectric healing-on-a-chip
Authors: Zajdel Tom J. , Shim Gawoon , Cohen Daniel J.
Published: December 2020

There is a growing interest in bioelectric wound treatment and electrotaxis, the process by which cells detect an electric field and orient their migration along its direction, has emerged as a potential cornerstone of the endogenous wound healing response. Despite recognition of the importance of electrotaxis in wound healing, no experimental system to date demonstrates that the actual closing of a wound can be accelerated solely by the electrotaxis response itself, and in vivo systems are too complex to resolve cell migration from other healing stages such as proliferation and inflammation. This uncertainty has led to a lack of standardization between stimulation methods, model systems, and electrode technology required for device development. In this paper, we present a ‘healing-on-chip’ approach that is a standardized, low-cost, model for investigating electrically accelerated wound healing. Our device provides the first convergent field geometry used in a stimulation device. We validate this device by using electrical stimulation to close a 1.5 mm gap between two large (30 mm2) primary skin keratinocyte layers to double the rate of healing over an unstimulated tissue. This proves that convergent electrotaxis is both possible and can accelerate healing, and offers a new ‘healing-on-a-chip’ platform to explore future bioelectric interfaces.
SARS-CoV-2 spike glycoprotein S1 induces neuroinflammation in BV-2 microglia
Authors: Olajide Olumayokun A , Iwuanyanwu Victoria U , Adegbola Oyinkansola D , Al-Hindawi Alaa A
Published: December 2020

In addition to respiratory complications produced by SARS-CoV-2, accumulating evidence suggests that some neurological symptoms are associated with the disease caused by this coronavirus. In this study, we investigated the effects of the SARS-CoV-2 spike protein S1 stimulation on neuroinflammation in BV-2 microglia. Analyses of culture supernatants revealed an increase in the production of TNFα, IL-6, IL-1β and iNOS/NO. S1 also increased protein levels of phospho-p65 and phospho-IκBα, as well as enhancing DNA binding and transcriptional activity of NF-κB. These effects of the protein were blocked in the presence of BAY11-7082 (1 μM). Exposure of S1 to BV-2 microglia also increased the protein levels of NLRP3 inflammasome and enhanced caspase-1 activity. Increased protein levels of p38 MAPK was observed in BV-2 microglia stimulated with the spike protein S1 (100 ng/mL), an action that was reduced in the presence of SKF 86002 (1 μM). Results of immunofluorescence microscopy showed an increase in TLR4 protein expression in S1-stimulated BV-2 microglia. Furthermore, pharmacological inhibition with TAK 242 (1 μM) and transfection with TLR4 siRNA resulted in significant reduction in TNFα and IL-6 production in S1-stimulated BV-2 microglia. These results have provided the first evidence demonstrating S1-induced neuroinflammation in BV-2 microglia. We propose that induction of neuroinflammation by this protein in the microglia is mediated through activation of NF-κB and p38 MAPK, possibly as a result of TLR4 activation. These results contribute to our understanding of some of the mechanisms involved in CNS pathologies of SARS-CoV-2.
Reduced complexity of brain and behavior due to MeCP2 disruption and excessive inhibition
Authors: Li Jingwen , Kells Patrick A. , Gautam Shree Hari , Shew Woodrow L.
Published: December 2020

Rett syndrome (RTT) is a devastating neurodevelopmental disorder, caused by disruptions to the MECP2 gene, and resulting in severe cognitive and motor impairment. Previous work strongly suggests that healthy MECP2 function is required to have a normal balance between excitatory and inhibitory neurons. However, the details of how neural circuit dynamics and motor function are disrupted remain unclear. How might imbalanced E/I cause problems for motor function in RTT? We addressed this question in the motor cortex of awake, freely behaving rats, comparing normal rats with a transgenic rat model of RTT. We recorded single-unit spiking activity while simultaneously recording body movement of the rats. We found that RTT rats tend to have excessive synchrony among neurons in the motor cortex and less complex body movements. Importantly, greater synchrony was correlated with greater stereotypy of relationships between neurons and body movements. To further test how our observations were related to an E/I imbalance, we pharmacologically altered inhibitory synaptic interactions. We were able to recapitulate many of the phenomena we found in MECP2-deficient rats by enhancing inhibition in normal rats. Our results suggest that RTT-related E/I imbalance in the motor cortex gives rise to excessive synchrony and, consequently, a stereotyped motor code, which may underlie abnormal motor function in RTT.
Hundreds of motif pairs may facilitate enhancer-promoter interactions
Authors: Wang Saidi , Hu Haiyan , Li Xiaoman
Published: December 2020

Previous studies have shown that pairs of interacting transcription factors (TFs) bind to enhancers and promoters and contribute to their physical interactions. However, to date, we have limited knowledge about these interacting TF pairs. To identify such TF pairs, we systematically studied the co-occurrence of TF-binding motifs in interacting enhancer-promoter (EP) pairs in seven human cell lines. We discovered hundreds of motif pairs that significantly co-occur in enhancers and promoters of interacting EP pairs. We demonstrated that these motif pairs are biologically meaningful and significantly enriched with motif pairs of known interacting TF pairs. We also showed that the identified motif pairs facilitated the discovery of the interacting EP pairs. The predicted motifs and motif pairs are available athttp://www.cs.ucf.edu/~xiaoman/ET/EPmotif/.
IHR-PVS National Bridging Workshops, a tool to operationalize the collaboration between human and animal health while advancing sector-specific goals in countries
Authors: Belot Guillaume , Caya François , Errecaborde Kaylee Myhre , Traore Tieble , Lafia Brice , Skrypnyk Artem , Montabord Djhane , Carron Maud , Corning Susan , Sreedharan Rajesh , Isla Nicolas , Schmidt Tanja , Gongal Gyanendra , Samhouri Dalia , Perez-Gutierrez Enrique , Riviere-Cinnamond Ana , Xing Jun , Chungong Stella , de la Rocque Stephane
Published: December 2020

Collaborative, One Health approaches support governments to effectively prevent, detect and respond to emerging health challenges, such as zoonotic diseases, that arise at the human-animal-environmental interfaces. To overcome these challenges, operational and outcome-oriented tools that enable animal health and human health services to work specifically on their collaboration are required. While international capacity and assessment frameworks such as the IHR-MEF (International Health Regulations - Monitoring and Evaluation Framework) and the OIE PVS (Performance of Veterinary Services) Pathway exist, a tool and process that could assess and strengthen the interactions between human and animal health sectors was needed. Through a series of six phased pilots, the IHR-PVS National Bridging Workshop (NBW) method was developed and refined. The NBW process gathers human and animal health stakeholders and follows seven sessions, scheduled across three days. The outputs from each session build towards the next one, following a structured process that goes from gap identification to joint planning of corrective measures. The NBW process allows human and animal health sector representatives to jointly identify actions that support collaboration while advancing evaluation goals identified through the IHR-MEF and the OIE PVS Pathway. By integrating sector-specific and collaborative goals, the NBWs help countries in creating a realistic, concrete and practical joint road map for enhanced compliance to international standards as well as strengthened preparedness and response for health security at the human-animal interface.
Mechanical alterations of the hippocampus in the APP/PS1 Alzheimer’s disease mouse model
Authors: Antonovaite Nelda , Hulshof Lianne A. , Huffels Christiaan F.M. , Hol Elly M. , Wadman Wytse J. , Iannuzzi Davide
Published: December 2020

There is increasing evidence of altered tissue mechanics in neurodegeneration. However, due to difficulties in mechanical testing procedures and the complexity of the brain, there is still little consensus on the role of mechanics in the onset and progression of neurodegenerative diseases. In the case of Alzheimer’s disease (AD), magnetic resonance elastography (MRE) studies have indicated viscoelastic differences in the brain tissue of AD and healthy patients. However, there is a lack of viscoelastic data from contact mechanical testing at higher spatial resolution. Therefore, we report viscoelastic maps of the hippocampus obtained by a dynamic indentation on brain slices from the APP/PS1 mouse model where individual brain regions are resolved. A comparison of viscoelastic parameters shows that regions in the hippocampus of the APP/PS1 mice are significantly stiffer than wild-type (WT) mice and have increased viscous dissipation. Furthermore, indentation mapping at the cellular scale directly on the plaques and their surroundings did not show local alterations in stiffness although overall mechanical heterogeneity of the tissue was high (SD~40%). Therefore, reported mechanical alterations at a tissue scale indicates global remodeling of the brain tissue structure.
Multi-dimensional transcriptome analysis reveals modulation of cholesterol metabolism as highly integrated response to brain injury
Authors: Gourain Victor , Armant Olivier , Lübke Luisa , Diotel Nicolas , Rastegar Sepand , Strähle Uwe
Published: December 2020

Background

Zebrafish is an attractive model to investigate regeneration of the nervous system. Despite major progress in our understanding of the underlying processes, the transcriptomic changes are largely unknown. We analysed the transcriptome of the regenerating telencephalon for changes in the expression of mRNAs, their splice variants and investigated the putative role of regulatory RNAs in the modulation of these transcriptional changes.

Results

Profound changes in the expression of genes and their splice variants engaged in many distinct processes were observed. As exemplified by the coordinated regulation of the cholesterol synthesizing enzymes and transporters, the genome responded to injury of the telencephalon in a multi-tiered manner with distinct and interwoven changes in expression of enzymes, transporters and their regulatory molecules. This coordinated genomic response involved a decrease of the mRNA of the key transcription factor SREBF2, induction of microRNAs(miR- 182, miR-155, miR-146, miR-31)targeting cholesterol genes, shifts in abundance of splice variants as well as regulation of long non-coding RNAs.

Conclusions

Differential transcription and splicing are important processes in response to injury of the telencephalon. Cholesterol metabolism is switched from synthesis to relocation of cholesterol. Based on ourin silicoanalysis, this switch involves complementary and synergistic inputs by different regulatory principles. Our studies suggest that adaptation of cholesterol metabolism appears to be a key process involved in regeneration of the injured zebrafish brain.
Pharmacoinformatics based elucidation and designing of potential inhibitors againstPlasmodium falciparumto target importin α/β mediated nuclear importation
Authors: Oany Arafat Rahman , Pervin Tahmina , Moni Mohammad Ali
Published: December 2020

Plasmodium falciparum, the prime causative agent of malaria, is responsible for 4, 05,000 deaths per year and fatality rates are higher among the children aged below 5 years. The emerging distribution of the multi-drug resistantP. falciparumbecomes a worldwide concern, so the identification of unique targets and novel inhibitors is a prime need now. In the present study, we have employed pharmacoinformatics approaches to analyze 265 lead-like compounds from PubChem databases for virtual screening. Thereafter, 15 lead-like compounds were docked within the active side pocket of importin alpha. Comparative ligand properties and absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile were also assessed. Finally, a novel inhibitor was designed and assessed computationally for its efficacy. From the comparative analysis we have found that our screened compounds possess better results than the existing lead ivermectin; having the highest binding energy of −15.6 kcal/mol, whereas ivermectin has −12.4kcal/mol. The novel lead compound possessed more fascinating output without deviating any of the rules of Lipinski. It also possessed higher bioavailability and the drug-likeness score of 0.55 and 0.71, respectively compared to ivermectin. Furthermore, the binding study was confirmed by molecular dynamics simulation over 25 ns by evaluating the stability of the complex. Finally, all the screened compounds and the novel compound showed promising ADMET properties likewise. To end, we hope that our proposed screened compounds, as well as the novel compound, might give some advances to treat malaria efficiently in vitro and in vivo.