bluuebunny/crossref_metadata_2025 huggingface dataset:
How D-type H ii region expansion depends on numerical resolution
Authors: Pittard J M , Kupilas M M , Wareing C J
Published: December 2021

We investigate the resolution dependence of H ii regions expanding past their Strömgren spheres. We find that their structure and size, and the radial momentum that they attain at a given time, is in good agreement with analytical expectations if the Strömgren radius is resolved with $dr \le 0.3\, R_{\rm st}$. If this is not satisfied, the radial momentum may be over- or underestimated by factors up to 10 or more. Our work has significance for the amount of radial momentum that a H ii region can impart to the ambient medium in numerical simulations, and thus, on the relative importance of ionizing feedback from massive stars.
Momentum deposition of supernovae with cosmic rays
Authors: Rodríguez Montero Francisco , Martin-Alvarez Sergio , Sijacki Debora , Slyz Adrianne , Devriendt Julien , Dubois Yohan
Published: December 2021

The cataclysmic explosions of massive stars as supernovae are one of the key ingredients of galaxy formation. However, their evolution is not well understood in the presence of magnetic fields or cosmic rays (CRs). We study the expansion of individual supernova remnants (SNRs) using our suite of 3D hydrodynamical (HD), magnetohydrodynamical (MHD) and CRMHD simulations generated using ramses. We explore multiple ambient densities, magnetic fields, and fractions of supernova energy deposited as CRs (χCR), accounting for CR anisotropic diffusion and streaming. All our runs have comparable evolutions until the end of the Sedov-Taylor phase. However, our CRMHD simulations experience an additional CR pressure-driven snowplough phase once the CR energy dominates inside the SNR. We present a model for the final momentum deposited by supernovae that captures this new phase: $p_{\rm SNR} = 2.87\times 10^{5} (\chi _{\text{CR}} + 1)^{4.82}\left(\frac{n}{\text{cm}^{-3}}\right)^{-0.196} M_{\odot }$ km s−1. Assuming a 10 per cent fraction of SN energy in CRs leads to a 50 per cent boost of the final momentum, with our model predicting even higher impacts at lower ambient densities. The anisotropic diffusion of CRs assuming an initially uniform magnetic field leads to extended gas and CR outflows escaping from the supernova poles. We also study a tangled initial configuration of the magnetic field, resulting instead in a quasi-isotropic diffusion of CRs and earlier momentum deposition. Finally, synthetic synchrotron observations of our simulations using the polaris code show that the local magnetic field configuration in the interstellar medium modifies the overall radio emission morphology and polarization.
Anti-Ro/SS-A antibody is associated with worse pulmonary outcome and reduced overall survival in systemic sclerosis
Authors: Meridor Katya , Sagy Iftach , Molad Yair
Published: December 2021

Objective

We sought to determine the association of anti-Ro/SS-A antibody with organ involvement and disease outcome in patients with systemic sclerosis (SSc).

Methods

A retrospective, long-term study of a cohort of incident patients diagnosed with SSc and continuously followed at our rheumatology clinic during 1990–2018.

Results

Included were 105 patients with known anti-Ro/SS-A antibody status, 92.4% female, mean age at diagnosis 52.0 ± 15.6 years, and median follow-up of 10 years; 64% were diagnosed with limited cutaneous SSc, 18% with diffuse cutaneous SSc, and 18% had SSc siné scleroderma or undetermined disease type. Anti-Ro/SS-A antibody tested positive in 21% of patients. In univariate analysis, anti-Ro/SS-A antibody positivity was significantly associated with SSc overlap with Sjögren’s syndrome (p < .001). Predicted forced vital capacity deterioration at last encounter was significantly associated with anti-Ro/SS-A antibody positivity. In multivariate regression for anti-Ro/SS-A antibody-positive SSc patients and disease outcome [adjusted for age > 50 years, smoking, and baseline predicted forced vital capacity (pFVC) < 80%], positive anti-Ro/SS-A antibody was significantly associated with a higher all-cause mortality rate (HR 5.17, CI 95%, 1.18–22.67, p = .029), and greater deterioration of pFVC defined as a decrement of last available pFVC compared to first available pFVC of ≥10% (HR 3.65, CI 95%, 1.07–12.38, p = .038).

Conclusions

Anti-Ro/SS-A antibody is an independent risk factor for worse pulmonary outcome and higher all-cause mortality in patients with SSc.
Expression of pluripotency-related genes in human glioblastoma
Authors: Rios Álvaro Fabrício Lopes , Tirapelli Daniela Pretti da Cunha , Cirino Mucio Luiz de Assis , Rodrigues Andressa Romualdo , Ramos Ester S , Carlotti Carlos Gilberto
Published: December 2021

Background

Cancer is a group of heterogeneous diseases characterized by several disruptions of the genetic and epigenetic components of cell biology. Some types of cancer have been shown to be constituted by a mosaic of cells with variable differentiation states, with more aggressive tumors being more undifferentiated. In most cases, undifferentiated tumor cells express associated embryonic markers such as the OCT4, NANOG, SOX2, and CARM1 genes. The ectopic or reminiscent expression of some master regulator genes of pluripotency has been indicated as the cause of the poorly differentiated state of tumors, and based on the evidence of some reports, can be used as a possible therapeutic target. Considering this information, a more detailed investigation of the expression of pluripotency-associated genes is necessary to evaluate the roles of these genes in the etiology of some tumors and their use targets of therapy.

Methods

The expression of four pluripotency-related genes was investigated (OCT4, NANOG, SOX2, and CARM1) in the most malignant primary human brain tumor, glioblastoma (GBM).

Results and Conclusion

The results demonstrated a signature of OCT4/SOX2/CARM1 genes and a significant increase of CARM1 expression in GBM cases.
Currency Choice in Contracts
Authors: Drenik Andres , Kirpalani Rishabh , Perez Diego J
Published: December 2021

We study the interaction between the currency choice of private domestic contracts and optimal monetary policy. The optimal currency choice depends on the price risk of each currency, as well as on the covariance of its price and the relative consumption needs of the agents signing the contract. When a larger share of contracts is denominated in local currency, the government can use inflation more effectively to either redistribute resources or reduce default costs, which makes local currency more attractive for private contracts. When governments lack commitment, competitive equilibria can be constrained inefficient, thus providing a reason to regulate the currency choice of private contracts. We show that both the equilibrium use of local currency and the implications for regulation depend on the level of domestic policy risk. Our model can explain the wide use of the US dollar in international trade contracts and the observed hysteresis in dollarization.
Perioperative Hidden Blood Loss in Lumbar Disk Herniation Patients With Percutaneous Endoscopic Transforaminal Discectomy and Influencing Factors
Authors: Hu Man , Zhang Yu , Zhao Wen Jie , Liu Xin , Shi Peng Zhi , Wang Jun Wu , Cai Tong Chuan , Zhang Liang
Published: December 2021

Study Design:

This was a retrospective study.

Objectives:

This study aimed to evaluate hidden blood loss (HBL) and its influencing factors in lumbar disk herniation (LDH) patients treated with percutaneous endoscopic transforaminal discectomy (PETD).

Summary of Background Data:

PETD is a minimally invasive spine surgery and is widely used to treat LDH. It is generally believed that there is less bleeding during PETD. However, HBL during the perioperative period is always ignored.

Materials and Methods:

From January 2018 to March 2021, 74 LDH patients treated with PETD was selected. The patient’s sex, age, height, weight, previous medical history (hypertension and diabetes) and other basic information were recorded. The preoperative fibrinogen (FIB) level, activated partial thromboplastin time and prothrombin time were recoded. The hemoglobin, hematocrit, and platelet immediately after admission and the next day postoperative were recorded. The surgical time, intraoperative blood loss, intervertebral disk degeneration grade and soft tissue thickness of the PETD approach were recorded. The total blood loss was calculated according to the Gross formula, and then HBL was calculated based on total blood loss and visible blood loss (VBL). The influencing factors were analyzed by single factor correlation analysis and multivariate linear regression analysis.

Results:

Among the 74 patients, there were 34 males (20–68 y old) and 40 females (26–75 y old). The mean amount of VBL was (85.04±26.53) mL and HBL was (341.04±191.15) mL. There were statistically significant differences between HBL and VBL (P=0.000). Multiple linear regression analysis showed that sex (P=0.000), disk degeneration grade (P=0.000), preoperative FIB level (P=0.022) and preoperative platelet (P=0.026) were independent risk factors that contributed to HBL, but age (P=0.870), BMI (P=0.480), hypertension (P=0.867), diabetes (P=0.284), soft tissue thickness (P=0.701), preoperative prothrombin time (P=0.248) and preoperative activated partial thromboplastin time (P=0.521) were not.

Conclusions:

There was a large amount of HBL during the perioperative period of PETD in patients with LDH. Sex, disk degeneration grade, preoperative FIB level and preoperative platelet are the independent risk factors of HBL in the perioperative period of PETD. More attention should be paid to the patients with risk factors to ensure perioperative safety.
Patients With Preoperative Cervical Deformity Experience Similar Clinical Outcomes to Those Without Deformity Following 1–3 Level Anterior Cervical Decompression and Fusion
Authors: Karamian Brian A. , Mao Jennifer Z. , Viola Anthony , Ju Derek G. , Canseco Jose A. , Toci Gregory R. , Bowles Daniel R. , Reiter David M. , Semenza Nicholas C. , Woods Barrett I. , Lee Joseph K. , Hilibrand Alan S. , Kaye I. David , Kepler Christopher K. , Vaccaro Alexander R. , Schroeder Gregory D.
Published: December 2021

Study Design:

Retrospective cohort study.

Objective:

The aim was to compare the outcomes of patients with incompletely corrected cervical deformity against those without deformity following short-segment anterior cervical decompression and fusion for clinically significant radiculopathy or myelopathy.

Summary of Background Data:

Cervical deformity has increasingly been recognized as a driver of disability and has been linked to worse patient-reported outcomes measures (PROMs) after surgery.

Methods:

Patients 18 years or above who underwent 1–3 level anterior cervical decompression and fusion to address radiculopathy and/or myelopathy at a single institution between 2014 and 2018 with at least 1 year of PROMs were reviewed. Patients were categorized based on cervical deformity into 2 groups: sagittal vertebral axis (cSVA) ≥40 mm as the deformity group, and cSVA <40 mm as the nondeformity group. Patient demographics, surgical parameters, preoperative and postoperative radiographs, and minimum 1-year PROMs were compared.

Results:

Of the 230 patients, 191 (83%) were in the nondeformity group and 39 (17%) in the deformity group. Patients with deformity were more likely to be male (69.2% vs. 40.3%, P<0.001) and have a greater body mass index (32.8 vs. 29.7, P=0.028). The deformity group had significantly greater postoperative cSVA (44.2 vs. 25.1 mm, P<0.001) but also had significantly greater ∆cSVA (−4.87 vs. 0.25 mm, P=0.007) than the nondeformity group. Both groups had significant improvements in visual analog scale arm, visual analog scale neck, Short-Form 12 Physical Component Score, and neck disability index (NDI) (P<0.001). However, the deformity group experienced significantly greater ∆NDI and ∆mental component score (MCS)-12 scores (−19.45 vs. −11.11, P=0.027 and 7.68 vs. 1.32, P=0.009).

Conclusions:

Patients with preoperative cervical sagittal deformity experienced relatively greater improvements in NDI and MCS-12 scores than those without preoperative deformity. These results suggest that complete correction of sagittal alignment is not required for patients to achieve significant clinical improvement.

Level of Evidence:

III.
Predictive value of hypothermic machine perfusion parameters combined perfusate biomarkers in deceased donor kidney transplantation
Authors: Qiao Yuxi , Ding Chenguang , Li Yang , Tian Xiaohui , Tian Puxun , Ding Xiaoming , Xiang Heli , Zheng Jin , Xue Wujun
Published: December 2021

Background:

Delayed graft function (DGF) is the main cause of renal function failure after kidney transplantation. This study aims at investigating the value of hypothermic machine perfusion (HMP) parameters combined with perfusate biomarkers on predicting DGF and the time of renal function recovery after deceased donor (DD) kidney transplantation.

Methods:

HMP parameters, perfusate biomarkers and baseline characteristics of 113 DD kidney transplantations from January 1, 2019 to August 31, 2019 in the First Affiliated Hospital of Xi’an Jiaotong University were retrospectively analyzed using univariate and multivariate logistic regression analysis.

Results:

In this study, the DGF incidence was 17.7% (20/113); The multivariate logistic regression results showed that terminal resistance (OR: 1.879, 95% CI 1.145–3.56) and glutathione S-transferase (GST)(OR = 1.62, 95% CI 1.23–2.46) were risk factors for DGF; The Cox model analysis indicated that terminal resistance was an independent hazard factor for renal function recovery time (HR = 0.823, 95% CI 0.735–0.981). The model combining terminal resistance and GST (AUC = 0.888, 95% CI: 0.842–0.933) significantly improved the DGF predictability compared with the use of terminal resistance (AUC = 0.756, 95% CI 0.693–0.818) or GST alone (AUC = 0.729, 95% CI 0.591–0.806).

Conclusion:

According to the factors analyzed in this study, the combination of HMP parameters and perfusate biomarkers displays a potent DGF predictive value.
A syngeneic inoculation mouse model of endometriosis that develops multiple comorbid visceral and cutaneous pain like behaviours
Authors: Maddern Jessica , Grundy Luke , Harrington Andrea , Schober Gudrun , Castro Joel , Brierley Stuart M.
Published: December 2021

Endometriosis is a chronic and debilitating condition, commonly characterised by chronic pelvic pain (CPP) and infertility. Chronic pelvic pain can be experienced across multiple pelvic organs, with comorbidities commonly effecting the bowel, bladder, and vagina. Despite research efforts into endometriosis pathophysiology, little is known about how endometriosis induces CPP, and as such, therapeutic interventions are lacking. The aim of this study was to characterise a syngeneic mouse model of endometriosis that mimics naturally occurring retrograde menstruation, thought to precede endometriosis development in patients, and determine whether these mice exhibit signs of CPP and altered behaviour. We characterised the development of endometriosis over 10 weeks following uterine tissue inoculation, measured in vivo and ex vivo hypersensitivity to mechanical stimuli across multiple visceral organs, and assessed alterations in animal spontaneous behaviour. We confirmed that inoculated uterine horn tissue formed into endometriosis lesions throughout the peritoneal cavity, with significant growth by 8 to 10 weeks post inoculation. Additionally, we found that mice with fully developed endometriosis displayed hypersensitivity evoked by (1) vaginal distension, (2) colorectal distension, (3) bladder distension, and (4) cutaneous thermal stimulation, compared to their sham counterparts. Moreover, endometriosis mice displayed alterations in spontaneous behaviour indicative of (5) altered bladder function and (6) anxiety. This model creates a foundation for mechanistical studies into the diffuse CPP associated with endometriosis and the development of targeted therapeutic interventions to improve the quality of life of women with endometriosis.
Purinergic signaling between neurons and satellite glial cells of mouse dorsal root ganglia modulates neuronal excitability in vivo
Authors: Chen Zhiyong , Huang Qian , Song Xiaodan , Ford Neil C. , Zhang Chi , Xu Qian , Lay Mark , He Shao-Qiu , Dong Xinzhong , Hanani Menachem , Guan Yun
Published: December 2021

Primary sensory neurons in dorsal root ganglia (DRG) are wrapped by satellite glial cells (SGCs), and neuron-SGC interaction may affect somatosensation, especially nociceptive transmission. P2-purinergic receptors (P2Rs) are key elements in the two-way interactions between DRG neurons and SGCs. However, because the cell types are in such close proximity, conventional approaches such as in vitro culture and electrophysiologic recordings are not adequate to investigate the physiologically relevant responses of these cells at a population level. Here, we performed in vivo calcium imaging to survey the activation of hundreds of DRG neurons in Pirt-GCaMP6s mice and to assess SGC activation in GFAP-GCaMP6s mice in situ. By combining pharmacologic and electrophysiologic techniques, we investigated how ganglionic purinergic signaling initiated by α,β-methyleneadenosine 5′-triphosphate (α,β-MeATP) modulates neuronal activity and excitability at a population level. We found that α,β-MeATP induced robust activation of small neurons—likely nociceptors—through activation of P2X3R. Large neurons, which are likely non-nociceptive, were also activated by α,β-MeATP, but with a delay. Blocking pannexin 1 channels attenuated the late phase response of DRG neurons, indicating that P2R stimulation may subsequently induce paracrine ATP release, which could further activate cells in the ganglion. Moreover, ganglionic α,β-MeATP treatment in vivo sensitized small neurons and enhanced responses of spinal wide-dynamic-range neurons to subsequent C-fiber inputs, suggesting that modulation via ganglionic P2R signaling could significantly affect nociceptive neuron excitability and pain transmission. Therefore, targeting functional P2Rs within ganglia may represent an important new strategy for pain modulation.
The Principles and Practice of Primary Endonasal Rhinoplasty
Authors: Albert Mark G. , Constantian Mark B.
Published: December 2021

The purpose of this article is to provide a guide for plastic surgeons, regardless of experience level, seeking to improve his/her endonasal rhinoplasty skills and comfort level. We have presented the advantages of our technique and its unifying principles and demonstrated how endonasal rhinoplasty can be used to achieve safe, anatomical, and predictable outcomes. Endonasal rhinoplasty is a separate thought process from open rhinoplasty and should not be viewed as a competing but rather parallel technique that is broadly applicable to many nasal deformities.

We have described the basic goals of all rhinoplasties and highlighted 2 false assumptions that are responsible for most adverse rhinoplasty outcomes and 4 anatomical deficits that surgeons must recognize preoperatively to maximize function, proportion, and contour. Finally, the majority of primary rhinoplasties can be performed with 1 of 2 operative strategies that depend on the relationship of the dorsum to the lower nose. Because surgeons often presume that they will not be able to “see well enough” in endonasal rhinoplasty or worry they have not been adequately trained in the technique, we have provided a step-by-step guide to help overcome such fears and help these surgeons to achieve results that will exceed their patients' goals.
The Effect of Udenafil on Stasis Zone in an Experimental Burn Model
Authors: Ural Alper , Bilgen Fatma , Altıntaş Aykan Duygun , Koçarslan Sezen , Altıntaş Ural Dilan , Seyithanoğlu Muhammet , Bekerecioğlu Mehmet
Published: December 2021

Background

Management of the burn injuries is still a problematic issue because the stasis zone may become necrotic. We hypothesized that udenafil, a potent phospodiesterase inhibitor, can be beneficial in burn treatment by enhancing the viability of the stasis zone.

Methods

Fifteen Wistar rats were randomly divided into 3 groups. Comb burn injury model was conducted bilaterally on the back of rats in each subject. Group 1 received 1 mL/d of saline orally for 7 days. Group 2 received 10 mg/kg per day of udenafil for 7 days. Group 3 received 20 mg/kg per day of udenafil for 7 days. At the end of seventh day, gross morphological and histopathological samples of stasis zone survival were evaluated.

Results

Histopathological examination of groups 2 and 3 revealed that the stasis zone was mostly viable. The mean necrotic area and severity of inflammation was significantly higher in the control group compared with the treatment groups. Significant differences were determined in treatment groups compared with control group in terms of vital stasis zone area and histopathological parameters.

Conclusions

Udenafil treatment improved tissue survival on zone of stasis in. Future experimental studies should be conducted to develop zone of stasis treatment protocols combining udenafil with potent anti-inflammatory and antioxidant drugs.
Bounds on quantum information storage and retrieval
Authors: Dvali Gia
Published: December 2021

We present certain universal bounds on the capacity of quantum information storage and on the time scale of its retrieval for a generic quantum field theoretic system. The capacity, quantified by the microstate entropy, is bounded from above by the surface area of the object measured in units of a Goldstone decay constant. The Goldstone bosons are universally present due to the spontaneous breaking of Poincare and internal symmetries by the information-storing object. Applied to a black hole, the bound reproduces the Bekenstein–Hawking entropy. However, the relation goes beyond gravity. The minimal time-scale required for retrieving the quantum information from a system is equal to its volume measured in units of the same Goldstone scale. For a black hole, this reproduces the Page time as well as the quantum break-time. Again, the expression for the information retrieval time is very general and is shared by non-gravitational saturated states in gauge theories including QCD. All such objects exhibit universal signatures such as the emission of ultra-soft radiation. Similar bounds apply to non-relativistic many-body systems.

This article is part of the theme issue ‘Quantum technologies in particle physics’.
Single Amino Acid Change Mutation in the Hydrophobic Core of the N-terminal Domain of P22 TSP affects the Proteins Stability
Authors: Ayariga Joseph A. , Villafane Robert
Published: December 2021

The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has significantly shifted the attention of researchers to critically investigate most viruses to understand specific characteristics that impart their virulence. For instance, the SARS-CoV-2 has undergone several mutations, with some variants classified as “variants of concern”, e.g., the Omicron and Delta variant of SARS-CoV-2 are known for their rapid transmission and antigenicity due to mutation in the Spike protein. P22 bacteriophage is a bacterial virus that has a tailspike protein (TSP) that performs similar functions as the Spike protein of SARS-COV-2. We previously carried out a site-directed mutagenesis of the P22 TSP to bear disruptive mutations in the hydrophobic core of the N-terminal Domain (NTD), then partially characterized the properties of the mutant TSPs. In this process, the valine patch (triple valine residues that formed a hydrophobic core) was replaced with charged amino acids (Asp or lysine) or hydrophobic amino acids (Leucine or isoleucine). Some of the mutant TSPs characterized showed significant differences in migration in both native and SDS-PAGE. Mutants with such disruptive mutation are known to show non-native properties, and as expected, most of these mutants obtained showed significantly different properties from the WT P22 TSP. In this work, we further characterized these mutant species by computational and in vitro assays to demonstrate the validity of our previous inference that the valine patch is a critical player in the stability of the N-terminal domain of the P22 TSP.
anndata: Annotated data
Authors: Virshup Isaac , Rybakov Sergei , Theis Fabian J. , Angerer Philipp , Wolf F. Alexander
Published: December 2021

anndata is a Python package for handling annotated data matrices in memory and on disk (github.com/theislab/anndata), positioned between pandas and xarray. anndata offers a broad range of computationally efficient features including, among others, sparse data support, lazy operations, and a PyTorch interface.

Statement of need

Generating insight from high-dimensional data matrices typically works through training models that annotate observations and variables via low-dimensional representations. In exploratory data analysis, this involvesiterativetraining and analysis using original and learned annotations and task-associated representations. anndata offers a canonical data structure for book-keeping these, which is neither addressed by pandas (McKinney, 2010), nor xarray (Hoyer & Hamman, 2017), nor commonly-used modeling packages like scikit-learn (Pedregosa et al., 2011).
Well-Lit: A programmable and customizable assistant for manual multi-well plate pipetting
Authors: Gómez-Sjöberg Rafael , Cabrera Joana P. , Cote Andrew T.
Published: December 2021

A very large number of biology and biochemistry laboratory protocols require transferring liquid aliquots from individual containers into individual wells of a multi-well plate, from plates to individual containers, or from one plate to another. Doing this by hand without errors, such as skipping wells, placing two samples in the same well, or swapping sample locations, especially when using plates with 96 wells or more, is difficult and requires enormous operator focus and/or a tedious manual error checking system. We present here a device built to facilitate error-free pipetting of samples from individual barcoded tubes to a multi-well plate or between multi-well plates (both 96 and 384 wells are supported). The device is programmable, modular and easily customizable to accommodate plates with different form-factors, and different protocols. The main components are only a 12.3” touch screen, a small form-factor PC, and a barcode scanner, combined with custom-made parts can be easily fabricated with a laser cutter and a hobby-grade 3D printer. The total cost is between approximately US$550 and US$600, depending on the configuration.

Specifications table
Pre-clinical evaluation of antiviral activity of nitazoxanide against Sars-CoV-2
Authors: Driouich Jean-Sélim , Cochin Maxime , Touret Franck , Petit Paul-Rémi , Gilles Magali , Moureau Grégory , Barthélémy Karine , Laprie Caroline , Wattanakul Thanaporn , Chotsiri Palang , Hoglund Richard M. , Tarning Joel , Escudié Fanny , Scandale Ivan , Chatelain Eric , de Lamballerie Xavier , Solas Caroline , Nougairède Antoine
Published: December 2021

To address the emergence of SARS-CoV-2, multiple clinical trials in humans were rapidly started, including those involving an oral treatment by nitazoxanide, despite no or limited pre-clinical evidence of antiviral efficacy. In this work, we present a complete pre-clinical evaluation of the antiviral activity of nitazoxanide against SARS-CoV-2. First, we confirmed the in vitro efficacy of nitazoxanide and tizoxanide (its active metabolite) against SARS-CoV-2. Then, we demonstrated nitazoxanide activity in a reconstructed bronchial human airway epithelium model. In a SARS-CoV-2 virus challenge model in hamsters, oral and intranasal treatment with nitazoxanide failed to impair viral replication in commonly affected organs. We hypothesized that this could be due to insufficient diffusion of the drug into organs of interest. Indeed, our pharmacokinetic study confirmed that concentrations of tizoxanide in organs of interest were always below the in vitro EC50. These preclinical results suggest, if directly applicable to humans, that the standard formulation and dosage of nitazoxanide is not effective in providing antiviral therapy for Covid-19.
Prediction of high-risk liver cancer patients from their mutation profile: Benchmarking of mutation calling techniques
Authors: Patiyal Sumeet , Dhall Anjali , Raghava Gajendra P. S.
Published: December 2021

Identification of somatic mutations with high precision is one of the major challenges in prediction of high-risk liver-cancer patients. In the past, number of mutation calling techniques have been developed that include MuTect2, MuSE, Varscan2, and SomaticSniper. In this study, an attempt has been made to benchmark potential of these techniques in predicting prognostic biomarkers for liver cancer. Initially, we extracted somatic mutations in liver-cancer patients using VCF and MAF files from the cancer genome atlas. In terms of size, the MAF files are 42 times smaller than VCF files and containing only high-quality somatic mutations. Further, machine learning based models have been developed for predicting high-risk cancer patients using mutations obtain from different techniques. The performance of different techniques and data files have been compared based on their potential to discriminate high and low risk liver-cancer patients. Finally, univariate survival analysis revealed the prognostic role of highly mutated genes. Based on correlation analysis, we selected 80 genes negatively associated with the overall survival of the liver cancer patients. Single-gene based analysis showed that MuTect2 technique based MAF file has achieved maximum HRLAMC3 9.25 with p-value 1.78E-06. Further, we developed various prediction models using selected genes for each technique, and the results indicate that MuTect2 technique based VCF files outperform all other methods with maximum AUROC of 0.72 and HR 4.50 (p-value 3.83E-15). Eventually, VCF file generated using MuTect2 technique performs better among other mutation calling techniques to explore the prognostic potential of mutations in liver cancer. We hope that our findings will provide a useful and comprehensive comparison of various mutation calling techniques for the prognostic analysis of cancer patients.
A Single Molecule Investigation of I-Motif: Stability, Folding Kinetics, and Potential as an In-situ pH Sensor
Authors: Mustafa Golam , Gyawali Prabesh , Taylor Jacob A. , Maleki Parastoo , Nunez Marlon V. , Guntrum Michael C. , Balci Hamza
Published: December 2021

We present a collection of single molecule work on the i-motif structure formed by the human telomeric sequence. Even though it was largely ignored in earlier years of its discovery due to its modest stability and requirement for physiologically low pH levels (pH<6.5), the i-motif has been attracting more attention recently as both a physiologically relevant structure and as a potent pH sensor. In this manuscript, we establish single molecule Förster resonance energy transfer (smFRET) as a tool to study the i-motif over a broad pH and ionic conditions. We demonstrate pH and salt dependence of i-motif formation under steady state conditions and illustrate the kinetics of i-motif folding in real time at the single molecule level. We also show the prominence of intermediate folding states and reversible folding/unfolding transitions. We present an example of using the i-motif as an in-situ pH sensor and use this sensor establish the time scale for the pH drop in a commonly used oxygen scavenging system.
Unexpected arabinosylation after humanization of plant protein N-glycosylation
Authors: Bohlender Lennard L. , Parsons Juliana , Hoernstein Sebastian N. W. , Bangert Nina , Rodríguez-Jahnke Fernando , Reski Ralf , Decker Eva L.
Published: December 2021

As biopharmaceuticals, recombinant proteins have become indispensable tools in medicine. An increasing demand, not only in quantity but also in diversity, drives the constant development and improvement of production platforms. The N-glycosylation pattern on biopharmaceuticals plays an important role in activity, serum half-life and immunogenicity. Therefore, production platforms with tailored protein N-glycosylation are of great interest. Plant-based systems have already demonstrated their potential to produce pharmaceutically relevant recombinant proteins, although their N-glycan patterns differ from those in humans. Plants have shown great plasticity towards the manipulation of their glycosylation machinery, and some have already been glyco-engineered in order to avoid the attachment of plant-typical, putatively immunogenic sugar residues. This resulted in complex-type N-glycans with a core structure identical to the human one. Compared to humans, plants lack the ability to elongate these N-glycans with β1,4-linked galactoses and terminal sialic acids. However, these modifications, which require the activity of several mammalian enzymes, have already been achieved for Nicotiana benthamiana and the moss Physcomitrella. Here, we present the first step towards sialylation of recombinant glycoproteins in Physcomitrella, human β1,4-linked terminal N-glycan galactosylation, which was achieved by the introduction of a chimeric β1,4-galactosyltransferase (FTGT). This chimeric enzyme consists of the moss α1,4-fucosyltransferase transmembrane domain, fused to the catalytic domain of the human β1,4-galactosyltransferase. Stable FTGT expression led to the desired β1,4-galactosylation. However, additional pentoses of unknown identity were also observed. The nature of these pentoses was subsequently determined by Western blot and enzymatic digestion followed by mass spectrometric analysis and resulted in their identification as α-linked arabinoses. Since a pentosylation of β1,4-galactosylated N-glycans was reported earlier, e.g. on recombinant human erythropoietin produced in glyco-engineered Nicotiana tabacum, this phenomenon is of a more general importance for plant-based production platforms. Arabinoses, which are absent in humans, may prevent the full humanization of plant-derived products. Therefore, the identification of these pentoses as arabinoses is important as it creates the basis for their abolishment to ensure the production of safe biopharmaceuticals in plant-based systems.
Diversity and Divergence: Evolution of defense chemistry in the tropical tree genusInga
Authors: Forrister Dale L. , Endara María-José , Soule Abrianna J. , Younkin Gordon C. , Mills Anthony G. , Lokvam John , Dexter Kyle G. , Pennington R. Toby , Kidner Catherine A. , Nicholls James A. , Loiseau Oriane , Kursar Thomas A. , Coley Phyllis D.
Published: December 2021

Plants are widely recognized as chemical factories, with each species producing dozens to hundreds of unique secondary metabolites. These compounds shape the interactions between plants and their natural enemies. Here we explore how plants generate chemical diversity, and what evolutionary processes have led to novel compounds and unique chemical profiles.

We comprehensively characterized the chemical profile of one-third of the species of tropical rainforest trees in the genusInga(∼ 100, Fabaceae) and applied phylogenetic comparative methods to understand the mode of chemical defense evolution.

We show that: 1) EachIngaspecies produces exceptionally high levels of phytochemical diversity, despite costs, tradeoffs and biosynthetic constraints. 2) Closely related species have highly divergent defense profiles, with individual compounds, major compound classes and complete profiles showing little to no phylogenetic signal. 3) We show that the evolution of a species’ chemical profile shows a signature of divergent adaptation, implying that it is advantageous for a species to have distinct chemistry from close relatives to avoid shared natural enemies. 4) Finally, we hypothesize a model where deep homology of biosynthetic pathways and rapid changes in regulatory mechanisms may better explain the observed large shifts in defense chemicals between closely related taxa.
Percolation transition determines protein size limit for passive transport through the nuclear pore complex
Authors: Winogradoff David , Chou Han-Yi , Maffeo Christopher , Aksimentiev Aleksei
Published: December 2021

Nuclear pore complexes (NPCs) control biomolecular transport in and out of the nucleus. Disordered nucleoporins in the complex”s central pore form a permeation barrier, preventing unassisted transport of large biomolecules. Here, we combine coarse-grained simulations of an experimentally-derived NPC structure with a theoretical model to determine the microscopic mechanism of passive transport. Brute-force simulations of protein diffusion through the NPC reveal telegraph-like behavior, where prolonged diffusion on one side of the NPC is interrupted by rapid crossings to the other. We rationalize this behavior using a theoretical model that reproduces the energetics and kinetics of permeation solely from statistical analysis of transient voids within the disordered mesh. As the protein size increases, the mesh transforms from a soft to a hard barrier, enabling orders-of-magnitude reduction in permeation rate for proteins beyond the percolation size threshold. Our model enables exploration of alternative NPC architectures and sets the stage for uncovering molecular mechanisms of facilitated nuclear transport.
Bayesian inference in ring attractor networks
Authors: Kutschireiter Anna , Basnak Melanie A , Drugowitsch Jan
Published: December 2021

Working memories are thought to be held in attractor networks in the brain. These attractors should keep track of the uncertainty associated with each memory, so as to weigh it properly against conflicting new evidence. However, conventional attractors do not represent uncertainty. Here we show how uncertainty could be incorporated into an attractor, specifically a ring attractor that encodes head direction. First, we introduce the first rigorous normative framework (the circular Kalman filter) for benchmarking the performance of a ring attractor under conditions of uncertainty. Next we show that the recurrent connections within a conventional ring attractor can be re-tuned to match this benchmark. This allows the amplitude of network activity to grow in response to confirmatory evidence, while shrinking in response to poor-quality or strongly conflicting evidence. This “Bayesian ring attractor” performs near-optimal angular path integration and evidence accumulation. Indeed, we show that a Bayesian ring attractor is consistently more accurate than a conventional ring attractor. Moreover, near-optimal performance can be achieved without exact tuning of the network connections. Finally, we use large-scale connectome data to show that the network can achieve near-optimal performance even after we incorporate biological constraints. Our work demonstrates how attractors can implement a dynamic Bayesian inference algorithm in a biologically plausible manner, and it makes testable predictions with direct relevance to the head direction system, as well as any neural system that tracks direction, orientation, or periodic rhythms.

Significance Statement

Data from human subjects as well as animals shows that working memories are associated with a sense of uncertainty. Indeed, a sense of uncertainty is what allows an observer to properly weigh new evidence against their current memory. However, we do not understand how the brain tracks uncertainty. Here we describe a simple and biologically plausible network model that can track the uncertainty associated with a working memory. The representation of uncertainty in this model improves the accuracy of its working memory, as compared to conventional models, because it assigns the proper weight to new conflicting evidence. Our model provides a new interpretation for observed fluctuations in brain activity, and it makes testable new predictions.
In situcontrol of root–bacteria interactions using optical trapping in transparent soil
Authors: Ge Sisi , Wright Kathryn M , Humphris Sonia N , Dupuy Lionel X , MacDonald Michael P
Published: December 2021

Bacterial attachment on root surfaces is an important step preceding the colonisation or internalisation and subsequent infection of plants by pathogens. Unfortunately, bacterial attachment is not well understood because the phenomenon is difficult to observe. Here we assessed whether this limitation could be overcome using optical trapping approaches. We have developed a system based on counter-propagating beams and studied its ability to guidePectobacterium atrosepticum(Pba) cells to different root cell types within the interstices of transparent soils. Bacterial cells were successfully trapped and guided to root hair cells, epidermis cells, border cells and tissues damaged by laser ablation. Finally, we used the system to quantify the bacterial cell detachment rate of Pba cells on root surfaces following reversible attachment. Optical trapping techniques could greatly enhance our ability to deterministically characterise mechanisms linked to attachment and formation of biofilms in the rhizosphere.
Dynamics of DNA replication during male gametogenesis in the malaria parasite Plasmodium falciparum
Authors: Matthews Holly , McDonald Jennifer , Totanes Francis Isidore G. , Merrick Catherine J.
Published: December 2021

Malaria parasites undergo a single phase of sexual reproduction in their complex lifecycle, during which they cycle between mosquito and vertebrate hosts. Sexual reproduction occurs only at the point when parasites move into the mosquito host. It involves specialised, sexually committed cells called gametocytes, which develop very rapidly into mature gametes and then mate inside the mosquito midgut. The gamete development process is unique, involving unprecedentedly fast replication and cell division to produce male gametes. A single male gametocyte replicates its ∼23Mb genome three times over to produce 8 genomes, segregates these into newly-assembled flagellated gamete cells and releases them to seek out female gametes, all within ∼15 minutes. Here, for the first time, we use fluorescent labelling of de novo DNA synthesis to follow this process at the whole-cell and single-molecule levels, yielding several novel observations. Firstly, we confirm that no DNA replication occurs before gametogenesis is triggered, although the origin recognition complex protein Orc1 is abundant even in immature gametocytes. Secondly, between repeated rounds of DNA replication there is no detectable karyokinesis – in contrast to the repeated replicative rounds that occur in asexual schizonts. Thirdly, cytokinesis is clearly uncoupled from DNA replication, and can occur even if replication fails, implying a lack of cell cycle checkpoints. Finally the single-molecule dynamics of DNA replication are entirely different from those in asexual schizonts.
Reviving ghost alleles: Genetically admixed coyotes along the American Gulf Coast are critical for saving the endangered red wolf
Authors: vonHoldt Bridgett M. , Hinton Joseph W. , Shutt Amy C. , Adams Jennifer R. , Waits Lisette P. , Brzeski Kristin E.
Published: December 2021

The last red wolves were captured along the Gulf Coast in 1980, where they hybridized with coyote, to establish the captive breeding population. However, red wolf ancestry persists in local coyotes and could be leveraged by genomic innovations to support species persistence. We assessed genomic ancestry and morphology of coyotes in southwestern Louisiana, and find they carried 38-62% red wolf ancestry acquired in the last 30 years, which is enriched on land with minimal coyote hunting. These coyotes were also similar in ancestry to canids captured in the 1970s that initiated the red wolf captive breeding program. Further, we reported that coyotes with higher red wolf ancestry are larger in size. Our findings evidence the importance of hybrids as a reservoir of endangered species ancestry for contemporary conservation efforts. Admixed genomes are at the forefront of innovative solutions, with red wolf survival a prime candidate for this new paradigm.

Teaser

Coyotes along the American Gulf Coast carry genetic variation critical for the survival of the endangered red wolf species.
Household food waste and pathways to responsible consumer behaviour: evidence from Australia
Authors: Haque Amlan , Karunasena Gamithri Gayana , Pearson David
Published: December 2021

Purpose

This paper aims to stimulate the pursuit of waste-free food consumption and develop guidelines to avoid irresponsible consumer behaviours. In doing so, the paper answers the questions: How much food is thrown away by Australian households? What are the causes of food wasted? And, how motivated are Australian household members to reduce food waste?

Design/methodology/approach

An online survey was completed by a demographically representative sample of 5,272 households in Australia to address these questions. Using the state-wise data set and a structural equation modelling technique, this paper analyses behavioural and socio-demographic factors that influence household food waste in Australia.

Findings

The study identified that inedible food waste was the most common waste that people threw away (69%). The second-largest contribution towards waste came from meal leftovers (44%). The study identified household members not finishing their meal and cooking too much food as the leading causes of food waste from meal leftovers. Furthermore, household food members were unable to identify whether the food was safe to eat, uncertain whether they would eat prepared food that was saved for later consumption and remained confused about when to discard food. Finally, 42% indicated a high level of motivation to reduce food waste, while 34% indicated a moderated level.

Originality/value

This study's findings contribute to the practical challenges associated with the measurement of food waste in households. Further, the study provides insights to policymakers and practitioners to develop customised interventions to reduce household food waste.
Commentary: the unintended consequences of digital service technologies
Authors: Rosenbaum Mark S. , Walters Gabby , Edwards Karen L. , Gonzalez-Arcos Claudia Fernanda
Published: December 2021

Purpose

This commentary puts forth a conceptual framework, referred to as the consumer, organization, government framework of unintended digital technology service failures, that specifies consumer, organizational and governmental shortcomings that result in digital technologies failing in terms of negatively affecting consumer, communal, national and/or global welfare.

Design/methodology/approach

The authors conceptualize an original framework by engaging in a literature review regarding marketplace failures associated with digital service technologies.

Findings

The framework shows that three drivers explain why commercial digital technologies often fail. The first driver highlights misuse or criminal intent from individuals. The second involves organizations failing to prevent or to address technology failures. The third pertains to failures that stem from governmental institutions.

Research limitations/implications

The authors encourage researchers to build on their framework by putting forth research questions. To prevent or lessen opportunities for digital technologies to result in service failures, the authors also offer practitioners a “digital technology service failure audit.” This audit shows how digital technology creators and managers can anticipate and address consumer, organizational and governmental factors that often cause digital service technologies failures.

Social implications

Despite the absence of industry-specific regulations and the existence of some regulatory immunities, digital technology providers have an ethical duty, and may be obligated under applicable tort law principles, to take steps to prevent unintended harm to consumers before launching their service technologies.

Originality/value

This work reveals that digital technologies represent new and different threats to vulnerable consumers, who often rely on, but do not fully understand, these technologies in their everyday living. The framework helps consumers, organizations and government agencies to identify and remedy current and potential instances of harmful digital technologies.