bluuebunny/crossref_metadata_2025 huggingface dataset:
A new strategy to count and sort neutrophil‐derived extracellular vesicles: Validation in infectious disorders
Authors: Bonifay Amandine , Robert Stéphane , Champagne Belinda , Petit Paul‐Rémi , Eugène Aude , Chareyre Corinne , Duchez Anne‐Claire , Vélier Mélanie , Fritz Shirley , Vallier Loris , Lacroix Romaric , Dignat‐George Françoise
Published: April 2022

Newly recognized polymorphonuclear neutrophil (PMNs) functions include the ability to release subcellular mediators such as neutrophil‐derived extracellular vesicles (NDEVs) involved in immune and thrombo‐inflammatory responses. Elevation of their plasmatic level has been reported in a variety of infectious and cardiovascular disorders, but the clinical use of this potential biomarker is hampered by methodological issues. Although flow cytometry (FCM) is currently used to detect NDEVs in the plasma of patients, an extensive characterization of NDEVs has never been done. Moreover, their detection remains challenging because of their small size and low antigen density. Therefore, the objective of the present study was first to establish a surface antigenic signature of NDEVs detectable by FCM and therefore to improve their detection in biological fluids by developing a strategy allowing to overcome their low fluorescent signal and reduce the background noise. By testing a large panel of 54 antibody specificities already reported to be positive on PMNs, we identified a profile of 15 membrane protein markers, including 4 (CD157, CD24, CD65 and CD66c) never described on NDEVs. Among them, CD15, CD66b and CD66c were identified as the most sensitive and specific markers to detect NDEVs by FCM. Using this antigenic signature, we developed a new strategy combining the three best antibodies in a cocktail and reducing the background noise by size exclusion chromatography (SEC). This strategy allowed a significant improvement in NDEVs enumeration in plasma from sepsis patients and made it feasible to efficiently sort NDEVs from COVID‐19 patients. Altogether, this work opens the door to a more valuable measurement of NDEVs as a potential biomarker in clinical practice. A similar strategy could also be applied to improve detection by FCM of other rare subpopulations of EVs generated by tissues with limited access, such as vascular endothelium, cancer cells or placenta.
Transfusable neutrophil progenitors as cellular therapy for the prevention of invasive fungal infections
Authors: Sykes David B , Martinelli Michelle M , Negoro Paige , Xu Shuying , Maxcy Katrina , Timmer Kyle , Viens Adam L , Alexander Natalie J , Atallah Johnny , Snarr Brendan D , Baistrocchi Shane R , Atallah Natalie J , Hopke Alex , Scherer Allison , Rosales Ivy , Irimia Daniel , Sheppard Donald C , Mansour Michael K
Published: March 2022

The use of mature neutrophil (granulocyte) transfusions for the treatment of neutropenic patients with invasive fungal infections (IFIs) has been the focus of multiple clinical trials. Despite these efforts, the transfusion of mature neutrophils has resulted in limited clinical benefit, likely owing to problems of insufficient numbers and the very short lifespan of these donor cells. In this report, we employed a system of conditionally immortalized murine neutrophil progenitors that are capable of continuous expansion, allowing for the generation of unlimited numbers of homogenous granulocyte-macrophage progenitors (GMPs). These GMPs were assayed in vivo to demonstrate their effect on survival in 2 models of IFI: candidemia and pulmonary aspergillosis. Mature neutrophils derived from GMPs executed all cardinal functions of neutrophils. Transfused GMPs homed to the bone marrow and spleen, where they completed normal differentiation to mature neutrophils. These neutrophils were capable of homing and extravasation in response to inflammatory stimuli using a sterile peritoneal challenge model. Furthermore, conditionally immortalized GMP transfusions significantly improved survival in models of candidemia and pulmonary aspergillosis. These data confirm the therapeutic benefit of prophylactic GMP transfusions in the setting of neutropenia and encourage development of progenitor cellular therapies for the management of fungal disease in high-risk patients.
Effect of elevated fasting blood glucose level on the 1‐year mortality and sequelae in hospitalized COVID‐19 patients: A bidirectional cohort study
Authors: Chai Chen , Chen Kui , Li Shoupeng , Cheng Gang , Wang Wendan , Wang Hongxiang , Wei Dunshuang , Peng Cao , Sun Qi , Tang Zehai
Published: March 2022

To observe the predictive effect of fasting blood glucose (FBG) level on the prognosis, clinical sequelae, and pulmonary absorption in hospitalized coronavirus disease 2019 (COVID‐19) patients with and without a history of diabetes, respectively, and to evaluate the correlation between the dynamic changes of FBG and poor prognosis. In this bidirectional cohort study, we enrolled 2545 hospitalized COVID‐19 patients (439 diabetics and 2106 without a diabetic history) and followed up for 1 year. The patients were divided according to the level of admission FBG. The dynamic changes of FBG were compared between the survival and the death cases. The prediction effect of FBG on 1‐year mortality and sequelae was analyzed. The 1‐year all cause mortality rate and in‐hospital mortality rate of COVID‐19 patients were J‐curve correlated with FBG (p < 0.001 for both in the nondiabetic history group, p = 0.004 and p = 0.01 in the diabetic history group). FBG ≥ 7.0 mmol/L had a higher risk of developing sequelae (p = 0.025) and have slower recovery of abnormal lung scans (p < 0.001) in patients who denied a history of diabetes. Multivariable Cox regression analysis showed that FBG ≥ 7.0 mmol/L was an independent risk factor for the mortality of COVID‐19 regardless of the presence or deny a history of diabetes (hazard atio [HR] = 10.63, 95% confidence interval [CI]: 7.15−15.83, p < 0.001; HR = 3.9, 95% CI: 1.56−9.77, p = 0.004, respectively). Our study shows that FBG ≥ 7.0 mmol/L can be a predictive factor of 1‐year all‐cause mortality in COVID‐19 patients, independent of diabetes history. FBG ≥ 7.0 mmol/L has an advantage in predicting the severity, clinical sequelae, and pulmonary absorption in COVID‐19 patients without a history of diabetes. Early detection, timely treatment, and strict control of blood glucose when finding hyperglycemia in COVID‐19 patients (with or without diabetes) are critical for their prognosis.
Intelligent recognition of radar emitters with agile waveform based on deep reinforcement learning
Authors: Feng Yuntian , Wang Guoliang , Liu Zhipeng , Chen Xiang , Xu Xiong , Han Hui , Tai Ning , Wu Ruowu
Published: March 2022

In the traditional radar emitter recognition task, the number of emitter category tags is fixed and relatively small. We input the pulse characteristic parameters into the machine learning model to model the radar emitter. The radar emitters with agile waveform involves four different waveform categories. The number of specific emitter categories contained in different waveform categories is extremely unbalanced. Their parameters vary widely, so only using the same model or strategy to model each waveform category cannot effectively extract the core features of the radar emitters with agile waveform. The above is the main reason for the low recognition accuracy of the recognition task of radar emitters with agile waveform. In this paper, a deep reinforcement learning framework is designed to be used in the intelligent recognition task of radar emitters with agile waveform. The task is regarded as a two‐step decision game. We use CNN and Bi‐LSTM to model the radar emitter, and calculate the initial state and transition state of the game. At the same time, we design the penalty function in reinforcement learning and increase the penalty for the wrong decision in the first step to deal with the imbalance of the number of emitters between different waveform categories. Finally, the Q‐Learning algorithm with approximate values is used to learn the control strategy of the game, that is, the modeling and recognition strategy adopted for emitters of different waveform categories. The simulation experiment results show that the deep reinforcement learning framework constructed in the article can improve the recognition accuracy of 1.2% compared with the state‐of‐the‐art method in the intelligent recognition task of radar emitters with agile waveform.
Three‐stage CMOSamplifier: Frequency compensated using fully differential block
Authors: Bandari Mohammad Ali , Setoudeh Farbod , Tavakoli Mohammad Bagher , Dousti Massoud
Published: March 2022

The advancement of CMOS technology limits designers' options for multi‐stage configurations as a promising alternative to cascade structures. The main issue of designing multi‐stage amplifiers is frequency compensation since cascade structures are volatile. An efficient three‐stage amplifier, which is frequency compensated using a fully differential block, is proposed in this work. The differential block enhances the Miller effect to reduce the size of compensation capacitors, and this leads to less die occupation. The compensation network shares the differential block between two Miller loops while two Miller capacitors at the outputs of the differential block cause pole‐zero cancelation to increase operating frequency range. The proposed structure is modeled by a linear transfer function and simulated via HSPICE software using CMOS library. Simulation results indicate excellent performance and acceptable robustness against parameter mismatches and probable fabrication errors. According to the simulations, the proposed amplifier has a DC gain of , a gain‐bandwidth product of , a phase margin of , and a power dissipation of . The high performance of the proposed three‐stage amplifier with an enhanced figure of merit makes it a perfect alternative to the amplifiers based on the conventional reverse nested Miller compensation.
Volumetric differences in hippocampal subfields and associations with clinical measures in myalgic encephalomyelitis/chronic fatigue syndrome
Authors: Thapaliya Kiran , Staines Donald , Marshall‐Gradisnik Sonya , Su Jiasheng , Barnden Leighton
Published: March 2022

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients suffer from a cognitive and memory dysfunction. Because the hippocampus plays a key role in both cognition and memory, we tested for volumetric differences in the subfields of the hippocampus in ME/CFS. We estimated hippocampal subfield volumes for 25 ME/CFS patients who met Fukuda criteria only (ME/CFSFukuda), 18 ME/CFS patients who met the stricter ICC criteria (ME/CFSICC), and 25 healthy controls (HC). Group comparisons with HC detected extensive differences in subfield volumes in ME/CFSICC but not in ME/CFSFukuda. ME/CFSICC patients had significantly larger volume in the left subiculum head (p < 0.001), left presubiculum head (p = 0.0020), and left fimbria (p = 0.004). Correlations of hippocampus subfield volumes with clinical measures were stronger in ME/CFSICC than in ME/CFSFukuda patients. In ME/CFSFukuda patients, we detected positive correlations between fatigue and hippocampus subfield volumes and a negative correlation between sleep disturbance score and the right CA1 body volume. In ME/CFSICC patients, we detected a strong negative relationship between fatigue and left hippocampus tail volume. Strong negative relationships were also detected between pain and SF36 physical scores and two hippocampal subfield volumes (left: GC‐ML‐DG head and CA4 head). Our study demonstrated that volumetric differences in hippocampal subfields have strong statistical inference for patients meeting the ME/CFSICC case definition and confirms hippocampal involvement in the cognitive and memory problems of ME/CFSICC patients.
The role of the Near East surface pressure variations in recent past trends of wet season precipitation in the Levant
Authors: Krichak Simon O. , Alpert Pinhas
Published: March 2022

Using the ERA‐20C reanalysis and CRU TS4.03 observation based data, the study indicates a role of the rise in October–March mean seasonal surface pressure over the Near East (NE) in an intensification of moist air mass transport from Africa into the Eastern Mediterranean (EM) region during the last several decades. This yet non‐addressed relevant mechanism allows an explanation for the actual less intense than over the rest of the Mediterranean Region (MR) precipitation decline as well as the rise in frequency of extreme precipitation events in the southern part of the EM under the global warming conditions in recent decades. This factor appears to be contributing in slowing the global warming associated precipitation decline in the southeastern EM and significant changes in the structure of the regional precipitation leading to an increase in the contribution of extreme precipitation associated with an intensification of the moist air mass transport over northeastern Africa—Arabian Peninsula area.
Diurnal evolution of orographic precipitating clouds over the southernmost part of the Western Ghats of India during summer and winter monsoons
Authors: Subrahmanyam Kandula Venkata , Kumar Karanam Kishore
Published: March 2022

In the present communication, diurnal evolution of vertical structure of precipitating clouds over the southernmost part (7°–11°N) of the Western Ghats (WG) of Indian region during summer and winter monsoon periods is discussed using 17 years of Tropical Rainfall Measuring Mission (TRMM) precipitation radar measurements. This part of the WG experiences both summer and winter monsoons and provides a unique opportunity to study the orographical processes involved in the formation of precipitating clouds at diurnal scales during two contrasting background environments. During summer monsoon, the lower tropospheric winds are dominated by the presence of strong low‐level westerly jets, which interact with steep slopes of the WG whereas during winter monsoon, winds are very weak easterlies and encounter the WG from eastern side. The composite longitudinal distribution of vertical structure of precipitating clouds in terms of frequency of occurrence of radar reflectivities ≥23 dBZ is constructed at four local time intervals. The results are discussed in terms of bands of high frequency of occurrence of precipitating clouds and their longitudinal position with respect to the WG. A band of high frequency of occurrence of precipitation clouds is observed to be moving eastwards and their potential formation mechanism is attributed to the forced lifting over the upslope regions and to the upstream blocking over the offshore during the summer monsoon. During winter monsoon, a two band structure is observed one over the southern BOB, which is attributed to the persistent low‐pressure system observed over this region and another over the upslope of the WG from eastern side. Thus the present study for the first time brings out the diurnal evolution of the vertical structure of precipitating clouds during summer and winter monsoon over the southernmost part of the WG and discuss the potential physical processes involved in their formation.
Exploration of suitable in vitro simulated digestion model for lipid oxidation of flaxseed oil emulsion during digestion
Authors: Li Xiaowen , Huang Qingde , Wang Xintian , Zhang Mingkai , Quan Shuang , Geng Fang , Chen Hongjian , Deng Qianchun
Published: March 2022

BACKGROUND

The INFOGEST model is a standardized general in vitro digestion study, but it cannot accurately simulate the fatty acid release process of lipids in the stomach and small intestine. In this study, the internationally universal INFOGEST 2019 was used as the basic model and flaxseed oil emulsion was used as the research object. In various improvement models, the effect of fatty acid release rate on the oxidation stability of flaxseed oil was assessed by adding rabbit stomach extract and changing the order of bile salts addition.

RESULTS

With the presence of rabbit gastric extract, flaxseed oil emulsion flocculation and coalescence in stomach were reduced, and the absolute value of ζ‐potential increased. Moreover, the release rate of fatty acids in the small intestine increased by 12.14%. The amount of lipid oxidation product (i.e. hexanal) in the gastric and intestinal phases increased by 0.08 ppb. In addition, the fatty acid release rate in the small intestine phase increased by 5.85% and the hexanal content increased by 0.011 ppb in the digestion model of adding bile salts before adjusting the pH in the small intestine phase compared with the model of adjusting the pH first and then adding bile salts.

CONCLUSION

The results obtained from this study will contribute to finding the most suitable static digestion model for simulating digestion and oxidation of lipid during lipid gastrointestinal digestion. © 2022 Society of Chemical Industry.
Electrophoretic display comprising black, white, red, and yellow particles
Authors: Zang HongMei , Lin Craig , Du Hui , Gu Haiyan , Parent Mary , Chen Yajuan , Liu Lei
Published: April 2022

A four‐particle electrophoretic display (EPD), Spectra™ 3100, was released in 2021. It targets electronic shelf label applications and signage applications by providing four primary optical states of black, white, red, and yellow, as well as dithering capability to show graphic images. Specially engineered black, white, red, and yellow particles in the electrophoretic ink respond to different electric fields to show pigment intrinsic colors on the display. The imaging film produced from this technology can reach a typical contrast ratio of 30:1 while maintaining a maximum driving voltage of ±15 V. The vibrant red and yellow colors are ideal for highlighting. Consistent optical performances are achieved for all four optical states across the operating temperature range of 0°C to 40°C for a typical indoor environment. The electrophoretic ink is coated and sealed in a thin‐film Microcup® structure using an additive and high yield roll‐to‐roll manufacturing process to produce the imaging film. Active matrix (AM) module integration follows the conventional EPD module production process of lamination between the imaging film and thin‐film transistor (TFT) backplane.
Assessing meaning violations in Syrian refugees: A mixed‐methods cross‐cultural adaptation of the Global Meaning Violations Scale–ArabV
Authors: Matos Lisa , Água Joana , Sinval Jorge , Park Crystal L. , Indart Monica J. , Leal Isabel
Published: April 2022

Refugees are disproportionately affected by extreme traumatic events that can violate core beliefs and life goals (i.e., global meaning) and cause significant distress. This mixed‐methods study used an exploratory sequential design to assess meaning violations in a sample of Syrian refugees living in Portugal. For this purpose, we cross‐culturally adapted the Global Meaning Violations Scale (GMVS) for use with Arabic‐speaking refugees. In total, 43 war‐affected Syrian adults participated in the two‐phase study. Participants completed measures of trauma and narrated violations as they filled out the newly adapted GMVS‐ArabV. GMVS‐ArabV validity evidence based on response processes was investigated through Phase 1 focus groups (FGs;n = 2), whereas data from Phase 2 cognitive interviews (n = 38) were used to preliminarily explore the measure's internal structure through descriptive statistics as well as culture‐ and trauma‐informed content evidence through thematic analysis. The results suggested highest goal (M = 3.51,SD = 1.46) and lowest belief (M = 2.38,SD = 1.59) violations of educational goals and religious beliefs, respectively. Themes related to stressors, item formulation, response scale, and the global meaning construct suggested that (a) beliefs and goals can be differentially violated by different stressors; (b) much like war trauma, including torture, daily stressors can additionally shatter pretrauma global meaning; and (c) refugees reappraise meaning and suffer violations anew throughout their migration journeys. The GMVS‐ArabV offers a promising tool for exploring shattered cognitions in refugees and informs evidence‐based approaches to trauma recovery and psychological adjustment in postmigration settings (the Arabic abstract and keywords are available in theSupplementary Materials).
Eye Tracking and Motion Data Predict Endoscopic Sinus Surgery Skill
Authors: Berges Alexandra J. , Vedula S. Swaroop , Chara Alejandro , Hager Gregory D. , Ishii Masaru , Malpani Anand
Published: March 2022

Objective

Endoscopic surgery has a considerable learning curve due to dissociation of the visual‐motor axes, coupled with decreased tactile feedback and mobility. In particular, endoscopic sinus surgery (ESS) lacks objective skill assessment metrics to provide specific feedback to trainees. This study aims to identify summary metrics from eye tracking, endoscope motion, and tool motion to objectively assess surgeons' ESS skill.

Methods

In this cross‐sectional study, expert and novice surgeons performed ESS tasks of inserting an endoscope and tool into a cadaveric nose, touching an anatomical landmark, and withdrawing the endoscope and tool out of the nose. Tool and endoscope motion were collected using an electromagnetic tracker, and eye gaze was tracked using an infrared camera. Three expert surgeons provided binary assessments of low/high skill. 20 summary statistics were calculated for eye, tool, and endoscope motion and used in logistic regression models to predict surgical skill.

Results

14 metrics (10 eye gaze, 2 tool motion, and 2 endoscope motion) were significantly different between surgeons with low and high skill. Models to predict skill for 6/9 ESS tasks had an AUC >0.95. A combined model of all tasks (AUC 0.95, PPV 0.93, NPV 0.89) included metrics from eye tracking data and endoscope motion, indicating that these metrics are transferable across tasks.

Conclusions

Eye gaze, endoscope, and tool motion data can provide an objective and accurate measurement of ESS surgical performance. Incorporation of these algorithmic techniques intraoperatively could allow for automated skill assessment for trainees learning endoscopic surgery.

Level of Evidence

N/A Laryngoscope, 133:500–505, 2023
Seasonal shifts in diurnal variations of pCO2 and O2 in the lower Ganges River
Authors: Haque Md. Morshedul , Begum Most Shirina , Nayna Omme K. , Tareq Shafi M. , Park Ji‐Hyung
Published: April 2022

High‐frequency, paired measurements of the partial pressure of CO2 (pCO2) and dissolved O2 were combined with dissolved organic matter (DOM) characterization to investigate diurnal (7:00–19:00) and seasonal variations in CO2 dynamics in the lower Ganges River. Diurnal variations in pCO2 shifted seasonally, concurring with changes in DOM optical properties, biodegradable DOM, and O2 departures from atmospheric equilibrium (ΔO2). Increased pCO2 and CO2 flux (FCO2) in August–September corresponded to monsoonal floods carrying more terrestrial materials. Lower dry‐season pCO2 and FCO2 concurred with higher ΔO2, and exhibited strong relationships with DO and pH, indicating a dominant influence of phytoplankton production. Despite large variations in pCO2, the year‐long positive FCO2 implied that the lower Ganges acted as a CO2 source, reaching 122 mmol m−2 d−1. Increasing hydrologic variability and pollution in the Ganges Basin can amplify pCO2 variations linked to seasonal shifts in terrestrial inputs and phytoplankton production.
Broadband Single‐Chip Full Stokes Polarization‐Spectral Imaging Based on All‐Dielectric Spatial Multiplexing Metalens
Authors: Sun Ti , Hu Jingpei , Zhu Xiaojun , Xu Feng , Wang Chinhua
Published: March 2022

Compared with intensity imaging, more inherent information of objects can be obtained by polarization and multispectral imaging. Here, a broadband and highly integrated single‐chip full Stokes polarization‐spectral (FSPS) imaging is demonstrated using all‐dielectric spatially multiplexed metalens (SMM) in the wavelength band from 1400 to 1700 nm. The proposed FSPS‐SMM is composed of three sets of off‐axis sub‐metalens simultaneously working for pairs of 0°/90°, 45°/135° linear polarization (LP), and left‐handed/right‐handed circular polarization (CP), respectively. Experimental results show that the optical resolution of each sub‐metalens of the fabricated FSPS‐SMM reaches the diffraction limit of the full‐aperture metalens although the area of each sub‐metalens is only 1/3 of the entire metalens, the averaged polarization extinction ratio of both LP and CP reaches 32.8:1, and the energy efficiency reaches 81.8% at the design wavelength and 60% averagely in the whole 300 nm bandwidth, which breaks the 50% limit of conventional polarizer‐based methods. The proposed design provides a new idea for high‐efficiency and high‐resolution full Stokes polarization‐spectral imaging and multichannel information processing.
Enzyme‐Induced Ferrification of Hydrogels for Toughening of Functional Inorganic Compounds
Authors: Milovanovic Marko , Rauner Nicolas , Civelek Emre , Holtermann Tim , Jid Oualid El , Meuris Monika , Brandt Volker , Tiller Joerg C.
Published: April 2022

Enzyme‐induced mineralization (EIM) has been shown to greatly enhance the mechanical properties of hydrogels by precipitation of calcium salts. Another feature of such hydrogels is their high toughness even when containing finely nanostructured mineral content of ≈75 wt%. This might be useful for bendable materials with high content of functional inorganic nanostructures. The present study demonstrates that EIM can form homogeneous nanostructures of water‐insoluble iron salts within hydrogels. Crystalline iron(II) carbonate precipitates urease‐induced within polyacrylate‐based hydrogels and forms platelet structures that have the potential of forming self‐organized nacre‐like architectures. The platelet structure can be influenced by chemical composition of the hydrogel. Further, amorphous iron(II) phosphate precipitates within hydrogels with alkaline phosphatase, forming a nanostructured porous inorganic phase, homogeneously distributed within the double network hydrogel. The high amount of iron phosphate (more than 80 wt%) affords a stiffness of ≈100 MPa. The composite is still bendable with considerable toughness of 400 J m−2 and strength of 1 MPa. The high water content (>50%) may allow fast diffusion processes within the material. This makes the iron phosphate‐based composite an interesting candidate for flexible electrodes and demonstrates that EIM can be used to deliberately soften ceramic materials, rendering them bendable.
Bovine milk microbiota: Evaluation of different DNA extraction protocols for challenging samples
Authors: Schwenker Julia A. , Friedrichsen Meike , Waschina Silvio , Bang Corinna , Franke Andre , Mayer Ricarda , Hölzel Christina S.
Published: April 2022

The use of an adequate protocol that accurately extracts microbial DNA from bovine milk samples is of importance for downstream analysis such as 16S ribosomal RNA gene sequencing. Although sequencing platforms such as Illumina are very common, there are reservations concerning reproducibility in challenging samples that combine low bacterial loads with high amounts of host DNA. The objective of this study was to evaluate six different DNA extraction protocols applied to four different prototype milk samples (low/high level of colony‐forming units [cfu] and somatic cells). DNA extracts were sequenced on Illumina MiSeq with primers for the hypervariable regions V1V2 and V3V4. Different protocols were evaluated by analyzing the yield and purity of DNA extracts and the number of clean reads after sequencing. Three protocols with the highest median number of clean reads were selected. To assess reproducibility, these extraction replicates were resequenced in triplicates (n = 120). The most reproducible results for α‐ and β‐diversity were obtained with the modified DNeasy Blood & Tissue kit after a chemical pretreatment plus resuspension of the cream fraction. The unmodified QIAamp DNA Mini kit performed particularly weak in the sample representing unspecific mastitis. These results suggest that pretreatment in combination with the modified DNeasy Blood & Tissue kit is useful in extracting microbial DNA from challenging milk samples. To increase reproducibility, we recommend that duplicates, if not triplicates, should be sequenced. We showed that high counts of somatic cells challenged DNA extraction, which shapes the need to apply modified extraction protocols.
Corporate social responsibility and corporate innovation output: Empirical evidence based on Chinese listed companies
Authors: Bai Yun‐an
Published: March 2022

This study investigated the relation between corporate social responsibility (CSR) fulfillment and corporate innovation output based on a sample of 9165 Chinese listed companies. The present findings revealed that CSR fulfillment promoted corporate innovation output. Government subsidies and research and development investment showed significant mediating effects on the relation between CSR fulfillment and corporate innovation output. Additionally, the policy implementation of mixed ownership reform and corporate size had a significant moderating effect on this relation. Finally, the research revealed that CSR fulfillment not only promoted corporate innovation output but also improved corporate performance and the market value of a company.
Two‐step Ulm–Chebyshev‐like method for inverse singular value problems
Authors: Ma Wei
Published: April 2022

In this article, a two‐step Ulm–Chebyshev‐like method is proposed for solving inverse singular value problems. Under some mild assumptions, we prove that the proposed method converges cubically. Numerical implementations demonstrate the effectiveness of the new method.
Coronary microvascular function and visceral adiposity in patients with normal body weight and type 2 diabetes
Authors: Chowdhary Amrit , Thirunavukarasu Sharmaine , Jex Nicholas , Coles Lauren , Bowers Charles , Sengupta Anshuman , Swoboda Peter , Witte Klaus , Cubbon Richard , Xue Hui , Kellman Peter , Greenwood John , Plein Sven , Levelt Eylem
Published: March 2022

Objective

This study sought to assess whether diabetes affects coronary microvascular function in individuals with normal body weight.

Methods

Seventy‐five participants (30 patients with type 2 diabetes [T2D] who were overweight [O‐T2D], 15 patients with T2D who were lean [LnT2D], 15 healthy volunteers who were lean [LnHV], and 15 healthy volunteers who were overweight [O‐HV]) without established cardiovascular disease were recruited. Participants underwent magnetic resonance imaging for assessment of subcutaneous, epicardial, and visceral adipose tissue areas, adenosine stress myocardial blood flow (MBF), and cardiac structure and function.

Results

Stress MBF was reduced only in the O‐T2D group (mean [SD], LnHV = 2.07 [0.47] mL/g/min, O‐HV = 2.08 [0.42] mL/g/min, LnT2D = 2.16 [0.36] mL/g/min, O‐T2D = 1.60 [0.28] mL/g/min; p ≤ 0.0001). Accumulation of visceral fat was evident in the LnT2D group at similar levels to the O‐HV group (LnHV = 127 [53] cm2, O‐HV = 181 [60] cm2, LnT2D = 182 [99] cm2, O‐T2D = 288 [72] cm2; p < 0.0001). Only the O‐T2D group showed reductions in left ventricular ejection fraction (LnHV = 63% [4%], O‐HV = 63% [4%], LnT2D = 60% [5%], O‐T2D = 58% [6%]; p = 0.0008) and global longitudinal strain (LnHV = −15.1% [3.1%], O‐HV= −15.2% [3.7%], LnT2D = −13.4% [2.7%], O‐T2D = −11.1% [2.8%]; p = 0.002) compared with both control groups.

Conclusions

Patients with T2D and normal body weight do not show alterations in global stress MBF, but they do show significant increases in visceral adiposity. Patients with T2D who were overweight and had no prior cardiovascular disease showed an increase in visceral adiposity and significant reductions in stress MBF.

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Hepatocyte‐specific eNOS deletion impairs exercise‐induced adaptations in hepatic mitochondrial function and autophagy
Authors: Cunningham Rory P. , Moore Mary P. , Dashek Ryan J. , Meers Grace M. , Jepkemoi Vivien , Takahashi Takamune , Vieira‐Potter Victoria J. , Kanaley Jill A. , Booth Frank W. , Rector R. Scott
Published: March 2022

Objective

Endothelial nitric oxide synthase (eNOS) is a potential mediator of exercise‐induced hepatic mitochondrial adaptations.

Methods

Here, male and female hepatocyte‐specific eNOS knockout (eNOShep−/−) and intact hepatic eNOS (eNOSfl/fl) mice performed voluntary wheel‐running exercise (EX) or remained in sedentary cage conditions for 10 weeks.

Results

EX resolved the exacerbated hepatic steatosis in eNOShep−/− male mice. Elevated hydrogen peroxide emission (~50% higher in eNOShep−/− vs. eNOSfl/fl mice) was completely ablated with EX. Interestingly, EX increased [1‐14C] palmitate oxidation in eNOSfl/fl male mice, but this was blunted in the eNOShep−/− male mice. eNOShep−/− mice had lower markers of the energy sensors AMP‐activated protein kinase (AMPK)/phospho‐ (p)AMPK and mammalian target of rapamycin (mTOR) and p‐mTOR, as well as the autophagy initiators serine/threonine‐protein kinase ULK1 and pULK1, compared with eNOSfl/fl mice. Females showed elevated electron transport chain protein content and markers of mitochondrial biogenesis (transcription factor A, mitochondrial, peroxisome proliferator‐activated receptor‐gamma coactivator 1α).

Conclusions

Collectively, this study demonstrates for the first time, to the authors’ knowledge, the requirement of eNOS in hepatocytes in the EX‐induced increases in hepatic fatty acid oxidation in male mice. Deletion of eNOS in hepatocytes also appears to impair the energy‐sensing ability of the cell and inhibit the activation of the autophagy initiating factor ULK1. These data uncover the important and novel role of hepatocyte eNOS in EX‐induced hepatic mitochondrial adaptations.
Spatial Distribution of Intracellular Ion Concentrations in Aggregate‐Forming HeLa Cells Analyzed by μ‐XRF Imaging
Authors: Gräfenstein Andreas , Rumancev Christoph , Pollak Roland , Hämisch Benjamin , Galbierz Vanessa , Schroeder Walter H. , Garrevoet Jan , Falkenberg Gerald , Vöpel Tobias , Huber Klaus , Ebbinghaus Simon , Rosenhahn Axel
Published: April 2022

Protein aggregation is a hallmark of several severe neurodegenerative disorders such as Huntington's, Parkinson's, or Alzheimer's disease. Metal ions play a profound role in protein aggregation and altered metal‐ion homeostasis is associated with disease progression. Here we utilize μ‐X‐ray fluorescence imaging in combination with rapid freezing to resolve the elemental distribution of phosphorus, sulfur, potassium, and zinc in huntingtin exon‐1‐mYFP expressing HeLa cells. Using quantitative XRF analysis, we find a threefold increase in zinc and a 10‐fold enrichment of potassium that can be attributed to cellular stress response. While the averaged intracellular ion areal masses are significantly different in aggregate‐containing cells, a local intracellular analysis shows no different ion content at the location of intracellular inclusion bodies. The results are compared to corresponding experiments on HeLa cells forming pseudoisocyanine chloride aggregates. As those show similar results, changes in ion concentrations are not exclusively linked to huntingtin exon‐1 amyloid formation.
Integrative analysis of genomic and transcriptomic data of normal, tumour, and co‐occurring leukoplakia tissue triads drawn from patients with gingivobuccal oral cancer identifies signatures of tumour initiation and progression
Authors: Ghosh Arnab , Das Chitrarpita , Ghose Sandip , Maitra Arindam , Roy Bidyut , Majumder Partha P. , Biswas Nidhan K.
Published: March 2022

A thickened, white patch — leukoplakia — in the oral cavity is usually benign, but sometimes (in ~9% of individuals) it progresses to malignant tumour. Because the genomic basis of this progression is poorly understood, we undertook this study and collected samples of four tissues — leukoplakia, tumour, adjacent normal, and blood — from each of 28 patients suffering from gingivobuccal oral cancer. We performed multiomics analysis of the 112 collected tissues (four tissues per patient from 28 patients) and integrated information on progressive changes in the mutational and transcriptional profiles of each patient to create this genomic narrative. Additionally, we generated and analysed whole‐exome sequence data from leukoplakia tissues collected from 11 individuals not suffering from oral cancer. Nonsynonymous somatic mutations in the CASP8 gene were identified as the likely events to initiate malignant transformation, since these were frequently shared between tumour and co‐occurring leukoplakia. CASP8 alterations were also shown to enhance expressions of genes that favour lateral spread of mutant cells. During malignant transformation, additional pathogenic mutations are acquired in key genes (TP53, NOTCH1, HRAS) (41% of patients); chromosomal‐instability (arm‐level deletions of 19p and q, focal‐deletion of DNA‐repair pathway genes and NOTCH1, amplification of EGFR) (77%), and increased APOBEC‐activity (23%) are also observed. These additional alterations were present singly (18% of patients) or in combination (68%). Some of these alterations likely impact immune‐dynamics of the evolving transformed tissue; progression to malignancy is associated with immune suppression through infiltration of regulatory T‐cells (56%), depletion of cytotoxic T‐cells (68%), and antigen‐presenting dendritic cells (72%), with a concomitant increase in inflammation (92%). Patients can be grouped into three clusters by the estimated time to development of cancer from precancer by acquiring additional mutations (range: 4–10 years). Our findings provide deep molecular insights into the evolutionary processes and trajectories of oral cancer initiation and progression. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Antidepressant treatment effects on hippocampal protein turnover: Molecular and spatial insights from mass spectrometry
Authors: Turck Christoph W. , Webhofer Christian , Reckow Stefan , Moy Jeffrey , Wang Mei , Guillermier Christelle , Poczatek J. Collin , Filiou Michaela D.
Published: March 2022

A major challenge in managing depression is that antidepressant drugs take a long time to exert their therapeutic effects. For the development of faster‐acting treatments, it is crucial to get an improved understanding of the molecular mechanisms underlying antidepressant mode of action. Here, we used a novel mass spectrometry‐based workflow to investigate how antidepressant treatment affects brain protein turnover at single‐cell and subcellular resolution. We combined stable isotope metabolic labeling, quantitative Tandem Mass Spectrometry (qTMS) and Multi‐isotope Imaging Mass Spectrometry (MIMS) to simultaneously quantify and image protein synthesis and turnover in hippocampi of mice treated with the antidepressant paroxetine. We identified changes in turnover of individual hippocampal proteins that reveal altered metabolism‐mitochondrial processes and report on subregion‐specific turnover patterns upon paroxetine treatment. This workflow can be used to investigate brain protein turnover changes in vivo upon pharmacological interventions at a resolution and precision that has not been possible with other methods to date. Our results reveal acute paroxetine effects on brain protein turnover and shed light on antidepressant mode of action.
Characterizing pediatric lung ultrasound findings during a chemically induced bronchospasm
Authors: Gagnon Francois , Marzook Noah , Deragon Alexandre , Lands Larry C. , Zielinski David , Shapiro Adam J. , Rampakakis Emmanouil , Dubrovsky Alexander S.
Published: March 2022

Background

Lung ultrasound (LUS) has been shown to be a useful clinical tool in pediatrics, but very little is known about the LUS findings of asthma in children.

Objectives

The primary objective was to characterize LUS findings of pediatric patients before and after a chemically induced bronchospasm. The secondary objective was to evaluate the effect of bronchodilators on LUS findings.

Methods

Eligible children 6−17 years old presenting for a methacholine challenge test (MCT) in a pediatric respiratory clinic were recruited. Patients with viral symptoms were excluded. A six‐zone LUS protocol was performed before and after the MCT, and after bronchodilator administration; video recordings were analysed by an expert blinded to the patient characteristics and MCT results.

Results

Forty‐four patients were included in the study. Five patients had positive LUS findings at baseline. Nine patients out of 29 (31%) had new‐onset positive LUS following a reactive MCT. There was a significant association between having a chemically induced bronchospasm and a positive LUS post‐MCT (odds ratio [95% confidence interval]: 5.3 [1.0−27.7]; p = 0.05). Among patients who developed positive LUS findings post‐MCT, four out of nine returned to having a negative LUS postbronchodilator administration.

Conclusions

This is the first known report of an association between LUS findings and bronchospasm in pediatric patients. It is also the first documentation of resolution of LUS findings postbronchodilator administration. Most LUS findings observed were small and limited to a few intercostal spaces. Further research is required to quantify these findings and evaluate the effect of salbutamol on LUS.
Neonatal rodent ventilation and clinical correlation in congenital diaphragmatic hernia
Authors: Gupta Vikas S. , Wilson Cory , Popp Elizabeth C. , Zhaorigetu Siqin , Collum Scott , Jin Di , Khan Amir M. , Karmouty‐Quintana Harry , Lally Kevin P. , Harting Matthew T.
Published: March 2022

Introduction

Ventilator management is a critical part of managing congenital diaphragmatic hernia (CDH). We aimed to use a murine model and patient data to study CDH‐associated differences in oxygenation, airway resistance, and pulmonary mechanics by disease severity.

Methods

We used the nitrofen model of CDH. For control and CDH rodents, data were collected within the first hour of life. Oxygen saturations (SpO2) were collected using MouseOx, and large airway resistance and inspiratory capacities were collected using flexiVent. A single‐center, retrospective review of term CDH infants from 2014 to 2020 was performed. Tidal volumes were collected every 6 h for the first 48 h of life or until the patient was taken off conventional ventilation. Newborns that were mechanically ventilated but had no pulmonary pathology were used as controls. CDH severity was defined using the CDH Study Group (CDHSG) classification system.

Results

Control rodents had a median SpO2 of 94% (IQR: 88%–98%); CDH pups had a median SpO2 of 27.9% (IQR: 22%–30%) (p < 0.01). CDH rodents had lower inspiratory capacity than controls (median: 110 μl, IQR: 70–170 vs. median: 267 μl, IQR: 216–352; p < 0.01). CDH infants had a lower initial SpO2 than control infants. Overall, CDH infants had lower tidal volumes than control infants (median: 4.2 ml/kg, IQR: 3.3–5.0 vs. 5.4 ml/kg, IQR: 4.7–6.2; p = 0.03). Tidal volumes varied by CDHSG stage.

Conclusion

Newborns with CDH have lower SpO2 and lower, CDHSG stage specific, tidal volumes than control infants. The nitrofen model of CDH reflects these differences. Rodent models may be useful in studying therapeutic ventilatory strategies for CDH infants.
Mismatch repair deficiency and clinical implications in prostate cancer
Authors: Graham Laura S. , Schweizer Michael T.
Published: March 2022

Despite recent therapeutic advances, castration‐resistant prostate cancer (CRPC) remains a lethal disease and novel therapies are needed. Precision oncology provides an avenue for developing effective tailored approaches for treating malignancies based on a tumor's molecular profile. Indeed, the presence of mismatch repair deficiency (MMRd) has proven to be an important predictive biomarker for response to immune checkpoint blockade across multiple tumor types, including prostate cancer, and represents a major precision oncology success story. The mismatch repair (MMR) system is integral to maintaining genomic fidelity during cellular replication. Cancers with deficiencies in this system accumulate high numbers of mutations and express many neoantigens that may be recognized by the immune system. The checkpoint inhibitor pembrolizumab has recently been approved for all cancers that are MMR deficient, and several retrospective series have specifically shown that pembrolizumab is effective in MMRd prostate cancer. Although the prevalence of MMRd in CRPC is low (approximately 3%−5% of cases), this is an important subset of men that require a unique therapeutic approach. This review will focus on MMRd in prostate cancer, highlighting the clinical implications, role of immunotherapy, and areas of future research.
A treatment‐specific marginal structural Cox model for the effect of treatment discontinuation
Authors: Johnson Dana , Pieper Karen , Yang Shu
Published: March 2022

Patients taking a prescribed medication often discontinue their treatment; however, this may negatively impact their health outcomes. If doctors had statistical evidence that discontinuing some prescribed medication shortened, on average, the time to a clinical event (e.g., death), they could use that knowledge to encourage their patients to stay on the prescribed treatment. We describe a treatment‐specific marginal structural Cox model for estimation of the causal effect of treatment discontinuation on a survival endpoint. The effect of treatment discontinuation is quantified by the hazard ratio of the event hazard rate had the population followed the regime “take treatment until it is discontinued at some time ,” versus the event hazard rate had the population never discontinued treatment . Valid causal analysis requires control for treatment confounding, regime confounding, and censoring due to regime violation. We propose new inverse probability of regime compliance weights to address the three issues simultaneously. We apply the framework to data from the Global Anticoagulant Registry in the FIELD–Atrial Fibrillation (GARFIELD‐AF) study. Patients from this study are treated with one of two types of oral anticoagulants (OACs). We test whether the causal effect of treatment discontinuation differs by type of OAC, and we also estimate the size and direction of the effect. We find evidence that OAC discontinuation increases the hazard for certain events, but we do not find evidence that this effect differs by treatment.
Loss of Axdnd1 causes sterility due to impaired spermatid differentiation in mice
Authors: Hiradate Yuki , Harima Ryua , Yanai Rin , Hara Kenshiro , Nagasawa Kazue , Osada Makoto , Kobayashi Tomoe , Matsuyama Makoto , Kanno Shin‐ichiro , Yasui Akira , Tanemura Kentaro
Published: March 2022

Purpose

Spermiogenesis, the process of deformation of sperm head morphology and flagella formation, is a phenomenon unique to sperm. Axonemal dynein light chain proteins are localized to sperm flagella and are known to be involved in sperm motility. Here, we focused on the gene axonemal dynein light chain domain containing 1 (Axdnd1) with the aim to determine the function of its protein product AXDND1.

Methods

To elucidate the role of AXDND1 in spermatogenesis, we generated Axdnd1 knockout (KO) mice using the CRISPR/Cas9 system. The generated mice were subjected to fertility tests and analyzed by immunohistochemistry.

Result

The Axdnd1 KO mouse exhibited sterility caused by impaired spermiogenesis during the elongation step as well as abnormal nuclear shaping and manchette, which are essential for spermiogenesis. Moreover, AXDND1 showed enriched testicular expression and was localized from the mid‐pachytene spermatocytes to the early spermatids.

Conclusion

Axdnd1 is essential for spermatogenesis in the mouse testes. These findings improve our understanding of spermiogenesis and related defects. According to a recent report, deleterious heterozygous mutations in AXDND1 were found in non‐obstructive azoospermia (NOA) patients. Therefore, Axdnd1 KO mice could be used as a model system for NOA, which will greatly contribute to future NOA treatment studies.