bluuebunny/crossref_metadata_2025 huggingface dataset:
Broadly neutralizing antibody epitopes on HIV-1 particles are exposed after virus interaction with host cells
Authors: Rao Priyanka Gadam , Lambert Gregory S. , Upadhyay Chitra
Published: September 2023

The envelope (Env) glycoproteins on HIV-1 virions are the sole target of broadly neutralizing antibodies (bNAbs) and the focus of vaccines. However, many cross-reactive conserved epitopes are often occluded on virus particles, contributing to the evasion of humoral immunity. This study aimed to identify the Env epitopes that are exposed/occluded on HIV-1 particles and to investigate the mechanisms contributing to their masking. Using a flow cytometry-based assay, three HIV-1 isolates, and a panel of antibodies, we show that only select epitopes, including V2i, the gp120-g41 interface, and gp41-MPER, are accessible on HIV-1 particles, while V3, V2q, and select CD4bs epitopes are masked. These epitopes become accessible after allosteric conformational changes are induced by the pre-binding of select Abs, prompting us to test if similar conformational changes are required for these Abs to exhibit their neutralization capability. We tested HIV-1 neutralization where the virus-mAb mix was pre-incubated/not pre-incubated for 1 hour prior to adding the target cells. Similar levels of neutralization were observed under both assay conditions, suggesting that the interaction between virus and target cells sensitizes the virions for neutralization via bNAbs. We further show that lectin-glycan interactions can also expose these epitopes. However, this effect is dependent on the lectin specificity. Given that, bNAbs are ideal for providing sterilizing immunity and are the goal of current HIV-1 vaccine efforts, these data offer insight on how HIV-1 may occlude these vulnerable epitopes from the host immune response. In addition, the findings can guide the formulation of effective antibody combinations for therapeutic use.

IMPORTANCE

The human immunodeficiency virus (HIV-1) envelope (Env) glycoprotein mediates viral entry and is the sole target of neutralizing antibodies. Our data suggest that antibody epitopes including V2q (e.g., PG9, PGT145), CD4bs (e.g., VRC01, 3BNC117), and V3 (2219, 2557) are masked on HIV-1 particles. The PG9 and 2219 epitopes became accessible for binding after conformational unmasking was induced by the pre-binding of select mAbs. Attempts to understand the masking mechanism led to the revelation that interaction between virus and host cells is needed to sensitize the virions for neutralization by broadly neutralizing antibodies (bNAbs). These data provide insight on how bNAbs may gain access to these occluded epitopes to exert their neutralization effects and block HIV-1 infection. These findings have important implications for the way we evaluate the neutralizing efficacy of antibodies and can potentially guide vaccine design.
Deletion of a 7-amino-acid region in the porcine epidemic diarrhea virus envelope protein induces higher type I and III interferon responses and results in attenuation
in vivo
Authors: Li Zhiwei , Ma Zhiqian , Han Weiguo , Chang Chuanzhe , Li Yang , Guo Xuyang , Zheng Zifang , Feng Yingtong , Xu Lele , Zheng Haixue , Wang Xinglong , Xiao Shuqi
Published: September 2023

Porcine epidemic diarrhea virus (PEDV) leads to enormous economic losses for the pork industry. However, the commercial vaccines failed to fully protect against the epidemic strains. Previously, the rCH/SX/2016-S
HNXP
strain with the entire E protein and the rCH/SX/2015 strain with the deletion of 7-amino-acid (7-aa) at positions 23–29 in E protein were constructed and rescued. The pathogenicity assay indicated that rCH/SX/2015 is an attenuated strain, but rCH/SX/2016-S
HNXP
belongs to the virulent strains. Then, the recombination PEDV (rPEDV-E
Δaa23–aa29
)strain with a 7-aa deletion in the E protein was generated, using the highly virulent rCH/SX/2016-S
HNXP
strain (rPEDV-E
wt
) as the backbone. Compared with the rPEDV-E
wt
strain, the release and infectivity of the rPEDV-E
Δaa23–aa29
strain were significantly reduced
in vitro
, but stronger interferon (IFN) responses were triggered both
in vitro
and
in vivo
. The pathogenicity assay showed that the parental strain resulted in severe diarrhea (100%) and death (100%) in all piglets. Compared with the parental strain group, rPEDV-E
Δaa23–aa29
caused lower mortality (33%) and diminished fecal PEDV RNA shedding. At 21 days, all surviving pigs were challenged orally with rPEDV-E
wt
. No pigs died in the two groups. Compared with the mock group, significantly delayed and milder diarrhea and reduced fecal PEDV RNA shedding were detected in the rPEDV-E
Δaa23–aa29
group. In conclusion, the deletion of a 7-aa fragment in the E protein (E
Δaa23–aa29
) attenuated PEDV but retained its immunogenicity, which can offer new ideas for the design of live attenuated vaccines and provide new insights into the attenuated mechanism of PEDV.

IMPORTANCE

Porcine epidemic diarrhea virus (PEDV) causes high mortality in neonatal piglets and remains a large challenge to the pork industry. Unfortunately, no safe and effective vaccines are available yet. The pathogenesis and molecular basis of the attenuation of PEDV remain unclear, which seriously hinders the development of PEDV vaccines. This study found that the rPEDV carrying E
Δaa23–aa29
mutation in the E protein induced significantly higher IFN responses than the parental virus, partially attenuated, and remained immunogenic in piglets. For the first time, PEDV E was verified as an IFN antagonist in the infection context and identified as a virulence factor of PEDV. Our data also suggested that E
Δaa23–aa29
mutation can be a good target for the development of live attenuated vaccines for PEDV and also provide new perspectives for the attenuated mechanism of PEDV.
Candida
-induced granulocytic myeloid-derived suppressor cells are protective against polymicrobial sepsis
Authors: Esher Righi Shannon , Harriett Amanda J. , Lilly Elizabeth A. , Fidel Paul L. , Noverr Mairi C.
Published: September 2023

Polymicrobial intra-abdominal infections (IAI) can lead to life-threatening sepsis with significant morbidity and mortality, especially when pathogenic fungi are involved. We have employed an established clinically relevant mouse model of fungal/bacterial IAI and shown that immunization with low-virulence
Candida
species, that is,
Candida dubliniensis
, can induce responses that protect against sepsis via the suppression of lethal inflammation. This protection is dependent on long-lived Gr-1
+
polymorphonuclear leukocytes that display characteristics consistent with myeloid-derived suppressor cells (MDSCs) and trained innate immunity. Here we aimed to functionally and phenotypically characterize these protective Gr-1
+
leukocytes. Compared to nonimmunized control mice, we observed increased levels of CD11b
+
Gr-1
+
cells systemically and locally in the peritoneal cavity of immunized mice. Isolated peritoneal Gr-1
+
cells displayed hallmark MDSC phenotypes including increased T-cell suppressor activity and increased MDSC effector activity. Furthermore, we observed increased levels of the anti-inflammatory MDSC cytokine interleukin (IL)-10 in the peritoneal cavity of immunized mice and, in contrast, increased inflammatory responses when Gr-1
+
leukocytes were depleted from immunized mice prior to challenge. Flow cytometric analysis revealed that Ly6G
+
granulocytic MDSCs (G-MDSCs) were preferentially increased over Ly6C
+
monocytic MDSCs (M-MDSCs) in immunized mice. Importantly, G-MDSCs, but not M-MDSCs, as well as IL-10 production, are required for full protection against lethal sepsis. From these data, we conclude that the Gr-1
+
leukocytes that protect against polymicrobial sepsis are bona fide MDSCs and hypothesize that the mechanism of MDSC-mediated protection includes abrogation of lethal inflammation by IL-10.

IMPORTANCE

Polymicrobial intra-abdominal infections are serious clinical infections that can lead to life-threatening sepsis, which is difficult to treat in part due to the complex and dynamic inflammatory responses involved. Our prior studies demonstrated that immunization with low-virulence
Candida
species can provide strong protection against lethal polymicrobial sepsis challenge in mice. This long-lived protection was found to be mediated by trained Gr-1
+
polymorphonuclear leukocytes with features resembling myeloid-derived suppressor cells (MDSCs). Here we definitively characterize these cells as MDSCs and demonstrate that their mechanism of protection involves the abrogation of lethal inflammation, in part through the action of the anti-inflammatory cytokine interleukin (IL)-10. These studies highlight the role of MDSCs and IL-10 in controlling acute lethal inflammation and give support for the utility of trained tolerogenic immune responses in the clinical treatment of sepsis.
Antibiotic that inhibits
trans
-translation blocks binding of EF-Tu to tmRNA but not to tRNA
Authors: Marathe Neeraja , Nguyen Ha An , Alumasa John N. , Kuzmishin Nagy Alexandra B. , Vazquez Michael , Dunham Christine M. , Keiler Kenneth C.
Published: September 2023

trans-
Translation is conserved throughout bacteria and is essential in many species. High-throughput screening identified a tetrazole-based
trans
-translation inhibitor, KKL-55, that has broad-spectrum antibiotic activity. A biotinylated version of KKL-55 pulled down elongation factor thermo-unstable (EF-Tu) from bacterial lysates. Purified EF-Tu bound KKL-55
in vitro
with a
K
d
= 2 µM, confirming a high-affinity interaction. An X-ray crystal structure showed that KKL-55 binds in domain 3 of EF-Tu, and mutation of residues in the binding pocket abolished KKL-55 binding. RNA-binding assays
in vitro
showed that KKL-55 inhibits binding between EF-Tu and transfer-messenger RNA (tmRNA) but not between EF-Tu and tRNA. These data demonstrate a new mechanism for the inhibition of EF-Tu function and suggest that this specific inhibition of EF-Tu•tmRNA binding is a viable target for antibiotic development.

IMPORTANCE

Elongation factor thermo-unstable (EF-Tu) is a universally conserved translation factor that mediates productive interactions between tRNAs and the ribosome. In bacteria, EF-Tu also delivers transfer-messenger RNA (tmRNA)-SmpB to the ribosome during
trans
-translation. We report the first small molecule, KKL-55, that specifically inhibits EF-Tu activity in
trans
-translation without affecting its activity in normal translation. KKL-55 has broad-spectrum antibiotic activity, suggesting that compounds targeted to the tmRNA-binding interface of EF-Tu could be developed into new antibiotics to treat drug-resistant infections.
Complete genome sequence of
Cellulomonas
sp., strain ES6, a chromate-reducing bacterium isolated from chromium-contaminated subsurface sediment
Authors: Perea Katheryn R. , DeVeaux Linda C. , Lee Brady D. , Losey Nathaniel A.
Published: September 2023

Cellulomonas
sp. strain ES6 is a chromate-reducing bacterium isolated from chromium contaminated subsurface sediment. Illumina MiSeq and Oxford Nanopore sequencing were used to assemble the genome sequence which consisted of a single circular chromosome of 4.13 Mb, contained 3,960 protein encoding genes and with an overall G + C content 75.38%.
Supplemental Material: Westward underthrusting of thick North American crust: The dominant thickening process that built the Cordilleran orogenic plateau
Authors: Long Sean P.
Published: September 2023

Includes a figure with detailed versions of all seven cross sections, a summary of rock units on each cross section, and supporting data for cross section reconstructions, shortening and extension calculations, stratigraphic thicknesses, and measured thickening and thinning components.  
Management of epilepsy during pregnancy and lactation
Authors: Hope Omotola A , Harris Katherine MJ
Published: September 2023

Epilepsy is a group of neurological diseases characterized by susceptibility to recurrent seizures. Antiseizure medications (ASMs) are the mainstay of treatment, but many antiseizure medications with variable safety profiles have been approved for use. For women with epilepsy in their childbearing years, the safety profile is important for them and their unborn children, because treatment is often required to protect them from seizures during pregnancy and lactation. Since no large randomized controlled trials have investigated safety in this subgroup of people with epilepsy, pregnancy registries, cohort and case-control studies from population registries, and a few large prospective cohort studies have played an important role. Valproate, in monotherapy and polytherapy, has been associated with elevated risk of major congenital malformations and neurodevelopmental disorders in children born to mothers who took it. Topiramate and phenobarbital are also associated with elevated risks of congenital malformations and neurodevelopmental disorders, though the risks are lower than those of valproate. Lamotrigine and levetiracetam are relatively safe. Insufficient data exist to reach strong conclusions about the newest antiseizure medications such as eslicarbazepine, perampanel, brivaracetam, cannabidiol, and cenobamate. Besides antiseizure medications, other treatments such as vagal nerve stimulation, responsive neurostimulation, and deep brain stimulation are likely safe. In general, breastfeeding does not appear to add any additional long term risks to the child. Creative ways of optimizing registry enrollment and data collection are needed to enhance patient safety.
Centrifuge modeling of slope failure induced by elevated gas pressure in wet municipal solid waste landfill
Authors: Hu Jie , Chen Yun Min , Li Jing Hang , Ke Han , Li Jun Chao
Published: September 2023

Understanding triggering mechanisms of slope failure is of great importance to the stability analysis and safety warning of waste landfill. This paper presents a centrifuge model test on slope failure induced by elevated gas pressure in wet landfill. The formation process of liquid level and gas pressure in the landfill is simulated by means of liquid and gas injections under a centrifugal acceleration of 66.7 g. The injected liquid contains surfactants, which allow it to generate foam in the waste pores when mixed with the injected gas. The pore gas and liquid pressures under two-phase flow condition are monitored separately to clarify the instability process. It is found that the continuous gas injection makes the pore gas pressure increase to peak values of 83.0 kPa–100.8 kPa, which are higher than the peak liquid pressures of 61.3 kPa–75.6 kPa. The formation of high gas pressure zone is attributed to the low gas permeability, which is affected by high liquid saturation as well as foam generation. The slope failure occurs when the pore gas pressure increases to the peak value and the corresponding shear strength decreases to the critical value. Although the gas injection raises the liquid level, the factor of safety of landfill slope will be overestimated if only considering the effect of liquid pressure. According to the response curves of displacement to gas pressure rise, the critical ratios of gas pressure to earth pressure are determined to be 0.74–0.84, which fall within the range of the prototype landfill. The difference between foam and air on pore pressure distribution is also calculated and discussed.
α-Tocopherol reduces VLDL secretion through modulation of intracellular ER-to-Golgi transport of VLDL
Authors: Clay Ryan , Siddiqi Shaila , Siddiqi Shadab A.
Published: September 2023

Avoiding hepatic steatosis is crucial for preventing liver dysfunction, and one mechanism by which this is accomplished is through synchronization of the rate of very low density lipoprotein (VLDL) synthesis with its secretion. Endoplasmic reticulum (ER)-to-Golgi transport of nascent VLDL is the rate-limiting step in its secretion and is mediated by the VLDL transport vesicle (VTV). Recent in vivo studies have indicated that α-tocopherol (α-T) supplementation can reverse steatosis in nonalcoholic fatty liver disease, but its effects on hepatic lipoprotein metabolism are poorly understood. Here, we investigated the impact of α-T on hepatic VLDL synthesis, secretion, and intracellular ER-to-Golgi VLDL trafficking using an in vitro model. Pulse-chase assays using [3H]-oleic acid and 100 µmol/L α-T demonstrated a disruption of early VLDL synthesis, resulting in enhanced apolipoprotein B-100 expression, decreased expression in markers for VTV budding, ER-to-Golgi VLDL transport, and reduced VLDL secretion. Additionally, an in vitro VTV budding assay indicated a significant decrease in VTV production and VTV–Golgi fusion. Confocal imaging of lipid droplet (LD) localization revealed a decrease in overall LD retention, diminished presence of ER-associated LDs, and an increase in Golgi-level LD retention. We conclude that α-T disrupts ER-to-Golgi VLDL transport by modulating the expression of specific proteins and thus reduces VLDL secretion.
Tillage and nitrogen rate effects on winter wheat yield in a wheat–sorghum rotation
Authors: Majrashi Mosaed A. , Obour Augustine K. , Moorberg Colby J. , Lollato Romulo P. , Holman Johnathon D. , Du Juan , Mikha Maysoon M. , Assefa Yared
Published: September 2023

The objectives of this study were to quantify long-term tillage practice and nitrogen (N) fertilizer rate effects on yield and N use in a winter wheat ( Triticum aestivum L.)–grain sorghum ( Sorghum bicolor L. Moench)–fallow (W–S–F) rotation. The experimental design was a randomized complete block with a split–split-plot arrangement. The main plot treatments were crop rotation phases W–S–F, S–F–W, and F–W–S. The sub-plots were tillage practices, i.e., conventional tillage (CT), reduced tillage (RT), and no-tillage (NT). And the sub-sub-plot treatments were N rates of 0, 45, 90, and 134 kg ha−1. Wheat yield increased at rates of 15.6, 9.3, 22.8, and 25.7 kg ha−1 for a kg N ha−1 increase in very low-, low-, high-, and very high-yielding environments (average yields of ∼2000, 2500, 2800, and 4400 kg ha−1), respectively. On average, winter wheat yields were 7%–9% greater for CT compared with both NT and RT. Winter wheat removed about 52 kg N ha−1 from the unfertilized control treatment, but N uptake varied by N rate and growing conditions. Nitrogen use efficiency, N agronomic efficiency, and applied N recovery decreased as the N rate increased. Across environments, wheat yield increased by 16, 20, and 17 kg ha−1 for each additional kg ha−1 N applied under CT, NT, and RT, respectively, and additional 2–2.5 kg ha−1 yield increases for a mm increase in fallow precipitation. We concluded that wheat yield response to N is highly dependent on growing conditions, and NT required greater N fertilization than CT and RT for similar yields.
Array analysis of seismic noise at the Sos Enattos mine, the Italian candidate site for the Einstein Telescope
Authors: Saccorotti Gilberto , Giunchi Carlo , D’Ambrosio Michele , Gaviano Sonja , Naticchioni Luca , D’Urso Domenico , Rozza Davide , Cardini Alessandro , Contu Andrea , Dordei Francesca , Cadeddu Matteo , Tuveri Matteo , Migoni Carlo , Punturo Michele , Allocca Annalisa , Calloni Enrico , Cardello Giovanni Luca , D’Onofrio Luca , Davari Nazanin , Dell’Aquila Daniele , De Rosa Rosario , Carpinelli Massimo , Di Fiore Luciano , di Giovanni Matteo , Errico Luciano , Fiori Irene , Tringali Maria Concetta , Harms Jan , Koley Soumen , Longo Vittorio , Majorana Ettore , Mangano Valentina , Olivieri Marco , Paoletti Federico , Pesenti Luca , Puppo Paola , Rapagnani Piero , Razzano Massimiliano , Ricci Fulvio , Sipala Valeria , Tosta e Melo Iara , Trozzo Lucia
Published: September 2023

The area surrounding the dismissed mine of Sos Enattos (Sardinia, Italy) is the Italian candidate site for hosting Einstein Telescope (ET), the third-generation gravitational wave (GW) observatory. One of the goals of ET is to extend the sensitivity down to frequencies well below those currently achieved by GW detectors, i.e. down to 2 Hz. In the bandwidth [1,10] Hz, the seismic noise of anthropogenic origin is expected to represent the major perturbation to the operation of the infrastructure, and the site that will host the future detector must fulfill stringent requirements on seismic disturbances. In this paper we describe the operation of a temporary, 15-element, seismic array deployed in close proximity to the mine. Signals of anthropogenic origin have a transient nature, and their spectra are characterized by a wide spectral lobe spanning the [3,20] Hz frequency interval. Superimposed to this wide lobe are narrow spectral peaks within the [3,8] Hz frequency range. Results from slowness analyses suggest that the origin of these peaks is related to vehicle traffic along the main road running east of the mine. Exploiting the correlation properties of seismic noise, we derive a dispersion curve for Rayleigh waves, which is then inverted for a shallow velocity structure down to depths of $$\approx$$
≈
150 m. This data, which is consistent with that derived from analysis of a quarry blast, provide a first assessment of the elastic properties of the rock materials at the site candidate to hosting ET.
Tackling Industrial Downtimes with Artificial Intelligence in Data-Driven Maintenance
Authors: Hoffmann Marcel André , Lasch Rainer
Published: September 2023

The application of
Artificial Intelligence (AI)
approaches in industrial maintenance for fault detection and prediction has gained much attention from scholars and practitioners. This survey systematically assesses and classifies the state-of-the-art algorithms applied to data-driven maintenance in recent literature. The taxonomy provides a so far not existing overview and decision aid for research and practice regarding suitable AI approaches for each maintenance application. Moreover, we consider trends and further research demand in this area. Finally, a newly developed holistic maintenance framework contributes to a practice-oriented implementation of AI and considers crucial managerial aspects of an efficient maintenance system.
Group Threat and Social Control: Who, What, Where, and When
Authors: Vogel Matt , Messner Steven F.
Published: September 2023

Group threat theory has stimulated an impressive number of studies over the course of the past several decades. Our review takes stock of this literature, focusing on core issues of concern to the criminological community. We begin by documenting the theoretical origins of group threat theory and discussing the early research informed by the theory. We then highlight the ways in which criminologists have built on and extended the early research by expanding the theory's scope, clarifying mechanisms, and addressing methodological issues. In our concluding remarks, we direct attention to the more consequential limitations of the work to date and offer suggestions about areas for fruitful growth in the future.
Making Sense of Censored Covariates: Statistical Methods for Studies of Huntington's Disease
Authors: Lotspeich Sarah C. , Ashner Marissa C. , Vazquez Jesus E. , Richardson Brian D. , Grosser Kyle F. , Bodek Benjamin E. , Garcia Tanya P.
Published: September 2023

The landscape of survival analysis is constantly being revolutionized to answer biomedical challenges, most recently the statistical challenge of censored covariates rather than outcomes. There are many promising strategies to tackle censored covariates, including weighting, imputation, maximum likelihood, and Bayesian methods. Still, this is a relatively fresh area of research, different from the areas of censored outcomes (i.e., survival analysis) or missing covariates. In this review, we discuss the unique statistical challenges encountered when handling censored covariates and provide an in-depth review of existing methods designed to address those challenges. We emphasize each method's relative strengths and weaknesses, providing recommendations to help investigators pinpoint the best approach to handling censored covariates in their data.
Study of a GaN/InGaN-based Light Emitting Diode with an Indium Gallium Oxide Current Blocking Layer, Silver Nanoparticles, and a Gallium Oxide Surface Passivation Layer
Authors: Wang Ming-Han , Jian Jia-Jiu , Yao Pao-Chi , Hsu Wei-Chou , Liu Wen-Chau
Published: September 2023

An interesting GaN/InGaN-based light emitting diode (LED) structure incorporating silver (Ag) nanoparticles (NPs), an indium gallium oxide (IGO) current blocking layer (CBL), and a gallium oxide (Ga2O3) surface passivation layer (SPL), is manufactured and proposed. Based on the designed structure, the light extraction characteristics and the current distributing properties can be substantially enhanced, and the surface leakage current is remarkably reduced. In this work, under the injected current of 400 mA, the studied Device D with Ag NPs, a 30 nm-thick IGO CBL, and a 50 nm-thick Ga2O3 SPL shows the improvement of 20.4% in light output power (LOP) compared to a traditional LED device. Additionally, the studied Device D shows enhanced performance on far-field radiation. Hence, the proposed structure provides a reliable solution to manufacture high-efficiency GaN/InGaN-based LEDs.
Enhancement in Performance and Reliability of Transparent IGZO Thin-Film Transistors by ITO/Ti Stacked Source/Drain Contacts
Authors: Li Y. B. , Chen T. P.
Published: September 2023

Enhancement in performance and reliability of transparent IGZO thin-film transistor (TFT) was achieved by adopting a laminated structure with a thin ITO layer and an ultrathin Ti layer as the source/drain (S/D) contacts. Compared with the transparent TFT with pure ITO S/D contacts, the transparent TFT with the ITO/Ti S/D contacts showed three times of enhancement in field-effect mobility from 4.75 to 12.10 cm2/Vs, two times of enhancement in on/off current ratio from 7.0 × 107 to 1.54 × 108, three times of reduction in contact resistance from 15.74 to 4.64 kΩ, and a decrease in threshold voltage from 3.11 V to 2.80 V. The TFT with the ITO/Ti S/D contacts also maintained an extremely low leakage current at zero gate bias (for the device with channel width/channel length of 40 μm/5 μm, the leakage current was ∼1 × 10−13 A). In addition, the TFT with the ITO/Ti S/D contacts showed a hump-free transfer curve and a smaller shift in threshold voltage under negative bias illumination stress. The enhancement in performance and reliability makes the transparent TFT with the ITO/Ti S/D contacts very promising in transparent display applications.
Volume responsiveness revisited: an observational multicenter study of continuous versus binary outcomes combining echocardiography and venous return physiology
Authors: Aneman Anders , Schulz Luis , Prat Gwenaël , Slama Michel , Vignon Philippe , Vieillard-Baron Antoine
Published: September 2023

The analog mean systemic filling pressure and the pressure gradient for venous return combined with echocardiography predict continuous changes in stroke volume following a passive leg raising maneuver. The confounding effects of impaired right ventricular function and increased intra-abdominal pressure can be identified. Using a binary cutoff for the fractional change in stroke volume, common in previous clinical research, fails to identify the importance of variables relevant to venous return physiology and confounding conditions.
Age-associated increases in middle cerebral artery pulsatility differ between men and women
Authors: Lefferts Wesley K. , Reed Krista S. , Rosonke Rachel E. , Augustine Jacqueline A. , Moreau Kerrie L.
Published: September 2023

We identify sex-specific associations between increasing age and cerebral pulsatility and its vascular mechanisms. When compared with men, women in our cross-sectional analysis exhibited greater age-associated increases in carotid stiffness, carotid pulse pressure, and cerebral pulsatility particularly during midlife. These data suggest that the rapid expansion of pulse pressure during midlife contributes to an exaggerated increase in cerebral pulsatility among women and suggest a potential mechanism contributing to sex differences in brain aging.
Sympathetic neural overdrive and diminished exercise capacity in reduced ejection fraction heart failure related to anthracycline-based chemotherapy
Authors: Rodrigues Amanda G. , Sales Allan R. K. , Faria Diego , Fonseca Silvia M. R. , Bond Marina M. K. , Jordão Camila P. , de Souza Francis R. , Bittar Cristina S. , Dos Santos Marília H. H. , Sarmento Adriana O. , Negrao Marcelo V. , Hajjar Ludhmila A. , Negrão Carlos E. , Kalil Filho Roberto
Published: September 2023

Patients with heart failure with reduced ejection fraction related to anthracycline-based chemotherapy have increased sympathetic nerve activity and decreased exercise capacity. These alterations in autonomic control and physical capacity are similar to those observed in patients with heart failure due to other etiologies. These findings highlight the importance of special care of oncological patients treated with chemotherapy.
Detection of Driving Distractions and Their Impacts
Authors: Shajari Arian , Asadi Houshyar , Glaser Sebastien , Arogbonlo Adetokunbo , Mohamed Shady , Kooijman Lars , Abu Alqumsan Ahmad , Nahavandi Saeid
Published: September 2023

For decades, road crashes have caused many deaths and injuries and generally have had a severe social and economic impact on societies. According to studies, driver distraction has led to an increase in driving-related risks. In recent years, there have been more distracting factors that commonly affect drivers, highlighting the need for a resolution. Therefore, as technology is becoming more advanced, there is an opportunity to minimize these risks, for which driver distraction detection would be required. As there are a variety of distractions that might affect drivers and their performance, there are many studies focusing on this topic. To better understand the field of driver distraction detection, this paper has reviewed the existing studies in this field. For this purpose, different variables of the existing methodologies and experimental setups are identified and explained. Also, the results of these experiments and the impacts of different distraction factors on drivers’ physiological responses, visual signals, or their performances are categorized and described. Furthermore, this study discusses the factors of the existing methodologies and their results, along with pointing out the research gaps. The purpose of this study is to assist future research and investigation in this field, by creating a review that comprehensively covers different aspects of existing studies and discusses and assesses their methodologies and findings.
Design and Analysis of Target Simulator Using All Spherical System with High Matching Rate
Authors: Li Shijie , Zhang Xiaojing , Zhao Kai , Li Zihuai , Li Xiong , Zhao Lumin , Zhang Jin , Cai Changlong
Published: September 2023

To achieve low wavefront error and high throughput with vignetting-free target simulators, a concave-convex-concaveoff-axis spherical system is designed in this paper, which effectively eliminates astigmatism and coma of the system by fields of view (FOVs) and aperture offset and provides theoretical basis for the realization of 100% matching between the exit pupil of the field lens and entrance pupil of the three-mirror anastigmat (TMA) system. Only spherical mirror element is used in this target simulator, which not only reduces the difficulty of manufacturing and cost but also greatly reduces the difficulty of assembling and adjusting. It provides an effective scheme for the design of target simulator and has strong engineering application value.
The Frequency of Intestinal Parasitic Infections in COVID-19 Patients: A Case-Control Study in Tehran, Capital of Iran
Authors: Taghipour Ali , Pirestani Majid , Hamidi Farahani Ramin , Barati Mohammad
Published: September 2023

The present study was done to evaluate the prevalence of intestinal parasitic infections (IPIs) in patients with COVID-19 in health care centers (Imam Reza and Golestan hospitals), Tehran, capital of Iran. By designing a matched case-control study, 200 fecal samples were collected for each of the COVID-19 patients and healthy individuals. Nasopharyngeal/oropharyngeal swab samples were collected from all participants for the diagnosis of COVID-19. RNA extraction was performed, and then real time reverse-transcription polymerase chain reaction (rRT-PCR) assay was applied to detect viral RNA. Considering the lung complications, 25%> lung complications was detected in 49 patients, 25–49% in 42 patients, and 50%≤ in 109 patients. Fecal samples were examined using different parasitological techniques. After nested-PCR, sequencing was applied to identify Cryptosporidium spp. and microsporidia spp. A relatively lower prevalence of IPIs was detected among control group (7.5%), than in COVID-19 patients (13%), though not significant

P
=
0.13

. The most prevalent parasite among patients was Blastocystis sp. (6%). Also, 13.76% of IPIs were detected in inpatients with more than 50% lung complication. As well, a remarkably significant difference in IPIs was observed among diarrheic COVID-19 patients, in comparison with nondiarrheic patients

P
<
0.00001

. Moreover, the isolated sequences in the present study belonged to C. parvum subtype IIa and Enterocytozoon bieneusi genotypes D and Peru 8. In conclusion, more epidemiological and clinical research studies are needed to better understand the status and interaction of IPI in COVID-19 in Iran and other countries.
Safety Evaluation for Highway Geometric Design Based on Spatial Path Properties
Authors: Wang Lu
Published: September 2023

Safety is an important aspect of road design. In highway geometric design, road engineers use a two-stage design method due to its convenience, but the available two-dimensional design tools on the market are believed to impose limitations. Horizontal and vertical alignment parameters are considered and determined at the designer’s discretion, potentially downplaying the three-dimensional characters of spatial curves. This study focuses on the three-dimensional characteristics of highway alignments and investigates a safety evaluation method to establish the relationship between crash rate and spatial curve properties. This will necessitate an analytical investigation into the effects of higher-order properties, such as curvature and torsion, on the geometry of spatial Cartesian curves. First, these combinations of horizontal and vertical alignments were categorized into six classifications, each with its own spatial expression in mathematical form. After manipulating the curvature and torsion of the spatial curve algebraically, the correlation between geometric design variables and crash rate was ultimately established. A few cases involving geometric design data and crash facts were utilized for verification. The results revealed a considerable positive correlation between curvature or torsion variance and crashes per million vehicles kilometers, as a slight difference between curvature and torsion could also be spotted. And curvature distribution is correlated with collision frequency more closely than torsion spatial variation.
Antiviral Drugs and Vaccines for Omicron Variant: A Focused Review
Authors: Garg Nidhi , Kunamneni Ananya Sree , Garg Pankaj , Sharma Sandeep , Sharma Divakar , Kunamneni Adinarayana
Published: September 2023

The Omicron variant of concern (VOC) replaced the delta variant rapidly and became the predominant strain due to more mutations in spike protein and receptor-binding domain (RBD) enhancing its infectivity and binding affinity. The severity of the illness is less than that of the delta variant. Omicron is nonsusceptible to REGEN-COV™ and bamlanivimab with etesevimab. Drugs that are effective against the Omicron variant are oral antiviral drugs such as Paxlovid (nirmatrelvir/ritonavir), remdesivir, sotrovimab, and molnupiravir. The potency of sotrovimab is reduced to 3-fold against Omicron, and 8-fold reduction in potency with sotrovimab is found in a particular variant of Omicron with a R346K substitution in spike protein. There are neither clinical trials comparing the efficacy of these 4 therapies with each other nor any data on a combination of two or more therapies. The current recommendation for mild-moderate, nonhospitalized patients who are at a high risk of disease progression is to use Paxlovid as the first-line option. If Paxlovid is not available or cannot be administered due to drug interactions, then the next best choice is sotrovimab. The third choice is remdesivir if sotrovimab is also not available and molnupiravir is to be given if the other three options are not available or cannot be administered. For prevention, 2130 (cilgavimab) in combination with COV2-2196 (tixagevimab) has been effective against BA.2 only. LY-CoV1404 (bebtelovimab) is recently authorized as it is effective against all sublineages of the Omicron variant. Regarding vaccine efficacy (VE), the 3-dose VE with mRNA vaccines at 14–60 days was found to be 71.6%, and after 60 days, it is 47.4%. There is a 34–38-fold reduction of neutralizing activity with prebooster sera and a 19-fold reduction with booster sera for the Omicron variant. This probably explains the reason for worldwide breakthrough infections with the Omicron variant with waning immunity. The neutralizing antibody response against Omicron elicited by the bivalent vaccine is superior to that of the ancestral Wuhan strain, without any safety concerns. For future advances, the ribosome display technology can be applied for the generation of human single-chain fragment variable (scFv) antibodies from B cells of recovered patients against Omicron and other Coronavirus variants as they are easier and faster to produce and have high affinity and high specificity.
The Importance of Follow-Up and Evaluation of Intraoperative Findings to Determine Surgical Indications for Retractile Testis
Authors: Kikkawa Kazuro , Ueda Yuko , Yamashita Shimpei , Kohjimoto Yasuo , Hara Isao
Published: September 2023

Objectives. Ascending testis or acquired undescended testis develops in approximately 30% of cases of retractile testis, and orchiopexy is recommended for these cases. This study aimed at assessing the intraoperative anatomical findings of ascending testis and acquired undescended testis in search of better management for retractile testis. Methods. We retrospectively collected data of patients with confirmed diagnosis of retractile testis between February 2012 and November 2021. Orchiopexy was performed for cases with ascending testis and for patients with increasing difference of right and left testicular volume. The site of gubernaculum attachment and patent processus vaginalis were evaluated during surgery. Results. A total of 119 testes in 71 patients with retractile testis were included in this study. Sixteen retractile testes in 12 patients (17%) underwent orchiopexy. The weight at birth was significantly higher, and bilateral retractile testes were significantly more common in the follow-up group than in the surgical intervention group. In the surgical intervention group, the abnormal site of gubernaculum attachment was found in 12 out of 16 testes (75%), and patent PV was found in nine out of sixteen testes (56%). Sites of gubernaculum attachment in testes with patent PV were significantly higher than in sites with closed processus vaginalis, and all testes with patent processus vaginalis had abnormal site of gubernaculum attachment. Conclusion. Patients with ascending testis and acquired undescended testis have clinical features and intraoperative abnormal findings similar to a cryptorchidism. Therefore, our surgical indication for retractile testis is considered appropriate.
System Level Extropy of the Past Life of a Coherent System
Authors: Kayid M. , Alshehri Mashael A.
Published: September 2023

In this paper, we take a new approach to uncertainty in a coherent system, where components are assumed to be all inactive in a given time. In particular, the signature-based method is used to quantify the extropy of the past lifetime of the system, which serves as a valuable indicator of its predictability. The results provide several key findings, including some bounds and stochastic ordering aspects for this measure. We also introduce a new formula to select the system that is preferable based on its relative extropy in the past. The results of this work can provide insights for designing systems to improve their reliability and resilience.
SHP2: A Pleiotropic Target at the Interface of Cancer and Its Microenvironment
Authors: Sodir Nicole M. , Pathria Gaurav , Adamkewicz Joanne I. , Kelley Elizabeth H. , Sudhamsu Jawahar , Merchant Mark , Chiarle Roberto , Maddalo Danilo
Published: September 2023

The protein phosphatase SHP2/PTPN11 has been reported to be a key modulator of proliferative pathways in a wide range of malignancies. Intriguingly, SHP2 has also been described as a critical regulator of the tumor microenvironment. Based on this evidence SHP2 is considered a multifaceted target in cancer, spurring the notion that the development of direct inhibitors of SHP2 would provide the twofold benefit of tumor intrinsic and extrinsic inhibition. In this review, we will discuss the role of SHP2 in cancer and the tumor microenvironment, and the clinical strategies in which SHP2 inhibitors are leveraged as combination agents to improve therapeutic response.

Significance:

The SHP2 phosphatase functions as a pleiotropic factor, and its inhibition not only hinders tumor growth but also reshapes the tumor microenvironment. Although their single-agent activity may be limited, SHP2 inhibitors hold the potential of being key combination agents to enhance the depth and the durability of tumor response to therapy.
Supplementary Table 1 from Nanoparticle Delivery of Immunostimulatory Alu RNA for Cancer Immunotherapy
Authors: Garland Kyle M. , Kwiatkowski Alexander J. , Tossberg John T. , Crooke Philip S. , Aune Thomas M. , Wilson John T.
Published: September 2023

Clinical Characteristics from Anagnostou et al.
FIGURE 3 from Nanoparticle Delivery of Immunostimulatory Alu RNA for Cancer Immunotherapy
Authors: Garland Kyle M. , Kwiatkowski Alexander J. , Tossberg John T. , Crooke Philip S. , Aune Thomas M. , Wilson John T.
Published: September 2023

In vitro characterization of AluJb RNA (Left Arm)/D-PDB. A, Agarose gel of AluJb RNA (Left Arm) with and without various amounts of D-PDB, as indicated. 1 µg RNA/lane. The TrackIt 100 bp DNA Ladder was employed. B, DLS analysis of Alu-NPs and Edited Alu-NPs (i.e., AluJb RNA (Left Arm)/D-PDB at an N/P ratio of 4 and Inactive AluJB (Left Arm)/D-PDB at an N/P ratio of 4) relative to D-PDB. C, TEM images of D-PDB NPs, Edited Alu-NPs, and Alu-NPs. Scale bars, 100 µm. RAW-Dual (D) and THP1-Dual (E) reporter cell assays of Alu-NPs, Edited Alu-NPs, D-PDB, D-B Alu NPs, and Free AluJB RNA (Left Arm). All curves are normalized to the maximum value of the Alu-NPs. All experiments were performed at least twice.
Zusammenhänge zwischen seriellen intravitrealen Anti-VEGF-Injektionen und trockenem Auge
Authors: Siebelmann Sebastian
Published: September 2023

Purpose: To investigate the effects of serial intravitreal injections (IVIs) on the ocular surface and meibomian glands (MGs) in patients treated with anti-vascular endothelial growth factor (anti-VEGF) for neovascular age-related macular degeneration (nAMD). Design: Retrospective, controlled, observational study. Participants: Patients with nAMD receiving unilateral IVIs with anti-VEGF agents. The fellow eye was used as control. Methods: Tear film and ocular surface examinations were performed on a single occasion at a minimum of 4 weeks after IVI. A pre-IVI asepsis protocol with povidone-iodine (PVP-I) was applied. Main outcome measures: Upper and lower MG loss, tear meniscus height (TMH), bulbar redness (BR) score, noninvasive tear break-up time (NIBUT), tear film osmolarity (TOsm), Schirmer test, corneal staining, fluorescein tear film break-up time (TBUT), meibomian gland expressibility (ME), and meibum quality. Results: Ninety patients with a mean age of 77.5 years (standard deviation [SD], 8.4; range 54–95) were included. The median number of IVIs in treated eyes was 19.5 (range, 2–132). Mean MG loss in the upper eyelid was 19.1% (SD, 11.3) in treated eyes and 25.5% (SD, 14.6) in untreated fellow eyes (P = 0.001). For the lower eyelid, median MG loss was 17.4% (interquartile range [IQR], 9.4–29.9) in treated eyes and 24.5% (IQR, 14.2–35.2) in fellow eyes (P < 0.001). Mean BR was 1.32 (SD, 0.46) in treated eyes versus 1.44 (SD, 0.45) in fellow eyes (P = 0.017). Median TMH was 0.36 mm (IQR, 0.28–0.52) in treated eyes and 0.32 mm (IQR, 0.24–0.49) in fellow eyes (P = 0.02). There were no differences between treated and fellow eyes regarding NIBUT, TOsm, Schirmer test, corneal staining, fluorescein TBUT, ME, or meibum quality. Conclusions: Repeated IVIs with anti-VEGF with preoperative PVP-I application was associated with reduced MG loss, increased tear volume, and reduced signs of inflammation compared with fellow nontreated eyes in patients with nAMD. This regimen may thus have a beneficial effect on the ocular surface.
Extracellular Perinexal Separation Is a Principal Determinant of Cardiac Conduction
Authors: Adams William P. , Raisch Tristan B. , Zhao Yajun , Davalos Rafael , Barrett Sarah , King D. Ryan , Bain Chandra B. , Colucci-Chang Katrina , Blair Grace A. , Hanlon Alexandra , Lozano Alicia , Veeraraghavan Rengasayee , Wan Xiaoping , Deschenes Isabelle , Smyth James W. , Hoeker Gregory S. , Gourdie Robert G. , Poelzing Steven
Published: September 2023

BACKGROUND:

Cardiac conduction is understood to occur through gap junctions. Recent evidence supports ephaptic coupling as another mechanism of electrical communication in the heart. Conduction via gap junctions predicts a direct relationship between conduction velocity (CV) and bulk extracellular resistance. By contrast, ephaptic theory is premised on the existence of a biphasic relationship between CV and the volume of specialized extracellular clefts within intercalated discs such as the perinexus. Our objective was to determine the relationship between ventricular CV and structural changes to micro- and nanoscale extracellular spaces.

METHODS:

Conduction and Cx43 (connexin43) protein expression were quantified from optically mapped guinea pig whole-heart preparations perfused with the osmotic agents albumin, mannitol, dextran 70 kDa, or dextran 2 MDa. Peak sodium current was quantified in isolated guinea pig ventricular myocytes. Extracellular resistance was quantified by impedance spectroscopy. Intercellular communication was assessed in a heterologous expression system with fluorescence recovery after photobleaching. Perinexal width was quantified from transmission electron micrographs.

RESULTS:

CV primarily in the transverse direction of propagation was significantly reduced by mannitol and increased by albumin and both dextrans. The combination of albumin and dextran 70 kDa decreased CV relative to albumin alone. Extracellular resistance was reduced by mannitol, unchanged by albumin, and increased by both dextrans. Cx43 expression and conductance and peak sodium currents were not significantly altered by the osmotic agents. In response to osmotic agents, perinexal width, in order of narrowest to widest, was albumin with dextran 70 kDa; albumin or dextran 2 MDa; dextran 70 kDa or no osmotic agent, and mannitol. When compared in the same order, CV was biphasically related to perinexal width.

CONCLUSIONS:

Cardiac conduction does not correlate with extracellular resistance but is biphasically related to perinexal separation, providing evidence that the relationship between CV and extracellular volume is determined by ephaptic mechanisms under conditions of normal gap junctional coupling.