bluuebunny/crossref_metadata_2025 huggingface dataset:
Diamide-based screening method for the isolation of improved oxidative stress tolerance phenotypes in
Bacillus
mutant libraries
Authors: Walgraeve Jonathan , Ferrero-Bordera Borja , Maaß Sandra , Becher Dörte , Schwerdtfeger Ruth , van Dijl Jan Maarten , Seefried Michael
Published: October 2023

The bacterium
Bacillus subtilis
is of high importance both as a model organism for Gram-positive bacteria and as an industrial workhorse in the production of biomolecules. In recent years, advancements have been made to engineer the bacterium even further toward industrial applications. In this study, we present a novel screening method for mutant libraries using diamide, an oxidizing agent that binds free thiols and creates disulfide bonds between them, thereby causing a so-called “disulfide stress” in bacteria. The method shows promise to selectively identify phenotypes in
B. subtilis
with improved tolerance toward oxidative and disulfide-associated stress. Phenotypes initially identified by transposon mutagenesis were recreated through targeted gene deletions. Among the resulting deletion mutants, the largest difference in diamide tolerance compared to the parental strain was observed for
pfkA
and
ribT
deletion strains. A proteomics analysis showed that diamide tolerance can be achieved through different routes involving increased expression of stress management proteins and reduced availability or activity of the RNA degradosome. We conclude that our screening method allows the facile identification of
Bacillus
strains with improved oxidative stress tolerance phenotypes.

IMPORTANCE

During their life cycle, bacteria are exposed to a range of different stresses that need to be managed appropriately in order to ensure their growth and viability. This applies not only to bacteria in their natural habitats but also to bacteria employed in biotechnological production processes. Oxidative stress is one of these stresses that may originate either from bacterial metabolism or external factors. In biotechnological settings, it is of critical importance that production strains are resistant to oxidative stresses. Accordingly, this also applies to the major industrial cell factory
Bacillus subtilis
. In the present study, we, therefore, developed a screen for
B. subtilis
strains with enhanced oxidative stress tolerance. The results show that our approach is feasible and time-, space-, and resource-efficient. We, therefore, anticipate that it will enhance the development of more robust industrial production strains with improved robustness under conditions of oxidative stress.
Impact of Mexican Border rift structural inheritance on Laramide rivers of the Tornillo basin, west Texas (USA): Insights from detrital zircon provenance
Authors: Kortyna Cullen , Stockli Daniel F. , Lawton Timothy F. , Covault Jacob A. , Sharman Glenn R.
Published: October 2023

Late Cretaceous to Eocene Laramide basement–involved shortening fragmented the Sevier and Mexican foreland basins. This resulted in a major drainage reorganization in response to the emerging topography of Laramide basement–cored uplifts and Mexican inverted Border rift basins. This study presents new depth-profile detrital zircon U-Pb data (3679 ages from 28 samples) from Upper Cretaceous–Eocene fluvial strata of the Tornillo basin in west Texas to determine sedimentary provenance and reconstruct sediment dispersal through the U.S.-Mexico border region. Detrital zircon U-Pb data are dominated by Hauterivian–Coniacian (130–87 Ma; ~20%) and Coniacian–Ypresian (87–52 Ma; ~30%) ages that represent Cordilleran and Laramide arc magmatism, respectively. Subordinate age groups are Paleoproterozoic–Mesoproterozoic (1900–1300 Ma; ~12%), Ectasian–Tonian (1300–900 Ma; ~8%), Tonian–Pennsylvanian (900–300 Ma, ~10%); Permian–Triassic (300–200 Ma; ~8%), and Jurassic–Early Cretaceous (200–130 Ma; ~11%). Detrital zircon maximum depositional ages provide new constraints on the chronostratigraphic framework of the Tornillo Group, the stratigraphic nature of the Cretaceous-Paleogene boundary, and the stratigraphic level of the Paleocene–Eocene thermal maximum. Depth-profile core-rim age pairs yielded Paleoproterozoic–Mesoproterozoic and Jurassic cores with Cretaceous–Paleogene rims, which represent zircons derived from Laramide magmatic rocks that intruded Yavapai-Mazatzal basement and Cordilleran-Nazas magmatic rocks. Zircon grains with Ectasian–Tonian cores and Paleozoic rims likely represent Appalachian-derived and/or Coahuila terrane zircons recycled from the inverted Mesozoic Bisbee basin and Chihuahua trough. These results demonstrate that fluvial strata in the Tornillo basin were sourced from Laramide and Cordilleran magmatic rocks, Yavapai-Mazatzal basement, and recycled Mexican Border rift sedimentary rocks in the southwest United States and northern Sonora, and these sediments were delivered via a large (>103-km-long), axial-trunk river. Additional recycled detritus from Mexican Border rift sedimentary rocks in the Chihuahua fold belt was delivered via transverse tributaries. This drainage reconstruction indicates that the Tornillo river flowed along an inversion-flank drainage corridor adjacent to topography formed by the inverted Mexican Border rift. Therefore, inherited Mexican Border rift architecture represented a first-order control on sediment routing to the Tornillo basin.
The eight architectural zones of nonmarine basins
Authors: Loughney Katharine M. , Holland Steven M.
Published: October 2023

One of the goals of sequence stratigraphy is to model the conditions that generate stratigraphic architecture at outcrop to basin scales. Accommodation and sedimentation are the principal variables included in sequence-stratigraphic models that describe facies architecture in marine successions. Similar models exist to describe wholly nonmarine architecture. Distinct models are commonly applied to basins containing predominantly lacustrine or predominantly fluvial facies, which can make it difficult to apply models to the entire history of a basin that may include both lacustrine-dominated or fluvial-dominated phases, depending on climatic and tectonic conditions. To account for these changing conditions over the history of nonmarine basins, we present a conceptual three-dimensional model that describes the potential architectural patterns under specific combinations of accommodation, sediment flux, and water balance. Sectors of the model delineate where basins are underfilled or overfilled with respect to accommodation and limited with respect to sediment and water, creating eight zones with different implications for the development of facies architecture. Different types of basins (e.g., foreland, extensional, pull-apart, intracratonic) show broadly different trends in architecture through time. Subtle changes in accommodation, sedimentation, and water balance in the model correspond to shifts in facies architecture between lithostratigraphic units, but architectural transitions within individual basins are more important indicators of evolving basin conditions than comparisons among all basins. This model may serve as a guide for comparing the influence of distinct drivers of architecture among different types of basins as well as identifying important intervals of change during the history of basin filling. The availability of commensurate data on the history of accommodation, sedimentation, and water balance is, however, an ongoing challenge to reconstructing complete basin histories. Future analyses will test how well predicted facies stacking patterns compare to observed nonmarine stratigraphic successions resulting from the combination of accommodation, sediment flux, and water balance during the history of basin filling.
Association between the extension of smoke-free legislation and incident acute myocardial infarctions in Singapore from 2010 to 2019: an interrupted time-series analysis
Authors: Ho Jamie S Y , Ho Andrew F W , Jou Eric , Liu Nan , Zheng Huili , Aik Joel
Published: October 2023

Background

We examined the association between smoke-free laws implemented in the outdoors and the common areas of residential apartment blocks and reported acute myocardial infarctions (AMI) in Singapore.

Methods

We used an interrupted time-series design and seasonal autoregressive integrated moving average models to examine the effect of the smoke-free law extensions in 2013 (common areas of residential blocks, covered pedestrian linkways, overhead bridges and within 5 m of bus stops), 2016 (parks) and 2017 (educational institutions, buses and taxis) on the monthly incidence rate of AMIs per 1 000 000 population.

Results

We included 133 868 AMI reports from January 2010 to December 2019. Post-2013, there was a decrease in the AMI incidence trend (β=−0.6 per month, 95%CI −1.0 to –0.29) and 2097 (95% CI 2094 to 2100) more AMIs may have occurred without the extension. There was a significant step-decline in male AMIs and a non-significant step-increase in female AMIs post-2013. Those 65 years and older experienced a greater decline to the postlegislation 2013 trend (β=−5.9, 95% CI −8.7 to –3.1) compared with those younger (β=−0.4, 95% CI −0.6 to –0.2), while an estimated 19 591 (15 711 to 23472) additional AMI cases in those 65 years and above may have occurred without the extension. We found a step-increase in monthly AMI incidence post-2016 (β=14.2, 95%CI 3.3 to 25.0).

Conclusion

The 2013 smoke-free law extension to residential estates and other outdoor areas were associated with a decline in AMIs and those above the age of 65 years and men appeared to be major beneficiaries. Additional epidemiological evidence is required to support the expanded smoke-free legislation to parks, educational institutions, buses and taxis.
Performance of predictive algorithms in estimating the risk of being a zero-dose child in India, Mali and Nigeria
Authors: Biswas Arpita , Tucker John , Bauhoff Sebastian
Published: October 2023

Introduction

Many children in low-income and middle-income countries fail to receive any routine vaccinations. There is little evidence on how to effectively and efficiently identify and target such ‘zero-dose’ (ZD) children.

Methods

We examined how well predictive algorithms can characterise a child’s risk of being ZD based on predictor variables that are available in routine administrative data. We applied supervised learning algorithms with three increasingly rich sets of predictors and multiple years of data from India, Mali and Nigeria. We assessed performance based on specificity, sensitivity and the F1 Score and investigated feature importance. We also examined how performance decays when the model is trained on older data. For data from India in 2015, we further compared the inclusion and exclusion errors of the algorithmic approach with a simple geographical targeting approach based on district full-immunisation coverage.

Results

Cost-sensitive Ridge classification correctly classifies most ZD children as being at high risk in most country-years (high specificity). Performance did not meaningfully increase when predictors were added beyond an initial sparse set of seven variables. Region and measures of contact with the health system (antenatal care and birth in a facility) had the highest feature importance. Model performance decreased in the time between the data on which the model was trained and the data to which it was applied (test data). The exclusion error of the algorithmic approach was about 9.1% lower than the exclusion error of the geographical approach. Furthermore, the algorithmic approach was able to detect ZD children across 176 more areas as compared with the geographical rule, for the same number of children targeted.

Interpretation

Predictive algorithms applied to existing data can effectively identify ZD children and could be deployed at low cost to target interventions to reduce ZD prevalence and inequities in vaccination coverage.
The response to COVID-19 in Timor-Leste: lessons learnt
Authors: Francis Joshua R , de Araujo Rui Maria , da Silva Viegas Odete , Lobo Sergio , Coelho Danina , Mathur Arvind , Bothra Vinay , Yu Dongbao , Draper Anthony D K , Yan Jennifer , Martins Nelson
Published: October 2023

The response to the COVID-19 pandemic in Timor-Leste offers lessons that may be useful for incorporating into future responses to infectious disease outbreaks in similar resource-limited settings. In this paper, we identify nine key areas for learning from Timor-Leste’s experience of the COVID-19 pandemic: (1) the importance of prior preparation for health emergencies, (2) the establishment of effective leadership and governance structures, (3) the protective impact of early border restrictions, (4) the rapid expansion of diagnostic laboratory capacity, (5) the impact of effective health communications in supporting the vaccine roll-out, (6) the opportunity to build capacity for clinical care, (7) the use of public health interventions that were found to have limited public health impact, (8) the broader effects of the pandemic and the public health response and (9) translation of lessons from COVID-19 to other public health priorities.
Sustaining a culture of safety and optimising patient outcomes while implementing zero harm programme: a 2-year project of the nursing services – SBAHC
Authors: Obaid Lina Mohammed , Ali Ibrahim , Al Baker Ahmad , Al Shiekh Abdallah Wisal Othman , Plando Rhez Legaspi , Khawaldeh Mohammed Elian , Panaligan Ria Kharen Joy
Published: October 2023

This quality improvement report details how Sultan Bin Abdulaziz Humanitarian City (The City), the largest rehabilitation facility within Middle East with a capacity of 511 beds and more than 20 nursing in-patient units improved the quality and patient safety culture in nursing services after successfully adopting and implementing the zero harm programme.

In healthcare settings, the idea of zero harm including zero incidents, zero injuries and injury-free are commonly used to highlight the importance of patient safety. Patient injuries and deaths resulting from hospital-acquired illnesses such as medication administration errors, falls, central line-associated bloodstream infections, hospital-acquired pressure injuries and catheter-associated urinary tract infection are largely preventable and grossly unacceptable occurrences. Achieving zero incidents of such critical measures can significantly impact treatment plan and enhance patient experience.

The projects’ purpose was to build a new culture of safety by implementing innovative strategy designed to protect patients from preventable harm while maintaining an extraordinary high standard of quality patient care. Additionally, the programme was established with the aim of instilling a sense of commitment to every nurse working in this organisation to anticipate potential harms and to be vigilant to prevent it before it reaches the patient.

This document also describes a set of initiatives aimed at mitigating preventable incidents and ultimately achieving zero harm on our organisation. The result showed a significant increase by 95% between the percentage of nursing units that had 365 days of zero harm in 2020 and 2021. This improvement indicates that the concept of zero harm had been successfully inculcated among nursing units and had motivated nursing staff to uphold a higher culture of patient safety. Furthermore, by incorporating the Just Culture model into the electronic reporting system, the reporting rate of occurrences in the zero-harm programme was supported and sustained.
Evaluation of procedural pain for neonates in a neonatal intensive care unit: a single-centre study
Authors: Luo Feixiang , Zhu Huaiyu , Mei Lingli , Shu Qi , Cheng Xiaoying , Chen Xiaofei , Zhao Yisheng , Chen Shuohui , Pan Yun
Published: October 2023

Background

To evaluate the procedural pain experienced by neonates in a neonatal intensive care unit (NICU) setting and determine the corresponding pain grades.

Methods

Two experienced nurses independently used the Neonatal Infant Pain Scale (NIPS) to evaluate the neonatal pain during procedures taking place in the tertiary NICU and two level-two neonatal care units in the Children’s Hospital of Zhejiang University School of Medicine. The mean and distribution of NIPS pain scores and the corresponding pain grades of participants when experiencing clinical painful procedures were analysed.

Results

A total of 957 neonates exposed to 15 common clinical painful procedures were included in the study. The clinical painful procedures experienced by 957 participants could be divided into three groups: severe pain (NIPS score 5–7: peripheral intravenous cannulation, arterial catheterisation, arterial blood sampling, peripherally inserted central catheter placement and nasopharyngeal suctioning), mild to moderate pain (NIPS score 3–4: finger prick, intramuscular injection, adhesive removal, endotracheal intubation suctioning, heel prick, lumbar puncture and subcutaneous injection) and no pain to mild pain (NIPS score 0–2: gastric tube insertion, enema and intravenous injection).

Conclusions

The neonatal pain response to clinical procedures in NICU had certain pattern and preintervention drug analgesia could be taken for painful procedures with clustered high NIPS pain scores. Meanwhile, full coverage non-drug pain relief measures could be taken for procedures that are with scattered pain scores, and real-time pain evaluation should be provided to determine whether further drug analgesia is required.
Clinical safety and efficacy of allogenic human adipose mesenchymal stromal cells-derived exosomes in patients with mild to moderate Alzheimer’s disease: a phase I/II clinical trial
Authors: Xie Xinyi , Song Qingxiang , Dai Chengxiang , Cui Shishuang , Tang Ran , Li Suke , Chang Jing , Li Ping , Wang Jintao , Li Jianping , Gao Chao , Chen Hongzhuan , Chen Shengdi , Ren Rujing , Gao Xiaoling , Wang Gang
Published: October 2023

Background

There have been no effective treatments for slowing or reversing Alzheimer’s disease (AD) until now. Growing preclinical evidence, including this study, suggests that mesenchymal stem cells-secreted exosomes (MSCs-Exos) have the potential to cure AD.

Aims

The first three-arm, drug-intervention, phase I/II clinical trial was conducted to explore the safety and efficacy of allogenic human adipose MSCs-Exos (ahaMSCs-Exos) in patients with mild to moderate AD.

Methods

The eligible subjects were assigned to one of three dosage groups, intranasally administrated with ahaMSCs-Exos two times per week for 12 weeks, and underwent follow-up visits at weeks 16, 24, 36 and 48.

Results

No adverse events were reported. In the medium-dose arm, Alzheimer’s Disease Assessment Scale–Cognitive section (ADAS-cog) scores decreased by 2.33 (1.19) and the basic version of Montreal Cognitive Assessment scores increased by 2.38 (0.58) at week 12 compared with baseline levels, indicating improved cognitive function. Moreover, the ADAS-cog scores in the medium-dose arm decreased continuously by 3.98 points until week 36. There were no significant differences in altered amyloid or tau deposition among the three arms, but hippocampal volume shrank less in the medium-dose arm to some extent.

Conclusions

Intranasal administration of ahaMSCs-Exos was safe and well tolerated, and a dose of at least 4×108particles could be selected for further clinical trials.

Trial registration number

NCT04388982.
Investigating the influence of selected leadership styles on patient safety and quality of care: a systematic review and meta-analysis
Authors: Singh Ankit , Yeravdekar Rajiv , Jadhav Sammita
Published: October 2023

Background

There is a popular belief that transformational leadership (TL) and servant leadership (SL) styles are influential in establishing a patient safety (PS) culture and improving the quality of care (QC). However, there are very few review articles investigating this phenomenon.

Purpose

This study performs a systematic review and meta-analysis to ascertain the influences of TL and SL on PS and QC.

Methods

Published research work indexed in the two popular databases, that is, Scopus and PubMed, was selected based on the inclusion criteria. The systematic review was performed as per Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data such as country of publication, year, data type, research design, target population, sample size and conclusion were selected from the studies.

Results

There are pieces of evidence suggesting a medium to strong effect of TL on PS. At the same time, the effect of TL on QC is not direct but indirect and is mediated through variables such as fostering positive organisational culture and enhancing organisational outcomes such as job satisfaction, leader effectiveness and willingness of nurses to spend some extra effort. A total of 27 studies were selected for final evaluation and 11 reported a relationship between TL and PS. The ‘Fisher r-to-z transformed correlation coefficients’ ranged from 0.3769 to 0.8673. Similarly, a total of four studies reported the relationship between TL and QC, ‘Fisher r-to-z transformed correlation coefficients’ ranged from 0.0802 to 0.5101, with most estimates being positive (80%).

Conclusion

TL has a strong and positive effect on PS but a positive and weak effect on the QC. There is not much evidence to establish SL’s influence on PS and QC.
Impact of f(ℜ,𝒯2) theory on stable Finch–Skea gravastar model
Authors: Sharif M. , Naz Saba
Published: October 2023

This paper examines the structure of a gravitational vacuum star (also known as gravastar) in the background of [Formula: see text] theory. This hypothetical object can be treated as a substitute of a black hole, with three regions: (i) the internal region, (ii) the intrinsic shell and (iii) the outer region. We examine these geometries using Finch–Skea metric for the radial metric component along with the particular [Formula: see text] model. We determine singularity-free solutions for both the inner as well as thin-shell domains. The smooth matching of the interior region with external Schwarzschild spacetime is obtained through Israel matching constraints. Finally, we study various characteristics of gravastar domains including the equation-of-state parameter, proper length, entropy, energy as well as surface redshift. It is found that the compact gravastar structure is a viable alternate to the black hole in the perspective of this gravity.
Optical scatterings in layered systems
Authors: Chiu Chih-Wei , Liu Chang-Ting , Lin Chiun-Yan , Lin Ming-Fa
Published: October 2023

This paper presents a theoretical framework for exploring the optical properties of layered materials. The derived analytical formulas for reflectance and transmittance spectra incorporate vertical valence-state transitions and appropriate boundary conditions for finite-width bulk materials, integrated with the generalized tight-binding model to account for intrinsic interactions and external fields. The study reveals distinct structures in the spectra of multilayer graphene for different stacking layers at low energies (∼0.2–0.8[Formula: see text]eV), attributed to interband transitions at the K point. Furthermore, the high-energy part (≳5[Formula: see text]eV) highlights thickness-dependent plasmon effects characterized by unique resonance frequencies in the optical spectra. These features depend on the dimensionality, interlayer coupling, and electronic structure of the material. This work provides a deeper understanding of the optical properties of layered structures, facilitating their exploration and characterization for diverse applications.
Exploring Networked Airborne Computing: A Comprehensive Approach with Advanced Simulator and Hardware Testbed
Authors: Zhang Haomeng , Wang Baoqian , Wu Ruitao , Xie Junfei , Wan Yan , Fu Shengli , Lu Kejie
Published: October 2023

In recent years, networked airborne computing (NAC) has emerged as a promising paradigm because it can leverage the collaborative capabilities of unmanned aerial vehicles (UAVs) for distributed computing tasks. Despite the burgeoning interests in NAC and UAV-based computing, many existing studies depend on over-simplified simulations for performance evaluation. This reliance has led to a gap in our understanding of NAC’s true potential and challenges. To fill this gap, this paper presents a comprehensive approach: the creation of a realistic simulator and a novel hardware testbed. The simulator, developed using ROS and Gazebo, emulates networked UAVs, focusing on resource-sharing and distributed computing capabilities. This tool offers a cost-effective, scalable, and adaptable environment, making it ideal for preliminary investigations across a myriad of real-world scenarios. In parallel, our hardware testbed comprises multiple quadrotors, each equipped with a Pixhawk control unit, a Raspberry Pi computing module, a real-time kinematic (RTK) positioning system, and multiple communication units. Through extensive simulations and hardware tests, we delve into the key determinants of NAC performance, such as computation task size, number of UAVs, communication quality, and UAV mobility. Our findings not only underscore the inherent challenges in optimizing NAC performance but also provide pivotal insights for future enhancements. These insights encompass refining the simulator, reducing computation overheads, and equipping the hardware testbed with cutting-edge communication devices.
An Efficient Approach to Include Transport Effects in Thin Coating Layers in Electrochemo-Mechanical Models for All-Solid-State Batteries
Authors: Sinzig Stephan , Schmidt Christoph P. , Wall Wolfgang A.
Published: October 2023

A novel approach is presented to efficiently include transport effects in thin active material coating layers of all-solid-state batteries using a dimensionally reduced formulation embedded into a three-dimensionally resolved coupled electrochemo-mechanical continuum model. In the literature, the effect of coating layers is so far captured by additional zero-dimensional resistances to circumvent the need for an extremely fine mesh resolution. However, a zero-dimensional resistance cannot capture transport phenomena along the coating layer, which can become significant, as we will show in this work. Thus, we propose a model which resolves the thin coating layer in a two-dimensional manifold based on model assumptions in the direction of the thickness. This two-dimensional formulation is monolithically coupled with a three-dimensional model representing the other components of a battery cell. The approach is validated by showing conservation properties and convergence and by comparing the results with those computed with a fully resolved model. Results for realistic microstructures of a battery cell, including coating layers as well as design recommendations for a preferred coating layer, are presented. Based on those results, we show that existing modeling approaches feature remarkable errors when transport along the coating layer is significant, whereas the novel approach resolves this.
Preparation of LiFe0.99Mn0.01PO4 Cathode Material with Lower Fe-Li Antisite via Wet-Lithiation Following by Tavorite-Olivine Phase Transition
Authors: Ren Xugang , Li Yunjiao , He Zhenjiang , Xi Xiaoming , Yang Jiachao , Hao Shuaipeng , Shen Xinjie , Wu Qing
Published: October 2023

Mn doping is widely used to improve the kinetic properties of LiFePO4 cathode materials. In this work, we synthesized LiFe0.99Mn0.01PO4 cathode material by a novel phase transition from the tavorite LiFePO4OH structure to the olivine LiFePO4 structure at 600 °C. A lower crystallization temperature not only results in a looser lattice for LiFePO4 material but also prevents crystal growth in higher temperatures and shortens the ion diffusion path. Experiments reveal that Mn doping can further broaden the lattice on this basis and thus ameliorate the Li+ diffusion property. The Density-Functional Theory (DFT) calculations not only support the above argument, but also predict that the LiFePO4 cathodes obtained from LiFePO4OH-to-LiFePO4 phase transition own lower Fe-Li antisite concentration (due to the high Fe-Li antisite formation energy of pre-lithiated precursor LiFePO4OH). As a result, the obtained LiFe0.99Mn0.01PO4 yields a discharge capacity close to the theoretical capacity of 169.2 mAh g−1 at a low rate of 0.2 C, 142.9 mAh g−1 at a high rate of 10 C and a capacity retention of 97.8% till 1000 cycles at 1 C. These findings indicate that the LiFePO4OH enabled by prelithiation in liquid provides a new idea for realizing substitution-modified LiFePO4 with optimal electrochemical performance.
Novel perspectives regarding the physiologic mechanisms by which gliflozins induce reticulocytosis and erythrocytosis
Authors: Heyman Samuel N. , Armaly Zaher , Hamo-Giladi Dalit B. , Abassi Zaid
Published: October 2023

Gliflozins provide a breakthrough in the management of type-2 diabetes. In addition to facilitating normoglycemia, these sodium-glucose cotransporter type 2 (SGLT2) inhibitors attenuate obesity, hypertension, dyslipidemia, and fluid retention, reduce cardiovascular morbidity, retard the progression of renal dysfunction, and improve survival. The administration of gliflozins also triggers erythropoietin (EPO) production, with the consequent induction of reticulocytosis and erythrocytosis. The mechanism(s) by which gliflozins induce erythropoiesis is a matter of debate. Whereas the canonical pathway of triggering EPO synthesis is through renal tissue hypoxia, it has been suggested that improved renal oxygenation may facilitate EPO synthesis via noncanonical trails. The latter proposes that recovery of peritubular interstitial fibroblasts producing erythropoietin (EPO) is responsible for enhanced erythropoiesis. According to this hypothesis, enhanced glucose/sodium reuptake by proximal tubules in uncontrolled diabetes generates cortical hypoxia, with injury to these cells. Once transport workload declines with the use of SGLT2i, they recover and regain their capacity to produce EPO. In this short communication, we argue that this hypothesis is incorrect. First, there is no evidence for interstitial cell injury related to hypoxia in the diabetic kidney. Tubular, rather than interstitial cells are prone to hypoxic injury in the diabetic kidney. Moreover, hypoxia, not normoxia, stimulates EPO synthesis by hypoxia-inducible factors (HIFs). Hypoxia regulates EPO synthesis as it blocks HIF prolyl hydroxylases (that initiate HIF alpha degradation), hence stabilizing HIF signals, inducing HIF-dependent genes, including EPO located in the deep cortex, and its production is initiated by the apocrinic formation of HIF-2, colocalized in these same cells.
Active Vibration Control of Wind Turbine Using Virtual TMD Algorithm Based on Aerodynamic-Structure-Servo Coupling Model
Authors: Long Tao , Yang Qingshan , Wang Qi , Huang Guoqing , Zhou Xuhong , Yang Yu
Published: October 2023

In order to extract more wind energy, the wind turbine rotor becomes larger and the tower becomes taller. With more flexibility and smaller damping, wind turbine tower is prone to vibrate in winds. Meanwhile, the tower suffers the periodic loadings caused by the rotor rotation in the operational condition. The excessive vibrations could not only significantly affect the power generation but shorten the structural life due to the fatigue as well. It is challenging to reduce the vibration caused by the rotor rotation using the passive tuned mass damper (TMD) and traditional LQR controller due to the limited effective bandwidth. Therefore, an active tuned mass damper (ATMD) using a virtual TMD algorithm is proposed to mitigate the along-wind vibration of the tower under parked and operational conditions. The virtual TMD algorithm exhibits wide effective bandwidth and only requires the acceleration information on the top of the tower or the relative displacement of the active TMD. Firstly, the aerodynamic-structure-servo coupling (ASSC) model of the wind turbine is established which considers the interaction among the aerodynamic load, structure, and servo system. Secondly, the accuracy of the ASSC model is then verified using the onshore 5 MW wind turbine by the National Renewable Energy Laboratory (NREL). Thirdly, the ATMD feedback control force is designed by the virtual TMD algorithm. Finally, the reduction effect on the along-wind vibration by the proposed controller is evaluated at both of operational and parked conditions using the ASSC model. The TMD and LQR controller are utilized for comparison. The numerical results demonstrate that tuned mass damper (TMD) system with fixed parameters becomes detuned and may loses its effectiveness at different wind speeds. In contrast, active control can suppress the vibration of wind turbines at different wind speeds. Compared to the LQR controller, the proposed controller can enhance the reduction effect of wind turbine response with smaller stroke and control force at operational conditions.
FAK Drives Resistance to Therapy in HPV-Negative Head and Neck Cancer in a p53-Dependent Manner
Authors: Pifer Phillip M. , Yang Liangpeng , Kumar Manish , Xie Tongxin , Frederick Mitchell , Hefner Andrew , Beadle Beth , Molkentine David , Molkentine Jessica , Dhawan Annika , Abdelhakiem Mohamed , Osman Abdullah A. , Leibowitz Brian J. , Myers Jeffrey N. , Pickering Curtis R. , Sandulache Vlad C. , Heymach John , Skinner Heath D.
Published: October 2023

Purpose:

Radiation and platinum-based chemotherapy form the backbone of therapy in human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC). We have correlated focal adhesion kinase (FAK/PTK2) expression with radioresistance and worse outcomes in these patients. However, the importance of FAK in driving radioresistance and its effects on chemoresistance in these patients remains unclear.

Experimental Design:

We performed an in vivo shRNA screen using targetable libraries to identify novel therapeutic sensitizers for radiation and chemotherapy.

Results:

We identified FAK as an excellent target for both radio- and chemosensitization. Because TP53 is mutated in over 80% of HPV-negative HNSCC, we hypothesized that mutant TP53 may facilitate FAK-mediated therapy resistance. FAK inhibitor increased sensitivity to radiation, increased DNA damage, and repressed homologous recombination and nonhomologous end joining repair in mutant, but not wild-type, TP53 HPV-negative HNSCC cell lines. The mutant TP53 cisplatin-resistant cell line had increased FAK phosphorylation compared with wild-type, and FAK inhibition partially reversed cisplatin resistance. To validate these findings, we utilized an HNSCC cohort to show that FAK copy number and gene expression were associated with worse disease-free survival in mutant TP53, but not wild-type TP53, HPV-negative HNSCC tumors.

Conclusions:

FAK may represent a targetable therapeutic sensitizer linked to a known genomic marker of resistance.
CD38 x ICAM-1 Bispecific Antibody Is a Novel Approach for Treating Multiple Myeloma and Lymphoma
Authors: Chen Xiaocheng , Wong Oi Kwan , Reiman Lauren , Sherbenou Daniel W. , Post Leonard
Published: October 2023

The cluster of differentiation 38 (CD38) is a well-validated target for treating multiple myeloma. Although anti-CD38 mAbs have demonstrated outstanding initial responses in patients with multiple myeloma, nearly all patients eventually develop resistance and relapse. In addition, currently approved CD38 targeting therapies have failed to show monotherapy efficacy in lymphomas, where CD38 expression is present but at lower levels. To effectively target CD38 on tumor cells, we generated an antibody-dependent cellular cytotoxicity (ADCC) enhanced bispecific CD38 x intercellular cell adhesion molecule 1 (ICAM-1) antibody, VP301. This bispecific antibody targets unique epitopes on CD38 and ICAM-1 on tumor cells with reduced red blood cell binding compared with the benchmark CD38 antibody daratumumab. VP301 demonstrated potent ADCC and antibody-dependent cellular phagocytosis activities on a selected set of myeloma and lymphoma cell lines even those with low CD38 expression. In an ex vivo drug sensitivity assay, we observed responses to VP301 in multiple myeloma primary samples from relapsed/refractory patients. Moreover, VP301 demonstrated potent tumor inhibition activities in in vivo myeloma and lymphoma models. Interestingly, combination of VP301 with the immunomodulatory drug, lenalidomide, led to synergistic antitumor growth activity in an in vivo efficacy study. In conclusion, the CD38 x ICAM-1 bispecific antibody VP301 demonstrated promising efficacy and specificity toward CD38+ and ICAM-1+ tumor cells and represents a novel approach for treating multiple myeloma and lymphoma.
TABLE 3 from The Inherited KRAS-variant as a Biomarker of Cetuximab Response in NSCLC
Authors: Weidhaas Joanne B. , Hu Chen , Komaki Ritsuko , Masters Gregory A. , Blumenschein George R. , Chang Joe Y. , Lu Bo , Dicker Adam P. , Bogart Jeffrey A. , Garces Yolanda I. , Narayan Samir , Robinson Clifford G. , Kavadi Vivek S. , Greenberger Joel S. , Koprowski Christopher D. , Welsh James , Gore Elizabeth M. , MacRae Robert M. , Paulus Rebecca , Bradley Jeffrey D.
Published: October 2023

LF within non-variant patients by as-treated cetuximab
TABLE 2 from The Inherited KRAS-variant as a Biomarker of Cetuximab Response in NSCLC
Authors: Weidhaas Joanne B. , Hu Chen , Komaki Ritsuko , Masters Gregory A. , Blumenschein George R. , Chang Joe Y. , Lu Bo , Dicker Adam P. , Bogart Jeffrey A. , Garces Yolanda I. , Narayan Samir , Robinson Clifford G. , Kavadi Vivek S. , Greenberger Joel S. , Koprowski Christopher D. , Welsh James , Gore Elizabeth M. , MacRae Robert M. , Paulus Rebecca , Bradley Jeffrey D.
Published: October 2023

OS models within KRAS-variant: time-varying cetuximab effect
Usability and Acceptability of a Corneal-Plane α-Opic Light Logger in a 24-h Field Trial
Authors: Balajadia Eljoh , Garcia Sophie , Stampfli Janine , Schrader Björn , Guidolin Carolina , Spitschan Manuel
Published: October 2023

Introduction: Exposure to light fundamentally influences human physiology and behaviour by synchronising our biological clock to the external light-dark cycle and controlling melatonin production. In addition to well-controlled laboratory studies, more naturalistic approaches to examining these “non-visual” effects of light have been developed in recent years. As naturalistic light exposure is quite unlike well-controlled stimulus conditions in the laboratory, it is critical to measure light exposure in a person-referenced way, the “spectral diet.” To this end, light loggers have been developed to capture personalised light exposure. As an alternative to light sensors integrated into wrist-worn actimeters, pendants, or brooch-based light loggers, a recently developed wearable light logger laterally attached to spectacle frames enables the measurement of biologically relevant quantities in the corneal plane. Methods: Here, we examine the usability and acceptability of using the light logger in an undergraduate student sample (n = 18, mean±1SD: 20.1 ± 1.7 years; 9 female; Oxford, UK) in real-world conditions during a 24-h measurement period. We probed the acceptability of the light logger using rating questionnaires and open-ended questions. Results: Our quantitative results show a modest acceptability of the light logger. A thematic analysis of the open-ended questions reveals that the form factor of the device, in particular, size, weight, and stability, and reactions from other people to the wearer of the light logger, were commonly mentioned aspects. Conclusion: In sum, the results indicate the miniaturisation of light loggers and “invisible” integration into extant everyday objects as key areas for future technological development, facilitating the availability of light exposure data for developing personalised intervention strategies in both research, clinical and consumer contexts.
Myopic Vascular Changes Revealed by Optical Tomography Angiography and Their Association with Myopic Fundus Manifestations
Authors: Xu Yijia , Yang Weiming , Niu Lingling , Wang Xiaoying , Zhou Xingtao , Li Meiyan
Published: October 2023

Introduction: We aimed to quantify and evaluate fundal vascular changes at different severities of myopia using optical tomography angiography (OCTA) and explore their association with fundus changes captured by ultra-widefield (UWF) fundus cameras. Methods: Seventy-four participants with myopia were enrolled in the study and underwent basic ophthalmic examination, OCTA, and UWF fundus photography. Multiple parameters were obtained using OCTA (flow area, structure thickness, and vessel density) and UWF fundus cameras (tessellation and parapapillary atrophy [PPA]). Results: The right eye of 30 participants with low and moderate myopia and 44 participants with high myopia (HM) were included. Patients with HM had a larger flow area of the outer retina (FA-OR) and a smaller thickness of choroid (TC). Axial length was significantly correlated with retinal and choroidal flow area and thickness in the different zones. The PPA area was positively correlated with FA-OR and negatively correlated with TC. Tessellation exhibited different levels of correlation with OCTA parameters regarding the flow area, thickness, and vessel density of the fundal layers, mainly in the inner retina. Conclusion: FA-OR and TC exhibited sensitive changes in patients with HM and axial elongation; therefore, they could serve as predictive OCTA biomarkers. The PPA and tessellation were connected to the vascular and structural changes revealed by OCTA.
A Preliminary Discussion on the Safety of Mild Therapeutic Hypothermia in Target Vessels after Endovascular Intervention in Acute Large Vessel Occlusion Cerebral Infarction
Authors: Li Jiang , Tang Shaonian , Liu Juanli , He Wenlin , Yan Jinjin , Huang Zhiyong , Li Xuesong
Published: October 2023

Introduction: The aim of this study was to discuss the safety of rapid administration of 4°C hypothermic normal saline into the occluded vessels using an intra-arterial catheter to induce mild hypothermia following endovascular thrombectomy in patients with acute large vessel occlusion cerebral infarction. Methods: We selected 78 patients with acute large vessel occlusion cerebral infarction who underwent endovascular thrombectomy in the Department of Neurology of our hospital from January 2020 to July 2022 and achieved TICI 2b recanalization. Result: Twenty-five patients were administered 500 mL of 4°C hypothermic normal saline in the occluded vessels at a rate of 25 mL/min to induce mild hypothermia. Twenty pairs of subjects conformed to strict matching and were finally included in the statistical analysis. The two groups of patients differed significantly in white blood cell count and percentage of neutrophils (p < 0.05); however, there were no significant differences in D-dimer, procalcitonin, and BNP levels. The two groups of patients did not differ significantly with respect to the incidence of the following indicators: upper gastrointestinal bleeding; pulmonary infection; venous thrombosis; vasospasms; seizures; and chills (p > 0.05). Conclusion: Mild therapeutic hypothermia in target vessels plus endovascular thrombectomy was shown to be safe in patients with acute large vessel occlusion cerebral infarction.
The Effects of Dialysis Modality and Emotional Distress on Fatigue in Patients Undergoing Dialysis
Authors: Ouyang Qin , Yang Fengjie , Wu Hong , Tang Shiqi , Peng Xinyue , Li Yuxin , Wang Jianwen
Published: October 2023

Introduction: Fatigue is a common but often overlooked symptom in dialysis patients. Factors affecting fatigue in dialysis patients are currently unclear. There are few studies on the effects of mental factors and dialysis modality on fatigue. This study aims to explore the potential relationship between fatigue and insomnia, as well as psychiatric disorders such as anxiety and depression among patients who undergo peritoneal dialysis (PD) or hemodialysis (HD). Methods: There were 96 HD patients and 160 PD patients at our hospital who voluntarily participated in the survey. A questionnaire survey was conducted to gather general characteristics of the patients and to evaluate fatigue, sleep quality, anxiety, and depression levels among PD and HD patients. Results: The overall fatigue score was 53.83 ± 14.22 for the PD group and 57.92 ± 16.35 for the HD group. Notably, the fatigue level was lower in the PD group compared to the HD group (p < 0.05). Univariate analysis indicated that fatigue was associated with occupational status and income in the PD group, as well as educational level and income in the HD group (p < 0.05). Correlation analysis revealed that patients in both groups who were older and had higher scores for insomnia, anxiety, and depression experienced more severe fatigue. Moreover, body mass index was positively correlated with fatigue status in the PD group, while duration of dialysis showed a positive association with fatigue in the HD group. Multivariate regression analysis identified income and depression as major factors influencing fatigue in the PD group, and duration of dialysis, income, and depression in the HD group. Conclusion: Patients who undergo dialysis exhibit high levels of fatigue, with the severity of fatigue being less pronounced in the PD group compared to the HD group. Fatigue in these patients is associated with the duration of dialysis, income level, and presence of depression.
Aortic Stiffness Is Independently Associated with Intracranial Carotid Artery Calcification in Patients with Ischemic Stroke
Authors: Gozdalski Jacek , Nowicki Tomasz K. , Kwarciany Mariusz , Kowalczyk Kamil , Narkiewicz Krzysztof , Gasecki Dariusz
Published: October 2023

Introduction: Intracranial carotid artery calcification (ICAC), as a strong contributor to the occurrence of ischemic stroke, might be present in the medial or intimal arterial layer. Traditional cardiovascular risk factors (CVRFs) are associated with ICAC; however, its association with new markers of vascular function is less understood. The paper aimed to evaluate the relationship between carotid-femoral pulse wave velocity (CF-PWV) and ICAC subtypes. Methods: We enrolled 65 patients with ischemic stroke. CF-PWV, systolic, diastolic, mean blood pressure, and pulse pressure were measured within 6 ± 2 days after stroke onset, and CT was performed within 24 h. ICAC on the stroke site was classified by two methods: volume and score based. Tertiles of ICAC volume were determined, and low-grade ICAC (T1) was regarded as a reference. According to the score-based method, (dominant) medial and (dominant) intimal ICAC subtypes were determined. Data were analyzed with multivariate logistic regression. Results: Medial and intimal ICAC subtypes were found in 34 (52%) and 24 (37%) patients, respectively. In 11% of patients, no ICAC calcifications were found. CF-PWV was higher in patients with high-grade ICAC (OR = 1.56, 95% CI = 1.03–2.35, p = 0.035). CF-PWV was higher in patients with the medial ICAC subtype (OR = 1.60, 95% CI = 1.00–2.55, p = 0.049) after adjustment for traditional CVRFs. Conclusion: Our study demonstrates that among patients with ischemic stroke, aortic stiffness is independently associated with ICAC and that medial ICAC, compared with intimal ICAC, is accompanied by more advanced aortic stiffness.