bluuebunny/crossref_metadata_2025 huggingface dataset:
Modulation of autophagy, apoptosis and oxidative stress: a clue for repurposing metformin in photoaging
Authors: Mostafa Dalia Kamal , Nayel Omnia A. , Abdulmalek Shaymaa , Abdelbary Ahmed A. , Ismail Cherine A.
Published: August 2022

Long-term sun exposure is the commonest cause of photoaging, where mutual interplay between autophagy, oxidative stress, and apoptosis is incriminated. In combating photoaging, pharmacological approaches targeted to modulate autophagy are currently gaining more ground. This study aimed to examine repurposing metformin use in such context with or without the antioxidant coenzyme Q10 (coQ10) in ultraviolet A (UVA) irradiation-induced skin damage. The study was conducted on 70 female CD1 mice that were randomly assigned into seven groups (10/group): normal control, vehicle-treated-UVA-exposed mice, three metformin UVA-exposed groups (Topical 1 and 10%, and oral 300 mg/kg), topical coQ10 (1%)-treated mice, and combined oral metformin with topical coQ10-treated UVA-exposed mice. After UVA-exposure for 10 weeks (3 times/week), macroscopic signs of photoaging were evaluated. Mice were then euthanized, and the skin was harvested for biochemical estimation of markers for oxidative stress, inflammation, matrix breakdown, and lysosomal function. Histopathological signs of photoaging were also evaluated with immunohistochemical detection of associated changes in autophagic and apoptotic markers. Metformin, mainly by topical application, improved clinical and histologic signs of photoaging. This was associated with suppression of the elevated oxidative stress, IL-6, matrix metalloproteinase 1, and caspase, with induction of cathepsin D and subsequent change in anti-LC3 and P62 staining in skin tissue. In addition to metformin antioxidant, anti-inflammatory, and antiapoptotic activities, its anti-photoaging effect is mainly attributed to enhancing autophagic flux by inducing cathepsin D. Its protective effect is boosted by coQ10, which supports their potential use in photoaging.
Deviatoric behaviour of compacted unsaturated soils within ($${\varvec{q}},\boldsymbol{ }{{\varvec{v}}}_{\mathbf{w}},\boldsymbol{ }{\varvec{p}}$$) space—an experimental study
Authors: Abeyrathne Arunodi , Jayasundara Chathurika , Costa Susanga , Kodikara Jayantha
Published: August 2022

The coexistence of air and water as a mixture in void spaces in unsaturated soils, makes its mechanical behaviour relatively complex and difficult to be addressed by classical saturated soil mechanics principles. In addition, many engineering problems encountered in practical situations had some part to deal with unsaturated soils and therefore the clear understanding of various behavioural patterns of unsaturated soils is crucial. To date, a large number of attempts are reported in evaluating the mechanical behaviour of unsaturated soils in different stress spaces. The present study evaluates the deviatoric behaviour of compacted unsaturated soils in deviator stress–specific water volume–mean net stress ($$q, {v}_{\mathrm{w}}, p$$q,vw,p) space. The effect of moisture content, confinement and the stress history on the behaviour of compacted unsaturated kaolin subjected to triaxial compression was assessed and the results showed that there exists a critical state surface for compacted unsaturated soils in$$q- {v}_{\mathrm{w}}- p$$q-vw-pspace.
The Prognostic Role of Baseline Eosinophils in HPV-Related Cancers: a Multi-institutional Analysis of Anal SCC and OPC Patients Treated with Radical CT-RT
Authors: Rimini Margherita , Franco Pierfrancesco , Bertolini Federica , Berardino De Bari , giulia Zampino Maria , Stefano Vegge , Andrikou Kalliopi , Arcadipane Francesca , Napolitano Martina , Buno Lavajo Vieira , Alessandra Gerardi Marianna , Olivero Francesco , Ferreri Filippo , Ricardi Umberto , Cascinu Stefano , Casadei-Gardini Andrea
Published: August 2022

Background and Aim

Anal squamous cell carcinoma (SCC) and oropharyngeal cancer (OPC) are rare tumors associated with HPV infection. Bioumoral predictors of response to chemoradiation (CT-RT) are lacking in these settings. With the aim to find new biomarkers, we investigated the role of eosinophils in both HPV-positive anal SCC and HPV-related oropharyngeal cancer (OPC).

Methods

We retrieved clinical and laboratory data of patients with HPV-positive anal SCC treated with CT-RT in 5 institutions, and patients with locally advanced OPC SCC treated with CT-RT in 2 institutions. We examined the association between baseline eosinophil count (the best cutoff has been evaluated by ROC curve analysis: 100 × 10^9/L) and disease-free survival (DFS). Unadjusted and adjusted hazard ratios by baseline characteristics were calculated using the Cox proportional hazards model.

Results

Three hundred four patients with HPV-positive anal SCCs and 168 patients with OPCs (122 HPV-positive, 46 HPV-negative diseases) were analyzed. In anal SCC, low eosinophil count (< 100 × 10^9/L) correlates to a better DFS (HR = 0.59; p = 0.0392); likewise, in HPV-positive OPC, low eosinophil count correlates to a better DFS (HR = 0.50; p = 0.0428). In HPV-negative OPC, low eosinophil count confers worse DFS compared to high eosinophil count (HR = 3.53; p = 0.0098). After adjustment for age and sex, eosinophils were confirmed to be independent prognostic factors for DFS (HR = 4.55; p = 0.0139).

Conclusion

Eosinophil count could be used as a prognostic factor in anal HPV-positive SCC. The worse prognosis showed in HPV-positive patients with high eosinophil count is likely to derive from an unfavorable interaction between the HPV-induced immunomodulation and eosinophils, which may hamper the curative effect of RT.
Validation of the Attitude Scale to Lesbian, Gay, Bisexual and Transgender Old Age in a Colombian Sample
Authors: Sánchez-Fuentes María del Mar , Parra-Barrera Sandra M. , Fernandes de Araújo Ludgleydson , Pereira Monteiro Renan
Published: August 2022

The Attitude Scale to Lesbian, Gay, Bisexual and Transgender Old Age (EAFV-LGBT) evaluates attitudes towards LGBT older adults. The main goal of this research was to adapt and examine the psychometric properties in a Spanish-speaking sample. The sample consisted of 521 Colombian adults (36.3% men and 63.7% women) with a mean age equal to 27.39 (SD = 9.27). Participants completed a Socio-Demographic and Sexual History Questionnaire, the Hispanic translations of the EAFV-LGBT, the Subtle and Manifest Prejudice Scale towards Homosexuals, and the Big Five Personality Trait Short Questionnaire. The results showed that the Colombian EAFV-LGBT has good psychometric properties. The structure of the scale was unidimensional, and the internal consistency reliability was also adequate. Likewise, the convergent validity of the scale was verified by correlating it with another measure that evaluates explicit and implicit homophobia. In addition, it was found that there was a relationship between personality traits and attitudes towards LGBT adults. Specifically, participants with lower openness, extraversion, and agreeableness reported more negative attitudes toward older LGBT people.
Common Upper Extremity Injuries in Pediatric Athletes
Authors: Watkins Rhonda A. , De Borja Celina , Ramirez Faustine
Published: August 2022

Purpose of Review

The aim of this study is to review the most recent literature on common upper extremity injuries in pediatric athletes and discuss their diagnosis, management, and outcomes. We also highlight ultrasound as a tool in their evaluation.

Recent Findings

Shoulder conditions presented include little league shoulder, glenohumeral rotation deficit, acute traumatic shoulder dislocation, and multidirectional shoulder instability. Elbow conditions include capitellar OCD, medial epicondyle avulsion fracture, and medial epicondylitis. We also review scaphoid fractures and gymnast wrist. Not all physeal injuries lead to long-term growth disruption. Ultrasound has been shown to be useful in the diagnosis of scaphoid fracture, medial epicondyle avulsion fractures, and capitellar OCD. It can also be helpful in assessing risk for shoulder and elbow injuries in overhead athletes.

There is a rising burden of upper extremity injuries among pediatric athletes. Knowledge of their sport specific mechanics can be helpful in diagnosis. As long-term outcome data become available for these conditions, it is clear, proper diagnosis and management are critical to preventing adverse outcomes. We highlight many of these injuries, best practice in care, and controversies in care in hopes of improving outcomes and preventing injury for pediatric athletes.
Triangulating Surfaces with Bounded Energy
Authors: Borodzik Maciej , Szczepanowska Monika
Published: August 2022

We show that if a closed Lipschitz surface in $${\mathbb {R}}^n$$

R

n

has bounded Kolasinski–Menger energy, then it can be triangulated with triangles whose number is bounded by the energy and the area. Each of the triangles is an image of a subset of a plane under a diffeomorphism whose distortion is bounded by $$\sqrt{2}$$

2

.
Continuing the Classification of Homogeneous Kobayashi-Hyperbolic Manifolds with High-Dimensional Automorphism Group
Authors: Herrington Elliot
Published: August 2022

We classify all homogeneous Kobayashi-hyperbolic manifolds of dimension$$n \ge 2$$n≥2whose group of holomorphic automorphisms has dimension either$$n^2 - 7$$n2-7or$$n^2 - 8.$$n2-8.This paper continues the work of A. Isaev, who classified all such manifolds with automorphism group dimension$$n^2 - 6$$n2-6and greater.
Racial Discrimination, Black Identity, and Critical Consciousness in Spain
Authors: Cea D’Ancona M.ª Ángeles
Published: August 2022

This article analyzes the relationship of racial discrimination on the identity and critical consciousness of 1369 African and Afro-descendant respondents to the first nationwide survey conducted in Spain in 2020. The survey not only showed the scope of experiences of discrimination based on skin color but has also opened the way for testing whether these experiences of racial discrimination end up affecting the identity and critical consciousness of black people, Africans, or Afro-descendants, based on the questions included in the survey and the rejection–identification hypothesis. According to the statistical models obtained by discriminant analysis, racial discrimination helps to strengthen racial identity. Having been discriminated by skin color was the variable that most differentiated those who self-identified with their country of origin from those who did not and the second most predictive of self-recognition as a black or Afro-descendant person. But when the influences of racial discrimination on racial identity and critical consciousness were jointly analyzed, applying structural equation modeling, the latter outweighed the former: racial discrimination contributes to the awakening black activism. Less clear seems to be the influence of racial identity on critical consciousness.
The Relation Between Socioeconomic Status and Risk Attitudes: A Nuclear Accident Scenario in Sweden
Authors: Rasmussen Joel , Ewald Jens
Published: August 2022

Nuclear power plant (NPP) disasters are complex and dreaded scenarios. However, existing recovery plans presuppose that citizens will return to live in decontaminated areas following evacuation. Research on natural disasters has shown that high socioeconomic status (SES) influences people to continue living in their homes in recovery areas. This study examines the association between SES and citizens’ risk attitudes to a radiological emergency scenario and demonstrates instead that high SES implies a greater likeliness to move away from the accident-affected area. This is substantiated by survey data of Swedish citizens’ (N = 2,291) attitudes to a scenario where an NPP accident, evacuation, and remediation occur. More specifically, the study provides statistically significant results to show that high income is associated with less worry over ionizing radiation. Still, high-income individuals also appear to be more likely to move if their neighborhood is affected by radioactive fallout than low-income individuals. Moreover, the results for education show that low education is associated with remaining in the decontamination area, and the relation between education and worry over ionizing radiation provides some support for assumptions about the “anxious middle.” Overall, this study finds that decontamination is complicated by a majority of people preferring permanent relocation as well as by indications that more resourceful citizens are generally more likely to leave the area permanently, which may impede the fulfillment of state agencies’ plans for recovery.
Research on prestressed loading strut of cable supported portal frame
Authors: Liu Shuhong , Wu Junqi , Wang Cong , Xin Yajun
Published: August 2022

In this study, a novel type of loading strut device is presented, which is introduced in portal frame external prestressing reinforcement and used to constitute a cable-supported portal frame structural system. The strut device was found to be capable of elongating by rotating the middle screw and applying prestress to the steel strand in the system. In this study, the new loading strut is simulated and analyzed using the ANSYS finite element analysis software. Moreover, it is used for the reinforcement test of a practical project. During the test, the prestress load is applied through the novel strut, and the changes of strain, mid span deflection and prestress of the steel strand at the key positions before and after the reinforcement are investigated. Based on the analysis of the simulation and test results, it is found that this novel type of loading strut is simple, safe and reliable to operate, and could be employed in the cable-supported structure system without tensioning the steel strand to achieve loading.
A Meta-Regression Analysis of Consumer Willingness to Pay for Aquaculture Products
Authors: Smetana Kerri , Melstrom Richard T. , Malone Trey
Published: August 2022

This article uses meta-regression analysis to examine variation in willingness to pay (WTP) for farm-raised seafood and aquaculture products. We measure the WTP premiums that consumers have for common product attributes and examine how WTP varies systematically across study design elements, populations of interest, and sample characteristics. Based on metadata from 45 studies, the meta-regression analysis indicates that WTP estimates differ significantly with the availability of attributes such as domestic and environmental certification, but also with sample income and gender representation.
Barriers to Care for Poststroke Visual Deficits in Alberta, Canada
Authors: Manhas Kiran Pohar , Damji Karim , Brehon Katelyn , Jiang Jennis , Faris Peter , Costello Fiona
Published: August 2022

Poststroke visual impairment (VI) negatively affects rehabilitation potential and quality of life for stroke survivors. In this cross-sectional observational study, stroke survivors and providers were surveyed to quantify perspectives regarding care for poststroke VI in Alberta, Canada (n = 46 survivors; n = 87 providers). Few patients (35%) felt prepared to cope with VI at the time of discharge from acute stroke and inpatient rehabilitation settings. Less than 25% of stroke survivors, and <16% of providers, felt referral processes were adequate. 95.2% of providers and 82% of stroke survivors advocated for a provincial clinical pathway to improve care quality for poststroke VI.
A novel maturity index for assessing medical device startups
Authors: Richmond Frances J. , Zapotoczny Grzegorz , Green Brian , Lokappa Sowmya , Rudnick Katy , Espinoza Juan ,   the ICRS-CTIP Collaborative for Regulatory Research
Published: August 2022

Background:

Startup companies in the healthcare sector often fail because they lack sufficient entrepreneurial, regulatory, and business development expertise. Maturity models provide useful frameworks to assess the state of business elements more systematically than heuristic assessments. However, previous models were developed primarily to characterize the business state of larger nonmedical companies. A maturity index designed specifically for startup companies in the medical product sector could help to identify areas in which targeted interventions could assist business development.

Methods:

A novel MedTech Startup Maturity Index (SMI) was developed by a collaborative team of academic and industry experts and refined through feedback from external stakeholders. Pediatric medical device startups associated with the West Coast Consortium for Technology & Innovation in Pediatrics (CTIP) were scored and ranked according to the SMI following semi-structured interviews. The CTIP executive team independently ranked the maturity of each company based on their extensive experiences with the same companies.

Results:

SMI scores for 16 companies ranged from 1.2 to 3.8 out of 4. These scores were well aligned with heuristic CTIP rankings for 14 out of 16 companies, reflected by strong correlations between the two datasets (Spearman’s rho = 0.721,P= 0.002, and Kendall’s tau-b = 0.526,P= 0.006).

Conclusions:

The SMI yields maturity scores that correlate well with expert rankings but can be assessed without prior company knowledge and can identify specific areas of concern more systematically. Further research is required to generalize and validate the SMI as a pre-/post-evaluation tool.
Nucleation effects on cavitation about a sphere
Authors: Brandner Paul A. , Venning James A. , Pearce Bryce W.
Published: August 2022

The influence of nucleation on cavitation about a sphere from inception through to supercavitation at a transcritical Reynolds number of$1.5\times 10^{6}$is investigated experimentally. Two extreme free-stream nuclei populations, deplete and abundant, were investigated. Unsteady surface pressures from two sensors on opposing sides of the sphere were acquired simultaneous with high-resolution high-speed photography at cavitation numbers between 1.0 and 0.3. High-resolution spectrograms derived from these measurements reveal principally bi-modal shedding in attached and detached regimes. Correlations between unsteady pressure measurements show the high modes to be axisymmetric and low modes asymmetric. Modal topology is also discerned from the high-speed imaging. The bi-modal shedding for lower cavitation numbers is driven by coupled re-entrant jet formation and upstream shockwave propagation. The attached regime is shown to have two sub-regimes. For the abundant case, the continuous supply of activated nuclei around the sphere periphery in the first bi-modal regime has the effect of driving the high symmetric mode preferentially over the asymmetric low mode compared with the deplete case. For the first bi-modal regime, frequencies were unaffected by nucleation changes although peak responses were centred at a cavitation number of about 0.8 for the deplete and 0.825 for the abundant. For the second attached regime, where cavity lengths are of the order of the sphere size, changes in nucleation altered frequencies and amplitudes of peak unsteady pressures. For the abundant case, the continuous nuclei supply significantly reduced coherence with modal peak amplitudes reduced by an order compared with the deplete case. Continuous nuclei activation increased the probability of the high mode over the low compared with the deplete case but to a lesser extent than the first regime. Nuclei activations also significantly reduced inter-cavity and cavity durations, but not growth and collapse phases, which increased modal frequencies compared with the deplete case. The second regime asymmetric low mode topology, for both nucleation cases, is shown to be alternate shedding of oblique vortices from diametrically opposing sides of the sphere similar to low Reynolds number shedding about spheres and other axisymmetric bluff bodies in single-phase flows.
Crossing the line: Effect of border representation in perceptual dialectology
Authors: Benson Erica J. , Williams Anneli
Published: August 2022

This study investigates the effect of differing representations of state boundaries on the draw-a-map task in perceptual dialectology in a region of the United States. The typical draw-a-map survey instrument represents state borders with solid lines. Would respondents react differently to maps with dashed-line state borders? More specifically, would respondents draw more dialect areas that cross state lines on maps with dashed-line state borders versus solid-line state borders? These questions are explored through two datasets, and similarities and differences emerge. For example, respondents of both map types draw more single-state dialect areas than multistate dialect areas, and respondents with dashed-line maps draw more dialect areas on average than respondents with solid state maps. While dataset 1 showed a significant association between map type and multistate dialect area with respondents using dashed-line border maps drawing more multistate dialect areas than respondents with solid-line maps,H(1) = 5.13,P= .017, this association was not significant in dataset 2,H(1) = .06,P= .798.
ALMOST THEOREMS OF HYPERARITHMETIC ANALYSIS
Authors: SHORE RICHARD A.
Published: August 2022

Theorems of hyperarithmetic analysis (THAs) occupy an unusual neighborhood in the realms of reverse mathematics and recursion theoretic complexity. They lie above all the fixed (recursive) iterations of the Turing Jump but below ATR
$_{0}$
(and so
$\Pi _{1}^{1}$
-CA
$_{0}$
or the hyperjump). There is a long history of proof theoretic principles which are THAs. Until Barnes, Goh, and Shore [ta] revealed an array of theorems in graph theory living in this neighborhood, there was only one mathematical denizen. In this paper we introduce a new neighborhood of theorems which are almost theorems of hyperarithmetic analysis (ATHAs). When combined with ACA
$_{0}$
they are THAs but on their own they are very weak. We generalize several conservativity classes (
$\Pi _{1}^{1}$
, r-
$\Pi _{2}^{1}$
, and Tanaka) and show that all our examples (and many others) are conservative over RCA
$_{0}$
in all these senses and weak in other recursion theoretic ways as well. We provide denizens, both mathematical and logical. These results answer a question raised by Hirschfeldt and reported in Montalbán [2011] by providing a long list of pairs of principles one of which is very weak over RCA
$_{0}$
but over ACA
$_{0}$
is equivalent to the other which may be strong (THA) or very strong going up a standard hierarchy and at the end being stronger than full second order arithmetic.
Adding Insult to Injury: The Justification Frame in Official Narratives of Officer-Involved Killings
Authors: Burch Traci
Published: August 2022

This article identifies the justification frame as a common narrative used by public officials to justify the use of lethal force by police. Officials deploy the justification frame to obfuscate the use of force or claim that victims posed a threat to officers in order to justify civilian deaths. I examine initial statements given in the aftermath of officer-involved deaths in 2016, focusing on incidents where an on-duty officer used force against victims who did not pose a threat when they were killed. I find that elements of the justification frame appear frequently in the explanations issued after these incidents. Statements about Black decedents are more likely to deploy the justification frame.
Biographies of Labor Activists: Trajectories, Daringness, and Challenges
Authors: Fortes Alexandre , Schmidt Benito Bisso
Published: August 2022

This comment discusses three topics. First, John French's biography of Luiz Inácio Lula da Silva is located in the broader trajectory of the production of biographical narratives of activists under the auspices of the historiography of the labour movement. Second, French's daring gesture of comparing the trajectories of Lula and August Bebel, who lived in such different contexts, and the impact of this in terms of a more sophisticated understanding of labour history in Brazil is discussed. Finally, we look at some of the challenges faced by writers of biographies of working-class leaders, notably in relation to the intersectionality between class, race, and gender.
Be Explicit: Identifying and Addressing Misaligned Goals in Collaborative Research Teams
Authors: Haas Nicholas
Published: August 2022

The misalignment of goals among researchers, external organizational partners (OPs), and study participants is thought to pose a challenge to the successful implementation of collaborative research projects. However, the goals of different collaborative team members almost never are elicited, making identification of misalignment and its potential consequences a difficult task. In this evaluation of a United Nations Nonviolent Communication Program conducted in Bangladesh, the Maldives, and Sri Lanka, I collected qualitative and quantitative data on OPs’ and study participants’ expected program impacts. I find that there are differences in OP and participant goals and that misalignment appears to bear some responsibility for participant dissatisfaction with the program. I also observe evidence that as the program progressed, participants’ expected program impacts began to more closely approximate those of the OPs. I conclude with thoughts on the benefits of explicitly measuring research team goals and expectations and addressing their misalignment.
Total body irradiation using volumetric modulated arc therapy, experience of a cancer hospital in Pakistan
Authors: Sadaf Tabinda , Rashid Asma , Imam Bokhari Waqas , Samuel Eileen , Shahid Aqueel , Mukhtar Raheel , Zafar Umair , Iqbal Khalid
Published: August 2022

Introduction:

To report the planning parameters, efficacy and toxicity of total body irradiation using volumetric modulated arc therapy (VMAT).

Methods:

From July 2019 till May 2021, nine patients treated with VMAT-based total body irradiation as a part of the myeloablative regimen for homologous stem cell transplant were evaluated. The CT acquisition, planning parameters, doses to target volume and critical structures were evaluated retrospectively.

Results:

Median age was 24 with median height 172 cm. Average Mean Lung dose was 9·5 Gy, mean dose to kidney was kidney dose 8·4 Gy, planning target volume (PTV) 95% was 98 % and mean heterogeneity index of PTV was 1·2 all patients. Total fraction delivery time including setup was 3·1 h while beam on time was 23 min. Main toxicity observed was mucositis and fatigue, while no Grade 3 or more acute radiation toxicity was observed.

Conclusion:

At our institution, high dose TBI performed with multi-isocentric VMAT is now a standard procedure. Though it is cumbersome and time-consuming process but VMAT offers an advantage of increased dose homogeneity in the target volume with reduction in doses to critical organs especially lungs and kidneys in comparison to standard source to skin distance technique, longer follow-up time is necessary to evaluate our method and long-term toxicity.
Multi-degrees-of-freedom soft robotic ankle-foot orthosis for gait assistance and variable ankle support
Authors: Thalman Carly M. , Hertzell Tiffany , Debeurre Marielle , Lee Hyunglae
Published: August 2022

This paper presents the design, modeling, analysis, fabrication, and experimental characterization of the soft robotic ankle-foot orthosis (SR-AFO), which is a wearable soft robot designed for ankle assistance, and a pilot human study of its use. Using two novel pneumatically powered soft actuators, the SR-AFO is designed to assist the ankle in multiple degrees-of-freedom during standing and walking tasks. The flat fabric pneumatic artificial muscle (ff-PAM) contracts upon pressurization and assists ankle plantarflexion in the sagittal plane. The multi-material actuator for variable stiffness (MAVS) aids in supporting ankle inversion/eversion in the frontal plane. Analytical models of the ff-PAM and MAVS were created to understand how the changing of the design parameters affects tensile force generation and stiffness support, respectively. The models were validated by both finite element analysis and experimental characterization using a universal testing machine. A set of human experiments was performed with able-bodied participants to evaluate: (a) lateral ankle support during quiet standing, (b) lateral ankle support during walking over compliant surfaces, and (c) plantarflexion assistance during push-off in treadmill walking. Group results revealed increased lateral ankle stiffness during quiet standing with the MAVS active, reduced lateral ankle deflection while walking over compliant surfaces with the MAVS active, and reduced muscle effort in ankle platarflexors during 40–60% of the gait cycle with the dual ff-PAM active. The SR-AFO shows promising results in providing lateral ankle support and plantarflexion assistance with able-bodied participants, which suggests a potential to help restore the gait of impaired users in future trials.
Cardiomyocyte-specific knockout of ADAM17 ameliorates left ventricular remodeling and function in diabetic cardiomyopathy of mice
Authors: Xue Fei , Cheng Jing , Liu Yanping , Cheng Cheng , Zhang Meng , Sui Wenhai , Chen Wenqiang , Hao Panpan , Zhang Yun , Zhang Cheng
Published: August 2022

Angiotensin-converting enzyme 2 (ACE2) has proven beneficial in attenuating diabetic cardiomyopathy (DCM) but has been found to be a substrate of a disintegrin and metalloprotease protein-17 (ADAM17). However, whether ADAM17 plays a role in the pathogenesis and intervention of DCM is obscure. In this study, we created cardiomyocyte-specific knockout of ADAM17 (A17α-MHCKO) mice, and left ventricular dimension, function, pathology and molecular biology were assessed in ADAM17fl/fl control, A17α-MHCKO control, ADAM17fl/fl diabetic and A17α-MHCKO diabetic mice. Both differentiated H9c2 cells and neonatal rat cardiomyocytes (NRCMs) were used to explore the molecular mechanisms underlying the effect of ADAM17 on DCM. The results showed that protein expression and activity of ADAM17 were upregulated whereas the protein expression of ACE2 was downregulated in the myocardium of diabetic mice. Cardiomyocyte-specific knockout of ADAM17 mitigated cardiac fibrosis and cardiomyocyte apoptosis and ameliorated cardiac dysfunction in mice with DCM. Bioinformatic analyses detected a number of genes enriched in metabolic pathways, in particular the AMPK signaling pathway, expressed differentially between the hearts of A17α-MHCKO and ADAM17fl/fl diabetic mice. The mechanism may involve activated AMPK pathway, increased autophagosome formation and improved autophagic flux, which reduced the apoptotic response in cardiomyocytes. In addition, hypoxia-inducible factor-1α (HIF-1α) might act as an upstream mediator of upregulated ADAM17 and ADAM17 might affect AMPK signaling via α1 A-adrenergic receptor (ADRA1A). These results indicated that ADAM17 activity and ACE2 shedding were enhanced in DCM, which was reversed by cardiomyocyte-specific ADAM17 knockout. Thus, inhibition of ADAM17 may provide a promising approach to the treatment of DCM.
High-content imaging of human hepatic spheroids for researching the mechanism of duloxetine-induced hepatotoxicity
Authors: Liu Juan , Li Ruihong , Zhang Tingting , Xue Rui , Li Tingting , Li Zheng , Zhuang Xiaomei , Wang Qi , Chen Yu Ann , Dong Jiahong , Zhang Youzhi , Wang Yunfang
Published: August 2022

Duloxetine (DLX) has been approved for the successful treatment of psychiatric diseases, including major depressive disorder, diabetic neuropathy, fibromyalgia and generalized anxiety disorder. However, since the usage of DLX carries a manufacturer warning of hepatotoxicity given its implication in numerous cases of drug-induced liver injuries (DILI), it is not recommended for patients with chronic liver diseases. In our previous study, we developed an enhanced human-simulated hepatic spheroid (EHS) imaging model system for performing drug hepatotoxicity evaluation using the human hepatoma cell line HepaRG and the support of a pulverized liver biomatrix scaffold, which demonstrated much improved hepatic-specific functions. In the current study, we were able to use this robust model to demonstrate that the DLX-DILI is a human CYP450 specific, metabolism-dependent, oxidative stress triggered complex hepatic injury. High-content imaging analysis (HCA) of organoids exposed to DLX showed that the potential toxicophore, naphthyl ring in DLX initiated oxidative stress which ultimately led to mitochondrial dysfunction in the hepatic organoids, and vice versa. Furthermore, DLX-induced hepatic steatosis and cholestasis was also detected in the exposed EHSs. We also discovered that a novel compound S-071031B, which replaced DLX’s naphthyl ring with benzodioxole, showed dramatically lower hepatotoxicities through reducing oxidative stress. Thus, we conclusively present the human-relevant EHS model as an ideal, highly competent system for evaluating DLX induced hepatotoxicity and exploring related mechanisms in vitro. Moreover, HCA use on functional hepatic organoids has promising application prospects for guiding compound structural modifications and optimization in order to improve drug development by reducing hepatotoxicity.
Targeting TPC2 sensitizes acute lymphoblastic leukemia cells to chemotherapeutics by impairing lysosomal function
Authors: Geisslinger Franz , Müller Martin , Chao Yu-Kai , Grimm Christian , Vollmar Angelika M. , Bartel Karin
Published: August 2022

Despite novel therapy regimens and extensive research, chemoresistance remains a challenge in leukemia treatment. Of note, recent studies revealed lysosomes as regulators of cell death and chemotherapy response, suggesting this organelle is a novel target for chemosensitization. Interestingly, drug-resistant VCR-R CEM acute lymphoblastic leukemia (ALL) cells have an increased expression of the lysosomal cation channel Two-Pore-Channel 2 (TPC2) compared to drug-naïve CCRF-CEM ALL cells. Concurrently, knockout (KO) of TPC2 sensitized drug-resistant VCR-R CEM cells to treatment with cytostatics. The chemosensitizing effect could be confirmed in several cell lines as well as in heterogeneous, patient-derived xenograft ALL cells, using the pharmacological TPC2 inhibitors naringenin and tetrandrine. We reveal that a dual mechanism of action mediates chemo sensitization by loss of lysosomal TPC2 function. First, because of increased lysosomal pH, lysosomal drug sequestration is impaired, leading to an increased nuclear accumulation of doxorubicin and hence increased DNA damage. Second, lysosomes of TPC2 KO cells are more prone to lysosomal damage as a result of morphological changes and dysregulation of proteins influencing lysosomal stability. This leads to induction of lysosomal cell death (LCD), evident by increased cathepsin B levels in the cytosol, truncation of pro-apoptotic Bid, as well as the reversibility of cell death by co-treatment with the cathepsin B inhibitor CA-074Me in TPC2 KO cells. In summary, this study establishes TPC2 as a novel, promising, druggable target for combination therapy approaches in ALL to overcome chemoresistance, which could be exploited in the clinic in the future. Additionally, it unravels LCD signaling as an important death-inducing component upon loss of TPC2 function.
Photochemical spin-state control of binding configuration for tailoring organic color center emission in carbon nanotubes
Authors: Zheng Yu , Han Yulun , Weight Braden M. , Lin Zhiwei , Gifford Brendan J. , Zheng Ming , Kilin Dmitri , Kilina Svetlana , Doorn Stephen K. , Htoon Han , Tretiak Sergei
Published: August 2022

Incorporating fluorescent quantum defects in the sidewalls of semiconducting single-wall carbon nanotubes (SWCNTs) through chemical reaction is an emerging route to predictably modify nanotube electronic structures and develop advanced photonic functionality. Applications such as room-temperature single-photon emission and high-contrast bio-imaging have been advanced through aryl-functionalized SWCNTs, in which the binding configurations of the aryl group define the energies of the emitting states. However, the chemistry of binding with atomic precision at the single-bond level and tunable control over the binding configurations are yet to be achieved. Here, we explore recently reported photosynthetic protocol and find that it can control chemical binding configurations of quantum defects, which are often referred to as organic color centers, through the spin multiplicity of photoexcited intermediates. Specifically, photoexcited aromatics react with SWCNT sidewalls to undergo a singlet-state pathway in the presence of dissolved oxygen, leading to ortho binding configurations of the aryl group on the nanotube. In contrast, the oxygen-free photoreaction activates previously inaccessible para configurations through a triplet-state mechanism. These experimental results are corroborated by first principles simulations. Such spin-selective photochemistry diversifies SWCNT emission tunability by controlling the morphology of the emitting sites.
Tuning lower dimensional superconductivity with hybridization at a superconducting-semiconducting interface
Authors: Kamlapure Anand , Simonato Manuel , Sierda Emil , Steinbrecher Manuel , Kamber Umut , Knol Elze J. , Krogstrup Peter , Katsnelson Mikhail I. , Rösner Malte , Khajetoorians Alexander Ako
Published: August 2022

The influence of interface electronic structure is vital to control lower dimensional superconductivity and its applications to gated superconducting electronics, and superconducting layered heterostructures. Lower dimensional superconductors are typically synthesized on insulating substrates to reduce interfacial driven effects that destroy superconductivity and delocalize the confined wavefunction. Here, we demonstrate that the hybrid electronic structure formed at the interface between a lead film and a semiconducting and highly anisotropic black phosphorus substrate significantly renormalizes the superconductivity in the lead film. Using ultra-low temperature scanning tunneling microscopy and spectroscopy, we characterize the renormalization of lead’s quantum well states, its superconducting gap, and its vortex structure which show strong anisotropic characteristics. Density functional theory calculations confirm that the renormalization of superconductivity is driven by hybridization at the interface which modifies the confinement potential and imprints the anisotropic characteristics of the semiconductor substrate on selected regions of the Fermi surface of lead. Using an analytical model, we link the modulated superconductivity to an anisotropy that selectively tunes the superconducting order parameter in reciprocal space. These results illustrate that interfacial hybridization can be used to tune superconductivity in quantum technologies based on lower dimensional superconducting electronics.
Combined comparative genomics and clinical modeling reveals plasmid-encoded genes are independently associated with Klebsiella infection
Authors: Vornhagen Jay , Roberts Emily K. , Unverdorben Lavinia , Mason Sophia , Patel Alieysa , Crawford Ryan , Holmes Caitlyn L. , Sun Yuang , Teodorescu Alexandra , Snitkin Evan S. , Zhao Lili , Simner Patricia J. , Tamma Pranita D. , Rao Krishna , Kaye Keith S. , Bachman Michael A.
Published: August 2022

Members of the Klebsiella pneumoniae species complex frequently colonize the gut and colonization is associated with subsequent infection. To identify genes associated with progression from colonization to infection, we undertook a case-control comparative genomics study. Concordant cases (N = 85), where colonizing and invasive isolates were identical strain types, were matched to asymptomatically colonizing controls (N = 160). Thirty-seven genes are associated with infection, 27 of which remain significant following adjustment for patient variables and bacterial phylogeny. Infection-associated genes are not previously characterized virulence factors, but instead a diverse group of stress resistance, regulatory and antibiotic resistance genes, despite careful adjustment for antibiotic exposure. Many genes are plasmid borne, and for some, the relationship with infection is mediated by gut dominance. Five genes were validated in a geographically-independent cohort of colonized patients. This study identifies several genes reproducibly associated with progression to infection in patients colonized by diverse Klebsiella.
Combi-seq for multiplexed transcriptome-based profiling of drug combinations using deterministic barcoding in single-cell droplets
Authors: Mathur L. , Szalai B. , Du N. H. , Utharala R. , Ballinger M. , Landry J. J. M. , Ryckelynck M. , Benes V. , Saez-Rodriguez J. , Merten C. A.
Published: August 2022

Anti-cancer therapies often exhibit only short-term effects. Tumors typically develop drug resistance causing relapses that might be tackled with drug combinations. Identification of the right combination is challenging and would benefit from high-content, high-throughput combinatorial screens directly on patient biopsies. However, such screens require a large amount of material, normally not available from patients. To address these challenges, we present a scalable microfluidic workflow, called Combi-Seq, to screen hundreds of drug combinations in picoliter-size droplets using transcriptome changes as a readout for drug effects. We devise a deterministic combinatorial DNA barcoding approach to encode treatment conditions, enabling the gene expression-based readout of drug effects in a highly multiplexed fashion. We apply Combi-Seq to screen the effect of 420 drug combinations on the transcriptome of K562 cells using only ~250 single cell droplets per condition, to successfully predict synergistic and antagonistic drug pairs, as well as their pathway activities.
Levels of SARS-CoV-2 antibodies among fully vaccinated individuals with Delta or Omicron variant breakthrough infections
Authors: Stærke Nina Breinholt , Reekie Joanne , Nielsen Henrik , Benfield Thomas , Wiese Lothar , Knudsen Lene Surland , Iversen Mette Brouw , Iversen Kasper , Fogh Kamille , Bodilsen Jacob , Juhl Maria Ruwald , Lindvig Susan Olaf , Øvrehus Anne , Madsen Lone Wulff , Klastrup Vibeke , Andersen Sidsel Dahl , Juhl Anna Karina , Andreasen Signe Rode , Ostrowski Sisse Rye , Erikstrup Christian , Fischer Thea K. , Tolstrup Martin , Østergaard Lars , Johansen Isik Somuncu , Lundgren Jens , Søgaard Ole Schmeltz
Published: August 2022

SARS-CoV-2 variants of concern have continuously evolved and may erode vaccine induced immunity. In this observational cohort study, we determine the risk of breakthrough infection in a fully vaccinated cohort. SARS-CoV-2 anti-spike IgG levels were measured before first SARS-CoV-2 vaccination and at day 21–28, 90 and 180, as well as after booster vaccination. Breakthrough infections were captured through the Danish National Microbiology database. incidence rate ratio (IRR) for breakthrough infection at time-updated anti-spike IgG levels was determined using Poisson regression. Among 6076 participants, 127 and 364 breakthrough infections due to Delta and Omicron variants were observed. IRR was 0.29 (95% CI 0.15–0.56) for breakthrough infection with the Delta variant, comparing the highest and lowest quintiles of anti-spike IgG. For Omicron, no significant differences in IRR were observed. These results suggest that quantitative level of anti-spike IgG have limited impact on the risk of breakthrough infection with Omicron.
Xist exerts gene-specific silencing during XCI maintenance and impacts lineage-specific cell differentiation and proliferation during hematopoiesis
Authors: Yang Tianqi , Ou Jianhong , Yildirim Eda
Published: August 2022

X chromosome inactivation (XCI) is a dosage compensation phenomenon that occurs in females. Initiation of XCI depends on Xist RNA, which triggers silencing of one of the two X chromosomes, except for XCI escape genes that continue to be biallelically expressed. In the soma XCI is stably maintained with continuous Xist expression. How Xist impacts XCI maintenance remains an open question. Here we conditionally delete Xist in hematopoietic system of mice and report differentiation and cell cycle defects in female hematopoietic stem and progenitor cells (HSPCs). By utilizing female HSPCs and mouse embryonic fibroblasts, we find that X-linked genes show variable tolerance to Xist loss. Specifically, XCI escape genes exhibit preferential transcriptional upregulation, which associates with low H3K27me3 occupancy and high chromatin accessibility that accommodates preexisting binding of transcription factors such as Yin Yang 1 (YY1) at the basal state. We conclude that Xist is necessary for gene-specific silencing during XCI maintenance and impacts lineage-specific cell differentiation and proliferation during hematopoiesis.
mRNA vaccines induce rapid antibody responses in mice
Authors: Gebre Makda S. , Rauch Susanne , Roth Nicole , Gergen Janina , Yu Jingyou , Liu Xiaowen , Cole Andrew C. , Mueller Stefan O. , Petsch Benjamin , Barouch Dan H.
Published: August 2022

mRNA vaccines can be developed and produced quickly, making them prime candidates for immediate outbreak responses. Furthermore, clinical trials have demonstrated rapid protection following mRNA vaccination. Thus, we sought to investigate how quickly mRNA vaccines elicit antibody responses compared to other vaccine modalities. We first compared the immune kinetics of mRNA and DNA vaccines expressing SARS-CoV-2 spike in mice. We observed rapid induction of antigen-specific binding and neutralizing antibodies by day 5 following mRNA (4 µg/mouse), but not DNA (50 µg/mouse), immunization. Comparing innate responses hours post immunization, the mRNA vaccine induced increased levels of IL-5, IL-6, and MCP-1 cytokines which maybe promoting humoral responses downstream. We then evaluated the immune kinetics of an HIV-1 mRNA vaccine in comparison to DNA, protein, and rhesus adenovirus 52 (RhAd52) vaccines of the same HIV-1 envelope antigen in mice. Again, induction of envelope-specific antibodies was observed by day 5 following mRNA vaccination, whereas antibodies were detected by day 7–14 following DNA, protein, and RhAd52 vaccination. Thus, eliciting rapid humoral immunity may be a unique and advantageous property of mRNA vaccines for controlling infectious disease outbreaks.
Transfer learning based generalized framework for state of health estimation of Li-ion cells
Authors: Sahoo Subhasmita , Hariharan Krishnan S. , Agarwal Samarth , Swernath Subramanian B. , Bharti Roshan , Han Seongho , Lee Sangheon
Published: August 2022

Estimating the state of health (SOH) of batteries powering electronic devices in real-time while in use is a necessity. The applicability of most of the existing methods is limited to the datasets that are used to train the models. In this work, we propose a generic method for SOH estimation with much wider applicability. The key problem is the identification of the right feature set which is derived from measurable voltage signals. In this work, relative rise in voltage drop across cell resistance with aging has been used as the feature. A base artificial neural network (ANN) model has been used to map the generic relation between voltage and SOH. The base ANN model has been trained using limited battery data. Blind testing has been done on long cycle in-house data and publicly available datasets. In-house data included both laboratory and on-device data generated using various charge profiles. Transfer learning has been used for public datasets as those batteries have different physical dimensions and cell chemistry. The mean absolute error in SOH estimation is well within 2% for all test cases. The model is robust across scenarios such as cell variability, charge profile difference, and limited variation in temperature.