bluuebunny/crossref_metadata_2025 huggingface dataset:
Enzymes for consumer products to achieve climate neutrality
Authors: Molina-Espeja Patricia , Sanz-Aparicio Julia , Golyshin Peter N , Robles-Martín Ana , Guallar Víctor , Beltrametti Fabrizio , Müller Markus , Yakimov Michail M , Modregger Jan , van Logchem Moniec , Corvini Philippe , Shahgaldian Patrick , Degering Christian , Wieland Susanne , Timm Anne , de Carvalho Carla C C R , Re Ilaria , Daniotti Sara , Thies Stephan , Jaeger Karl-Erich , Chow Jennifer , Streit Wolfgang R , Lottenbach Roland , Rösch Rainer , Ansari Nazanin , Ferrer Manuel ,   (The FuturEnzyme Consortium)
Published: March 2023

Today, the chemosphere’s and biosphere’s compositions of the planet are changing faster than experienced during the past thousand years. CO2 emissions from fossil fuel combustion are rising dramatically, including those from processing, manufacturing and consuming everyday products; this rate of greenhouse gas emission (36.2 gigatons accumulated in 2022) is raising global temperatures and destabilizing the climate, which is one of the most influential forces on our planet. As our world warms up, our climate will enter a period of constant turbulence, affecting more than 85% of our ecosystems, including the delicate web of life on these systems, and impacting socioeconomic networks. How do we deal with the green transition to minimize climate change and its impacts while we are facing these new realities? One of the solutions is to use renewable natural resources. Indeed, nature itself, through the working parts of its living systems, the enzymes, can significantly contribute to achieve climate neutrality and good ecological/biodiversity status. Annually they can help decreasing CO2 emissions by 1–2.5 billion-tons, carbon demand by about 200 million-tons, and chemical demand by about 90 million-tons. With current climate change goals, we review the consequences of climate change at multiple scales and how enzymes can counteract or mitigate them. We then focus on how they mobilize sustainable and greener innovations in consumer products that have a high contribution to global carbon emissions. Finally, key innovations and challenges to be solved at the enzyme and product levels are discussed.
Circulating metabolic signatures of heart failure in precision cardiology
Authors: Xie Huijing , Zhang Bowen , Xie Maodi , Li Tao
Published: March 2023

Precision cardiology aims to implement personalized health care and precise medical decisions based on the specific characteristics of individuals. Metabolic remodeling plays a causal role in the pathogenesis of heart failure (HF). Changes in metabolic pathways such as substrate preference, high-energy phosphate metabolism and amino acid metabolism, are involved in pathological structural remodeling and functional impairment. These metabolic alterations are usually not restricted in the cardiac tissue, but also manifest in circulation. In clinical practice, blood sample is routinely used for HF screening. Metabolomics is an emerging omics technology that provides an efficient way to acquire dynamic metabolic profiles in circulation. An increasing number of metabolic biomarkers have been implicated in disease progression, making it possible to fight HF in a more effective and precise way. This review summarizes the modern analytical techniques in metabolomics as well as emerging circulating metabolites during the pathogenesis of HF, aiming to provide new insights into the prevention, diagnosis and treatment of HF in the era of precision medicine.
Efficacy and safety of golimumab in patients with non-radiographic axial spondyloarthritis: a withdrawal and retreatment study (GO-BACK)
Authors: Weinstein Cindy L J , Sliwinska-Stanczyk Paula , Hála Tomas , Stanislav Marina , Tzontcheva Anjela , Yao Ruji , Berd Yuliya , Curtis Sean P , Philip George
Published: March 2023

Objectives

The GO-BACK study was designed to evaluate the efficacy and safety of golimumab (GLM) treatment withdrawal in adults with non-radiographic axial spondyloarthritis (nr-axSpA) who demonstrate inactive disease during a 10-month open-label (OL) GLM run-in.

Methods

Eligible participants received OL GLM in period 1. In period 2, participants who achieved inactive disease were randomized 1:1:1 to receive double-blind (DB) treatment with monthly placebo (PBO, treatment withdrawal) or continued GLM treatment given monthly (GLM QMT) or every 2 months (GLM Q2MT). Participants who did not have a disease flare continued DB treatment for ∼12 months. Participants with a disease flare discontinued DB treatment and resumed monthly OL GLM. Primary endpoint compared the proportion of participants without a disease flare in the continued GLM treatment groups (QMT or Q2MT) vs PBO in a multiplicity-controlled, step-down fashion. Safety follow-up continued for ∼3 months after last treatment.

Results

A total of 188 patients, out of the 323 enrolled, were eligible for participation in period 2. Both GLM QMT and GLM Q2MT were superior to treatment withdrawal (PBO) in preventing disease flare (P < 0.001), with a treatment-difference vs PBO of 50.4% and 34.4% for the GLM QMT and GLM Q2MT groups, respectively. The time-to-first flare was significantly longer (log-rank P < 0.0001) with GLM treatment compared with PBO. Of 53 participants (in Q2MT or PBO) who had a confirmed disease flare, 51 (96.2%) attained a clinical response within 3 months of restarting OL GLM. Adverse events were consistent with the known GLM safety profile.

Conclusion

Among participants with active nr-axSpA who attained inactive disease after 10 months of GLM treatment, continued GLM treatment is well tolerated and provides superior protection against disease flares compared with GLM withdrawal. (EudraCT: 2015-004020-65, registered on 30 March 2022; NCT: 03253796, registered on 18 August 2017.)
FETAL DOSE ESTIMATION DURING PREGNANCY USING GATE MONTE CARLO SIMULATION: APPLICATION OF HODGKIN’S LYMPHOMA RADIOTHERAPY
Authors: Benameur Yassine , Tahiri Maroine , Mkimel Mounir , El Baydaoui Redouane , Najeh Mohammed , Sahraoui Souha , Benchekroun Nadia , Bougteb Mustapha , El Hariri Bouazza , Mesradi Mohammed Reda , Hilali Abderraouf , Saad El madani
Published: March 2023

The aim of this study is to estimate the fetal radiation dose for a pregnant patient treated for Hodgkin’s lymphoma. Due to the supradiaphragmatic extensions, two plans are used for this treatment, one for supra-clavicular and the other for cervical lymph nodes, with beam energies of 18 and 6 MV, respectively. We model the ELEKTA accelerator (Versa HD Ltd, Crawly, UK) and the pregnant patient using GATE code. The accelerator is modelled based on the vendor-supplied data and the pregnant patient is modeled with a voxelized pregnant woman phantom (Katja, 29 years old) at the 24th week of pregnancy. In each plan, we estimate the absorbed dose of each fetus organ by delivering a 2 Gy for one fraction and then multiplying the result by 15 fractions to get the total prescribed dose, then we calculate the mean fetal absorbed dose. The results indicate that the mean absorbed fetal dose was 26.18 mGy.
Microstructural and Microvascular Alterations in Psychotic Spectrum Disorders: A Three-Compartment Intravoxel Incoherent Imaging and Free Water Model
Authors: McKenna Faye , Gupta Pradeep Kumar , Sui Yu Veronica , Bertisch Hilary , Gonen Oded , Goff Donald C , Lazar Mariana
Published: March 2023

Background and Hypothesis

Microvascular and inflammatory mechanisms have been hypothesized to be involved in the pathophysiology of psychotic spectrum disorders (PSDs). However, data evaluating these hypotheses remain limited.

Study Design

We applied a three-compartment intravoxel incoherent motion free water imaging (IVIM-FWI) technique that estimates the perfusion fraction (PF), free water fraction (FW), and anisotropic diffusion of tissue (FAt) to examine microvascular and microstructural changes in gray and white matter in 55 young adults with a PSD compared to 37 healthy controls (HCs).

Study Results

We found significantly increased PF, FW, and FAt in gray matter regions, and significantly increased PF, FW, and decreased FAt in white matter regions in the PSD group versus HC. Furthermore, in patients, but not in the HC group, increased PF, FW, and FAt in gray matter and increased PF in white matter were significantly associated with poor performance on several cognitive tests assessing memory and processing speed. We additionally report significant associations between IVIM-FWI metrics and myo-inositol, choline, and N-acetylaspartic acid magnetic resonance spectroscopy imaging metabolites in the posterior cingulate cortex, which further supports the validity of PF, FW, and FAt as microvascular and microstructural biomarkers of PSD. Finally, we found significant relationships between IVIM-FWI metrics and the duration of psychosis in gray and white matter regions.

Conclusions

The three-compartment IVIM-FWI model provides metrics that are associated with cognitive deficits and may reflect disease progression.
Aberrant Large-Scale Network Interactions Across Psychiatric Disorders Revealed by Large-Sample Multi-Site Resting-State Functional Magnetic Resonance Imaging Datasets
Authors: Ishida Takuya , Nakamura Yuko , Tanaka Saori C , Mitsuyama Yuki , Yokoyama Satoshi , Shinzato Hotaka , Itai Eri , Okada Go , Kobayashi Yuko , Kawashima Takahiko , Miyata Jun , Yoshihara Yujiro , Takahashi Hidehiko , Morita Susumu , Kawakami Shintaro , Abe Osamu , Okada Naohiro , Kunimatsu Akira , Yamashita Ayumu , Yamashita Okito , Imamizu Hiroshi , Morimoto Jun , Okamoto Yasumasa , Murai Toshiya , Kasai Kiyoto , Kawato Mitsuo , Koike Shinsuke
Published: March 2023

Background and Hypothesis

Dynamics of the distributed sets of functionally synchronized brain regions, known as large-scale networks, are essential for the emotional state and cognitive processes. However, few studies were performed to elucidate the aberrant dynamics across the large-scale networks across multiple psychiatric disorders. In this paper, we aimed to investigate dynamic aspects of the aberrancy of the causal connections among the large-scale networks of the multiple psychiatric disorders.

Study Design

We applied dynamic causal modeling (DCM) to the large-sample multi-site dataset with 739 participants from 4 imaging sites including 4 different groups, healthy controls, schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BD), to compare the causal relationships among the large-scale networks, including visual network, somatomotor network (SMN), dorsal attention network (DAN), salience network (SAN), limbic network (LIN), frontoparietal network, and default mode network.

Study Results

DCM showed that the decreased self-inhibitory connection of LIN was the common aberrant connection pattern across psychiatry disorders. Furthermore, increased causal connections from LIN to multiple networks, aberrant self-inhibitory connections of DAN and SMN, and increased self-inhibitory connection of SAN were disorder-specific patterns for SCZ, MDD, and BD, respectively.

Conclusions

DCM revealed that LIN was the core abnormal network common to psychiatric disorders. Furthermore, DCM showed disorder-specific abnormal patterns of causal connections across the 7 networks. Our findings suggested that aberrant dynamics among the large-scale networks could be a key biomarker for these transdiagnostic psychiatric disorders.
Effects of selected blood-derived factors on innate immunity in the human body louse
Authors: Kress Lauren , Tegethoff Benjamin , Pietri Jose E
Published: March 2023

Background

The human body louse (Pediculus humanus humanus) is a host-specific hematophagous ectoparasite that frequently infests populations experiencing a breakdown of hygienic conditions. Body lice are also vectors for several bacterial human pathogens, including Bartonella quintana, the agent of trench fever. However, the factors that influence immunity and infection in body lice are poorly understood. Human infection with B. quintana is associated with alcoholism and homelessness and can coincide with elevated circulating levels of the cytokine IL-10 and the inflammatory marker neopterin. Hematophagous arthropods are capable of responding physiologically and immunologically to a variety of biomolecules present in the blood of their hosts. Therefore, we sought to investigate whether ingestion of alcohol, its metabolic product acetaldehyde, IL-10 or neopterin could affect innate immunity and infection in the body louse.

Methods

Groups of lice were provisioned multiple blood meals containing physiological concentrations of alcohol, acetaldehyde, IL-10 or neopterin, and expression of six previously identified immunity-related genes (Defensin 1, Defensin 2, Prophenoloxidase, Hemocytin, Noduler and Dual Oxidase) was examined by qRT-PCR.

Results

Alcohol, acetaldehyde and IL-10 had no significant effects on gene expression relative to blood-fed controls while ingestion of neopterin significantly downregulated expression of Defensin 1 and Defensin 2. Nonetheless, ingestion of neopterin concurrent with B. quintana had no significant effect on the load of infection, indicating that neopterin-induced repression of Defensin expression is insufficient to reduce resistance to the pathogen.

Conclusions

Our findings demonstrate that the immune system of body lice can be affected by factors present in the blood of their human hosts and suggest potential conservation of the function of some immune molecules from human host to ectoparasite. Further, the discord between the effects of neopterin on immunity-related gene expression and B. quintana load highlights the complexity of the regulation of pathogen infection in the louse vector.
Vestibular Vertigo and Disparities in Healthcare Access Among Adults in the United States
Authors: Min Youn Gun , Shah Jay P. , Agrawal Yuri , Wei Eric X.
Published: March 2023

Objective:

Vertigo and dizziness have a high lifetime prevalence with significant impacts on daily life. We sought to explore differences in access to and ability to afford care among adults with vestibular vertigo by race/ethnicity, income, and insurance type.

Design:

This is a cross-sectional study using the 2016 National Health Interview Survey. A total of 32,047 adults who completed the 2016 National Health Interview Survey Balance Supplement were analyzed. We used a previously validated definition of vertigo defined as (1) positional vertigo, (2) rotational vertigo, or (3) recurrent dizziness with nausea and either oscillopsia or imbalance. We examined several self-reported measures of healthcare utilization and access.

Results:

Among adults with vestibular vertigo, African Americans had significantly increased odds of delayed care due to lack of transportation; Hispanic ethnicity was associated with decreased odds of skipping medication doses and asking a doctor for a lower-cost medication. Adults with public insurance had significantly lower odds of reporting delayed care due to worry about cost, not receiving medical care due to cost, and delayed filling of a prescription, but had greater odds of reporting delayed care due to lack of transportation. Lack of insurance and lower income were associated with increased odds of delaying and not receiving care due to cost.

Conclusion:

These findings demonstrate significant differences in access to care among adults with vestibular vertigo in the United States based on race, income, and health insurance status.
Using Machine Learning and Deep Learning Algorithms to Predict Postoperative Outcomes Following Anterior Cervical Discectomy and Fusion
Authors: Khazanchi Rushmin , Bajaj Anitesh , Shah Rohan M. , Chen Austin R. , Reyes Samuel G. , Kurapaty Steven S. , Hsu Wellington K. , Patel Alpesh A. , Divi Srikanth N.
Published: March 2023

Study Design:

A retrospective cohort study from a multisite academic medical center.

Objective:

To construct, evaluate, and interpret a series of machine learning models to predict outcomes related to inpatient health care resource utilization for patients undergoing anterior cervical discectomy and fusion (ACDF).

Summary of Background Data:

Reducing postoperative health care utilization is an important goal for improving the delivery of surgical care and serves as a metric for quality assessment. Recent data has shown marked hospital resource utilization after ACDF surgery, including readmissions, and ED visits. The burden of postoperative health care use presents a potential application of machine learning techniques, which may be capable of accurately identifying at-risk patients using patient-specific predictors.

Methods:

Patients 18-88 years old who underwent ACDF from 2011 to 2021 at a multisite academic center and had preoperative lab values within 3 months of surgery were included. Outcomes analyzed included 90-day readmissions, postoperative length of stay, and nonhome discharge. Four machine learning models—Extreme Gradient Boosted Trees, Balanced Random Forest, Elastic-Net Penalized Logistic Regression, and a Neural Network—were trained and evaluated through the Area Under the Curve estimates. Feature importance scores were computed for the highest-performing model per outcome through model-specific metrics.

Results:

A total of 1026 cases were included in the analysis cohort. All machine learning models were predictive for outcomes of interest, with the Random Forest algorithm consistently demonstrating the strongest average area under the curve performance, with a peak performance of 0.84 for nonhome discharge. Important features varied per outcome, though age, body mass index, American Society of Anesthesiologists classification >2, and medical comorbidities were highly weighted in the studied outcomes.

Conclusions:

Machine learning models were successfully applied and predictive of postoperative health utilization after ACDF. Deployment of these tools can assist clinicians in determining high-risk patients.

Level of Evidence:

III.
Sleep Disturbances in Cervical Spondylotic Myelopathy
Authors: Bisson Erica F. , Mummaneni Praveen V. , Michalopoulos Giorgos D. , El Sammak Sally , Chan Andrew K. , Agarwal Nitin , Wang Michael Y. , Knightly John J. , Sherrod Brandon A. , Gottfried Oren N. , Than Khoi D. , Shaffrey Christopher I. , Goldberg Jacob L. , Virk Michael S. , Hussain Ibrahim , Shabani Saman , Glassman Steven D. , Tumialan Louis M. , Turner Jay D. , Uribe Juan S. , Meyer Scott A. , Lu Daniel C. , Buchholz Avery L. , Upadhyaya Cheerag , Shaffrey Mark E. , Park Paul , Foley Kevin T. , Coric Domagoj , Slotkin Jonathan R. , Potts Eric A. , Stroink Ann R. , Chou Dean , Fu Kai-Ming G. , Haid Regis W. , Asher Anthony L. , Bydon Mohamad
Published: March 2023

Study Design:

Prospective observational study, level of evidence 1 for prognostic investigations.

Objectives:

To evaluate the prevalence of sleep impairment and predictors of improved sleep quality 24 months postoperatively in cervical spondylotic myelopathy (CSM) using the quality outcomes database.

Summary of Background Data:

Sleep disturbances are a common yet understudied symptom in CSM.

Materials and Methods:

The quality outcomes database was queried for patients with CSM, and sleep quality was assessed through the neck disability index sleep component at baseline and 24 months postoperatively. Multivariable logistic regressions were performed to identify risk factors of failure to improve sleep impairment and symptoms causing lingering sleep dysfunction 24 months after surgery.

Results:

Among 1135 patients with CSM, 904 (79.5%) had some degree of sleep dysfunction at baseline. At 24 months postoperatively, 72.8% of the patients with baseline sleep symptoms experienced improvement, with 42.5% reporting complete resolution. Patients who did not improve were more like to be smokers [adjusted odds ratio (aOR): 1.85], have osteoarthritis (aOR: 1.72), report baseline radicular paresthesia (aOR: 1.51), and have neck pain of ≥4/10 on a numeric rating scale. Patients with improved sleep noted higher satisfaction with surgery (88.8% vs 72.9%, aOR: 1.66) independent of improvement in other functional areas. In a multivariable analysis including pain scores and several myelopathy-related symptoms, lingering sleep dysfunction at 24 months was associated with neck pain (aOR: 1.47) and upper (aOR: 1.45) and lower (aOR: 1.52) extremity paresthesias.

Conclusion:

The majority of patients presenting with CSM have associated sleep disturbances. Most patients experience sustained improvement after surgery, with almost half reporting complete resolution. Smoking, osteoarthritis, radicular paresthesia, and neck pain ≥4/10 numeric rating scale score are baseline risk factors of failure to improve sleep dysfunction. Improvement in sleep symptoms is a major driver of patient-reported satisfaction. Incomplete resolution of sleep impairment is likely due to neck pain and extremity paresthesia.
The Need for Additional Surgery after Passive versus Active Approaches to Syndromic Craniosynostosis: A Meta-analysis
Authors: Grosser Joshua A. , Kogan Samuel , Layton Ryan G. , Pontier Joshua F. , Bins Griffin P. , Runyan Christopher M.
Published: March 2023

Background:

Endoscopically assisted craniofacial surgery (EACS) has numerous advantages over traditional, open approaches, such as fronto-orbital advancement in treating nonsyndromic craniosynostosis. However, several articles report high reoperation rates in syndromic patients treated with EACS. This meta-analysis and review examines undesirable outcome rates (UORs), defined as reoperation or Whitaker category III/IV, in syndromic patients undergoing primary EACS compared with procedures that actively expand the cranial vault.

Methods:

PubMed and Embase were searched in June 2022 to identify all articles reporting primary reoperation or Whitaker outcomes for syndromic patients undergoing cranial vault expanding surgery or suturectomy. A meta-analysis of proportions was performed comparing UORs, and a trim-and-fill adjustment method was used to validate sensitivity and assess publication bias.

Results:

A total of 721 articles were screened. Five EACS articles (83 patients) and 22 active approach articles (478 patients) met inclusion criteria. Average UORs for EACS and active approaches were 26% (14%–38%) and 20% (13%–28%), respectively (P = 0.18). Reoperation occurred earlier in EACS patients (13.7 months postprimary surgery versus 37.1 months for active approaches, P = 0.003). Relapse presentations and reason for reoperation were also reviewed. Subjectively, EACS UORs were higher in all syndromes except Apert, and Saethre-Chotzen patients had the highest UOR for both approaches.

Conclusions:

There was no statistically significant increase in UORs among syndromic patients treated with EACS compared with traditional approaches, although EACS patients required revision significantly sooner. Uncertainties regarding the long-term efficacy of EACS in children with syndromic craniosynostosis should be revisited as more data become available.
Outcomes of Ventral Hernia Repair After Orthotopic Liver Transplant Using Component Separation and Onlay Biologic Mesh
Authors: Soto Edgar , Zoog Evon , Nolte Michael D. , Fang H. Amanda , de la Torre Jorge I.
Published: March 2023

Introduction

The management of ventral hernias (VHs) after orthotopic liver transplant (OLT) can be uniquely challenging because of immunosuppression coupled with large laparotomy size that can compromise the quality of the abdominal wall. The component separation with multipoint suture onlay acellular dermis fixation technique has proven to be effective in high-risk abdominal wall reconstructions. The goal of this study was to elucidate the factors that affect safety and efficacy of VH repair in post-OLT patients.

Methods

A retrospective review of 345 patients who underwent repair of VH with compartment separation and onlay acellular dermal matrix reinforcement from a single surgeon from 2012 to 2020 was conducted. Of these, 27 patients were identified with a history of OLT and were stratified based on whether the defect was a initial or recurrent hernia repair. The majority of patients had a standard chevron incision (70%). Data abstraction was performed for preoperative risk factors, hernia characteristics, surgical site complications, and postoperative course including hernia recurrence.

Results

A majority of cases in the study period were initial hernia repairs (59%) with no significant differences in the patient demographics and size of VH defects (190 ± 112.69 cm2). Comorbidities were similar between the groups with the exception of a significantly higher baseline creatinine levels and higher history of smoking in the recurrent hernia repair group (P< 0.05). Of the 27 cases, there were no demonstrable hernia recurrences noted and an overall 11% complication rate. Univariate analysis noted a statistically significant difference in surgical site complication rate (P= 0.017), with the initial hernia repair group having the lowest rate of surgical site complications.

Conclusions

In complex post-OLT patients with large VH, modified component separation with onlay acellular mesh was shown to have acceptable medium-term results. Further studies investigating the factors leading to postoperative complications are necessary to reduce recurrence in this evolving patient population.
Early warnings for multi-stage transitions in dynamics on networks
Authors: MacLaren Neil G. , Kundu Prosenjit , Masuda Naoki
Published: March 2023

Successfully anticipating sudden major changes in complex systems is a practical concern. Such complex systems often form a heterogeneous network, which may show multi-stage transitions in which some nodes experience a regime shift earlier than others as an environment gradually changes. Here we investigate early warning signals for networked systems undergoing a multi-stage transition. We found that knowledge of both the ongoing multi-stage transition and network structure enables us to calculate effective early warning signals for multi-stage transitions. Furthermore, we found that small subsets of nodes could anticipate transitions as well as or even better than using all the nodes. Even if we fix the network and dynamical system, no single best subset of nodes provides good early warning signals, and a good choice of sentinel nodes depends on the tipping direction and the current stage of the dynamics within a multi-stage transition, which we systematically characterize.
Categorizing update mechanisms for graph-structured metapopulations
Authors: Yagoobi Sedigheh , Sharma Nikhil , Traulsen Arne
Published: March 2023

The structure of a population strongly influences its evolutionary dynamics. In various settings ranging from biology to social systems, individuals tend to interact more often with those present in their proximity and rarely with those far away. A common approach to model the structure of a population is evolutionary graph theory. In this framework, each graph node is occupied by a reproducing individual. The links connect these individuals to their neighbours. The offspring can be placed on neighbouring nodes, replacing the neighbours—or the progeny of its neighbours can replace a node during the course of ongoing evolutionary dynamics. Extending this theory by replacing single individuals with subpopulations at nodes yields a graph-structured metapopulation. The dynamics between the different local subpopulations is set by an update mechanism. There are many such update mechanisms. Here, we classify update mechanisms for structured metapopulations, which allows to find commonalities between past work and illustrate directions for further research and current gaps of investigation.
Performance analysis and optimization of inverted inorganic CsGeI
3
perovskite cells with carbon/copper charge transport materials using SCAPS-1D
Authors: Ahmad Waqar , Noman Muhammad , Tariq Jan Shayan , Khan Adnan Daud
Published: March 2023

Organic–inorganic perovskite solar cells (PSCs) have achieved the power conversion efficiencies (PCEs) of more than 25%. However, the organic compound in the material is causing structural degradation of the PSC owing to heat (thermal instability), humidity and moisture. This has led to the exploration of only inorganic perovskite materials. Inorganic PSCs such as caesium have seen a breakthrough by achieving highly stable PSC with PCE exceeding 15%. In this work, the inorganic non-toxic PSC of caesium germanium tri-iodide (CsGeI
3
) is numerically modelled in SCAPS-1D with two carbon-based electron transport layers (ETLs) and two copper-based hole transport layers (HTLs). This study introduces in-depth numerical modelling and analysis of CsGeI
3
through continuity and Poisson equations. Cu HTLs are selected to increase the electric conductivity of the cell, while carbon-based ETL is used to increase the thermal conductivity of the PSC. A total of four unique PSC structures are designed and presented. A systematic approach is adopted to obtain the optimized PSC design parameters for maximum performance. From the optimized results, it is observed that the C
60
/CsGeI
3
/CuSCN structure is the highest performance PSC, with open-circuit voltage (
V
oc
) of 1.0169 V, short-circuit current density (
J
sc
) of 19.653 mA cm
−2
, fill factor of 88.13% and the PCE of 17.61%. Moreover, the effect of quantum efficiency, electric field, interface recombination, interface defects, layer thickness, defect density, doping concentration, working temperature and reflection coating on the cell performance are studied in detail.
Topology optimization with local stress constraints and continuously varying load direction and magnitude: towards practical applications
Authors: Senhora Fernando V. , Menezes Ivan F. M. , Paulino Glaucio H.
Published: March 2023

Topology optimization problems typically consider a single load case or a small, discrete number of load cases; however, practical structures are often subjected to infinitely many load cases that may vary in intensity, location and/or direction (e.g. moving/rotating loads or uncertain fixed loads). The variability of these loads significantly influences the stress distribution in a structure and should be considered during the design. We propose a locally stress-constrained topology optimization formulation that considers loads with continuously varying direction to ensure structural integrity under more realistic loading conditions. The problem is solved using an Augmented Lagrangian method, and the continuous range of load directions is incorporated through a series of analytic expressions that enables the computation of the worst-case maximum stress over all possible load directions. Variable load intensity is also handled by controlling the magnitude of load basis vectors used to derive the worst-case load. Several two- and three-dimensional examples demonstrate that topology-optimized designs are extremely sensitive to loads that vary in direction. The designs generated by this formulation are safer, more reliable, and more suitable for real applications, because they consider realistic loading conditions.
Top predator restricts the niche breadth of prey: effects of assisted colonization of Tasmanian devils on a widespread omnivorous prey
Authors: Scoleri Vincent P. , Ingram Janeane , Johnson Christopher N. , Jones Menna E.
Published: March 2023

Few landscape-scale experiments test the effects of predators on the abundance and distribution of prey across habitat gradients. We use the assisted colonization of a top predator, the Tasmanian devil (Sarcophilus harrisii), to test the impacts of predation on the abundance, habitat use and temporal activity of a widespread prey species, the omnivorous common brushtail possum (Trichosurus vulpecula). Before introduction of devils to Maria Island, Tasmania, Australia, in 2012, possums were abundant in open grasslands as well as forests. Predation by devils caused high mortality of possums in grasslands, but individuals with access to trees had a higher survival probability. Possum abundance declined across the whole island from 2012–2016, as possums disappeared almost completely from grasslands and declined in drier forests with more open understorey. Abundance remained stable in wet forests, which are not preferred habitat for possums but provide better refuge from devils. Abundance and habitat use of possums remained unchanged at a control site on the adjacent Tasmanian mainland, where the devil population was low and stable. This study demonstrates how spatial variation in predator-caused mortality can limit both abundance and habitat breadth in generalist prey species, excluding them entirely from certain habitats.
Mapping nationally and globally at-risk species to identify hotspots for (and gaps in) conservation
Authors: Hardouin Marie E. , Hargreaves Anna L.
Published: March 2023

Protecting habitat of species at risk is critical to their recovery, but can be contentious. For example, protecting species that are locally imperilled but globally common is often thought to distract from protecting globally imperilled species. However, such perceived trade-offs are based on the assumption that threatened groups have little spatial overlap, which is rarely quantified. We compiled range maps of terrestrial species at risk in Canada to assess the geographic overlap of nationally and globally at-risk species with each other, among taxonomic groups, and with protected areas. While many nationally at-risk taxa only occur in Canada at their northern range edge, they are not significantly more peripheral in Canada than globally at-risk species. Further, 56% of hotspots of nationally at-risk taxa are also hotspots of globally at-risk species, undercutting the perceived trade-off in their protection. While strong spatial overlap across threat levels and taxa should facilitate efficient habitat protection, less than 7% of the area in Canada's at-risk hotspots is protected, and two-thirds of nationally and globally at-risk species in Canada have less than 10% of their Canadian range protected. Our results counter the perception that protecting nationally versus globally at-risk species are at odds, and identify critical areas to target as Canada strives to increase its protected areas and promote recovery of species at risk.
Multiscale mapping of transcriptomic signatures for cardiotoxic drugs
Authors: Hansen Jens , Xiong Yuguang , Dhanan Priyanka , Hu Bin , Yadaw Arjun S. , Jayaraman Gomathi , Tolentino Rosa , Chen Yibang , Beaumont Kristin G. , Sebra Robert , Vidovic Dusica , Schürer Stephan C. , Goldfarb Joseph , Gallo James , Birtwistle Marc R. , Sobie Eric A. , Azeloglu Evren U. , Berger Seth , Chan Angel , Schaniel Christoph , Dubois Nicole C. , Iyengar Ravi
Published: March 2023

Drug-induced gene expression profiles can identify potential mechanisms of toxicity. We focused on obtaining signatures for cardiotoxicity of FDA-approved tyrosine kinase inhibitors (TKIs) in human induced pluripotent stem cell-derived cardiomyocytes. Using bulk transcriptomics profiles, we applied singular value decomposition to identify drug-selective patterns in cell lines obtained from multiple healthy human subjects. Cellular pathways affected by highly cardiotoxic TKIs include energy metabolism, contractile, and extracellular matrix dynamics. Projecting these pathways to single cell expression profiles indicates that TKI responses can be evoked in both cardiomyocytes and fibroblasts. Whole genome sequences of the cell lines, using outlier responses enabled us to correctly reidentify a genomic variant associated with anthracycline cardiotoxicity and predict genomic variants potentially associated with TKI cardiotoxicity. We conclude that mRNA expression profiles when integrated with publicly available genomic, pathway, and single cell transcriptomic datasets, provide multiscale predictive understanding of cardiotoxicity for drug development and patient stratification.

One sentence summary

Genes, pathways, and cell types of the human heart associated with antineoplastic drug cardiotoxicity.
Impact and cost-effectiveness of measles vaccination through microarray patches in 70 low- and middle-income countries: a modelling study
Authors: Fu Han , Abbas Kaja , Malvolti Stefano , Gregory Christopher , Ko Melissa , Amorij Jean-Pierre , Jit Mark
Published: March 2023

Background

Microarray patches are a promising technology being developed to reduce barriers to vaccine delivery based on needles and syringes. To address the evidence gap on the public health value of applying this potential technology to immunisation programmes, we evaluated the health impact on measles burden and resulting cost-effectiveness of introducing measles-rubella microarray patches (MR-MAPs) in 70 low- and middle-income countries (LMICs).

Methods

We used an age-structured dynamic model of measles transmission and vaccination to project measles cases, deaths, and disability-adjusted life years during 2030⍰2040. Compared to the baseline scenarios with continuing current needle-based immunisation practice, we evaluated the introduction of MR-MAPs under different assumptions on measles vaccine coverage projections and MR-MAP introduction strategies. Costs were calculated based on the ingredients approach, including direct cost of measles treatment, vaccine procurement, and vaccine delivery. Model-based burden and cost estimates were derived for individual countries and country income groups. We compared the incremental cost-effectiveness ratios of introducing MR-MAPs to health opportunity costs.

Results

MR-MAPs introduction could prevent 27%⍰37% of measles burden between 2030⍰2040 in 70 LMICs. The largest health impact could be achieved under lower coverage projection and accelerated introduction strategy, with 39 million measles cases averted. Cost of measles treatment is a key driver of the net cost of introduction. In LMICs with a relatively higher income, introducing MR-MAPs could be a cost-saving intervention due to reduction in measles treatment costs. Compared to country-specific health opportunity costs, introducing MR-MAPs would be cost-effective in 16⍰81% of LMICs, depending on the MR-MAPs procurement price and vaccine coverage projections.

Conclusions

Introducing MR-MAPs in LMICs can be a cost-effective strategy to revitalise measles immunisation programmes with stagnant uptake and reach under-vaccinated children. Sustainable introduction and uptake of MR-MAPs has the potential to improve vaccine equity within and between countries and accelerate progress towards measles elimination.
A Transcriptomic Atlas of the Human Brain Reveals Genetically Determined Aspects of Neuropsychiatric Health
Authors: Bledsoe Xavier , Gamazon Eric R.
Published: March 2023

Imaging features associated with neuropsychiatric traits can provide valuable insights into underlying pathophysiology. Using data from the UK biobank, we perform tissue-specific TWAS on over 3,500 neuroimaging phenotypes to generate a publicly accessible resource detailing the neurophysiologic consequences of gene expression. As a comprehensive catalog of neuroendophenotypes, this resource represents a powerful neurologic gene prioritization schema that can improve our understanding of brain function, development, and disease. We show that our approach generates reproducible results in internal and external replication datasets. Notably, genetically determined expression alone is shown here to enable high-fidelity reconstruction of brain structure and organization. We demonstrate complementary benefits of cross-tissue and single-tissue analyses towards an integrated neurobiology and provide evidence that gene expression outside the central nervous system provides unique insights into brain health. As an application, we show that over 40% of genes previously associated with schizophrenia in the largest GWAS meta-analysis causally affect neuroimaging phenotypes noted to be altered in schizophrenic patients.
PD-1/LAG-3 Dysfunctionality Signatures in Human Cancers
Authors: Chocarro Luisa , Fernandez-Rubio Leticia , García-Granda María Jesús , Blanco Ester , Bocanegra Ana , Echaide Miriam , Garnica Maider , Zuazo Miren , Johnston Colette , Edwards Carolyn J. , Legg James , Pierce Andrew J , Arasanz Hugo , Vera Ruth , Ausin Karina , Santamaría Enrique , Fernández-Irigoyen Joaquín , Kochan Grazyna , Escors David
Published: March 2023

A significant number of cancer patients do not benefit from PD-L1/PD-1 blockade immunotherapies. PD-1 and LAG-3 co-upregulation in T-cells is one of the major mechanisms of resistance by establishing a highly dysfunctional state in T-cells. To identify shared features associated to PD- 1/LAG-3 dysfunctionality in human cancers and T-cells, multiomic expression profiles were obtained for all TCGA cancers with high T-cell infiltration. A PD-1/LAG-3 dysfunctional signature was found which regulated immune, metabolic, genetic and epigenetic pathways. These results were validated in T-cell lines with constitutively active PD-1, LAG-3 pathways and their combination. These results uncovered distinct degrees of T-cell dysfunctionality. Global changes were cross-evaluated among T- cell lines with multiomic biopsy data to identify genetic, metabolic, and proteomic programmes regulated by PD-1/LAG-3 dysfunctionality. One of these relied on differential regulation of E3 ubiquitin ligases CBL-B and C-CBL. PD-1/LAG-3 co-blockade with a bispecific drug under clinical development but not with a combination of anti-PD-1/anti-LAG-3 antibodies achieved both CBL-B and C-CBL inhibition, reverting T-cell dysfunctionality in lung cancer patients resistant to PD-L1/PD- 1 blockade.
Development of a Rapid and Specific MALDI-TOF Mass Spectrometric Assay for SARS-CoV-2 Detection
Authors: Kollhoff Lydia , Kipping Marc , Rauh Manfred , Ceglarek Uta , Barka Guenes , Barka Frederik , Sinz Andrea
Published: March 2023

We have developed a rapid and highly specific assay for detecting and monitoring SARS-CoV-2 infections by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). As MALDI-TOF mass spectrometers are available in a clinical setting, our assay has the potential to serve as alternative to the commonly used reverse transcriptase quantitative polymerase chain reaction (RT-qPCR). Sample preparation prior to MALDI-TOF-MS involves the tryptic digestion of SARS-CoV-2 proteins, followed by an enrichment of virus-specific peptides from SARS-CoV-2 nucleoprotein via magnetic antibody beads. Our MALDI-TOF-MS method allows the detection of SARS-CoV-2 nucleoprotein as low as 8 amol/microliter. MALDI-TOF mass spectra are obtained in just a few seconds, which makes our MS-based assay suitable for a high-throughput screening of SARS-CoV-2 in healthcare facilities in addition to PCR. Due to the specific detection of virus peptides, different SARS-CoV-2 variants are readily distinguished from each other. Specifically, we show that our MALDI-TOF-MS assay discriminates SARS-CoV-2 strain B.1.617.2 delta variant from all other variants in patients' samples, making our method highly valuable to monitor the emergence of new virus variants.
Testing a polygenic risk score for morphological microglial activation in Alzheimer’s disease and aging
Authors: Tio Earvin S. , Hohman Timothy J. , Milic Milos , Bennett David A. , Felsky Daniel ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: March 2023

Neuroinflammation and the activation of microglial cells are among the earliest events in Alzheimer’s disease (AD). However, direct observation of microglia in living people is not currently possible. Here, we indexed the heritable propensity for neuroinflammation with polygenic risk scores (PRS), using results from a recent genome-wide analysis of a validated post-mortem measure of morphological microglial activation. We sought to determine whether a PRS for microglial activation (PRSmic) could augment the predictive performance of existing AD PRSs for late-life cognitive impairment. First, PRSmicwere calculated and optimized in a calibration cohort (Alzheimer’s Disease Neuroimaging Initiative (ADNI), n=450), with resampling. Second, predictive performance of optimal PRSmicwas assessed in two independent, population-based cohorts (total n=212,237). Our PRSmicshowed no significant improvement in predictive power for either AD diagnosis or cognitive performance. Finally, we explored associations of PRSmicwith a comprehensive set of imaging and fluid AD biomarkers in ADNI. This revealed some nominal associations, but with inconsistent effect directions. While genetic scores capable of indexing risk for neuroinflammatory processes in aging are highly desirable, more well-powered genome-wide studies of microglial activation are required. Further, biobank-scale studies would benefit from phenotyping of proximal neuroinflammatory processes to improve the PRS development phase.
FRESH™ 3D Bioprinted Cardiac Tissue, a Bioengineered Platform for in vitro Toxicology and Pharmacology
Authors: Finkel Samuel , Sweet Shannon , Locke Tyler , Smith Sydney , Wang Zhefan , Sandini Christopher , Imredy John P. , He Yufang , Durante Marc , Lagrutta Armando , Feinberg Adam , Lee Andrew
Published: March 2023

There is critical need for a predictive model of human cardiac physiology in the drug development process for assessment of compound toxicology and pharmacology. In vitro two-dimensional monolayer culture of cardiomyocytes provides biochemical and cellular readouts, and in vivo small and large animal models provide information on systemic cardiovascular response. However, there remains a significant gap in these models due to an incomplete recapitulation of adult human cardiovascular physiology, which results in more difficult safety interpretations. Recent efforts in developing in vitro models from engineered heart tissues have demonstrated potential for bridging this gap using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) in a three-dimensional tissue structure. Here we advance this paradigm by implementing FRESH™ 3D bioprinting to build human cardiac tissues in a medium throughput, well-plate format with controlled tissue architecture, tailored cellular composition, and native-like physiological function, specifically in its adrenergic agonist drug response. To do this, we combined hiPSC-CMs, endothelial cells and fibroblasts in a cellular bioink and FRESH™ 3D bioprinted this mixture in the format of a thin tissue strip stabilized on a tissue fixture. Our results confirmed that FRESH™ 3D bioprinted cardiac tissues could be fabricated directly in a 24-well plate format, were composed of dense and highly aligned hiPSC-CMs at >600 million cells/mL, and within 14 days demonstrated reproducible calcium transients and fast conduction velocity of ∼25 cm/s. Interrogation of these cardiac tissues with the ß-adrenergic receptor agonist isoproterenol showed native-like positive chronotropic and inotropic responses, a combination of responses that is not typically observed in 2D monolayer models or standard 3D engineered heart tissue approaches. These results confirm that FRESH™ 3D bioprinted cardiac tissues represents a novel in vitro platform that enables early in vitro pharmacology and toxicology screening.