bluuebunny/crossref_metadata_2025 huggingface dataset:
Population pharmacokinetic analysis of tepotinib, an oral MET kinase inhibitor, including data from the VISION study
Authors: Xiong Wenyuan , Papasouliotis Orestis , Jonsson E. Niclas , Strotmann Rainer , Girard Pascal
Published: April 2022

Purpose

Tepotinib is a highly selective, potent, mesenchymal–epithelial transition factor (MET) inhibitor, approved for the treatment of non-small cell lung cancer (NSCLC) harboring MET exon 14 skipping. Objectives of this population pharmacokinetic (PK) analysis were to evaluate the dose–exposure relationship of tepotinib and its major circulating metabolite, MSC2571109A, and to identify the intrinsic/extrinsic factors that are predictive of PK variability.

Methods

Data were included from 12 studies in patients with cancer and in healthy participants. A sequential modeling approach was used to analyze the parent and metabolite data, including covariate analyses. Potential associations between observed covariates and PK parameters were illustrated using bootstrap analysis-based forest plots.

Results

A two-compartment model with sequential zero- and first-order absorption, and a first-order elimination from the central compartment, best described the plasma PK of tepotinib in humans across the dose range of 30–1400 mg. The bioavailability of tepotinib was shown to be dose dependent, although bioavailability decreased primarily at doses above the therapeutic dose of 500 mg. The intrinsic factors of race, age, sex, body weight, mild/moderate hepatic impairment and mild/moderate renal impairment, along with the extrinsic factors of opioid analgesic and gefitinib intake, had no relevant effect on tepotinib PK. Tepotinib has a long effective half-life of ~ 32 h.

Conclusions

Tepotinib shows dose proportionality up to at least the therapeutic dose, and time-independent clearance with a profile appropriate for once-daily dosing. None of the covariates identified had a clinically meaningful effect on tepotinib exposure or required dose adjustments.
Proposed diagnostic volumetric bone mineral density thresholds for osteoporosis and osteopenia at the cervicothoracic spine in correlation to the lumbar spine
Authors: Rühling Sebastian , Scharr Andreas , Sollmann Nico , Wostrack Maria , Löffler Maximilian T. , Menze Bjoern , Sekuboyina Anjany , El Husseini Malek , Braren Rickmer , Zimmer Claus , Kirschke Jan S.
Published: April 2022

Objectives

To determine the correlation between cervicothoracic and lumbar volumetric bone mineral density (vBMD) in an average cohort of adults and to identify specific diagnostic thresholds for the cervicothoracic spine on the individual subject level.

Methods

In this HIPPA–compliant study, we retrospectively included 260 patients (59.7 ± 18.3 years, 105 women), who received a contrast-enhanced or non-contrast-enhanced CT scan. vBMD was extracted using an automated pipeline (https://anduin.bonescreen.de). The association of vBMD between each vertebra spanning C2–T12 and the averaged values at the lumbar spine (L1–L3) was analyzed before and after semiquantitative assessment of fracture status and degeneration, and respective vertebra-specific cut-off values for osteoporosis were calculated using linear regression.

Results

In both women and men, trabecular vBMD decreased with age in the cervical, thoracic, and lumbar regions. vBMD values of cervicothoracic vertebrae showed strong correlations with lumbar vertebrae (L1–L3), with a median Pearson value of r = 0.87 (range: rC2 = 0.76 to rT12 = 0.96). The correlation coefficients were significantly lower (p < 0.0001) without excluding fractured and degenerated vertebrae, median r = 0.82 (range: rC2 = 0.69 to rT12 = 0.93). Respective cut-off values for osteoporosis peaked at C4 (209.2 mg/ml) and decreased to 83.8 mg/ml at T12.

Conclusion

Our data show a high correlation between clinically used mean L1–L3 values and vBMD values elsewhere in the spine, independent of age. The proposed cut-off values for the cervicothoracic spine therefore may allow the determination of low bone mass even in clinical cases where only parts of the spine are imaged.

Key Points

vBMD of all cervicothoracic vertebrae showed strong correlation with lumbar vertebrae (L1–L3), with a median Pearson’s correlation coefficient of r = 0.87 (range: rC2 = 0.76 to rT12 = 0.96).

The correlation coefficients were significantly lower (p < 0.0001) without excluding fractured and moderate to severely degenerated vertebrae, median r = 0.82 (range: rC2 = 0.69 to rT12 = 0.93).

We postulate that trabecular vBMD < 200 mg/ml for the cervical spine and < 100 mg/ml for the thoracic spine are strong indicators of osteoporosis, similar to < 80 mg/ml at the lumbar spine.
Osteoporosis in children and adolescents: when to suspect and how to diagnose it
Authors: Ciancia Silvia , van Rijn Rick R. , Högler Wolfgang , Appelman-Dijkstra Natasha M. , Boot Annemieke M. , Sas Theo C. J. , Renes Judith S.
Published: April 2022

Early recognition of osteoporosis in children and adolescents is important in order to establish an appropriate diagnosis of the underlying condition and to initiate treatment if necessary. In this review, we present the diagnostic work-up, and its pitfalls, of pediatric patients suspected of osteoporosis including a careful collection of the medical and personal history, a complete physical examination, biochemical data, molecular genetics, and imaging techniques. The most recent and relevant literature has been reviewed to offer a broad overview on the topic. Genetic and acquired pediatric bone disorders are relatively common and cause substantial morbidity. In recent years, there has been significant progress in the understanding of the genetic and molecular mechanistic basis of bone fragility and in the identification of acquired causes of osteoporosis in children. Specifically, drugs that can negatively impact bone health (e.g. steroids) and immobilization related to acute and chronic diseases (e.g. Duchenne muscular dystrophy) represent major risk factors for the development of secondary osteoporosis and therefore an indication to screen for bone mineral density and vertebral fractures. Long-term studies in children chronically treated with steroids have resulted in the development of systematic approaches to diagnose and manage pediatric osteoporosis.

Conclusions: Osteoporosis in children requires consultation with and/or referral to a pediatric bone specialist. This is particularly relevant since children possess the unique ability for spontaneous and medication-assisted recovery, including reshaping of vertebral fractures. As such, pediatricians have an opportunity to improve bone mass accrual and musculoskeletal health in osteoporotic children.

What is Known:• Both genetic and acquired pediatric disorders can compromise bone health and predispose to fractures early in life.• The identification of children at risk of osteoporosis is essential to make a timely diagnosis and start the treatment, if necessary.

What is New:• Pediatricians have an opportunity to improve bone mass accrual and musculoskeletal health in osteoporotic children and children at risk of osteoporosis.• We offer an extensive but concise overview about the risk factors for osteoporosis and the diagnostic work-up (and its pitfalls) of pediatric patients suspected of osteoporosis.
Middle fossa approach for a facial nerve schwannoma: how I do it
Authors: González-López Pablo , Martorell-Llobregat Carlos , Beneš Vladimír , Daniel Roy T.
Published: April 2022

Background

Facial nerve schwannomas can extend to the middle fossa or the cerebellopontine angle through the labyrinthine and cisternal segments of the facial nerve. The middle fossa approach (MFA) and its extensions provide a wide approach to deal with a large variety of lesions located in the middle and posterior cranial fossa junction.

Methods

We describe the MFA along with its advantages and limitations to treat a facial nerve schwannoma involving the middle and posterior cranial fossa.

Conclusions

The MFA is a well-established route to surgically deal with tumors located in and around the proximal four segments of the facial nerve.
Endoscopic treatment of sagittal suture synostosis — a critical analysis of current management strategies
Authors: Fassl Verena , Ellermann Laura , Reichelt Gabriele , Pape Phillipe , Blecher Christoph , Hoffmann Christian , Ringel Florian , Al-Nawas Bilal , Heider Julia , Ottenhausen Malte
Published: April 2022

While many centers nowadays offer minimally invasive techniques for the treatment of single suture synostosis, surgical techniques and patient management vary significantly. We provide an overview of how scaphocephaly treated with endoscopic techniques is managed in the reported series and analyze the crucial steps that need to be dealt with during the management process. We performed a review of the published literature including all articles that examined sagittal-suture synostosis treated with endoscopic techniques as part of single- or multicenter studies. Fourteen studies reporting results of 885 patients were included. We identified 5 key steps in the management of patients. A total of 188 patients were female and 537 male (sex was only specified in 10 articles, for 725 included patients, respectively). Median age at surgery was between 2.6 and 3.9 months with a total range from 1.5 to 7.0 months. Preoperative diagnostics included clinical and ophthalmologic examinations as well as neuropsychological and genetic consultations if needed. In 5 publications, a CT scan was routinely performed. Several groups used anthropometric measurements, mostly the cephalic index. All groups analyzed equally recommended to perform endoscopically assisted craniosynostosis surgery with postoperative helmet therapy in children < 3 months of age, at least for non-syndromic cases. There exist significant variations in surgical techniques and patient management for children treated endoscopically for single suture sagittal synostosis. This heterogeneity constitutes a major problem in terms of comparability between different strategies.
Bulbostylis itremoensis (Abildgaardieae, Cyperaceae), a new sedge species from Madagascar
Authors: Rasaminirina Fitiavana , Rakotoarimanana Vonjison , Ralimanana Helene , Rabehevitra David , Larridon Isabel
Published: April 2022

An endemic species of Bulbostylis (Abildgaardieae, Cyperaceae) from Madagascar is described as new to science. Bulbostylis itremoensis is only known from two localities: the Itremo and Isalo massifs in the province of Fianarantsoa. The species can be recognised by its habit with numerous crowded culms, leaves and thick, soft roots with an outer mycorrhizal layer. Its culm is hairy, angular with about 10 rounded longitudinal ridges without conspicuous surface cells. The leaf sheaths are light brown to straw-coloured with numerous longitudinal nerves, densely short-hairy on the nerves but with numerous flexuose whitish hairs at their oblique orifices. Its inflorescence is a dense hemispherical head of c. 15 crowded spikelets with many erect or spreading involucral bracts. Its glumes are ovate, densely scabrid of which medium-reddish brown with a prominent 1 – 3-nerved green midrib ending below the obtuse apex or excurrent into a short mucro. This species is described, illustrated and compared to the other species of Bulbostylis that occur in the Itremo Massif Protected Area.
Hydrothermal treatment (HTT) for improving the fuel properties of biomass residues
Authors: Paczkowski Sebastian , Comi Julian , Küttner Immanuel , Knappe Victoria , Russ Michael , Robles Luis Alonzo Diaz , Jaeger Dirk , Pelz Stefan
Published: April 2022

Water leaching and hydrothermal carbonization are tools to upgrade biomass residues for combustion. Water leaching reduces the ash content, which increases the heating value, while hydrothermal carbonization (HTC) increases heating value and ash content and decreases the organic fraction of the fuel. The objective of this study is to investigate, whether low temperature hydrothermal treatment (HTT) of biomass residues can combine the positive aspects of both treatments and avoid the negative aspects: a decrease of the ash content (leaching) instead of an increase (HTC) and a strong increase of the heating value by deoxygenation (HTC) instead of a low increase by ash reduction (leaching). Sawdust, conifer bark, black locust bark, green cuttings, and leaves were treated at 150 °C, 170 °C and 185 °C in a batch reactor. The impact of the three treatments on combustion properties, inorganic element reduction, and organic compound formation in the liquid phase were investigated. All biomass residues, except sawdust treated at 150 °C, showed increased heating values and reduced ash contents. The intensity of the heating value increases, and the reduction rates of selected ash elements were discussed, including a comparison of literature values and a short review on organic reaction and formation processes at low temperature and pressure conditions.
Living with EU Law
Authors: Azoulai Loïc
Published: April 2022

The article is a discussion of Floris de Witte’s ‘Here be Dragons: Legal Geography and EU Law’. It argues that this essay is a direct challenge to the traditional institutional thinking of European integration. This new approach suggests a turn to new empirical studies. But it also implies the elaboration of a new conceptual language for Europe. This language is still to come.
On the potential of place and place of potential
Authors: Trotter Sarah
Published: April 2022

This contribution to the symposium on Legal Geography and EU Law reflects on Floris de Witte’s paper. It makes two points: one about the potential of thinking about place in (and for) EU law and a second about the idea that potentiality itself – a notion which alludes to what could be – could be thought of in spatial terms. The overarching suggestion is that these ways of thinking offer insights into the meaning of meaning in EU law.
European public law after empires
Authors: Larsen Signe Rehling
Published: April 2022

This article seeks to remedy a fundamental flaw in the debate about European integration and European Union (EU) law: the almost complete absence of a reckoning with the legacy of empire and imperialism. The article shows that the significance of EU law can be understood only against the background of the historical transformation of the European public law order with the decline of the European empires. European integration is an integral part of a new European public law order that finally replaced the public law order of the European empires – Droit Public de l’Europe or Jus Publicum Europaeum – in which the European states held a privileged place as the only ‘civilised’, and hence, sovereign states in the world. The post-World War II European public law order entailed a new vision for domestic public law, but also constituted intra-European relations anew, and established a new set of external relations between Europe and its former colonies. With the shift from ‘European’ international law to ‘universal’ international law in the twentieth century, European integration helped carve out a space for ‘Europe’ in a world where Europe was no longer the centre of gravity.
Comparison between window traps and pan traps in monitoring flower-visiting insects in agricultural fields
Authors: Shi Xiaoyu , Fu Daomeng , Xiao Haijun , Hodgson Jenny A. , Yan Dongyue , Zou Yi
Published: April 2022

Sampling flower-visiting insects in agricultural fields at large spatial and temporal scales is significant for understanding local insect pollinator communities. The most commonly used method, pan trap, has been criticized due to its attractant bias. A window trap (also referred to as the flight-intercept trap) is a non-attractant sampling method, which has been applied in forests and grasslands, but rarely in agricultural fields. We aim to test whether we can replace pan traps with window traps in agricultural fields by comparing species richness and species composition between the two methods, and to show whether flower-visiting insects collected in both traps can reflect flower-visiting activity recorded by camera observation. We conducted a 2-year study to compare the performance of these sampling methods in an oilseed rape field. Results showed that the relative abundance of dominant flower-visiting species was highly correlated between the window trap and the pan trap samples, while window traps caught more individuals and higher (rarefied) species richness than pan traps. The species composition of window traps was more similar to each other than that of pan traps. The proportion of honey bees (Apis spp.) collected in both traps underestimated their flower-visiting activity recorded by camera observations, while sweat bees (Halictidae) and butterflies (Lepidoptera) were overestimated. Our study suggests that the window trap has the potential to serve as an alternative sampling method of flower-visiting insects to the pan trap. However, we need to be cautious when using specimens caught in both traps as a proxy of their flower-visiting activity.
Delivery of a trauma-focused CBT group for heterogeneous single-incident traumas in adult primary care: a follow-on case study
Authors: Skilbeck Lilian , Spanton Christopher
Published: April 2022

Group therapy for adult post-traumatic stress disorder (PTSD) has been a subject of debate over the past few years. A recent update on five international clinical practice guidelines on the use of group-therapy for PTSD in adults ranged from moderate support (e.g. the International Society for Traumatic Stress Studies) to no recommendation (e.g. the National Institute for Health and Care Excellence, NICE). However, a unanimous recommendation was that practitioners collaborated with their clients and weighed up the guidelines and client preferences to make the appropriate decisions. The current case study was guided by these recommendations. A minority of clients presenting to the service expressed a preference for group therapy for their PTSD symptoms. The current study follows on from a previous shared-trauma therapy group. It illustrates how the service took the NICE guidelines fully into account alongside the clients’ needs and preferences to deliver a NICE-compliant heterogenous trauma-focused CBT group. Twenty-four clients presenting with PTSD from different single-incident traumas opted for group therapy. Clients attended one of three 8-session trauma-focused CBT groups depending on preference (e.g. date/time, location). The groups were conducted face-to-face on a weekly basis. Seventeen clients completed treatment. Eleven clients no longer showed clinically important symptoms of PTSD as assessed on the PCL-5 and interview. This was sustained at 3-month follow-up. Four other clients showed reliable change. Two clients showed minimal improvement. This study is discussed with reference to opportunities, challenges and recommendations for clinical practice and research.

Key learning aims

It is hoped that the reader of this case study will increase their understanding of the following:

(1)

Delivery of a trauma-focused CBT group for heterogeneous single-incident traumas.

(2)

Taking full consideration of the NICE guidelines alongside the clients’ needs and preferences.

(3)

Guiding the focus of therapy on processing the trauma memory and its aftermath.

(4)

Effective use of group processes to facilitate outcomes.
On the Inference of Tsunami Uncertainties From Landslide Run‐Out Observations
Authors: Zengaffinen‐Morris T. , Urgeles R. , Løvholt F.
Published: April 2022

Probabilistic tsunami hazard analysis (PTHA) due to submarine landslides is much less developed than PTHA for earthquake sources. This is partly because of less constrained data available for quantifying source probability, and partly because of the lack of knowledge related to the tsunami generation process due to landslide dynamics. This study provides a basis for estimating the uncertainty related to landslide dynamics for PTHA from submarine landslides based on a new landslide database in the Gulf of Cadiz. The establishment of this new database is described herein. We use submarine landslide run‐out statistics from this database to calibrate landslide parameters and related uncertainties employing the cohesive landslide model BingClaw. In turn, coupling the landslide motion to tsunami genesis is performed in order to characterize the inferred tsunami uncertainties. Important parameters that can explain the large tsunami uncertainties are the initial water depth of the landslide, the slope, the landslide volume, and the initial yield strength of the landslide material. Kinematic properties such as the initial landslide acceleration or the Froude number are found to strongly correlate with the tsunami‐genesis. In this study, we show how matching numerical landslide models with observed run‐out from past events in the field can give information about the uncertainty in their tsunami‐genic strength. This can in turn be applied in future PTHA for spanning uncertainty ranges due to the landslide dynamics on tsunami‐genesis, constrained by landslide run‐out data.
Design and optimization of metformin hydrophobic ion pairs for efficient encapsulation in polymeric drug carriers
Authors: Abd-El Hafeez Sara I. , Eleraky Nermin E. , Hafez Ehsan , Abouelmagd Sara A.
Published: April 2022

Loading small molecular weight hydrophilic drugs into polymeric carriers is a challenging task. Metformin hydrochloride (MET) is a highly soluble oral antidiabetic drug of small size and high cationic charge. Hydrophobic ion pairing (HIP) is an approach for reversible modulation of solubility and hydrophilicity of water-soluble drugs via complexation with oppositely charged molecules. Herein, we prepared MET ion pairs and carefully studied and characterized MET interaction with different ligands, with the aim of increasing MET lipophilicity and loading efficiency. HIP was successful using three hydrophilic anionic ligands; sodium dodecyl sulphate (SDS) Carbopol (CB) and tannic acid (TA). Electrostatic interaction and hydrogen bonding drove the complexation per spectroscopic and thermal studies. Complexation efficiency depended on ligand type and charge ratio. While complexes had varying interaction strengths, the excessive stability of TA/MET resulted in unfavorable poor MET dissociation. Notably, HIP imparted a 450 and tenfold lipophilicity increase for SDS/MET and CB/MET, respectively. The latter showed favorable controlled, yet complete release of MET at pH 6.8 and was loaded into alginate beads. Complex bulkiness and decreased lipophilicity resulted in a dramatic 88% increase of MET loading, demonstrating the success of HIP as a simple, efficient and applicable approach for modulating drug’s properties.
Transcriptomic analysis of cumulus cells shows altered pathways in patients with minimal and mild endometriosis
Authors: Da Luz Caroline Mantovani , Da Broi Michele Gomes , Koopman Larissa de Oliveira , Plaça Jessica Rodrigues , da Silva-Jr Wilson Araújo , Ferriani Rui Alberto , Meola Juliana , Navarro Paula Andrea
Published: April 2022

Endometriosis is a chronic inflammatory disorder that is highly associated with infertility. This association seems to be related to oocyte impairment, mainly in the initial stages of endometriosis (minimal and mild), where no distortions or adhesions are present. Nonetheless, invasive oocyte analyses are not routinely feasible; thus, indirect assessment of oocyte quality is highly desirable, and, in this context, cumulus cells (CCs) may be more suitable targets of analysis. CCs are crucial in oocyte development and could be used as an index of oocyte quality. Therefore, this prospective case–control study aimed to shed light on the infertility mechanisms of endometriosis I/II by analyzing the CCs’ mRNA transcription profile (women with endometriosis I/II, n = 9) compared to controls (women with tubal abnormalities or male factor, n = 9). The transcriptomic analyses of CCs from patients with minimal and mild endometriosis revealed 26 differentially expressed genes compared to the controls. The enrichment analysis evidenced some altered molecular processes: Cytokine-cytokine receptor interactions, Chemokine signaling, TNF signaling, NOD-like receptor signaling, NF-kappa B signaling, and inflammatory response. With the exception of CXCL12, all enriched genes were downregulated in CCs from patients with endometriosis. These findings provide a significant achievement in the field of reproductive biology, directing future studies to discover biomarkers of oocyte quality in endometriosis.
A register-based study on associations between pre-stroke physical activity and cognition early after stroke (part of PAPSIGOT)
Authors: Reinholdsson Malin , Abzhandadze Tamar , Palstam Annie , Sunnerhagen Katharina S.
Published: April 2022

The objective was to investigate if pre-stroke physical activity is associated with intact cognition early after stroke. The study design was a cross-sectional, register-based study. The study sample included 1111 adults with first stroke (mild or moderate severity) admitted to three Swedish stroke units. The main outcome was cognition. The associations of pre-stroke physical activity, age, sex, smoking, diabetes, atrial fibrillation, previous TIA, statin treatment, hypertension treatment, reperfusion therapies, stroke severity, and education on the outcome cognition were analyzed using binary logistic regression. Physical activity was assessed within 48 h of admittance, and cognition was screened during stroke unit care. The results were: mean age 70 years, 40% women, 61% pre-stroke physically active, and 53% with post-stroke cognitive impairment. Patients with pre-stroke light or moderate physical activity have higher odds for intact cognition compared to inactive: odds ratio (95% confidence interval) 1.32 (0.97-1.80) and 2.04 (1.18-3.53), respectively. In addition to pre-stroke physical activity, people with younger age, a higher level of education, less severe stroke (more mild than moderate), being non-diabetic, and non-smoking have higher odds for intact cognition. In conclusion physical activity before stroke is associated with intact cognition in patients with mild and moderate stroke.
Association mapping of autumn-seeded rye (Secale cereale L.) reveals genetic linkages between genes controlling winter hardiness and plant development
Authors: Båga Monica , Bahrani Hirbod , Larsen Jamie , Hackauf Bernd , Graf Robert J. , Laroche Andre , Chibbar Ravindra N.
Published: April 2022

Winter field survival (WFS) in autumn-seeded winter cereals is a complex trait associated with low temperature tolerance (LTT), prostrate growth habit (PGH), and final leaf number (FLN). WFS and the three sub-traits were analyzed by a genome-wide association study of 96 rye (Secale cerealL.) genotypes of different origins and winter-hardiness levels. A total of 10,244 single nucleotide polymorphism (SNP) markers were identified by genotyping by sequencing and 259 marker-trait-associations (MTAs;p < 0.01) were revealed by association mapping. The ten most significant SNPs (p < 1.49e−04) associated with WFS corresponded to nine strong candidate genes:Inducer of CBF Expression 1(ICE1),Cold-regulated 413-Plasma Membrane Protein 1(COR413-PM1),Ice Recrystallization Inhibition Protein 1(IRIP1),Jasmonate-resistant 1(JAR1),BIPP2C1-like protein phosphatase,Chloroplast Unusual Positioning Protein-1(CHUP1),FRIGIDA-like 4 (FRL4-like) protein,Chalcone Synthase 2(CHS2), andPhenylalanine Ammonia-lyase 8(PAL8). Seven of the candidate genes were also significant for one or several of the sub-traits supporting the hypothesis that WFS, LTT, FLN, and PGH are genetically interlinked. The winter-hardy rye genotypes generally carried additional allele variants for the strong candidate genes, which suggested allele diversity was a major contributor to cold acclimation efficiency and consistent high WFS under varying field conditions.
Imatinib inhibits SARS-CoV-2 infection by an off-target-mechanism
Authors: Strobelt Romano , Adler Julia , Paran Nir , Yahalom-Ronen Yfat , Melamed Sharon , Politi Boaz , Shulman Ziv , Schmiedel Dominik , Shaul Yosef
Published: April 2022

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causal agent of the COVID-19 pandemic. More than 274 million individuals have suffered from COVID-19 and over five million people have died from this disease so far. Therefore, there is an urgent need for therapeutic drugs. Repurposing FDA approved drugs should be favored since evaluation of safety and efficacy of de-novo drug design are both costly and time consuming. We report that imatinib, an Abl tyrosine kinase inhibitor, robustly decreases SARS-CoV-2 infection and uncover a mechanism of action. We show that imatinib inhibits the infection of SARS-CoV-2 and its surrogate lentivector pseudotype. In latter, imatinib inhibited both routes of viral entry, endocytosis and membrane-fusion. We utilized a system to quantify in real-time cell–cell membrane fusion mediated by the SARS-CoV-2 surface protein, Spike, and its receptor, hACE2, to demonstrate that imatinib inhibits this process in an Abl1 and Abl2 independent manner. Furthermore, cellular thermal shift assay revealed a direct imatinib-Spike interaction that affects Spike susceptibility to trypsin digest. Collectively, our data suggest that imatinib inhibits Spike mediated viral entry by an off-target mechanism. These findings mark imatinib as a promising therapeutic drug in inhibiting the early steps of SARS-CoV-2 infection.
Improving the computational accuracy of the dynamic electro-geometrical model using numerical solutions
Authors: Adekitan Aderibigbe Israel
Published: April 2022

The dynamic electro-geometrical model has been applied in various studies to investigate the probability of a lightning strike to parts of a structure. The numerical computation of the dynamic electro-geometrical model (DEGM) follows an iterative step by determining lightning strike points from above to a point on a structure of interest. This computation is often time-consuming and requires extensive computational resources. This study delves into the inner workings of DEGM striking distance computation. It highlights sources of computational numerical errors, such as the effect of the discretisation size. It proposes ways to eliminate such by using a conversion factor while also significantly reducing computation time from more than 14 h to approximately 6 min for a cuboid structure by eliminating ground surface points. The performance of the proposed improved DEGM (IDEGM) was investigated using a floating roof tank and a cuboid structure with a central air termination, and an interception efficiency of 61% was achieved. An alternative case using catenary wires with a total lightning interception efficiency of 99.1% was also implemented. The percentage strike probability for the cases considered shows a close approximation to published results, and this confirms the accuracy of the implemented model. The IDEGM has the benefit of generating results with a significantly reduced computation time of just a few minutes as compared to several hours in previous models.
Acute-phase serum amyloid A for early detection of hepatocellular carcinoma in cirrhotic patients with low AFP level
Authors: Wu Jin-Lin , Su Tung-Hung , Chen Pei-Jer , Chen Yun-Ru
Published: April 2022

Regular hepatocellular carcinoma (HCC) surveillance by ultrasonography in combination with the α-fetoprotein (AFP) examination is unsatisfactory in diagnostic sensitivity for early-stage HCC especially in cirrhotic patients. We conducted a prospective study in a tertiary medical center in Taiwan and consecutively collected serum samples from patients with chronic hepatitis, liver cirrhosis (LC), or HCC for new biomarker discovery. Overall, 166 patients were enrolled, including 40 hepatitis, 30 LC, and 96 HCC. Four acute-phase serum amyloid A (A-SAA) derived biomarkers including total A-SAA, A-SAA monomer and oligomer, and protein misfolding cyclic amplification (PMCA) signal were measured and compared between patients with and without HCC. A-SAA biomarkers significantly increased in the HCC group when compared to the hepatitis and LC groups, and generally increased in more advanced tumor stages. Among A-SAA biomarkers, the area under the receiver operator characteristic curves (AUROCs) for PMCA signal in discrimination of all-stage and early-stage HCC were 0.86 and 0.9 in cirrhotic patients, which is comparable to AFP. For cirrhotic patients with low AFP (< 7 ng/mL), PMCA signal maintained good capacity in prediction of early-stage HCC (AUROC: 0.94). Serum A-SAA and its prion-like property showed a potential to complement AFP in detection of early-stage HCC.
Glucose and unstructured physical activity coupling during sleep and wake in young adults with type 1 diabetes
Authors: Griggs Stephanie , Barbato Eric , Hernandez Estefania , Gupta Devansh , Margevicius Seunghee , Grey Margaret , Hickman Ronald L.
Published: April 2022

Glucose variations have a bidirectional relationship with the sleep/wake and circadian systems in type 1 diabetes (T1D); however, the mechanisms remain unclear. The aim of this study was to describe the coupling between glucose and unstructured physical activity over 168 h in young adults with T1D. We hypothesized that there would be differences in sleep and wake characteristics and circadian variations. Glucose was measured with a continuous glucose monitoring device every 5 min and activity with a non-dominant wrist-worn actigraph in 30-s epochs over 6–14 days. There was substantial glucose and unstructured physical activity coupling during sleep and wake, along with circadian variation based on the wavelet coherence analysis. The extent to which glucose fluctuations result in disrupted sleep over longer than one week should be examined considering the harmful effects on achieving glycemic targets. Further studies are needed to delineate the respective roles of glucose production and utilization and the potential for improved meal and insulin timing to optimize glucose and sleep in this population reliant on exogenous insulin.
Indole decreases the virulence of the bivalve model pathogens Vibrio tasmaniensis LGP32 and Vibrio crassostreae J2-9
Authors: Zhang Shanshan , Yang Qian , Fu Songzhe , Janssen Colin R. , Eggermont Mieke , Defoirdt Tom
Published: April 2022

Indole signaling plays an important role in bacterial pathogenesis. In this study, the impact of indole on biofilm formation, swimming and swarming motility were explored in Vibrio tasmaniensis LGP32 and Vibrio crassostreae J2-9, two model pathogens of bivalves. The results showed that indole decreased swimming and swarming motility in both strains, and decreased biofilm formation in V. crassostreae J2-9. Furthermore, indole affected a large number of genes at RNA level, including genes related to metabolism, ABC transporters, flagellar assembly, chemotaxis, and response regulators. Finally, the bacterial virulence towards mussel larvae was decreased by pretreatment with indole in both V. tasmaniensis LGP32 and V. crassostreae J2-9. After 5 days, the survival rate of mussel larvae increased 2.4-fold and 2.8-fold in mussel larvae challenged with V. tasmaniensis LGP32 pretreated with 200 µM and 500 µM indole, respectively. The survival rate of mussel larvae increased 1.5-fold and 1.9-fold in mussel larvae challenged with V. crassostreae J2-9 pretreated with 200 µM and 500 µM indole, respectively. These data indicate that indole has a significant impact on the virulence of V. tasmaniensis LGP32 and V. crassostreae J2-9, and indole signaling could be a promising target for antivirulence therapy.
Differentiating solitary brain metastases from glioblastoma by radiomics features derived from MRI and 18F-FDG-PET and the combined application of multiple models
Authors: Cao Xu , Tan Duo , Liu Zhi , Liao Meng , Kan Yubo , Yao Rui , Zhang Liqiang , Nie Lisha , Liao Ruikun , Chen Shanxiong , Xie Mingguo
Published: April 2022

This study aimed to explore the ability of radiomics derived from both MRI and 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) images to differentiate glioblastoma (GBM) from solitary brain metastases (SBM) and to investigate the combined application of multiple models. The imaging data of 100 patients with brain tumours (50 GBMs and 50 SBMs) were retrospectively analysed. Three model sets were built on MRI, 18F-FDG-PET, and MRI combined with 18F-FDG-PET using five feature selection methods and five classification algorithms. The model set with the highest average AUC value was selected, in which some models were selected and divided into Groups A, B, and C. Individual and joint voting predictions were performed in each group for the entire data. The model set based on MRI combined with 18F-FDG-PET had the highest average AUC compared with isolated MRI or 18F-FDG-PET. Joint voting prediction showed better performance than the individual prediction when all models reached an agreement. In conclusion, radiomics derived from MRI and 18F-FDG-PET could help differentiate GBM from SBM preoperatively. The combined application of multiple models can provide greater benefits.
Resident birds are more behaviourally plastic than migrants
Authors: Morelli Federico , Benedetti Yanina , Blumstein Daniel T.
Published: April 2022

Species subjected to more variable environments should have greater phenotypic plasticity than those that are more restricted to specific habitat types leading to the expectation that migratory birds should be relatively more plastic than resident birds. We tested this comparatively by studying variation in flight initiation distance (FID), a well-studied antipredator behaviour. We predicted that variation in FID would be greater for migratory species because they encountered a variety of locations during their lives and therefore had less predictable assessments of risk compared to more sedentary species. Contrary to our prediction, we found that non-migratory species (sedentary) had greater variation in FID than migratory ones. Migratory and partially migratory birds had greater average FIDs than sedentary birds, suggesting that they were generally more wary. These results suggest that the predictability associated with not migrating permits more nuanced risk assessment which was seen in the greater variation in FID of sedentary bird species.
Accurate evaluation of combustion enthalpy by ab-initio computations
Authors: Alibakhshi Amin , Schäfer Lars V.
Published: April 2022

Accurate evaluation of combustion enthalpy is of high scientific and industrial importance. Although ab-initio computation of the heat of reactions is one of the promising and well-established approaches in computational chemistry, reliable and precise computation of heat of combustion reactions by ab-initio methods is surprisingly scarce in the literature. A handful of works carried out for this purpose report significant inconsistencies between the computed and experimentally determined combustion enthalpies and suggest empirical corrections to improve the accuracy of the ab-initio predicted data. The main aim of the present study is to investigate the reasons behind those reported inconsistencies and propose guidelines for a high-accuracy estimation of heat of reactions via ab-initio computations. We show comparably accurate prediction of combustion enthalpy of 40 organic molecules based on a DSD-PBEP86 double-hybrid density functional theory approach and CCSD(T)-F12 coupled-cluster computations, with mean unsigned errors with respect to experimental data being below 0.5% for both methods.
Deletions of the Plasmodium falciparum histidine-rich protein 2/3 genes are common in field isolates from north-eastern Tanzania
Authors: Kaaya Robert D. , Kavishe Reginald A. , Tenu Filemon F. , Matowo Johnson J. , Mosha Franklin W. , Drakeley Chris , Sutherland Colin J. , Beshir Khalid B.
Published: April 2022

Plasmodium falciparum parasites lacking histidine-rich protein 2 and 3 (pfhrp2/3) genes have been reported in several parts of the world. These deletions are known to compromise the effectiveness of HRP2-based malaria rapid diagnostic tests (HRP2-RDT). The National Malaria Control Programme (NMCP) in Tanzania adopted HRP2-RDTs as a routine tool for malaria diagnosis in 2009 replacing microscopy in many Health facilities. We investigated pfhrp2/3 deletions in 122 samples from two areas with diverse malaria transmission intensities in Northeastern Tanzania. Pfhrp2 deletion was confirmed in 1.6% of samples while pfhrp3 deletion was confirmed in 50% of samples. We did not find parasites with both pfhrp2 and pfhrp3 deletions among our samples. Results from this study highlight the need for systematic surveillance of pfhrp2/3 deletions in Tanzania to understand their prevalence and determine their impact on the performance of mRDT.
Computer-aided optimal design for flexible cable in aerospace products based on dynamic analogy modeling
Authors: Du Hongwang , Jiang Qinwen , Xiong Wei
Published: April 2022

Due to large, complex deformations, the accurate design of cables has become a major problem in the manufacturing of aerospace products. The current design method often leads to large products, uncertain centroids, and poor reliability. To solve these problems, a computer-aided optimal design method for flexible cables was proposed based on dynamic analogy modeling. A nonlinear optimization model was established by combining Cosserat theory and the minimum potential energy principle. The total deformation energy was considered as the optimization object, and Euler parameters were used as control variables to describe the cable geometric shape. Considering the length and bending radius requirements, the normalized form of the cable constraints was expressed by the cross-section position and orientation matrix. An efficient method to solve this problem using finite element discretization and the primitive dual interior point method was proposed. A digital wiring module was developed based on an open source geometry kernel system, and a cable geometry test bench was built. To verify our model, a satellite wiring simulation example was implemented using the module, SolidWorks, and the test bench. Our method achieved the optimal design for the cable length and geometric shape. A theoretical and technical foundation for effectively solving the problem of large cable manufacturing errors and realizing the lightweight design of aerospace products was outlined.
A critical appraisal of the status and hydrogeochemical characteristics of freshwater springs in Kashmir Valley
Authors: Bhat Sami Ullah , Dar Shahid Ahmad , Hamid Aadil
Published: April 2022

With growing water scarcity, jeopardized by climate change, springs are likely to perform a vital role in meeting the domestic water demand in future. This paper examines the water quality status of Kashmir valley springs in relation to their geographical location, regional hydrogeological conditions, anthropogenic activities and climate change. We analyzed data for 258 springs from the whole Kashmir valley using water quality index (WQI) and geographic information system techniques. WQI ranged from 23 (excellent water) to 537 (water unsuitable for drinking). The WQI indicated that 39.5% of the springs had excellent waters, 47.7% had good water, 5% had poor water, 1.6% had very-poor water, and 6.2% of the springs had water unfit for drinking purposes. The Piper diagram identified Ca–Mg–HCO3, Ca–Mg–SO4, and Na–HCO3 as the most predominant hydro-chemical facies, whereas Gibbs diagram revealed that the water of springs in the study region is mainly controlled by rock weathering dominance. The results of the study offer inputs about the water quality to be used by the concerned departments and agencies at a bigger scale for drinking purposes. Our findings therefore suggest that springs which are in thousands in Kashmir landscape have the potential to offer viable solution to the rising drinking water demand and therefore merit an attention for their protection and management.
Two-step facile synthesis of Co3O4@C reinforced PbO2 coated electrode to promote efficient oxygen evolution reaction for zinc electrowinning
Authors: Jiang Wenhao , Wang Junli , Wang Xuanbing , Liao Jiang , Wei Jinlong , Xu Ruidong , Yang Linjing
Published: April 2022

We synthesized a PbO2-coated electrode consisting of three layers, with Pb–0.6%Sb alloy as the substrate, α-PbO2 as the intermediate layer, and the outermost β-PbO2-Co3O4@C as the active layer for boosting OER activity.
Modulation of Lactobacillus rhamnosus GG on the gut microbiota and metabolism in mice with Clostridioides difficile infection
Authors: Wu Zhengjie , Xu Qiaomai , Gu Silan , Wang Qiangqiang , Chen Yunbo , Lv Longxian , Zheng Beiwen , Wang Kaicen , Wang Shuting , Xia Jiafeng , Li Lanjuan
Published: April 2022

Clostridioides difficile infection (CDI) is a common nosocomial infection and is an urgent threat to public health.
Beshanzuamide A, an unprecedented prenylated indole alkaloid produced by Aspergillus sp. Y-2 from the critically endangered conifer Abies beshanzuensis
Authors: Zhu Yuan-Xing , Ding Wenxin , Hu Jin-Feng , Xiong Juan , Li Jiyang
Published: April 2022

A structurally unprecedented prenylated indole alkaloid, together with five known analogues, was isolated from an endophytic fungus associated with the endangered conifer Abies beshanzuensis.
Output feedback model predictive control for Hammerstein model with bounded disturbance
Authors: Ding Baocang , Wang Jun , Su Benji
Published: April 2022

This paper proposes two model predictive control (MPC) methods for a Hammerstein model with both unmeasurable state and bounded disturbance. First, a dynamic output feedback MPC is designed such that the dynamics of the state estimation error is decoupled from that of the estimated state. Hence, the separation principle holds and a part of the controller parameters can be designed off‐line. Second, a case is considered where Hammerstein nonlinearity is not exactly inverted, that is, a reserved static nonlinearity exists in the closed‐loop system. This reserved nonlinearity is merged into a polytopic description in combination with the linear dynamic part. The control move is then parameterized as a feedback law followed by the approximate inverse of Hammerstein nonlinearity. The recursive feasibility and closed‐loop stability of both approaches are guaranteed. Numerical examples are given in order to show effectiveness of the proposed approaches.
A wide range on‐line energy acquisition method for transmission lines based on resonant choke coil
Authors: Liu Zheng , Tan HengJing , Fan ShaoSheng
Published: April 2022

To the traditional transmission line induction energy acquisition method, large starting current and small output power are the key problems that hinder its wide application in transmission line detection system or detection robot. This paper proposes a wide range on‐line energy acquisition method to solve the problems. By analysing, how large the impedance of the transmission line determines how much power can be transmitted into the parallel connected devices. The novel method tries to couple a high impedance into the transmission line by using a choke coil that is parallel resonated with a matching capacitor. Consequently, the current shunt to the parallel‐connected load will increase and the power output can be significantly improved. Simulation and experiment results show that the novel method can harvest more output power than the conventional inductive acquisition method under the condition of the same bus current and the same magnetic core.