bluuebunny/crossref_metadata_2025_split huggingface dataset:
HIF-1 mediated activation of antimicrobial peptide LL-37 in type 2 diabetic patients
Authors: Mohanty Soumitra , Kamolvit Witchuda , Zambrana Silvia , Gonzales Eduardo , Tovi Jonas , Brismar Kerstin , Östenson Claes-Göran , Brauner Annelie 
Published: October 2021

Abstract
Infections are common in patients with diabetes, but increasing antibiotic resistance hampers successful bacterial clearance and calls for alternative treatment strategies. Hypoxia-inducible factor 1 (HIF-1) is known to influence the innate immune defense and could therefore serve as a possible target. However, the impact of high glucose on HIF-1 has received little attention and merits closer investigation. Here, we show that higher levels of proinflammatory cytokines and CAMP, encoding for the antimicrobial peptide cathelicidin, LL-37, correlate with HIF-1 in type 2 diabetic patients. Chemical activation of HIF-1 further enhanced LL-37, IL-1β, and IL-8 in human uroepithelial cells exposed to high glucose. Moreover, HIF-1 activation of transurethrally infected diabetic mice resulted in lower bacterial load. Drugs activating HIF-1 could therefore in the future potentially have a therapeutic role in clearing bacteria in diabetic patients with infections where antibiotic treatment failed.

Key messages
• Mohanty et al. “HIF-1 mediated activation of antimicrobial peptide LL-37 in type 2 diabetic patients.”
• Our study highlights induction of the antimicrobial peptide, LL-37, and strengthening of the innate immunity through hypoxia-inducible factor 1 (HIF-1) in diabetes.
• Our key observations are:
1. HIF-1 activation increased LL-37 expression in human urothelial cells treated with high glucose. In line with that, we demonstrated that patients with type 2 diabetes living at high altitude had increased levels of the LL-37.
2. HIF-1 activation increased IL-1β and IL-8 in human uroepithelial cells treated with high glucose concentration.
3. Pharmacological activation of HIF-1 decreased bacterial load in the urinary bladder of mice with hereditary diabetes.
• We conclude that enhancing HIF-1 may along with antibiotics in the future contribute to the treatment in selected patient groups where traditional therapy is not possible.
Biochemical and structural characterization of beta-carbonic anhydrase from the parasite Trichomonas vaginalis
Authors: Urbański Linda J. , Angeli Andrea , Mykuliak Vasyl V. , Azizi Latifeh , Kuuslahti Marianne , Hytönen Vesa P. , Supuran Claudiu T. , Parkkila Seppo 
Published: October 2021

Abstract
Trichomonas vaginalis is a unicellular parasite and responsible for one of the most common sexually transmittable infections worldwide, trichomoniasis. Carbonic anhydrases (CAs) are enzymes found in all lifeforms and are known to play a vital role in many biochemical processes in organisms including the maintenance of acid–base homeostasis. To date, eight evolutionarily divergent but functionally convergent forms of CAs (α, β, γ, δ, ζ, η, θ, and ι) have been discovered. The human genome contains only α-CAs, whereas many clinically significant pathogens express only β-CAs and/or γ-CAs. The characterization of pathogenic β- and γ-CAs provides important knowledge for targeting these biomolecules to develop novel anti-invectives against trichomoniasis. Here, we report the recombinant production and characterization of the second β-CA of T. vaginalis (TvaCA2). Light scattering analysis revealed that TvaCA2 is a dimeric protein, which was further supported with in silico modeling, suggesting similar structures between TvaCA2 and the first β-CA of T. vaginalis (TvaCA1). TvaCA2 exhibited moderate catalytic activity with the following kinetic parameters: kcat of 3.8 × 105 s−1 and kcat/KM of 4.4 × 107 M−1 s−1. Enzyme activity inhibition was studied with a set of clinically used sulfonamides and sulfonamide derivates. Twenty-seven out of the 39 compounds resulted in inhibition with a nanomolar range. These initial results encourage for future work entailing the design of more potent inhibitors against TvaCA2, which may provide new assets to fight trichomoniasis.

Key messages
• Protozoan parasite Trichomonas vaginalis has two β-carbonic anhydrases (TvaCA1/2).
• TvaCA1/TvaCA2 represents promising targets for antitrichomonal drug development.
• TvaCA2 is a dimer of 20.3 kDa and possesses moderate catalytic activity.
• The most efficient inhibitor was clinical drug acetazolamide with KI of 222.9 nM.
• The 39 tested sulfonamides form the basis for the design of more potent inhibitors.
The zebrafish (Danio rerio) anxiety test battery: comparison of behavioral responses in the novel tank diving and light–dark tasks following exposure to anxiogenic and anxiolytic compounds
Authors: Fontana Barbara D. , Alnassar Nancy , Parker Matthew O. 
Published: October 2021

Abstract

Rationale
Triangulation of approaches (i.e., using several tests of the same construct) can be extremely useful for increasing the robustness of the findings being widely used when working with behavioral testing, especially when using rodents as a translational model. Although zebrafish are widely used in neuropharmacology research due to their high-throughput screening potential for new therapeutic drugs, behavioral test battery effects following pharmacological manipulations are still unknown.

Methods
Here, we tested the effects of an anxiety test battery and test time following pharmacological manipulations in zebrafish by using two behavioral tasks: the novel tank diving task (NTT) and the light–dark test (LDT). Fluoxetine and conspecific alarm substance (CAS) were chosen to induce anxiolytic and anxiogenic-like behavior, respectively.

Results
For non-drug-treated animals, no differences were observed for testing order (NTT → LDT or LDT → NTT) and there was a strong correlation between performances on the two behavioral tasks. However, we found that during drug treatment, NTT/LDT responses are affected by the tested order depending on the test time being fluoxetine effects higher at the second behavioral task (6 min later) and CAS effects lower across time.

Conclusions
Overall, our data supports the use of baseline behavior assessment using this anxiety test battery. However, when working with drug exposure, data analysis must carefully consider time-drug-response and data variability across behavioral tasks.
Preclinical characterization of [18F]T-008, a novel PET imaging radioligand for cholesterol 24-hydroxylase
Authors: Koike Tatsuki , Constantinescu Cristian C. , Ikeda Shuhei , Nishi Toshiya , Sunahara Eiji , Miyamoto Maki , Cole Patricia , Barret Olivier , Alagille David , Papin Caroline , Morley Thomas , Fowles Krista , Seibyl John , Tamagnan Gilles , Kuroita Takanobu 
Published: October 2021

Abstract
Purpose
Cholesterol 24-hydroxylase (CH24H) is a brain-specific enzyme that plays a major role in brain cholesterol homeostasis by converting cholesterol into 24S-hydroxycholesterol. The selective CH24H inhibitor soticlestat (TAK-935) is being pursued as a drug for treatment of seizures in developmental and epileptic encephalopathies. Herein, we describe the successful discovery and the preclinical validation of the novel radiolabeled CH24H ligand (3-[18F]fluoroazetidin-1-yl){1-[4-(4-fluorophenyl)pyrimidin-5-yl]piperidin-4-yl}methanone ([18F]T-008) and its tritiated analog, [3H]T-008.

Methods
In vitro autoradiography (ARG) studies in the CH24H wild-type (WT) and knockout (KO) mouse brain sections were conducted using [3H]T-008. PET imaging was conducted in two adult rhesus macaques using [18F]T-008. Each macaque received two test–retest baseline scans and a series of two blocking doses of soticlestat administered prior to [18F]T-008 to determine the CH24H enzyme occupancy. PET data were analyzed with Logan graphical analysis using plasma input. A Lassen plot was applied to estimate CH24H enzyme occupancy by soticlestat.

Results
In ARG studies, binding of [3H]T-008 was specific to CH24H in the mouse brain sections, which was not observed in CH24H KO or in wild-type mice after pretreatment with soticlestat. In rhesus PET studies, the rank order of [18F]T-008 uptake was striatum > cortical regions > cerebellum, which was consistent with CH24H distribution in the brain. Pre-blocking with soticlestat reduced the maximum uptake and increased the washout in all brain regions in a dose-dependent manner. Calculated global occupancy values for soticlestat at a dose of 0.89 mg/kg were 97–98%, indicating maximum occupancy.

Conclusion
The preclinical in vitro and in vivo evaluation of labeled T-008 demonstrates that [18F]T-008 is suitable for imaging CH24H in the brain and warrants further studies in humans.

Graphical abstract
Spatial Tools for Integrated and Inclusive Landscape Governance: Toward a New Research Agenda
Authors: Ros-Tonen Mirjam A. F. , Willemen Louise , McCall Michael K. 
Published: October 2021

AbstractParticipatory spatial tools—community mapping, PGIS, and others—find increasing resonance among research and non-governmental organizations to make stakeholder claims and community perspectives explicit for more inclusive landscape governance. In this paper, we situate the use of participatory spatial tools in debates on integrated landscape approaches and inclusive development. We show that using such spatial tools is not new but argue that their application for inclusive landscape governance requires a new research agenda that focuses on expanding the scope of application of the tools, improving the inclusivity of the processes, and developing new technologies.
Cyclonic activity in the Mediterranean region from a high-resolution perspective using ECMWF ERA5 dataset
Authors: Aragão Leonardo , Porcù Federico 
Published: October 2021

AbstractThis study focuses on developing a new Cyclone Detection and Tracking Method (CDTM) to take advantage of the recent availability of a high-resolution reanalysis dataset of ECMWF ERA5. The proposed algorithm is used to perform a climatological analysis of the cyclonic activity in the Mediterranean Region (MR) into a 40-year window (1979–2018). The tuning of the new CDTM was based on the comparison with currently available CDTMs and verified through careful subjective analysis to fully exploit the finer details of MR cyclones features. The application of the new CDTM to the ERA5 high-resolution dataset resulted in an increase of 40% in the annual number of cyclones, mainly associated with subsynoptic and baroclinic driven lows. The main cyclogenetic areas and seasonal cycle were properly identified into the MR context, including areas often underestimated, such as the Aegean Sea, and emerging new ones with cyclogenetic potential such as the coast of Tunisia and Libya. The better cyclone features description defined three distinct periods of cyclonic activity in the MR with peculiar and persistent characteristics. In the first period (Apr–Jun), cyclones develop more frequently and present higher velocities and deepening rates. In the second (Jul–Sep), the cyclonic activity is governed by thermal lows spreading slowly over short tracks without reaching significant depths. In the last and longest season (Oct–Mar), cyclones become less frequent, but with the highest deepening rates and the lowest MSLP values, ranking this period as the most favourable to intense storms.
Influence of CO2 on the rheology of melts from the Colli Albani Volcanic District (Italy): foidite to phonolite
Authors: Kleest Christin , Webb Sharon L. 
Published: October 2021

AbstractIn this study, the influence of CO2 on the rheology of silica poor and K-rich melts from highly explosive eruptions from the Colli Albani Volcanic District (Italy) (CAVD) is measured for the first time. The investigated melts range from foidite to tephri-phonolite to tephrite from the CAVD to a phonolite from the Vesuvius (Italy) with CO2 concentrations up to 0.50 wt%. Viscosity and calorimetric measurements are performed in the glass transition range Tg between 600 and 780 °C. Although nominally anhydrous, the investigated melts contain H2O concentrations up to 0.23 wt%. The data exhibit a decrease in viscosity of approx. 100.40 Pa s for the phonolitic composition with ~ 0.07 wt% CO2 and a Tg reduced by approx. 14 °C. For the tephritic composition, Tg is approx. 5 °C lower and has a viscosity reduced by 100.25 Pa s for the sample containing ~ 0.5 wt% CO2. Calorimetric measurements of the tephri-phonolite show lowered onset of Tg by approx. 6 °C for the melt with ~ 0.11 wt% CO2 and Tg of the foidite appears not to be influenced by a CO2 concentration of ~ 0.37 wt% CO2. However, these tephri-phonolitic and foiditic melts foamed during calorimetric measurements preventing a reliable measurement. It would appear that most of this overall drop in viscosity is caused by the small amounts of H2O in the melts with CO2 slightly reducing the viscosity or having no effect on viscosity. Additionally, it is shown that the reduction in viscosity decreases with an increasing degree of the depolymerisation for the investigated melts. Consequently, the explosive style of the CAVD eruptions is mainly caused by crystals and bubbles which form and rise during magma storage and ascent which increases the magma viscosity whereas the CO2 in the melt slightly reduces the viscosity.
The impact of the UK COVID-19 pandemic on patient-reported health outcomes after stroke: a retrospective sequential comparison
Authors: Ozkan Hatice , Ambler Gareth , Banerjee Gargi , Chan Edgar , Browning Simone , Mitchell John , Perry Richard , Leff Alex P. , Simister Robert J. , Werring David J. ,   the SIGNaL collaborators, Jager Rolf , Ward Nick , Nachev Parashkev 
Published: October 2021

Abstract
Background and purpose
The COVID-19 pandemic and related social isolation measures are likely to have adverse consequences on community healthcare provision and outcome after acute illnesses treated in hospital, including stroke. We aimed to evaluate the impact of the COVID-19 pandemic on patient-reported health outcomes after hospital admission for acute stroke.

Methods
This retrospective study included adults with acute stroke admitted to the University College Hospital NHS Foundation Trust Hyperacute Stroke Unit. We included two separate cohorts of consecutively enrolled patients from the same geographical population at two time points: 16th March–16th May 2018 (pre-COVID-19 pandemic); and 16th March–16th May 2020 (during the COVID-19 pandemic). Patients in both cohorts completed the validated Patient Reported Outcomes Measurement Information System–29 (PROMIS-29 version 2.0) at 30 days after stroke.

Results
We included 205 patients who were alive at 30 days (106 admitted before and 99 admitted during the COVID-19 pandemic), of whom 201/205 (98%) provided patient-reported health outcomes. After adjustment for confounding factors, admission with acute stroke during the COVID-19 pandemic was independently associated with increased anxiety (β = 28.0, p < 0.001), fatigue (β = 9.3, p < 0.001), depression (β = 4.5, p = 0.002), sleep disturbance (β = 2.3, p = 0.018), pain interference (β = 10.8, p < 0.001); and reduced physical function (β = 5.2, p < 0.001) and participation in social roles and activities (β = 6.9, p < 0.001).

Conclusion
Compared with the pre-pandemic cohort, patients admitted with acute stroke during the first wave of the COVID-19 pandemic reported poorer health outcomes at 30 day follow-up in all domains. Stroke service planning for any future pandemic should include measures to mitigate this major adverse impact on patient health.
Population pharmacogenomics: an update on ethnogeographic differences and opportunities for precision public health
Authors: Zhou Yitian , Lauschke Volker M. 
Published: October 2021

AbstractBoth safety and efficacy of medical treatment can vary depending on the ethnogeographic background of the patient. One of the reasons underlying this variability is differences in pharmacogenetic polymorphisms in genes involved in drug disposition, as well as in drug targets. Knowledge and appreciation of these differences is thus essential to optimize population-stratified care. Here, we provide an extensive updated analysis of population pharmacogenomics in ten pharmacokinetic genes (CYP2D6, CYP2C19, DPYD, TPMT, NUDT15 and SLC22A1), drug targets (CFTR) and genes involved in drug hypersensitivity (HLA-A, HLA-B) or drug-induced acute hemolytic anemia (G6PD). Combined, polymorphisms in the analyzed genes affect the pharmacology, efficacy or safety of 141 different drugs and therapeutic regimens. The data reveal pronounced differences in the genetic landscape, complexity and variant frequencies between ethnogeographic groups. Reduced function alleles of CYP2D6, SLC22A1 and CFTR were most prevalent in individuals of European descent, whereas DPYD and TPMT deficiencies were most common in Sub-Saharan Africa. Oceanian populations showed the highest frequencies of CYP2C19 loss-of-function alleles while their inferred CYP2D6 activity was among the highest worldwide. Frequencies of HLA-B*15:02 and HLA-B*58:01 were highest across Asia, which has important implications for the risk of severe cutaneous adverse reactions upon treatment with carbamazepine and allopurinol. G6PD deficiencies were most frequent in Africa, the Middle East and Southeast Asia with pronounced differences in variant composition. These variability data provide an important resource to inform cost-effectiveness modeling and guide population-specific genotyping strategies with the goal of optimizing the implementation of precision public health.
Move your virtual body: differences and similarities in brain activation patterns during hand movements in real world and virtual reality
Authors: Kober Silvia Erika , Settgast Volker , Brunnhofer Marlies , Augsdörfer Ursula , Wood Guilherme 
Published: October 2021

AbstractVirtual reality (VR) is a promising tool for neurological rehabilitation, especially for motor rehabilitation. In the present study, we investigate whether brain activation patterns that are evoked by active movements are comparable when these movements are carried out in reality and in VR. Therefore, 40 healthy adults (20 men, mean age 25.31 years) performed hand movements and viewed these movements in a first-person view in reality, a VR scene showing realistic virtual hands, and a VR scene showing abstract virtual hands, in a randomized order. The VR conditions were presented via an immersive 3D head-mounted display system. EEG activity was assessed over the hand motor areas during and after movement execution. All three conditions led to typical EEG activation patterns over the motor cortex. Hence, brain activation patterns were largely comparable between conditions. However, the VR conditions, especially the abstract VR condition, led to a weaker hemispheric lateralization effect compared to the real-world condition. This indicates that hand models in VR should be realistic to be able to evoke activation patterns in the motor cortex comparable to real-world scenarios.
Use of antipsychotics and long-term risk of parkinsonism
Authors: d’Errico Angelo , Strippoli Elena , Vasta Rosario , Ferrante Gianluigi , Spila Alegiani Stefania , Ricceri Fulvio 
Published: October 2021

AbstractIntroductionFew epidemiological studies have assessed the risk of parkinsonisms after prolonged use of neuroleptics. We aimed to examine the long-term risk of degenerative parkinsonisms (DP) associated with previous use of neuroleptics.MethodsAll residents in Piedmont, Northern-west Italy, older than 39 years (2,526,319 subjects), were retrospectively followed up from 2013 to 2017. Exposure to neuroleptics was assessed through the regional archive of drug prescriptions. The development of DP was assessed using the regional archives of both drug prescriptions and hospital admissions. We excluded prevalent DP cases at baseline as well as those occurred in the first 18 months (short-term risk). The risk of DP associated with previous use of neuroleptics was examined through Cox regression, using a matched cohort design.ResultsThe risk of DP was compared between 63,356 exposed and 316,779 unexposed subjects. A more than threefold higher risk of DP was observed among subjects exposed to antipsychotics, compared to those unexposed (HR = 3.27, 95% CI 3.00–3.57), and was higher for exposure to atypical than typical antipsychotics. The risk decreased after 2 years from therapy cessation but remained significantly elevated (HR = 2.38, 95% CI 1.76–3.21).ConclusionsThese results indicate a high risk of developing DP long time from the start of use and from the cessation for both typical and atypical neuroleptics, suggesting the need of monitoring treated patients even after long-term use and cessation.
Symmetric power functoriality for holomorphic modular forms
Authors: Newton James , Thorne Jack A. 
Published: October 2021

AbstractLet$f$fbe a cuspidal Hecke eigenform of level 1. We prove the automorphy of the symmetric power lifting$\operatorname{Sym}^{n} f$Symnffor every$n \geq 1$n≥1.We establish the same result for a more general class of cuspidal Hecke eigenforms, including all those associated to semistable elliptic curves over$\mathbf{Q}$Q.
Migration and non-breeding ecology of the Yellow-breasted Chat Icteria virens
Authors: Mancuso Kristen A. , Hodges Karen E. , Alexander John D. , Grosselet Manuel , Bezener A. Michael , Morales Luis , Martinez Sarahy C. , Castellanos-Labarcena Jessica , Russello Michael A. , Rockwell Sarah M. , Bieber Matthias E. , Bishop Christine A. 
Published: October 2021

AbstractDetailed information spanning the full annual cycle is lacking for most songbird populations. We examined breeding, migration, and non-breeding sites for the Yellow-breasted Chat (Icteria virens,chat). We deployed archival GPS tags and light-level geolocators on breeding chats in British Columbia and light-level geolocators in California from 2013 to 2017 to determine migration routes and non-breeding sites. We examined whether chats overwintered in protected areas and characterized the percent of land cover within 1 km. We used a combination of genetics and stable hydrogen isotopes from feathers collected on non-breeding chats in Nayarit, Mexico (2017–2019) and migrating chats in Chiapas, Mexico (2018) and Veracruz, Mexico (2014–2015) to determine subspecies and infer breeding location. Endangered chats in British Columbia followed the Pacific Flyway and spent the non-breeding period in Sinaloa and Nayarit, Mexico. Two out of five chats spent the non-breeding period in protected areas, and the most common landcover type used was tropical or subtropical broadleaf deciduous forest. We found no mixing of eastern and western chats in our Mexico sites, suggesting strong migratory connectivity at the subspecies level. Western chats likely originating from multiple breeding latitudes spent the non-breeding period in Nayarit. Eastern Yellow-breasted Chats likely breeding across various latitudes migrated through Veracruz and Chiapas. Our results provide precise migration routes and non-breeding locations, and describe habitat cover types for chats, notably an endangered population in British Columbia, which may be valuable for habitat protection and conservation efforts.
Central Limit Theorem and Moderate Deviation Principle for McKean-Vlasov SDEs
Authors: Suo Yongqiang , Yuan Chenggui 
Published: October 2021

AbstractUnder a Lipschitz condition on distribution dependent coefficients, the central limit theorem and the moderate deviation principle are obtained for solutions of McKean-Vlasov type stochastic differential equations, which generalize the corresponding results for classical stochastic differential equations to the distribution dependent setting.