bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fluorescent pH-sensing bandage for point-of-care wound diagnostics
Authors: Al-Hawat Marie-Lynn , Tricou Léo-Paul , Cherifi Katia , Lamontagne Stéphanie , Tran Minh , Ching Yie Ngu Amy , Manrique Gabriela , Guirguis Natalie , Israel Machuca-Parra Arturo , Matoori Simon 
Published: October 2023

AbstractDiabetic foot ulcers (DFUs) are a serious and prevalent complication of diabetes. Current diagnostic options are limited to macroscopic wound analysis such as wound size, depth, and infection. Molecular diagnostics promise to improve DFU diagnosis, staging, and assessment of treatment response. Here, we developed a rapid and easy-to-use fluorescent pH-sensing bandage for wound diagnostics. In a fluorescent dye screen, we identified pyranine as the lead compound due to its suitable pH-sensing properties in the clinically relevant pH range of 6 to 9. To minimize the release of this dye into the wound bed, we screened a library of ionic microparticles and found a strong adhesion of the anionic dye to a cationic polymeric microparticle. These dye-loaded microparticles showed a strong fluorescence response in the clinically relevant pH range of 6 to 9 and a dye release below 1% after one day in biological media. The dye-loaded microparticles were subsequently encapsulated in a calcium alginate hydrogel to minimize the interaction of the microparticles with the wound tissue. This pH-sensing diagnostic wound dressing was tested on full thickness dorsal wounds of mice, and a linear fluorescence response (R2= 0.9909) to clinically relevant pH values was observed. These findings encourage further development of this pH-sensing system for molecular diagnostics in DFUs.
Relating strain amplitude, strain threshold and bone formation rate to exogenous forcing frequency
Authors: Prasad Jitendra , Aruva Achsah Marlene , Shekhar Himanshu , Singh Sanjay , Singh Satwinder Jit 
Published: October 2023

AbstractThe literature supports the existence of a strain threshold, above which cortical bone adapts to exogenous mechanical loading by forming new bone. This strain threshold, however, varies with loading conditions, locations, waveforms, frequency etc. and there is a need to mathematically express the strain threshold in terms of these parameters. There have been several parametric, mathematical or numerical models in the literature for the cortical bone’s adaptation to mechanical loading, which may be already fitting some of the experimental data; however, they may not be easily and confidently derived from the first principles. To fill the gap, this work has attempted to derive the corresponding bone formation rate (BFR) rather from the first principles, namely using the energy principles. The derived model has been compared to the existing parametric models and validated with respect to the diverse experimental data available in the literature. The developed model is able to not only predict the BFR, but also helps to understand the nature and possible mathematical form of the strain threshold for cortical bone’s adaptation to mechanical loading.
Transthalamic input to higher-order cortex selectively conveys state information
Authors: Neske Garrett T. , Cardin Jessica A. 
Published: October 2023

SUMMARYCommunication among different neocortical areas is largely thought to be mediated by long-range synaptic interactions between cortical neurons, with the thalamus providing only an initial relay of information from the sensory periphery. Higher-order thalamic nuclei receive strong synaptic inputs from the cortex and send robust projections back to other cortical areas, providing a distinct and potentially critical route for cortico-cortical communication. However, the relative contributions of corticocortical and thalamocortical inputs to higher-order cortical function remain unclear. Using imaging of cortical neurons and projection axon terminals in combination with optogenetic manipulations, we find that the higher-order visual thalamus of mice conveys a specialized stream of information to higher-order visual cortex. Whereas corticocortical projections from lower cortical areas convey robust visual information, higher-order thalamocortical projections convey strong behavioral state information. Together, these findings suggest a key role for higher-order thalamus in providing contextual signals that flexibly modulate sensory processing in higher-order cortex.
Increased entrainment and decreased excitability predict efficacious treatment of closed-loop phase-locked rTMS for treatment-resistant depression
Authors: Sun Xiaoxiao , Doose Jayce , Faller Josef , McIntosh James R. , Saber Golbarg T. , Huffman Sarah , Pantazatos Spiro P. , Yuan Han , Goldman Robin I. , Brown Truman R. , George Mark S. , Sajda Paul 
Published: October 2023

AbstractTranscranial magnetic stimulation (TMS) is an FDA-approved therapy for major depressive disorder (MDD), specifically for patients who have treatment-resistant depression (TRD). However, TMS produces response or remission in about 50% of patients but is ineffective for the other 50%. Limits on efficacy may be due to individual patient variability, but to date, there are no good biomarkers or measures of target engagement. In addition, TMS efficacy is typically not assessed until a six-week treatment ends, precluding the evaluation of intermediate improvements during the treatment duration. Here, we report on results using a closed-loop phase-locked repetitive TMS (rTMS) treatment that synchronizes the delivery of rTMS based on the timing of the pulses relative to a patient’s individual electroencephalographic (EEG) prefrontal alpha oscillation informed by functional magnetic resonance imaging (fMRI). We find that, in responders, synchronized delivery of rTMS produces two systematic changes in brain dynamics. The first change is a decrease in global cortical excitability, and the second is an increase in the phase entrainment of cortical dynamics. These two effects predict clinical outcomes in the synchronized treatment group but not in an active-treatment unsynchronized control group. The systematic decrease in excitability and increase in entrainment correlated with treatment efficacy at the endpoint and intermediate weeks during the synchronized treatment. Specifically, we show that weekly tracking of these biomarkers allows for efficacy prediction and potential of dynamic adjustments through a treatment course, improving the overall response rates.
PolymorphismQ223Rof the leptin receptor (LEPR) - a possible relationship with adaptation to non-tropical climate in Yakuts
Authors: Pavlova N.I. , Bochurov A.A. , Alekseev V.A. , Krylov A.V. , Sydykova L.A. , Kurtanov Kh.A. 
Published: October 2023

AbstractObesity is an energy imbalance that occurs due to a lack of energy intake and consumption. We studied the variability of theQ223Rpolymorphism of theLEPRgene in the Yakut population and the relationship with body mass index (BMI) and abdominal obesity in a sample of Yakuts (n=336), consisting of individuals with obesity (n=185) and normal weight (n=151). For genotyping, we used the classical methods of PCR-RFLP analysis. A comparative analysis of the obtained data on the frequencies of alleles and genotypes with data on other populations of the world was also carried out. The G variant allele frequency was 79.5% in normal weight patients and 82.7% in obese patients. Genotype analysis showed a high frequency of genotypes GG - 64.2% and GA - 30.5% in the group with normal BMI and GG - 69.7% and GA - 25.9% in the group with high BMI. There was no significant difference in the frequency of alleles and genotypes of theQ223Rpolymorphism between the groups. It was established that the frequency of the G allele of the Yakuts (79.5%) with the populations of East Asia (86.9%). When analyzing the average anthropometric values, depending on the genotype, a statistically significant difference in waist circumference was found in persons with abdominal obesity (p = 0.03), so it was greater in carriers of the heterozygous AG genotype than in carriers of the GG genotype.In conclusion, our study demonstrates that SNPQ223R(LEPR) is possible and has some effect on anthropometric parameters in the Yakut population, but differs from studies conducted on samples of European ethnicity. It can be assumed that the accumulation of the G allele of theQ223Rpolymorphism (LEPR) in the Yakut population, as well as in the populations of East Asia, is probably the result of metabolic adaptation to living conditions in a non-tropical climate.
Therapeutic journey of patients affected by stroke: cohort study
Authors: Santos de Mendonça Marcirene , de Paula Caio Lopes Pinheiro , Santos Douglas dos , da Silva Marcelo Nunes , Júlia Oliveira Ramos Maria , de Magalhães Soares Pinheiro Fernanda Gomes 
Published: October 2023

AbstractThe therapeutic journey of patients affected by a stroke cause health impacts and deaths. Stroke is an acute neurological dysfunction, classified as hemorrhagic or ischemic. This study aimed to compare the therapeutic journey in the access of patients affected by stroke in hospitals in the Brazilian Northeast.Prospective cohort study, carried in all public hospitals that had a neuroimaging service in the State of Sergipe. The collection instrument sought sociodemographic characterization and timeline. The data were exported to the R Core Team 2022 software. After being coded and tabulated, they were analyzed using descriptive statistics. The hypothesis of independence was tested using Pearson Chi-Square and Fisher Exact tests.A total of 159 patients cared for in the hinterland region of the State and 91 in the capital city (Aracaju) participated in the study, with a median age of 66 years old (SD:55.5-75) in the capital and with a median age of 72 years old (SD:60-82) in the hinterland. There was a predominance in females, 76.6% and 64.1%, respectively. It was found a higher incidence of the ischemic stroke (IS) (p<0.002). The decision time between the onset of signs and symptoms and the decision to call up transportation, it was observed that patients with IS cared for in the hinterland take three times longer (p=0.002). Regarding the time between the stroke detection and the CT scan, it was five times longer for those from the hinterland (p<0.001) in cases of IS. In cases of HS, the time was 1.4 longer for those from the hinterland. Concerning the neurological evaluation, in cases of IS and HS, the rates found were 76.6%vs78.3% in the hinterland, while 100% of patients were evaluated for both types of stroke episodes in the capital city (p<0.001).The therapeutic journey of patients cared for in the hinterland of the State has a longer period of time.
Persistent Inequities in Intravenous Thrombolysis for Acute Ischemic Stroke in the United States: Results from the Nationwide Inpatient Sample
Authors: Sun Philip , Zheng Ling , Lin Michelle , Cen Steven , Hammond Gmerice , Maddox Karen E. Joynt , Kim-Tenser May , Sanossian Nerses , Mack William , Towfighi Amytis 
Published: October 2023

AbstractBackgroundDespite its approval for use in acute ischemic stroke (AIS) >25 years ago, intravenous thrombolysis (IVT) remains underutilized, with inequities by age, sex, race/ethnicity, and geography. Little is known about IVT rates by insurance status. We aimed to assess temporal trends in the inequities in IVT use.MethodsWe assessed trends from 2002 to 2015 in IVT for AIS in the Nationwide Inpatient Sample by sex, age, race/ethnicity, hospital location/teaching status, and insurance, using survey-weighted logistic regression, adjusting for sociodemographics, comorbidities, and hospital characteristics. We calculated odds ratios for IVT for each category in 2002-2008 (Period 1) and 2009-2015 (Period 2).ResultsAmong AIS patients (weighted N=6,694,081), IVT increased from 1.0% in 2002 to 6.8% in 2015 (adjusted annual relative ratio (AARR) 1.15, 95% CI 1.14-1.16). Individuals ≥85 years had the most pronounced increase from 2002 to 2015 (AARR 1.18, 1.17-1.19), but were less likely to receive IVT compared to those aged 18-44 years in both Period 1 (adjusted odds ratio (aOR) 0.23, 0.21-0.26) and Period 2 (aOR 0.36, 0.34-0.38). Women were less likely than men to receive IVT, but the disparity narrowed over time (Period 1 aOR 0.81, 0.78-0.84, Period 2 aOR 0.94, 0.92-0.97). Inequities in IVT by race/ethnicity resolved for Hispanic individuals in Period 2 but not for Black individuals (Period 2 aOR 0.81, 0.78-0.85). The disparity in IVT for Medicare patients, compared to privately insured patients, lessened over time (Period 1 aOR 0.59, 0.56-0.52, Period 2 aOR 0.75, 0.72-0.77). Patients treated in rural hospitals were less likely to receive IVT than those treated in urban hospitals; a more dramatic increase in urban areas widened the inequity (Period 2 urban non-teaching vs. rural aOR 2.58, 2.33-2.85, urban teaching vs. rural aOR 3.90, 3.55-4.28).ConclusionFrom 2002 through 2015, IVT for AIS increased among adults. Despite encouraging trends, only 1 in 15 AIS patients received IVT and persistent inequities remained for Black individuals, women, government-insured, and those treated in rural areas, highlighting the need for intensified efforts at addressing inequities.
Engineered Active Zymogen of Microbial Transglutaminase
Authors: Ariyoshi Ryutaro , Matsuzaki Takashi , Sato Ryo , Minamihata Kosuke , Hayashi Kounosuke , Wakabayashi Rie , Goto Masahiro , Kamiya Noriho 
Published: October 2023

AbstractMicrobial transglutaminase (MTG) has shown to be a powerful biocatalytic glue for site-specific crosslinking of a range of biomolecules and synthetic molecules, those handled with an MTG-reactive moiety. The preparation of active recombinant MTG requires the posttranslational proteolytic digestion of propeptide working as an intramolecular chaperon to assist the correct folding of MTG zymogen (MTGz) in the biosynthesis. Herein, we propose anengineered activezymogen of MTG (EzMTG) that is expressed as soluble form in the hostE. colicytosol and exhibits the cross-linking activity without limited proteolysis. Based on the 3D structure of MTGz and serendipitous findings, saturated mutagenesis of K10 or Y12 in propeptide domain leads to generate several active MTGz mutants. In particular, K10D/Y12G mutant exhibited the catalytic activity comparable with a mature form. However, the expression level was low possibly due to the reduction of chaperone activity and/or the promiscuous substrate specificity of MTG, which is potentially harmful to the host cells. By contrast, soluble K10R/Y12A mutant is expressed in the cytosol of hostE. coliand exhibited unique substrate-dependent reactivity toward peptidyl substrates. The quantitative analysis of the binding affinity of mutated propeptide to the active site suggested the trade-off relationship of EzMTGs between the binding affinity and the catalytic activity. Our proof-of-concept study provides insights into the design of a new biocatalyst by using the zymogen as a scaffold and will convey a potential route to the high-throughput screening of MTG mutants for bioconjugation applications.
Triple-action inhibitory mechanism of allosteric TYK2-specific inhibitors
Authors: Wang Jimin , Batista Victor S. , Bunick Christopher G. 
Published: October 2023

AbstractDeucravacitinib, 6-(cyclopropanecarbonylamido)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide, is a highly selective inhibitor of protein tyrosine kinase 2 (TYK2) that targets the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway. The structural basis for its selectivity and allosteric inhibition remains poorly understood. Here, we investigate the inhibition mechanism through analysis of available structures relevant to the STAT pathway, including crystal structures of the truncated TYK2 FERM-SH2 domain bound to the IFNα type I receptor (IFNαR1) and the truncated TYK2 JH2-JH1 domain. Our computational analysis provides a mechanistic hypothesis for the relatively rapid interferon-induced gene expression mediated by TYK2 relative to other cytokines. We find that deucravacitinib inhibits TYK2 kinase in three distinct states: the autoinhibited state and two activated states for autophosphorylation and phosphorylation of downstream protein substrates. Its binding to the TYK2 pseudokinase domain in the autoinhibited state restricts the essential dynamics of the TYK2 kinase domain required for kinase activity. Furthermore, it binds competitively with ATP in the pseudokinase domain, and also directly prevents formation of the active state of TYK2 through steric clashes.
CaMKIIα and CaMKIIβ hub domains adopt distinct oligomeric states and stabilities
Authors: Özden Can , MacManus Sara , Adafia Ruth , Samkutty Alfred , Ocampo Ana Torres , Garman Scott C. , Stratton Margaret M. 
Published: October 2023

ABSTRACTCa2+/calmodulin-dependent protein kinase II (CaMKII) is a multidomain serine/threonine kinase that plays important roles in the brain, heart, muscle tissue, and eggs/sperm. The N-terminal kinase and regulatory domain is connected by a flexible linker to the C-terminal hub domain. The hub domain drives the oligomeric organization of CaMKII, assembling the kinase domains into high local concentration. Previous structural studies have shown multiple stoichiometries of the holoenzyme as well as the hub domain alone. Here we report a comprehensive study of the hub domain stoichiometry and stability in solution. We solved two crystal structures of the CaMKIIβ hub domain that show 14mer (3.1 Å) and 16mer (3.4 Å) assemblies. Both crystal structures were determined from crystals grown in the same drop, which suggests that CaMKII oligomers with different stoichiometries likely coexist. To further interrogate hub stability, we employed mass photometry and temperature denaturation studies of CaMKIIβ and α hubs, which highlight major differences between these highly similar domains. We created a dimeric CaMKIIβ hub unit using rational mutagenesis, which is significantly less stable than the oligomer. Both hub domains populate an intermediate during unfolding. We found that multiple CaMKIIβ hub stoichiometries are present in solution and that larger oligomers are more stable. CaMKIIα had a narrower distribution of molecular weight and was distinctly more stable than CaMKIIβ.
Lateral entorhinal cortex subpopulations represent experiential epochs surrounding reward
Authors: Issa John B. , Radvansky Brad A. , Xuan Feng , Dombeck Daniel A. 
Published: October 2023

AbstractDuring goal-directed navigation, “what” information, which describes the experiences occurring in periods surrounding a reward, can be combined with spatial “where” information to guide behavior and form episodic memories1,2. This integrative process is thought to occur in the hippocampus3, which receives spatial information from the medial entorhinal cortex (MEC)4; however, the source of the “what” information and how it is represented is largely unknown. Here, by establishing a novel imaging method, we show that the lateral entorhinal cortex (LEC) of mice represents key experiential epochs during a reward-based navigation task. We discover a population of neurons that signals goal approach and a separate population of neurons that signals goal departure. A third population of neurons signals reward consumption. When reward location is moved, these populations immediately shift their respective representations of each experiential epoch relative to reward, while optogenetic inhibition of LEC disrupts learning of the new reward location. Together, these results indicate the LEC provides a stable code of experiential epochs surrounding and including reward consumption, providing reward-centric information to contextualize the spatial information carried by the MEC. Such parallel representations are well-suited for generating episodic memories of rewarding experiences and guiding flexible and efficient goal-directed navigation5–7.
The neural basis of swap errors in working memory
Authors: Alleman Matteo , Panichello Matthew , Buschman Timothy J. , Johnston W. Jeffrey 
Published: October 2023

AbstractWhen making decisions in a cluttered world, humans and other animals often have to hold multiple items in memory at once – such as the different items on a shopping list. Psychophysical experiments in humans and other animals have shown remembered stimuli can sometimes become confused, with participants reporting chimeric stimuli composed of features from different stimuli. In particular, subjects will often make “swap errors” where they misattribute a feature from one object as belonging to another object. While swap errors have been described behaviorally, their neural mechanisms are unknown. Here, we elucidate these neural mechanisms through trial-by-trial analysis of neural population recordings from posterior and frontal brain regions while monkeys perform two multi-stimulus working memory tasks. In these tasks, monkeys were cued to report the color of an item that either was previously shown at a corresponding location (requiring selection from working memory) or will be shown at the corresponding location (requiring attention to a position). Animals made swap errors in both tasks. In the neural data, we find evidence that the neural correlates of swap errors emerged when correctly remembered information is selected incorrectly from working memory. This led to a representation of the distractor color as if it were the target color, underlying the eventual swap error. We did not find consistent evidence that swap errors arose from misinterpretation of the cue or errors during encoding or storage in working memory. These results suggest an alternative to established views on the neural origins of swap errors, and highlight selection from and manipulation in working memory as crucial – yet surprisingly brittle – neural processes.
The active degree of written questions in the Macau Legislative Assembly: a qualitative comparative analysis (QCA)
Authors: Tang Chunlin , Liu Sike , Deng Si 
Published: October 2023

PurposeThis study intends to explore the configuration that affects the active degree of written questions in the Macau Legislative Assembly.Design/methodology/approachThis study takes the members elected by the sixth Legislative Assembly of Macau as samples and uses the fuzzy set qualitative comparative analysis method. Five conditional factors are discussed, including multiple concurrent factors and complex causal mechanisms, which lead to the difference in the active degree of written questions.FindingsThe main conclusions are as follows: (1) Not Serving in the government is a necessary condition for a high active degree of the written question, and (2) The driving mechanism of a high active degree of written question can be divided into two paths. Among them, direct election into the Legislative Assembly is the crucial factor.Originality/valueTraditional research mainly uses quantitative research methods. This study uses qualitative comparative analysis (QCA), which is a hybrid method designed to bridge the qualitative (case-oriented) and quantitative (variable-oriented) research gap.