bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanisms of Antimicrobial Agent Cetylpyridinium Chloride Mitochondrial Toxicity in Rodent and Primary Human Cells: Super-resolution Microscopy Reveals Nanostructural Disruption
Authors: Weller Sasha R. , Burnell John E. , Aho Brandon M. , Obeng Bright , Ledue Emily L. , Shim Juyoung K. , Hess Samuel T. , Gosse Julie A. 
Published: September 2022

AbstractPeople are exposed to high concentrations of antibacterial agent cetylpyridinium chloride (CPC) via personal care and food products, despite little information regarding CPC effects on eukaryotes. CPC is used as an antibacterial agent via a detergent mechanism when above ∼600- 900 μM. While three previous studies suggested CPC mitochondrial toxicity, this phenomenon is not well-studied. Here, we show that low-micromolar CPC inhibits mitochondrial ATP production in primary human keratinocytes, mouse NIH-3T3 fibroblasts, and rat RBL-2H3 immune mast cells, in galactose media, which causes cells to produce ATP via mitochondria. ATP inhibition via CPC (EC501.7LJµM) is nearly as potent as that caused by canonical mitotoxicant CCCP (EC501.2LJµM). CPC inhibition of oxygen consumption rate (OCR) tracks with that of ATP: OCR is halved due to 1.75 μM CPC in RBL-2H3 cells and 1.25 μM in primary human keratinocytes. Here we demonstrate that CPC is more potent as a mitotoxicant than as an immune mast cell signaling inhibitor, an effect published previously. Mitochondrial [Ca2+] changes can cause mitochondrial dysfunction. Here we show, using a novel plate reader assay with reporter CEPIA2mt, that CPC causes mitochondrial Ca2+efflux from mast cells via an ATP-inhibition mechanism. Using super-resolution microscopy (fluorescence photoactivation localization) in live cells, we have discovered that CPC causes mitochondrial nanostructural defects in fibroblasts, including the formation of spherical structures with donut-like cross section, as quantified by novel Fourier transform analysis. This work reveals CPC as a mitotoxicant despite widespread use, highlighting the importance of further research into its toxicological safety.
Twist1 and balanced retinoic acid signaling act to suppress cortical folding in mice
Authors: Ho-Nguyen Khue-Tu , Jain Manav , Matrongolo Matt J. , Ang Phillip S. , Schaper Samantha , Tischfield Max A. 
Published: September 2022

AbstractEvolution of cortical folding in gyrencephalic animals enabled higher cognitive functions and complex behaviors. Gene expression patterns and signaling molecules that control cortical folding have only recently been described and thus are still not well understood. In transgenic mouse models with induced cortical folding, amplification of neuroprogenitor cells or loss of their adhesion from the apical ventricular surface leads to gyri formation, whereas decreased cell adhesion in migrating projection neurons causes abnormal neuronal clustering and development of cortical fissures that resemble sulci. We now report that loss ofTwist1expression in the primitive meninx results in cortical folding and sulci formation in the dorsolateral telencephalon. In developing sulcal regions, generation of apical and basal neuroprogenitor cells is normal. Instead, cell proliferation in the developing meninges is reduced, leading to loss of arachnoid fibroblasts that express Raldh2, an enzyme required for retinoic acid synthesis. Maternal retinoic acid supplementation rescues cortical folding and sulci formation. Our results suggest that balanced retinoic acid signaling from the meninges is required to maintain lissencephaly in mice, and in a manner independent from neuroprogenitor cell amplification.
Combinatorial control of biofilm development by quorum-sensing and nutrient-sensing regulators inPseudomonas aeruginosa
Authors: Chen Gong , Fanouraki Georgia , Rangarajan Aathmaja Anandhi , Winkelman Bradford T. , Winkelman Jared T. , Waters Christopher M. , Mukherjee Sampriti 
Published: September 2022

ABSTRACTThe human pathogenPseudomonas aeruginosa, a leading cause of hospital-acquired infections, inhabits and forms sessile antibiotic-resistant communities called biofilms in a wide range of biotic and abiotic environments. In this study, we examined how two global sensory signaling pathways – the RhlR quorum-sensing system and the CbrA/CbrB nutritional adaptation system – intersect to control biofilm development. Previous work has shown that individually these two systems repress biofilm formation. Here, we used biofilm analyses, RNA-seq, and reporter assays to explore the combined effect of information flow through RhlR and CbrA on biofilm development. We find that the ΔrhlRΔcbrAdouble mutant exhibits a biofilm morphology and an associated transcriptional response distinct from wildtype and the parent ΔrhlR andΔcbrAmutants indicating codominance of each signaling pathway. The ΔrhlRΔcbrAmutant rapidly gains suppressor mutations that map to the carbon catabolite repression protein Crc. The combined absence of RhlR and CbrA leads to drastic reduction in the abundance of the Crc antagonist small RNA CrcZ. Thus, CrcZ acts as the molecular convergence point for quorum- and nutrient-sensing cues. Furthermore, in the absence of antagonism by CrcZ, Crc promotes the expression of biofilm matrix components – Pel exopolysaccharide, and CupB and CupC fimbriae. Therefore, this study uncovers a regulatory link between nutritional adaption and quorum sensing with potential implications for anti-biofilm targeting strategies.AUTHOR SUMMARYBacterial pathogens often form multicellular communities encased in an extra cytoplasmic matrix called biofilms as a virulence strategy. Biofilm development is controlled by various environmental stimuli that are decoded and converted into appropriate cellular responses. How information from two or more stimuli is integrated is poorly understood. UsingPseudomonas aeruginosabiofilm formation as a model, we studied the intersection of two global sensory signaling pathways – quorum sensing and nutritional adaptation. We find parallel regulation by each pathway that converges on the abundance of a small RNA. Thus, we describe a regulatory link betweenP. aeruginosaquorum-sensing and nutritional adaptation pathways that allows integration of information from each system into the control of biofilm development. These results expand our understanding of the genetic regulatory strategies that allowP. aeruginosato successfully colonize host during chronic infections.
Common population codes produce extremely nonlinear neural manifolds
Authors: De Anandita , Chaudhuri Rishidev 
Published: September 2022

AbstractPopulations of neurons represent sensory, motor and cognitive variables via patterns of activity distributed across the population. The size of the population used to encode a variable is typically much greater than the dimension of the variable itself, and thus the corresponding neural population activity occupies lower-dimensional subsets of the full set of possible activity states. Given population activity data with such lower-dimensional structure, a fundamental question asks how close the low-dimensional data lies to a linear subspace. The linearity or non-linearity of the low-dimensional structure reflects important computational features of the encoding, such as robustness and generalizability. Moreover, identifying such linear structure underlies common data analysis methods such as Principal Component Analysis. Here we show that for data drawn from many common population codes the resulting point clouds and manifolds are exceedingly nonlinear, with the dimension of the best-fitting linear subspace growing at least exponentially with the true dimension of the data. Consequently, linear methods like Principal Component Analysis fail dramatically at identifying the true underlying structure, even in the limit of arbitrarily many data points and no noise.
L1 retrotransposition is regulated post-transcriptionally In High-Grade Serous Ovarian Cancer
Authors: Pradhan Barun , Zhang Kaiyang , Li Yilin , Lavikka Kari , Muranen Taru , Huhtinen Kaisa , Badge Richard , Burns Kathleen H. , Hynninen Johanna , Hietanen Sakari , Oikkonen Jaana , Hautaniemi Sampsa , Kauppi Liisa 
Published: September 2022

AbstractL1 retrotransposons are the only protein-coding active transposable elements in the human genome. Although silenced during normal conditions, they are highly expressed in human epithelial cancers including high-grade serous ovarian cancer (HGSC), where they transcribe to form L1 mRNA and subsequently integrate into the genome by a process called retrotransposition. Despite of high L1 protein expression in the earliest phases of HGSC, these tumors do not accrue many somatic L1 insertions. To understand this unexplained disconnect, we monitored the transcription and retrotransposition activity of two frequently expressed retrotransposition-competent (RC)-L1 (RC-L1) in 64 clinical tumor specimens from 34 HGSC patients and found that despite the presence of RC-L1 mRNA, a third of samples did not acquire somatic L1 insertions. In addition to high inter-patient variability in retrotransposition frequency, there was remarkable intra-patient heterogeneity in L1 insertion patterns between tumor sites, indicating that L1 retrotransposition is highly dynamic in vivo. Comparison of genomic and transcriptomic features of L1-null tumors with L1-high tumors (those with ≥5 somatic L1 insertions) showed that retrotransposition was favored by increased rate of cell proliferation.
CDK4/6 inhibition and dsRNA sensor agonism co-operate to enhance anti-cancer effects through ER stress and immune modulation of tumour cells
Authors: Roulstone Victoria , Kyula Joan , Wright James , Yu Lu , Alonso Aida Barreiro , Melake Miriam , Choudhary Jyoti , Elliott Richard , Lord Christopher J. , Mansfield David , Matthews Nik , Chauhan Ritika , Jennings Victoria , Chan Charleen , Baldock Holly , Butera Francesca , Appleton Elizabeth , Nenclares Pablo , Pederson Malin , Foo Shane , Patin Emmanuel C. , Rullan Antonio , Tenev Tencho , Meier Pascal , Van Vloten Jacob , Vile Richard , Pandha Hardev , Melcher Alan , McLaughlin Martin , Harrington Kevin 
Published: September 2022

AbstractCytoplasmic pattern recognition receptors (PRRs) for double-stranded RNA (RIG-I/MDA5) are key mediators of anti-viral responses. PRR agonists, such as dsRNA oncolytic Reovirus type 3 Dearing (Rt3D), potently activate RNA sensors. We used an unbiased cytotoxicity screen to reveal synergistic drug-virotherapy combinations and found potent effects of Rt3D combined with the CDK4/6 inhibitor, palbociclib. The combination augmented oncolytic virus-induced endoplasmic reticulum (ER) stress/unfolded protein response (UPR) and the expression and activation/signaling of RNA sensors. Combined Rt3D-palbociclib treatment potently increased interferon production and signaling, and knockdown studies implicated key UPR proteins and the RNA sensor, RIG-I, as essential to the phenotype observed. Further experiments, using canonical RIG-I agonists and an ER stress inducer, thapsigargin, confirmed cross-talk between RNA sensing and ER stress pathways that augmented cancer cell death and interferon production. Combined Rt3D-palbociclib also increased innate immune activation within tumour cells and IFN-induced HLA expression. Analysis of the immunopeptidome revealed changes to HLA-captured peptides with Rt3D-palbociclib, including altered expression of peptides from cancer/testis antigens (CTA) and endogenous retroviral elements (ERVs). Our findings highlight cross-talk between UPR signaling and RNA-mediated PRR activation as a means of enhancing anti-cancer efficacy with potential pro-immunogenic consequences. This has implications for future clinical development of PRR agonists and oncolytic viruses, and broadens the therapeutic remit of CDK4/6 inhibitors to include roles as both ER stress and dsRNA PRR sensitizers.
Permeability transition pore-related changes in the proteome and channel activity of ATP synthase dimers and monomers
Authors: Nikiforova Anna B. , Baburina Yulia L. , Borisova Marina P. , Surin Alexey K. , Kharechkina Ekaterina S. , Krestinina Olga V. , Suvorina Maria Y. , Kruglova Svetlana A. , Kruglov Alexey G. 
Published: September 2022

AbstractMonomers, dimers, and individual FOF1-ATP synthase subunits are, presumably, involved in the formation of the mitochondrial permeability transition pore (PTP), which molecular structure, however, is still unknown. We hypothesized that upon the Ca2+-dependent assembly of PTP complex, F-ATP synthase (subunits) recruits mitochondrial proteins that do not interact or weakly interact with F-ATP synthase under normal conditions. Therefore, we examined whether the PTP opening in mitochondria before the separation of supercomplexes by BN-PAGE will increases the channel stability and channel-forming capacity of isolated F-ATP synthase dimers and monomers in planar lipid membranes. Besides, we studied the specific activity and protein composition of F-ATP synthase dimers and monomers from rat liver and heart mitochondria before and after PTP opening. By contrast to our expectations, preliminary PTP opening dramatically suppressed the high-conductance channel activity of F-ATP synthase dimers and monomers and decreased their specific “in gel” activity. The decline in the channel-forming activity correlated with the reduced levels of as few as two proteins in the bands: methylmalonate-semialdehyde dehydrogenase and prohibitin 2. These data indicate that proteins accompanying F-ATP synthase may be important players in the PTP formation and stabilization.
A full computational model of cell motility: Early spreading, cell migration and competing taxis
Authors: Betorz Joel , Bokil Gaurav R. , Deshpande Shreyas M. , Kulkarnic Shardool , Rolando Daniel , Venturini Chiara , Saez Pablo 
Published: September 2022

AbstractCell motility represents one of the most fundamental function in mechanobiology. Cell motility is directly implicated in development, cancer or tissue regeneration, but it also plays a key role in the future of tissue and biomedical engineering. Here, we derived a computational model of cell motility that incorporates the most important mechanisms toward cell motility: cell protrusion, polarization and retrograde flow. We first validate our model to explain two important types of cell migration, i.e. confined and ameboid cell migration, as well as all phases of the latter cell migration type, i.e. symmetric cell spreading, cell polarization and latter migration. Then, we use our model to investigate durotaxis and chemotaxis. The model predicts that chemotaxis alone induces larger migration velocities than durotaxis and that durotaxis is activated in soft matrices but not in stiff ones. More importantly, we analyze the competition between chemical and mechanical signals. We show that chemotaxis rules over durotaxis in most situations although durotaxis diminishes chemotaxis. Moreover, we show that inhibiting the effect of GTPases in actin polymerization at the cell front may allow durotaxis to take control over chemotaxis in soft substrates. Understanding how the main forces in cell motility cooperate, and how a precise manipulation of external cues may control directed cell migration is not only key for a fundamental comprehension of cell biology but also to engineer better biomimetic tissues. To this end, we provide a freely-available platform to predict all phases and modes of cell motility analyzed in this work.
Chemotaxonomy ofTapinomaand some Dolichoderinae ants from Europe and North Africa
Authors: Lenoir Alain , Perdereau Elfie , Berville Laurence 
Published: September 2022

AbstractCuticular hydrocarbons of some Dolichoderinae species from France and various places like Spain, North Africa, and Italy were studied. TheTapinoma nigerrimumgroup was particularly analyzed and replaced in the genusTapinoma. All species were correctly discriminated and a new hydrocarbons profile was found in Spanish mountains in theT. nigerrimumgroup, which was provisionally namedT. sp. Spain. We added numerous unknown spots for the distribution of these ants. We also tested aggression between someT. magnumcolonies and it appeared that this species forms supercolonies like other invasive species, but does not form giant supercolonies like the Argentine ant
Comparative Study of State-Dependent Cholesterol Binding Sites in Adenosine A2A and A1 Receptors Using Coarse-Grained Molecular Dynamics Simulations in Biologically Relevant Membranes
Authors: Tzortzini Efpraxia , Corey Robin A. , Kolocouris Antonios 
Published: September 2022

AbstractIn this study we used coarse-grained molecular dynamics (CG MD) simulations to study protein-cholesterol interactions for different activation states of the A2A adenosine receptor (A2AR) and A1 adenosine receptor (A1R). Three different membranes were used, of which a plasma mimetic membrane best matched cholesterol binding sites previously detected in X-ray structures and computationally for the inactive state of A2AR. Here, cholesterol binds stably between TM5 and TM6 in the intracellular leaf and between the extracellular part of TM6 and TM7. The stability of the identified binding sites to A1R with CG MD simulations were further investigated using potential of mean force calculations combined with umbrella sampling.Cholesterol binding to certain cavities in active or inactive state can stabilize a conformation of active or inactive state respectively and is important to identify these cavities. For the active state the cholesterol binding sites have much longer residence times compared to the inactive state for both A2AR and A1R.We observed for the active A1R two cholesterol binding sites in the extracellular membrane leaf in a cavity between TM2/TM3 and along TM3 in the intracellular leaf. We found a partially overlapped binding area between TM6 and TM7 in the extracellular membrane leaf for active state and inactive A1R state which can be antagonized by cholesterol molecules although the site has a much longer residence time for active A1R. For the active A2AR we predicted a high residence time cholesterol position between TM1 and TM7 in the middle region of TMD which is different from the binding sites calculated in active or inactive A1R and for the inactive A2AR. For the inactive A2AR cholesterol binds to the same extracellular area between TM6 and TM7 as in the inactive A1R.The differences in stable, long residence time cholesterol binding sites between active and inactive states of A1R and for A2AR can be important for functional activity and orthosteric agonist or antagonist affinity and can be used for the design of allosteric modulators which can bind through lipid pathways.
A robust numerical method for drawing the fluid flux-barrier geometry in the inner and outer rotor radial flux synchronous reluctance machines based on the finite difference method
Authors: Jamali Fard Ali , Mirsalim Mojtaba 
Published: September 2022

Purpose
Rotor shape optimization is crucial in designing synchronous reluctance machines (SynRMs) because the machine performance is directly proportional to the rotor’s magnetic saliency ratio. The rotor geometry in synchronous reluctance machines is complex, and many geometrical parameters must be optimized. When fluid flux-barrier geometry is desirable, using analytic equations to prepare the rotor geometry for finite element analysis could be tedious. This paper aims to provide a robust numerical procedure to draw the fluid flux-barrier geometry in transversally laminated radial flux inner and outer rotor SynRMs by directly solving the magnetic vector potential equation using the finite difference method..

Design/methodology/approach
In this paper, the goal is to have a robust procedure for drawing the rotor geometry for an arbitrary number of slots (Ns), poles (p) and flux-barrier layers (Nfb). Therefore, this paper targeted several combinations to investigate the performance of the proposed algorithm. The MATLAB software is used to implement the proposed algorithm. The ANSYS Maxwell software is used for counterpart finite element simulation to check the correctness of the results derived by the proposed method.

Findings
Several inner and outer rotor SynRMs considering a different number of poles and a different number of flux-barrier layers per pole are studied to investigate the performance of the proposed algorithm. Results corresponding to each case are presented, and it is shown that the method is robust, flexible and fast enough, which could be used for the generation of the rotor geometry for the finite element analysis effectively.

Originality/value
The value of the proposed algorithm is its simplicity and straightforwardness in its implementation for the preparation of the rotor geometry with the desired fluid flux-barrier layer curvature resolution suitable for the finite element analysis. The procedure presented in this paper is based on the ideal magnetic loading concept, and in future works, a similar idea could be used for linear and axial flux SynRMs.
Monetary penalties for refusal of mandatory Covid-19 vaccination: state’s right to regulate vs people’s rights and freedom in health care
Authors: Sefriani Sefriani , Mahardhika Nur Gemilang 
Published: September 2022

Purpose
The Covid-19 pandemic has persisted for almost three years. States have since then enforced laws, policies and measures believed to be the most effective to handle the global pandemic. Along this line, the Indonesian Government opted to implement mandatory vaccination and refusal of which entails monetary penalties. Hence, this study aims to analyze two legal issues that touch upon the realm of International Human Rights Law: first, whether state has the authority to implement the said mandatory vaccine program to those who refuse to be vaccinated, and second, how is the more appropriate legal policy to obligate vaccination but without coercive sanction.

Design/methodology/approach
This is a normative legal research that uses a qualitative method with case studies, conceptual, historical and comparative approaches. A descriptive-analytical deduction process was used in analyzing the issue.

Findings
The results present, as part of state’s right to regulate, it has the authority to enact mandatory vaccination with monetary penalties to fulfil its obligation to protect public health in times of emergency; this is legal and constitutional but only if it satisfies the requirements under the International Human Rights Law: public health necessity, reasonableness, proportionality and harm avoidance. Alternatively, herd immunity is achievable without deploying unnecessary coercive sanctions, such as improving public channels of communication and information, adopting legal policies that incentivize people’s compliance like exclusion from public services, subsidies revocation, employment restrictions, higher health insurance premiums, etc.

Research limitations/implications
This study analyzes in depth the following issues: of whether the government has the authority to apply mandatory vaccination laws enforced through monetary penalties for those who refused to be vaccinated and how does the government implement the appropriate legal policy to enforce mandatory vaccination without imposing penalties for non-compliance while maintaining a balance between the interests of protecting public health and the human rights of individuals to choose medical treatment for themselves, including whether they are willing to be vaccinated. Hence, the political affairs, economic matters and other non-legal related issues are excluded from this study.

Originality/value
This paper hence offers a suggestive insight for state in formulating a policy relating to the mandatory vaccination program. Although the monetary penalties do not directly violate the rule of law, a more non-coercive approach to the society would be more favorable.