bluuebunny/crossref_metadata_2025_split huggingface dataset:
Concatenated tandem constructs of BK channels reveal three distinct types of subunit stoichiometry in channel modulation by the auxiliary γ subunit and mutations in the channel pore region
Authors: Chen Guanxing , Li Qin , Yan Jiusheng 
Published: June 2023

AbstractThe large-conductance, Ca2+-activated K+(BK) channels consist of the Ca2+- and voltage-sensing and pore-forming α (BKα) subunits and regulatory auxiliary β or γ subunits. Concatenated tandem constructs have been proved to be necessary and powerful in understanding the subunit stoichiometry of K+channel gating and regulation by constraining the stoichiometry, organization, and mutation of individual subunits. However, because of its unique possession of an extra S0 transmembrane segment that puts the N- and C- termini on the opposite sides of the membrane, it is impossible to generate concatenated tandem subunit constructs of BK channels as those done with other K+channels. In order to investigate the molecular mechanisms of the atypical “all-or-none” modulatory function of the γ subunits and the subunit stoichiometry of BK channel gating, we have taken a novel strategy and generated functional concatenated tandem constructs containing 2 or 4 copies of the BKα subunits by splicing BKα into 2 protein constructs that can be co-expressed to form functional channels. We observed that the BK channels formed by concatenated tandem constructs are similar to intact channels in voltage and Ca2+gating properties. Interestingly, the BKγ1 subunit and mutations located at the S6 transmembrane segment and selectivity filter displayed 3 distinct types of subunit stoichiometry in BK channel modulation. By fusion of the BKγ1 subunit to the N-terminus of the concatenated tandem BKα constructs, we observed that a single molecule of BKγ1 subunit per tetrameric BKα channel is sufficient to fully modulate the channels. The Y294K, F303A, and L312A mutations at each BKα subunit has an incremental effect on BK channel gating. The V288A mutation at the selectivity filter produce an “all-or-none” effect but requires mutations at all 4 BKα subunits to have modulatory effect on channel gating, i.e., mutations at 1, 2, or 3 subunits have nearly no effect. Interestingly, the F307A mutation exhibited an atypical “all-or-none” modulatory function similar to that of the γ1 subunit. The diversity in subunit stoichiometry of BK channel modulation indicates distinct mechanisms in affecting BK channel gating. Overall, we have developed novel concatenated tandem constructs for BK channels and revealed three distinct types of subunit stoichiometry in BK channel modulation by the auxiliary γ subunit and mutations at the pore-lining S6 transmembrane segment and selectivity filter.
Trends in Complications among Patients undergoing Aortic Valve Replacement (AVR) in the United States
Authors: Harvey James E. , Kapadia Samir R. , Cohen David J. , Kalra Ankur , Irish William , Gunnarsson Candace , Ryan Michael , Chikermane Soumya , Thompson Christin , Puri Rishi 
Published: June 2023

ABSTRACTBackgroundThe treatment of severe aortic stenosis has evolved considerably since the introduction of transcatheter aortic valve replacement (TAVR), yet trends in in-hospital complications for patients undergoing TAVR or surgical aortic valve replacement (SAVR) at a national level have yet to be evaluated.MethodsWe performed a retrospective cohort study using Medicare data to evaluate temporal trends in complications among beneficiaries aged ≥65 years treated with elective isolated transfemoral TAVR or SAVR between 2012 and 2019. The study endpoint was the occurrence of a major complication during the index AVR hospitalization, defined as a composite outcome. Multivariable logistic regression was used to assess odds of complications for TAVR and SAVR, individually over time, after adjusting for baseline characteristics. Another risk-adjusted model assessed the risk of complications for TAVR vs SAVR, over time.ResultsThe cohort included 211,212 patients (mean age:78.6±7.3 years, female:45.0%). Complication rates following elective isolated AVR decreased from 49% in 2012 to 22% in 2019. These reductions were more pronounced for TAVR (41%->19%, delta=22%) than SAVR (51%->47%, delta=4%). After risk adjustment, the risk of any complication with TAVR was 47% (p<0.0001) lower compared to SAVR in 2012, and 78% (p<0.0001) lower in 2019. TAVR was independently associated with reduced odds of complications each year compared to 2012, with the magnitude of benefit increasing over time (2013 vs 2012: OR=0.89(0.81-0.97); 2019 vs 2012: OR=0.35(0.33-0.38)).ConclusionsBetween 2012-2019, the risk of complications after AVR among Medicare beneficiaries decreased significantly, with larger absolute and relative changes among patients treated with TAVR than SAVR.
All-optical mapping of cAMP transport reveals rules of sub-cellular localization
Authors: Xiang Katherine M. , Park Pojeong , Koren Shon A. , Hayward Rebecca Frank , Cohen Adam E. 
Published: June 2023

AbstractCyclic adenosine monophosphate (cAMP) is a second messenger that mediates diverse intracellular signals. Studies of cAMP transport in cells have produced wildly different results, from reports of nearly free diffusion to reports that cAMP remains localized in nanometer-scale domains. We developed an all-optical toolkit, termed cAMP-SITES, to locally perturb and map cAMP transport. In MDCK cells and in cultured neurons, cAMP had a diffusion coefficient of ∼120 µm2/s, similar to the diffusion coefficients of other small molecules in cytoplasm. In neuronal dendrites, a balance between diffusion and degradation led to cAMP domains with a length scale of ∼30 µm. Geometrical confinement by membranes led to subcellular variations in cAMP concentration, but we found no evidence of nanoscale domains or of distinct membrane-local and cytoplasmic pools. We introduce theoretical relations between cell geometry and small-molecule reaction-diffusion dynamics and transport to explain our observations.
A closer look at Type I left-handed β-helices provides a better understanding in their sequence-structure relationship: towards their rational design
Authors: Naudé Maxime , Faller Peter , Lebrun Vincent 
Published: June 2023

AbstractUnderstanding the sequence-structure relationship in protein is of fundamental interest, but has practical applications such as the rational design of peptides and proteins. This relationship in the Type I left-handed β–helix containing proteins is updated and revisited in this study. Analysing the available structures in the Protein Data Base, we could describe further in details the structural features that are important for the stability of this fold, as well as its nucleation and termination. This study is meant to complete previous work, as it provides a separate analysis of the N-terminal and C-terminal rungs of the helix. Particular sequence motifs of these rungs are described along with the structural element they form.
Temporal spiking sequences in visual cortex carry unique information about natural movies
Authors: Sotomayor-Gómez Boris , Battaglia Francesco P. , Vinck Martin 
Published: June 2023

ABSTRACTInformation in the nervous system is encoded by the spiking patterns of large populations of neurons. The analysis of such high-dimensional data is typically restricted to simple, arbitrarily defined features like spike rates, which discards information in the temporal structure of spike trains. Here, we use a recently developed method called SpikeShip based on optimal transport theory, which captures information from all of the relative spike-timing relations among neurons. We compared spike-rate and spike-timing codes in neural ensembles from six visual areas during natural video presentations. Temporal spiking sequences conveyed substantially more information about natural movies than population spike-rate vectors, especially for larger number of neurons. As previously, shown, population rate vectors exhibited substantial drift across repetitions and between blocks. Conversely, encoding through temporal sequences was stable over time, and did not show representational drift both within and between blocks. These findings reveal a purely spike-based neural code that is based on relative spike timing relations in neural ensembles alone.
Peripheral linker mediates ACP’s recognition of DH and stabilizes Mycobacterium tuberculosis FAS-I
Authors: Kumar Akhil , Sharma Manisha , Katkar Harshwardhan H. 
Published: June 2023

1SummaryIncomplete structural details of Mycobacterium tuberculosis (Mtb) fatty acid synthase-I (FAS-I) at near-atomic resolution have limited our understanding of the shuttling mechanism of its mobile acyl carrier protein (ACP). Here, we have performed atomistic molecular dynamics simulation of Mtb FAS- I with a homology-modelled structure of ACP stalled at dehydratase (DH), and identified key residues that mediate anchoring of the recognition helix of ACP near DH. The observed distance between catalytic residues of ACP and DH agrees with that reported for fungal FAS-I. Further, the conformation of the peripheral linker is found to be crucial in stabilizing ACP near DH. Correlated inter-domain motion is observed between DH, enoyl reductase (ER) and malonyl/palmitoyl transferase (MPT); consistent with prior experimental reports of fungal and Mtb FAS-I.
Physiological adaptation to high irradiance in duckweeds depends on light habitat niche and is ecotype and species-specific
Authors: Smith Kellie E. , Cowan Laura , Taylor Beth , McAusland Lorna , Heatley Matthew , Murchie Erik H. 
Published: June 2023

AbstractDuckweeds are free-floating aquatic organisms with species ranging from 2 mm-10 mm, where each plant is a single leaflike structure. Recognized as an emerging food crop, their fast growth rates offer potential for cultivation in closed systemsHowever the majority of available duckweed clones lack information regarding habitat origin and physiology. We describe a novel UK collection derived from low light (dLL) or high light (dHL) habitats and profiled for growth, photosynthesis and photoprotection (Non Photochemical Quenching, NPQ) responses. Multiple ecotypes of threeLemnaspecies and one ecotype ofSpirodela polyrhiza, were grown under low light (LL:100 μmol m-2s-1) and high light (HL:350 μmol m-2s-1). We found species and ecotypic variation in photosynthesis acclimation. Duckweeds grown under HL exhibited lower growth rate, biomass, chlorophyll and quantum yield of photosynthesis. In HL-compared to LL, carotenoid de-epoxidation state and NPQ were higher whilst photosystem II efficiency (ϕPSII) and chla:b ratios were unchanged. Interestingly dLL plants showed relatively stronger acclimation to HL compared to dHL plants: These ecotypes achieved faster growth in HL: by area and colony gain, higher carotenoid levels and less degradation of chlorophyll. We conclude that adaptation to local habitat among ecotypes strongly affects performance under controlled conditions.
Non-image forming vision as measured through ipRGC-mediated pupil constriction is not modulated by covert visual attention
Authors: Vilotijević Ana , Mathôt Sebastiaan 
Published: June 2023

AbstractIn brightness the pupil constricts, while in darkness the pupil dilates; this is known as the pupillary light response (PLR). The PLR is driven by all photoreceptors: rods and cones, which contribute to image-forming vision, as well as intrinsically photosensitive retinal ganglion cells (ipRGCs), which contribute to non-image-forming vision. Rods and cones cause immediate pupil constriction upon light exposure, whereas ipRGCs cause sustained constriction for as long as light exposure continues. Recent studies have shown that the initial PLR is modulated by covert attention; however, it remains unclear whether the same holds for the sustained PLR. Here, we investigated the effect of covert attention on sustained, ipRGC-mediated pupil constriction. We leveraged the fact that ipRGCs are predominantly responsive to blue light, causing the most prominent sustained constriction in response to blue light. Replicating previous studies, we found that the pupil constricted more when either directly looking at, or covertly attending to, bright as compared to dim stimuli (with the same color). We also found that the pupil constricted more when directly looking at blue as compared to red stimuli (with the same luminosity); crucially, however, we didnotfind any difference in pupil size when covertly attending to blue as compared to red stimuli. This suggests that ipRGC-mediated pupil constriction, and possibly non-image-forming vision more generally, is not modulated by covert attention.Significance statementWhen we think of vision, we generally think of image-forming vision, that is, seeing things. However, vision can also be “non-image-forming”; for example, our day-night rhythm and pupil size are regulated by visual input, but not in a way that gives rise to conscious visual awareness. While visual attention shapes image-forming vision, its influence on non-image forming vision remains unclear. We investigated this by using ipRGCs,which contribute to non-image-forming vision and are responsive to blue light. Aside from replicating the effect of covert attention on image-forming vision, we showed that pupil constriction differed between directly looking at blue/ red stimuli, but not during covert attention to these stimuli. This suggests that non-image forming vision is not influenced by covert visual attention.
The Salivary Microbiome and Predicted Metabolite Production are Associated with Progression from Barrett’s Esophagus to Esophageal Adenocarcinoma
Authors: Solfisburg Quinn S , Baldini Federico , Baldwin-Hunter Brittany L , Lee Harry H , Park Heekuk , Freedberg Daniel E , Lightdale Charles J , Korem Tal , Abrams Julian A 
Published: June 2023

AbstractEsophageal adenocarcinoma (EAC) is rising in incidence and associated with poor survival, and established risk factors do not explain this trend. Microbiome alterations have been associated with progression from the precursor Barrett’s esophagus (BE) to EAC, yet the oral microbiome, tightly linked to the esophageal microbiome and easier to sample, has not been extensively studied in this context. We aimed to assess the relationship between the salivary microbiome and neoplastic progression in BE to identify microbiome-related factors that may drive EAC development. We collected clinical data and oral health and hygiene history and characterized the salivary microbiome from 250 patients with and without BE, including 78 with advanced neoplasia (high grade dysplasia or early adenocarcinoma). We assessed differential relative abundance of taxa by 16S rRNA gene sequencing and associations between microbiome composition and clinical features and used microbiome metabolic modeling to predict metabolite production. We found significant shifts and increased dysbiosis associated with progression to advanced neoplasia, with these associations occurring independent of tooth loss, and the largest shifts were with the genusStreptococcus. Microbiome metabolic models predicted significant shifts in the metabolic capacities of the salivary microbiome in patients with advanced neoplasia, including increases in L- lactic acid and decreases in butyric acid and L-tryptophan production. Our results suggest both a mechanistic and predictive role for the oral microbiome in esophageal adenocarcinoma. Further work is warranted to identify the biological significance of these alterations, to validate metabolic shifts, and to determine whether they represent viable therapeutic targets for prevention of progression in BE.
Inadequate structural constraint on Fab approach rather than paratope elicitation limits HIV-1 MPER vaccine utility
Authors: Tan Kemin , Chen Junjian , Kaku Yu , Wang Yi , Donius Luke , Khan Rafiq Ahmad , Li Xiaolong , Richter Hannah , Seaman Michael S. , Walz Thomas , Hwang Wonmuk , Reinherz Ellis L. , Kim Mikyung 
Published: June 2023

AbstractBroadly neutralizing antibodies (bnAbs) against HIV-1 target conserved epitopes, thereby inhibiting viral entry. Yet surprisingly, those recognizing linear epitopes in the HIV-1 gp41 membrane proximal external region (MPER) are elicited neither by peptide nor protein scaffold vaccines. Here, we observe that while Abs generated by MPER/liposome vaccines may exhibit human bnAb-like paratopes, B-cell programming without constraints imposed by the gp160 ectodomain selects Abs unable to access the MPER within its native “crawlspace”. During natural infection, the flexible hinge of IgG3 partially mitigates steric occlusion of less pliable IgG1 subclass Abs with identical MPER specificity, until affinity maturation refines entry mechanisms. The IgG3 subclass maintains B-cell competitiveness, exploiting bivalent ligation resulting from greater intramolecular Fab arm length, offsetting weak antibody affinity. These findings suggest future immunization strategies.
Truly tiny acoustic biomolecules for ultrasound imaging and therapy
Authors: Ling Bill , Gungoren Bilge , Yao Yuxing , Dutka Przemysław , Smith Cameron A. B. , Lee Justin , Swift Margaret B. , Shapiro Mikhail G. 
Published: June 2023

ABSTRACTNanotechnology offers significant advantages for medical imaging and therapy, including enhanced contrast and precision targeting. However, integrating these benefits into ultrasonography has been challenging due to the size and stability constraints of conventional bubble-based agents. Here we describe bicones, truly tiny acoustic contrast agents based on gas vesicles, a unique class of air-filled protein nanostructures naturally produced in buoyant microbes. We show that these sub-80 nm particles can be effectively detected both in vitro and in vivo, infiltrate tumors via leaky vasculature, deliver potent mechanical effects through ultrasound-induced inertial cavitation, and are easily engineered for molecular targeting, prolonged circulation time, and payload conjugation.
Evolutionary potential of the monkeypox genome arising from interactions with human APOBEC3 enzymes
Authors: Delamonica Brenda , Davalos Liliana , Larijani Mani , Anthony Simon J , Liu Jia , MacCarthy Thomas 
Published: June 2023

AbstractAPOBEC3, an enzyme subfamily that plays a role in virus restriction by generating mutations at particular DNA motifs or mutational “hotspots,” can drive viral mutagenesis with host-specific preferential hotspot mutations contributing to pathogen variation. While previous analysis of viral genomes from the 2022 Mpox (formerly Monkeypox) disease outbreak has shown a high frequency of C>T mutations at TCmotifs, suggesting recent mutations are human APOBEC3-mediated, how emerging monkeypox virus (MPXV) strains will evolve as a consequence of APOBEC3-mediated mutations remains unknown. By measuring hotspot under-representation, depletion at synonymous sites, and a combination of the two, we analyzed APOBEC3-driven evolution in human poxvirus genomes, finding varying hotspot under-representation patterns. While the native poxvirus molluscum contagiosum exhibits a signature consistent with extensive coevolution with human APOBEC3, including depletion of TChotspots, variola virus shows an intermediate effect consistent with ongoing evolution at the time of eradication. MPXV, likely the result of recent zoonosis, showed many genes with more TChotspots than expected by chance (over-representation) and fewer GChotspots than expected (under-representation). These results suggest the MPXV genome: 1) may have evolved in a host with a particular APOBEC GChotspot preference, 2) has inverted terminal repeat (ITR) regions –which may be exposed to APOBEC3 for longer during viral replication– and longer genes likely to evolve faster, and therefore 3) has a heightened potential for future human APOBEC3-meditated evolution as the virus spreads in the human population. Our predictions of MPXV mutational potential can both help guide future vaccine development and identification of putative drug targets and add urgency to the task of containing human Mpox disease transmission and uncovering the ecology of the virus in its reservoir host.
Dose–response relationship between Frailty Index and Stroke among middle-aged and elderly Chinese
Authors: Yang Yifang , Ma Yuxia , Yang Tingting , He Xiang , Chen Junbo , Wu Tingting , Nan Jinhan , Feng Juanjuan , Han Lin 
Published: June 2023

AbstractBackgroundStroke has emerged as the leading cause of mortality in China, with the burden of the disease increasing with the aging population. Recent research has established a correlation between frailty and stroke, with the frailty index serving as a comprehensive measure of frailty in elderly populations. This study aimed to explore the dose-response relationship between frailty index and stroke, with the objective of providing a reference for effective stroke identification in middle-aged and elderly individuals, thereby preventing the onset of the disease.MethodsThe data used in this study were derived from the China Health and Retirement Longitudinal Study (CHARLS) database from 2011 to 2018. Proportional hazards model was utilized to investigate the impact of frailty index on stroke risk, while restricted cubic spline analysis was employed to examine the dose-response relationship between frailty index and stroke. Subgroup analysis was used to further understand whether the frailty index has an effect on the occurrence of stroke in different subgroups.ResultsA total of 11328 participants were included in the study, with 401 (3.3%) stroke patients. Frailty and pre-frailty were associated with a high risk of stroke events compared with robust group(HR, 3.89, 95%CI, 2.88-5.26), (HR, 2.09, 95%CI, 1.60-2.75), after adjusting for all covariates. There was a non-linear relationship between frailty index and stroke in the restricted cubic spline regression model. Frailty index was a risk factor of stroke when it exceeded 0.13. Taking the robust as reference, subgroup analysis results showed a significant interaction with the frailty index in all subgroup analyses except for the smoking group.ConclusionPre-frailty and frailty were significantly associated with stroke risk. Frailty index had a nonlinear relationship with stroke occurrence, and frailty index >0.13 was significantly correlated with stroke occurrence. Frailty index is an independent predictor of stroke occurrence.