bluuebunny/crossref_metadata_2025 huggingface dataset:
Cleft Rhinoplasty: Does Timing and Utilization of Cartilage Grafts Affect Perioperative Outcomes?
Authors: Kalmar Christopher L. , Carlson Anna R. , Patel Vijay A. , Zapatero Zachary D. , Kosyk Mychajlo S. , Bartlett Scott P. , Swanson Jordan W. , Taylor Jesse A.
Published: August 2022

Background:

The purpose of this study was to evaluate the epidemiology and perioperative complications of different reconstructive strategies to correct cleft nasal deformity, with particular attention paid to type and timing of cartilage grafting.

Methods:

Retrospective cohort study was conducted of cleft rhinoplasty performed between 2012 and 2017 in North America utilizing the American College of Surgeons National Surgical Quality Improvement Program- Pediatric hospital network. Medical/surgical complications, reoperations, and readmissions within 30 days postoperatively were analyzed with appropriate statistics.

Results:

During the study interval, 3317 pediatric patients underwent cleft rhinoplasty, with 8.0% involving the use of cartilage grafts. Ear cartilage was significantly more commonly used for intermediate repair, whereas rib cartilage was more commonly used for late repair (P=0.006). Overall, rhinoplasties with ear cartilage grafts had shorter procedure durations than those without cartilage grafts (P=0.005), whereas those with rib cartilage grafts had increased procedure duration (P<0.001). The use of cartilage grafts was not associated with increased complications in either intermediate or late cleft rhinoplasty. Patients with bilateral clefts were more likely to undergo rhinoplasty with cartilage grafts overall (P=0.047) and with cartilage grafts for late reconstruction (P=0.039).

Conclusions:

Ear cartilage is most frequently utilized for intermediate repair, whereas rib cartilage is most frequently utilized for late repair during cleft rhinoplasty. Ear cartilage grafts are associated with significantly decreased procedure duration, whereas rib cartilage grafts are associated with significantly increased procedure duration. Not surprisingly, cleft rhinoplasty is relatively safe, with a 2% overall short-term complication rate.
Factors Influencing the Acceptance of Endoscopic Thyroidectomy Via Oral Vestibular Approach (ETOVA) by Thyroid Surgery Candidates
Authors: Zhou Xuezhi , Deng Jiejie , Xiong Jing , Xia Daojing , Liu Tao , Li Xingqin , Duan Yuling , Huo Jinlong , Wang Cunchuan , Qu Rui
Published: August 2022

Objective:

To investigate the factors affecting the acceptance of endoscopic thyroidectomy via the oral vestibular approach (ETOVA) in Chinese patients before thyroid surgery.

Methods:

The enrolled patients were asked to answer a questionnaire postoperatively about their demographics, medical insurance coverage, sources of information, reasons for selection, and safety. The relationship between the collected data and the acceptance of ETOVA was analyzed.

Results:

Two hundred patients (40 males, 20%; 160 females, 80%) answered the questionnaire. One hundred sixty-two of them (81%) accepted ETOVA. Univariate analysis showed that the patients’ age, cosmetic effect, safety, results perception, and recommendations from family, friends, doctors, and nurses are correlated with the acceptance of ETOVA. Multivariate analysis showed that patients’ age (OR=0.966, P=0.015), cosmetic effect (OR=12.620, P=0.000), safety (OR=0.295, P=0.016), minimal invasion (OR=4.877, P=0.001), and doctors/nurses’ advance (OR=4.485, P=0.017) are statistically significant and were positively correlated with the acceptance of ETOVA. Education level, medical insurance coverage, family support, past surgical history, and operative-related symptoms were not statistically significant (P>0.05).

Conclusion:

Among thyroid surgery candidates in Southwest China, younger patients with cosmetic requirements and minimally invasive procedures desires are more likely to consider ETOVA at the urging of their physicians/nurses. Providing appropriate healthcare education, medical insurance coverage, and information options for surgical treatments is vital to improving patients’ acceptance of ETOVA.
Dynamics of Human Anelloviruses in Plasma and Clinical Outcomes Following Kidney Transplantation
Authors: Forqué Lorena , Fernández-Ruiz Mario , Albert Eliseo , Giménez Estela , Monzó Carolina , Chaves Javier , Redondo Natalia , Rodríguez-Goncer Isabel , Ruiz-Merlo Tamara , Parra Patricia , Andrés Amado , Aguado José María , Navarro David
Published: August 2022

Background.

Torque teno virus, the major member of the genus Alphatorquevirus, is an emerging biomarker of the net state of immunosuppression after kidney transplantation. Genetic diversity constitutes a main feature of the Anelloviridae family, although its posttransplant dynamics and clinical correlates are largely unknown.

Methods.

The relative abundance of Alphatorquevirus, Betatorquevirus, and Gammatorquevirus genera was investigated by high-throughput sequencing in plasma specimens obtained at various points during the first posttransplant year (n = 91 recipients). Total loads of all members of the Anelloviridae family were also quantified by an “in-house” polymerase chain reaction assay targeting conserved DNA sequences (n = 195 recipients). In addition to viral kinetics, clinical study outcomes included serious infection, immunosuppression-related adverse event (opportunistic infection and cancer)‚ and acute rejection.

Results.

Alphatorquevirus DNA was detected in all patients at every point, with an increase from pretransplantation to month 1. A variable proportion of recipients had detectable Betatorquevirus and Gammatorquevirus at lower frequencies. At least 1 change in the predominant genus (mainly as early transition to Alphatorquevirus predominance) was shown in 35.6% of evaluable patients. Total anelloviruses DNA levels increased from baseline to month 1, to peak by month 3 and decrease thereafter, and were higher in patients treated with T-cell depleting agents. There was a significant albeit weak-to-moderate correlation between total anelloviruses and TTV DNA levels. No associations were found between the predominant Anelloviridae genus or total anelloviruses DNA levels and clinical outcomes.

Conclusions.

Our study provides novel insight into the evolution of the anellome after kidney transplantation.
Psychotherapeutic interventions for childhood posttraumatic stress disorder: an update
Authors: Rossouw Jaco , Sharp Tamsin , Halligan Sarah , Seedat Soraya
Published: August 2022

Purpose of the review

We review treatment outcome studies and systematic reviews for childhood and adolescent posttraumatic stress disorder (PTSD) between January 2020 and August 2022, including studies involving younger children and different treatment delivery methods and models. We address predictors, moderators, treatment engagement, and attrition.

Recent findings

Recent randomised controlled trials corroborate earlier trials documenting trauma-focused cognitive behaviour therapy (TF-CBT) as a highly efficacious treatment for PTSD. Evidence for treatment effects in complex PTSD in youth is still sparse. Research on moderators and predictors of treatment continues to be hampered by multiple factors, including a lack of sufficiently large homogeneous trauma samples.

TF-CBT is a very effective treatment for children and adolescents with PTSD. Further work is needed to (i) demonstrate that task-shifting models utilising lay community health counsellors and peer counsellors can effectively and cost-effectively close the mental health treatment gap that exists world-wide in children and adolescents diagnosed with PTSD, but particularly within low- and middle income countries, and (ii) better understand moderators and predictors of treatment which remains a priority.
Emergence of ADC-5 Cephalosporinase in environmental Acinetobacter baumannii from a German tank milk with a novel Sequence Type
Authors: Sykes Ellen ME , Mateo-Estrada Valeria , Zhanel George , Dettman Jeremy , Chapados Julie , Gerdis Suzanne , Akineden Ömer , Khan Izhar , Castillo-Ramirez Santiago , Kumar Ayush
Published: August 2022

Bacteria resistant to antibiotics arguably pose the greatest threat to human health in the 21 st century. One such bacterium that typifies antibiotic resistance is Acinetobacter baumannii. Frequently, hospital strains of A. baumannii display multidrug resistant (MDR) or extreme drug resistant (XDR) phenotypes, often requiring the use of last resort antibiotics for treatment. In addition to hospital settings, A. baumannii has been isolated from many highly divergent sources including wastewater treatment plant effluent, soil, and agricultural run-off with global distribution. However, such isolates remain poorly characterized. In this study, we characterized a strain of A. baumannii, AB341-IK15, isolated from bulk tank milk in Germany that demonstrated resistance to ceftazidime and intermediate resistance to ceftriaxone and piperacillin/tazobactam. Further genetic characterization identified an ADC-5 cephalosporinase, first incidence in an environmental isolate; and an OXA-408 oxacillinase that may contribute to this phenotype. Interestingly, AB341-IK15 is of a novel sequence type. This research underscores the importance of studying isolates of A. baumannii of non-clinical origin to understand the antibiotic resistance and virulence potential of environmental isolates of A. baumannii as well to understand the diversity of this species.
Special Nuclear Layer Contacts Among Starburst Amacrine Cells in the Mouse Retina
Authors: Mu Shang , Turner Nicholas L. , Silversmith William M. , Jordan Chris S. , Kemnitz Nico , Sorek Marissa , David Celia , Jones Devon L. , Bland Doug , Moore Merlin , Sterling Amy Robinson , Seung H. Sebastian ,   the Eyewirers
Published: August 2022

We observed novel classes of cell-cell contacts between retinal starburst amacrine neurons, from finely detailed morphological reconstructions of cells from an electron microscopic image volume of a mouse retina. These contacts have peculiar morphological patterns and traits, different among the respective On and Off starburst amacrine subpopulations, but both occur within the soma layers as opposed to their regular laminae of contact within the inner plexiform layer.
Early Signaling Events in Renal Compensatory Hypertrophy Revealed by Multi-Omics
Authors: Kikuchi Hiroaki , Chou Chun-Lin , Yang Chin-Rang , Chen Lihe , Jung Hyun Jun , Limbutara Kavee , Carter Benjamin , Knepper Mark A.
Published: August 2022

Loss of a kidney results in compensatory growth of the remaining kidney, a phenomenon of considerable clinical importance. However, the mechanisms involved are largely unknown. Here, we used a multi-omic approach in a mouse unilateral nephrectomy model to identify signaling processes associated with compensatory hypertrophy of the renal proximal tubule. Morphometry applied to microdissected proximal tubules showed that growth of the proximal tubule involves a marked, rapid increase in cell volume rather than cell number. Measurements of DNA accessibility (ATAC-seq), transcriptome (RNA-seq) and proteome (quantitative protein mass spectrometry) independently identified patterns of change that are indicative of activation of the lipid-regulated transcription factor, PPARα. Activation of PPARα by fenofibrate administration increased proximal tubule cell size, while genetic deletion of PPARα in mice decreased it. The results indicate that PPARα is an important determinant of proximal tubule cell size and is a likely mediator of compensatory proximal tubule hypertrophy.
[1,2,4]Triazolo[3,4-b]benzothiazole scaffold as versatile nicotinamide mimic allowing nanomolar inhibition of different PARP enzymes
Authors: Murthy Sudarshan , Nizi Maria Giulia , Maksimainen Mirko M. , Massari Serena , Alaviuhkola Juho , Lippok Barbara E. , Vagaggini Chiara , Sowa Sven T. , Galera-Prat Albert , Ashok Yashwanth , Venkannagari Harikanth , Prunskaite-Hyyryläinen Renata , Dreassi Elena , Lüscher Bernhard , Korn Patricia , Tabarrini Oriana , Lehtiö Lari
Published: August 2022

Here we report [1,2,4]triazolo[3,4-b]benzothiazole (TBT) as a new inhibitor scaffold, which competes with nicotinamide in the binding pocket of human poly- and mono-ADP-ribosylating enzymes. The binding mode was studied through analogs and their crystal structures with TNKS2, PARP2, PARP14 and PARP15. Based on the substitution pattern, we were able to identify The 3-amino derivatives 21 (OUL243) and 27 (OUL232), as inhibitors of mono-ARTs PARP7, PARP10, PARP11, PARP12, PARP14 and PARP15 at nM potencies, with compound 27 being the most potent PARP10 inhibitor described to date with an IC50 of 7.8 nM and the first PARP12 inhibitor ever reported. On the contrary, hydroxy derivative 16 (OUL245) inhibits poly-ARTs with a selectivity towards PARP2. The scaffold does not possess inherent cell toxicity and the inhibitors can enter cells and engage with the target protein. This, together with favorable ADME properties, demonstrates the potential of the TBT scaffold for future drug development efforts towards selective inhibitors against specific enzymes.
RIM-BP2 regulates Ca2+channel abundance and neurotransmitter release at hippocampal mossy fiber terminals
Authors: Miyano Rinako , Sakamoto Hirokazu , Hirose Kenzo , Sakaba Takeshi
Published: August 2022

Synaptic vesicles dock and fuse at the presynaptic active zone (AZ), the specialized site for transmitter release. AZ proteins play multiple roles such as recruitment of Ca2+channels as well as synaptic vesicle docking, priming and fusion. However, the precise role of each AZ protein type remains unknown. In order to dissect the role of RIM-BP2 at mammalian cortical synapses having low release probability, we applied direct electrophysiological recording and super-resolution imaging to hippocampal mossy fiber terminals of RIM-BP2 KO mice. By using direct presynaptic recording, we found the reduced Ca2+currents. The measurements of EPSCs and presynaptic capacitance suggested that the initial release probability was lowered because of the reduced Ca2+influx and impaired fusion competence in RIM-BP2 KO. Nevertheless, larger Ca2+influx restored release partially. Consistent with presynaptic recording, STED microscopy suggested less abundance of P/Q-type Ca2+channels at AZs deficient in RIM-BP2. Our results suggest that the RIM-BP2 regulates both Ca2+channel abundance and transmitter release at mossy fiber synapses.
Transcriptomics-driven characterisation of novel T7-like temperate Pseudomonas phage LUZ100
Authors: Putzeys Leena , Poppeliers Jorien , Boon Maarten , Lood Cédric , Vallino Marta , Lavigne Rob
Published: August 2022

The Autographiviridae is a diverse yet distinct family of bacterial viruses marked by a strictly lytic lifestyle and a generally conserved genome organization. We here characterise Pseudomonas aeruginosa phage LUZ100, a distant relative of type phage T7. LUZ100 is a podovirus with a limited host range and identified LPS as the likely phage receptor. Interestingly, infection dynamics of LUZ100 indicated moderate adsorption rates and low virulence, hinting towards temperate behavior. This hypothesis was supported by genomic analysis, which showed that LUZ100 shares the conventional T7-like genome organization, yet encodes key genes associated with a temperate lifestyle. To unravel the peculiar characteristics of LUZ100, ONT-cappable-seq transcriptomics analysis was performed. This data generated a bird’s-eye view of the LUZ100 transcriptome and enabled the discovery of key regulatory elements, antisense RNA, and transcriptional unit structures. The transcriptional map of LUZ100 also allowed us to identify new RNAP-promoter pairs that can form the basis for biotechnological parts and tools for new synthetic transcription regulation circuitry. The ONT-cappable-seq data revealed that the LUZ100 integrase and a MarR-like regulator (proposed to be involved in the lytic/lysogeny decision), are actively co-transcribed in an operon. In addition, the presence of a phage-specific promoter transcribing the phage-encoded RNA polymerase, raises questions on the regulation of this polymerase, and suggests it is interwoven with the MarR-based regulation. This transcriptomics-driven characterisation of LUZ100 supports the increasing evidence that T7-like phages should not straightforwardly be marked as having a strictly lytic lifecycle.

Importance

Bacteriophage T7, considered the ‘model phage’ of the Autographiviridae family, is marked by a strictly lytic lifecycle and conserved genome organisation. Recently, novel phages of this clade are emerging and showing characteristics associated to a lysogenic lifecycle. Screening for temperate behaviour is of outmost importance in fields like phage therapy, where strictly lytic phages are generally required for therapeutic applications. In this study, we’ve used an omics-driven approach to characterise the T7-like Pseudomonas aeruginosa phage LUZ100. These results led to the identification of actively transcribed lysogeny-associated genes in the phage genome, pointing out that temperate T7-like phages are emerging more frequent than initially thought. In short, the combination of genomics and transcriptomics allowed us to obtain a better understanding of the biology of non-model Autographiviridae phages, which can be used to optimize the implementation of phages and their regulatory elements in phage therapy and biotechnological applications, respectively.
Effects of a Ketogenic and Low Fat Diet on the Human Metabolome, Microbiome and Food-ome in Adults at Risk for Alzheimer’s Disease
Authors: Dilmore Amanda Hazel , Martino Cameron , Neth Bryan J. , West Kiana A. , Zemlin Jasmine , Rahman Gibraan , Panitchpakdi Morgan , Meehan Michael J. , Weldon Kelly C. , Blach Colette , Schimmel Leyla , Kaddurah-Daouk Rima , Dorrestein Pieter C , Knight Rob , Craft Suzanne ,   Alzheimer’s Gut Microbiome Project Consortium
Published: August 2022

STRUCTURED ABSTRACT

INTRODUCTION

The ketogenic diet (KD) is an intriguing candidate for neuroprotection in Alzheimer’s disease (AD) given its protective effects against metabolic dysregulation and seizures. The diet’s neuroprotective effects have been shown to be gut microbiome-dependent in mice; thus we examined KD-induced changes in the gut microbiome and metabolome in patients at-risk for AD.

METHODS

We compared the low-carbohydrate modified Mediterranean Ketogenic Diet (MMKD) to the low-fat American Heart Association Diet (AHAD) in adults with mild cognitive impairment (MCI) and control participants. We collected stool samples for shotgun metagenomics and untargeted metabolomics at five timepoints to interrogate the microbiome and metabolome.

RESULTS

Individuals with MCI on the MMKD had lower levels of GABA-producing microbes Alistipes sp. CAG:514 and GABA, and higher levels of GABA-regulating microbes Akkermansia muciniphila.

DISCUSSION

We hypothesize that MMKD protects individuals with MCI in part via influencing on GABA levels and gut-transit time.
12-weeks of Slow Breathing Exercises Reduces Blood Pressure among Healthy Normotensive Subjects
Authors: Gamboa Alfredo , Nian Hui , Smith Emily C. , Paranjape Sachin , Nelson Katrina , Abraham Robert , Diedrich Andre , Birdee Gurjeet
Published: August 2022

Slow breathing exercises are a key component to many mind-body practices used for stress reduction and modulation of autonomic tone, and it has been shown to reduce blood pressure acutely. Long-term effects on blood pressure and autonomic tone are not well documented. We studied 95 healthy participants (41±4 years, 76% female) who performed slow breathing exercises for 12 weeks and examined the effect of slow breathing on systolic blood pressure, diastolic blood pressure, and autonomic tone.

At baseline average BP was 105±11/67±8 mmHg. Among the 11 participants with elevated blood pressure, BP was 126±11.0/ 80±5 mmHg. Our comparison group, that received no intervention, consisted of 30 participants with baseline mean BP 125±19/ 71±10 mmHg.

SBP and DBP decreased significantly (−2.4±7.3 and -1.6±5.5 mmHg, respectively) at 12 weeks for all participants who practiced slow breathing. The comparison group showed no significant changes in blood pressure. Blood pressure reduced further among slow breathing participants with baseline SBP over 120mmHg and/or DBP over 90mmHg (−10.3±7.9 and -3.8±5.5 mmHg, respectively). In our regression model, baseline SBP was associated with further decreases in SBP from baseline to 12 weeks. No significant changes were observed in spectral analyses from baseline to 12 weeks or correlations between spectral analyses in blood pressure.

In conclusion, 12-weeks of slow breathing exercises resulted in a significant reduction of blood pressure in the absence of significant changes in autonomic tone as measured by spectral analyses. Further research into the mechanisms and effectiveness of slow breathing on cardiovascular health is needed.
Structural and mechanistic insights into inhibition of the type I-F CRISPR-Cas surveillance complex by AcrIF4
Authors: Gao Zhengyu , Zhang Laixing , Ge Zihao , Wang Hao , Yue Yourun , Jiang Zhuobing , Wang Xin , Xu Chenying , Zhang Yi , Yang Maojun , Feng Yue
Published: August 2022

CRISPR-Cas system provides prokaryotes with protection against mobile genetic elements (MGEs) such as phages. In turn, phages deploy anti-CRISPR (Acr) proteins to evade this immunity. AcrIF4, an Acr targeting the type I-F CRISPR-Cas system, has been reported to bind the crRNA-guided surveillance (Csy) complex. However, it remains controversial whether AcrIF4 inhibits target DNA binding to the Csy complex. Here, we present structural and mechanistic studies into AcrIF4, exploring its unique anti-CRISPR mechanism. While the Csy-AcrIF4 complex displays decreased affinity for target DNA, it is still able to bind the DNA. Structural and functional analyses of the Csy-AcrIF4-dsDNA complex revealed that AcrIF4 binding prevents rotation of the helical bundle (HB) of Cas8f induced by dsDNA binding, therefore resulting in failure of Cas2/3 recruitment and DNA cleavage. Overall, our study provides an interesting example of attack on the nuclease recruitment event by an Acr, but not conventional mechanisms of blocking binding of target DNA.
Mechanotransduction coordinates extracellular matrix protein homeostasis promoting longevity inC. elegans
Authors: Teuscher Alina C. , Statzer Cyril , Goyala Anita , Domenig Seraina A. , Schoen Ingmar , Hess Max , Hofer Alexander M. , Fossati Andrea , Vogel Viola , Goksel Orcun , Aebersold Ruedi , Ewald Collin Y.
Published: August 2022

Although it is postulated that dysfunctional extracellular matrices (ECM) drive aging and disease, how ECM integrity assures longevity is unknown. Here, using proteomics andin-vivomonitoring of fluorescently tagged ECM proteins, we systematically examined the ECM composition duringCaenorhabditis elegansaging revealing three distinct collagen dynamics. We show that age-dependent stiffening of inert collagen was slowed by longevity interventions through prolonged replenishing of collagens. In genetic and automated lifespan screens for the regulators that drive this remodeling, we identify hemidesmosome-containing structures that span from the exoskeletal ECM through the hypodermis, basement membrane ECM, to the muscles, coupling mechanical forces to adjust ECM gene expression across tissues. The hemidesmosome tension-induced adaptation is mediated via transcriptional co-activator YAP. Our data reveal a novel mechanism of mechano-coupling and synchronizing of two functionally distinct and spatially distant ECMs that is indispensable for longevity. Thus, besides signaling molecules, mechanotransduction-coordinated ECM remodeling systemically promotes healthy aging.

Graphical Abstract

Highlights

Proteomics, genetics screen, and automated lifespan assays of >55’000 animals all point to hemidesmosome-containing structures for the mechano-regulation of ECM homeostasis and longevity

Coupling of biomechanical properties of two ECMs with underlying cellular signaling

Transcriptional co-activator YAP-1 is required for longevity and pressure-induced collagen homeostasis
Tracking subjects’ strategies in behavioural choice experiments at trial resolution
Authors: Maggi Silvia , Hock Rebecca M. , O’Neill Martin , Buckley Mark J. , Moran Paula M. , Bast Tobias , Sami Musa , Humphries Mark D
Published: August 2022

Investigating how, when, and what subjects learn during decision-making tasks requires tracking their choice strategies on a trial-by-trial basis. Here we present a simple but effective probabilistic approach to tracking choice strategies at trial resolution using Bayesian evidence accumulation. We show this approach identifies both successful learning and the exploratory strategies used in decision tasks performed by humans, non-human primates, rats, and synthetic agents. Both when subjects learn and when rules change the exploratory strategies of win-stay and lose-shift, often considered complementary, are consistently used independently. Indeed, we find the use of lose-shift is strong evidence that subjects have latently learnt the salient features of a new rewarded rule. Our approach can be extended to any discrete choice strategy, and its low computational cost is ideally suited for real-time analysis and closed-loop control.
Theoretical analysis of cargo transport by catch bonded motors in optical trapping assays
Authors: Sundararajan Naren , Guha Sougata , Muhuri Sudipto , Mitra Mithun K.
Published: August 2022

Dynein motors exhibit catch bonding, where the unbinding rate of the motors from microtubule filaments decreases with increasing opposing load. The implications of this catch bond on the transport properties of dynein-driven cargo are yet to be fully understood. In this context, optical trapping assays constitute an important means of accurately measuring the forces generated by molecular motor proteins. We investigate, using theory and stochastic simulations, the transport properties of cargo transported bycatch bondeddynein molecular motors - both singly and in teams in a harmonic potential, which mimics the variable force experienced by cargo in an optical trap. We estimate the biologically relevant measures offirst passage time- the time during which the cargo remains bound to the microtubule anddetachment force-the force at which the cargo unbinds from the microtubule, using both two-dimensional and one-dimensional force balance frameworks. Our results suggest that even for cargo transported by a single motor, catch bonding may play a role depending on the force scale which marks the onset of the catch bond. By comparing with experimental measurements on single dynein-driven transport, we estimate realistic bounds of this catch bond force scale. Generically, catch bonding results in increased persistent motion, and can also generate non-monotonic behaviour of first passage times. For cargo transported by multiple motors, emergent collective effects due to catch bonding can result in non-trivial re-entrant phenomena wherein average first passage times and detachment forces exhibit non-monotonic behaviour as a function of the stall force and the motor velocity.
Uni-Fold Symmetry: Harnessing Symmetry in Folding Large Protein Complexes
Authors: Li Ziyao , Yang Shuwen , Liu Xuyang , Chen Weijie , Wen Han , Shen Fan , Ke Guolin , Zhang Linfeng
Published: August 2022

Deep folding models have revolutionized the conventional methods of protein complex prediction. However, applying them to large protein oligomers is not easy. These models generally require copying the sequences of identical subunits to capture the in-between relationships. Accordingly, the scales of target protein complexes are strictly limited due to the cubic complexity of these models. To address this issue, we propose UF-Symmetry (Uni-Fold Symmetry), which is extricated from the need of sequence copying via harnessing the intrinsic symmetry of large protein oligomers. Taking the sequences of the asymmetric unit (AU) and a pre-specified symmetry group, UF-Symmetry learns to fold the AU and to assemble the complex structure in an end-to-end manner. By reducing the input scales from entire assemblies to AUs, UF-Symmetry allows to predict much larger assemblies with significant acceleration: for a complex of 4-fold cyclic symmetry (C4) and AU size of 512, UF-Symmetry achieves approximately 20 times acceleration to current methods. On a benchmark of recently released PDB multimers, UF-Symmetry approximately halves the failure rate of current methods and achieves approaching accuracy on commonly successful cases.
A Parcellation Scheme of Mouse Isocortex Based on Reversals in Connectivity Gradients
Authors: Reimann Michael W , Guyonnet-Hencke Timothé
Published: August 2022

The brain is composed of several anatomically clearly separated structures. This parcellation is often extended into the isocortex, based on anatomical, physiological or functional differences. Here, we derive a parcellation scheme based purely on the spatial structure of long-range synaptic connections within the cortex. To that end, we analyzed a publicly available dataset of average mouse brain connectivity, and split the isocortex into disjunct regions. Instead of clustering connectivity based on modularity, our scheme is inspired by methods that split sensory cortices into subregions where gradients of neuronal response properties, such as the location of the receptive field, reverse. We calculated comparable gradients from voxelized brain connectivity data and automatically detected reversals in them. This approach better respects the known presence of functional gradients within brain regions than clustering-based approaches. Placing borders at the reversals resulted in a parcellation into 41 subregions that differs significantly from an established scheme in nonrandom ways, but is comparable in terms of the modularity of connectivity between regions. It reveals unexpected trends of connectivity, such as a tripartite split of somatomotor regions along an anterior to posterior gradient. The method can be readily adapted to other organisms and data sources, such as human functional connectivity.
Monosynaptic trans-collicular pathways link mouse whisker circuits to integrate somatosensory and motor cortical signals
Authors: Martín-Cortecero Jesús , Isaías-Camacho Emilio Ulises , Boztepe Berin , Ziegler Katharina , Mease Rebecca Audrey , Groh Alexander
Published: August 2022

The superior colliculus (SC), a conserved midbrain-node with extensive long-range connectivity throughout the brain, is a key structure for innate behaviors. Descending cortical pathways are increasingly recognized as central control points for SC-mediated behaviors, but how cortico-collicular pathways coordinate SC activity at the cellular level is poorly understood. Moreover, despite the known role of the SC as a multisensory integrator, the involvement of the SC in the somatosensory system is largely unexplored in comparison to its involvement in the visual and auditory systems. Here, we mapped the connectivity of the whisker-sensitive region of the SC in mice with trans-synaptic and intersectional tracing tools and in vivo electrophysiology. The results reveal a novel trans-collicular connectivity motif in which neurons in motor- and somatosensory cortices impinge onto the brainstem-SC-brainstem sensory-motor arc and onto SC-midbrain output pathways via only one synapse in the SC. Intersectional approaches and optogenetically assisted connectivity quantificationsin vivoreveal convergence of motor and somatosensory cortical input on individual SC neurons, providing a new framework for sensory-motor integration in the SC. More than a third of the cortical recipient neurons in the whisker SC are GABAergic neurons, which include a hitherto unknown population of GABAergic projection neurons targeting thalamic nuclei and the zona incerta. These results pinpoint a whisker region in the SC of mice as a node for the integration of somatosensory and motor cortical signals via parallel excitatory and inhibitory trans-collicular pathways which link cortical and subcortical whisker circuits for somato-motor integration.
Transcription Factor Localization Dynamics and DNA Binding Drive Distinct Promoter Interpretations
Authors: Sweeney Kieran , McClean Megan N.
Published: August 2022

Environmental information may be encoded in the temporal dynamics of transcription factor (TF) activation and subsequently decoded by gene promoters to enact stimulus-specific gene expression programs. Previous studies of this behavior focused on the encoding and decoding of information in TF nuclear localization dynamics, yet cells control the activity of TFs in myriad ways, including by regulating their ability to bind DNA. Here, we use light-controlled mutants of the yeast TF Msn2 as a model system to investigate how promoter decoding of TF localization dynamics is affected by changes in the ability of the TF to bind DNA. We find that yeast promoters directly decode the light-controlled localization dynamics of Msn2 and that the effects of changing Msn2 affinity on that decoding behavior are highly promoter dependent, illustrating how cells could potentially regulate TF localization dynamics and DNA binding in concert for improved control of gene expression.
The condensin II/TOP-2 axis silences transcription during germline specification inC. elegans
Authors: Belew Mezmur D. , Chien Emilie , Wong Matthew , Michael W. Matthew
Published: August 2022

InC. elegans, the germline is specified via a preformation mechanism that relies on the PIE-1 protein’s ability to globally silence mRNA transcription in germline precursor cells, also known as the P-lineage. Recent work from our group has identified additional genome silencing events inC. elegansduring oogenesis and in starved L1 larvae, and these require the condensin II complex, topoisomerase II (TOP-2), and components of the H3K9me/heterochromatin pathway. Interestingly, silencing in oocytes also requires PIE-1, but this is not the case in starved L1s. Here, we ask if additional genome silencing components besides PIE-1 are required to repress gene expression in the P-lineage of early embryos, and we find that condensin II and TOP-2 are required and the H3K9me/heterochromatin pathway is not. We show that depletion of condensin II/TOP-2 activates the normally suppressed RNA polymerase II to inappropriately transcribe somatic genes in the P-lineage. We also present evidence that while both PIE-1 and condensin II/TOP-2 are required for genome silencing in the P-lineage, PIE-1 can silence transcription independently of condensin II/TOP-2 when misexpressed in somatic cells. Thus, in oocytes, all three genome silencing systems (TOP-2/condensin II, H3K9me, and PIE-1) are operational while in both early embryos and starved L1s two of the three are active (TOP- 2/condensin II and PIE-1 for early embryos, TOP-2/condensin II and H3K9me for starved L1s). Our data show that multiple, redundantly acting genome silencing mechanisms act in a mix and match manner to repress transcription at different developmental stages in theC. elegansgermline.
A paralog of Pcc1 is the fifth core subunit of KEOPS complex in Archaea
Authors: Daugeron Marie-Claire , Missoury Sophia , Da Cunha Violette , Lazar Noureddine , Collinet Bruno , van Tilbeurgh Herman , Basta Tamara
Published: August 2022

In Archaea and Eukaryotes, the synthesis of a universal tRNA modification, t6A, is catalyzed by the KEOPS complex composed of Kae1, Bud32, Cgi121 and Pcc1. A fifth subunit, Gon7, is found only in Fungi and Metazoa. Mutations in all five genes encoding human KEOPS subunits leads to Galloway-Mowat syndrome, a severe genetic disease causing childhood lethality. Here, we describe the discovery and biochemical characterization of the archaeal fifth KEOPS subunit. This protein, dubbed Pcc2, is a paralog of Pcc1 and is widely conserved in Archaea. Pcc1 and Pcc2 form a heterodimer in solution, show modest sequence conservation but very high structural similarity. The 5-subunit KEOPS lost its capacity to form dimers but its tRNA binding and t6A synthetic activity remained robust. Pcc2 can substitute Pcc1 but the resulting KEOPS complex is inactive suggesting a distinct function for the two paralogs. Comparative sequence and structure analyses point to a possible evolutionary link between archaeal Pcc2 and eukaryotic Gon7 proteins. Our work thus reveals that Pcc2 has evolved to regulate the oligomeric state of KEOPS complex thus adding another layer of complexity to the biosynthesis of t6A that seems to be conserved from Archaea to Eukaryotes.
Biosynthesis of the Fungal Nonribosomal Peptide Penilumamide A and Biochemical Characterization of a Pterin-Specific Adenylation Domain
Authors: Heard Stephanie C. , Winter Jaclyn M.
Published: August 2022

We report the characterization of the penilumamide A biosynthetic gene cluster from the marine-derived fungus Aspergillus flavipes CNL-338. In vitro reconstitution studies demonstrated that three Plm nonribosomal peptide synthetases encoding four modules are required for constructing the lumazine-containing tripeptide. Further investigations using dissected adenylation domains determined substrate specificity for methionine and anthranilic acid and led to the first biochemical characterization of an adenylation domain with selectivity for a pterin-derived building block.
Diffusive lensing as a mechanism of intracellular transport and compartmentalization
Authors: Venkatesh Achuthan Raja , Le Kathy H. , Weld David M. , Brandman Onn
Published: August 2022

While inhomogeneous diffusivity has been identified as a ubiquitous feature of the cellular interior, its implications for particle mobility and concentration at different length scales remain largely unexplored. In this work, we use agent-based simulations of diffusion to investigate how heterogeneous diffusivity affects movement and concentration of diffusing particles. We propose that a nonequilibrium mode of membraneless compartmentalization arising from the convergence of diffusive trajectories into low-diffusive sinks, which we call “diffusive lensing,” is relevant for living systems. Our work highlights the phenomenon of diffusive lensing as a potentially key driver of mesoscale dynamics in the cytoplasm, with possible far-reaching implications for biochemical processes.
Noninvasive method for monitoring breathing patterns in monkeys
Authors: Kunimatsu Jun , Akiyama Yusuke , Toyoshima Osamu , Matsumoto Masayuki
Published: August 2022

Respiration is strongly linked to internal states such as arousal, emotion, and even cognitive processes and provides objective biological information to estimate these states in humans and animals. However, the measurement of respiration has not been established in macaque monkeys that have been widely used as model animals for understanding various higher brain functions. In the present study, we developed a method to monitor the respiration of behaving monkeys. We first measured the temperature of their nasal breathing, which changes between inspiration and expiration phases, in an anesthetized condition and estimated the respiration pattern. We compared the estimated pattern with that obtained by a conventional chest band method that has been used in humans and applies to anesthetized, but not behaving, monkeys. These respiration patterns matched well, suggesting that the measurement of nasal air temperature can be used to monitor the respiration of monkeys. Furthermore, we confirmed that the respiration frequency in behaving monkeys monitored by the measurement of nasal air temperature was not affected by the orofacial movement of licking to obtain the liquid reward. We next examined the frequency of respiration when they listened to music or white noise. The respiratory frequency was higher when the monkeys listened to music than the noise. This result is consistent with a phenomenon in humans and indicates the accuracy of our monitoring method. These data suggest that the measurement of nasal air temperature enables us to monitor the respiration of behaving monkeys and thereby estimate their internal states.

Significance Statement

While respiration is linked with internal processing, such as emotional and cognitive states, methods have not been established for physiological research on monkeys. We developed a novel method that obtained respiration signals by measuring the nasal air temperatures of behaving monkeys. Our method was able to continuously track the respiration pattern without distortions evoked by orofacial movements to lick the liquid reward. The respiratory frequency increased while listening to music than when listening to white noise for all monkeys. These results demonstrate that nasal air temperature measurements can be used to monitor the respiration patterns of aroused monkeys, allowing us to understand their internal state. This will be useful for investigating the underlying neuronal mechanism of neuropsychiatric disorders using monkeys.
Lipotype acquisition during neural developmentin vivois not recapitulated in stem cell-derived neurons
Authors: Gopalan Anusha B. , van Uden Lisa , Sprenger Richard R. , Marx Nadine Fernandez-Novel , Bogetofte Helle , Neveu Pierre , Meyer Morten , Noh Kyung-Min , Diz-Muñoz Alba , Ejsing Christer S.
Published: August 2022

During development, different tissues acquire distinct lipotypes that are coupled to tissue function and homeostasis. In the brain, where complex membrane trafficking systems are required for neural function, specific glycerophospholipids, sphingolipids, and cholesterol are highly abundant, and defective lipid metabolism is associated with abnormal neural development and neurodegenerative disease. Notably, the production of tissue-specific lipotypes requires appropriate programming of the underlying lipid metabolic machinery, but when and how this occurs is unclear. To address this, we used high-resolution mass spectrometry-based (MSALL) lipidomics to perform a quantitative and comprehensive analysis of mouse brain development covering early embryonic and postnatal stages. We discovered a distinct bifurcation in the establishment of the neural lipotype, whereby the canonical brain lipid biomarkers 22:6-glycerophospholipids and 18:0-sphingolipids begin to be producedin utero, whereas cholesterol attains its characteristic high levels after birth. In contrast, when profiling rodent and human stem cell-derived neurons, we observed that these do not acquire a brain lipotypeper se. However, upon probing the lipid metabolic wiring by supplementing brain lipid precursors, we found that the stem cell-derived neurons were partially able to establish a brain-like lipotype, demonstrating that the cells are partially metabolically committed. Altogether, our report provides an extensive lipidomic resource for brain development and highlights a potential challenge in using stem cell-derived neurons for mechanistic studies of lipid biochemistry, membrane biology and biophysics that can be mitigated by further optimizingin vitrodifferentiation protocols.

Significance Statement

We report an extensive time-resolved resource of lipid molecule abundances across mouse brain development, starting as early as 10 days post-fertilization. The resource reveals a bifurcation in the establishment of the neural lipotype where the canonical 22:6-glycerophospholipid and 18:0-sphingolipid biomarkers are attainedin utero, whereas cholesterol is attained after birth. Furthermore, we uncover that the neural lipotype is not established in rodent and human stem cell-derived neuronsin vitro.
Crystal structures of two new divalent transition-metal salts of carboxybenzenesulfonate anions
Authors: Bettinger Reuben T. , Squattrito Philip J. , Aulakh Darpandeep , Gianopoulos Christopher G.
Published: August 2022

Hexaaquanickel(II) bis(3-carboxy-4-hydroxybenzenesulfonate) dihydrate, [Ni(H2O)6][C6H3(CO2H)(OH)SO3]2·2H2O, (I), crystallizes in the triclinic space group P\overline{1} with the nickel(II) aqua complexes on centers of inversion. The carboxylate group is protonated and neither it nor the sulfonate group is involved in direct coordination to the metal ions. The structure consists of alternating layers of inorganic cations and organic anions linked by O—H...O hydrogen bonds that also include non-coordinated water molecules of crystallization. The first-row divalent transition-metal salts of this anion are reported as both dihydrates and tetrahydrates, with two distinct structures for the dihydrates that are both layered but differ in the hydrogen-bonding pattern. Compound (I) represents the second known example of one of these structures. Hexaaquacobalt(II) bis(3-carboxybenzenesulfonate) dihydrate, [Co(H2O)6][C6H4(CO2H)SO3]2·2H2O, (II), also crystallizes in triclinic P\overline{1} with the cobalt(II) aqua complexes on centers of inversion. The structure is also built of alternating layers of complex cations and organic anions without direct coordination to the metal by the protonated carboxylate or unprotonated sulfonate groups. A robust O—H...O hydrogen-bonding network involving primarily the coordinated and non-coordinated water molecules and sulfonate groups directs the packing. This is the first reported example of a divalent transition-metal salt of the 3-carboxybenzenesulfonate anion.
Female projectionists on the move: Exhibiting socialist gender equality in rural China (1949–1966)
Authors: Guo Yanping
Published: August 2022

The gender discourse in Maoist China can be summed up in Mao's famous motto ‘men and women are the same’. Images of women operating various technologies were massively propagated in the 1950s and 1960s, illustrating that men and women were not only equal in political status but also in physical strength with the help of technology. In reality, however, women working in technical jobs were not on the same footing as their male counterparts. Taking female projectionists as the research subject, this article investigates how new professional women, assigned by the state, overcame gender bias in rural areas where a patriarchal culture prevailed. By examining the inconsistency between the Chinese Communist Party's gender policies that encouraged women's public participation and the rural culture that derided women in public space, this article contends that female projectionists’ experiences of performing screening techniques played a significant role in opening up new spaces for women's repositioning in the patriarchal society. While operating technology did not naturally give women the same social status as men, it was through female projectionists’ bodily practices that the socialist ideas of gender equality were disseminated in rural areas.
Can curiosity spark the fire of innovation? An investigation in China
Authors: Li Rui , Tian Jingyuan , Zhang Junhong , Wu Shaobo
Published: August 2022

Curiosity has been seen as an important driver of individual innovation. However, empirical evidence regarding the relationship between curiosity and innovation is equivocal. We draw on the situational strength perspective to develop and test a contingency model that focuses on the contextual boundary conditions of this relationship among Chinese employees. In a controlled experiment with 191 part‐time MBA students, in which curiosity was examined as a state, we found that (1) the main effect of curiosity on innovative behavioral intention was insignificant; (2) authoritarian leadership and job autonomy moderated the association of curiosity with innovative behavioral intention, such that this association was positively significant under circumstances of low authoritarian leadership or high job autonomy but not under circumstances of high authoritarian leadership or low job autonomy; and (3) job autonomy functioned as a mediator for the moderating effect of authoritarian leadership. These findings were constructively replicated in a field study of 206 subordinate–supervisor dyads in which curiosity was examined as a trait and innovative behavior was rated by supervisors. Theoretical and practical implications of our findings and directions for future research are discussed.