bluuebunny/crossref_metadata_2025 huggingface dataset:
Unilateral Double Eyelid Formation after Botulinum Toxin A Injection: A Case Report
Authors: Jiang Liya , Liu Yue , Wang Lianzhao , Hu Jintian
Published: August 2023

Botulinum toxin injection has been widely used for facial rejuvenation, with high rates of efficacy and patient satisfaction. In this article, we describe a reproducible phenomenon of unilateral double eyelid formation with the treatment of upper facial rhytides using botulinum toxin. A 38-year-old man was given onabotulinum toxin A injections in the frontal stria and glabellar lines. The procedure was repeated after 6 months. Unilateral double eyelids were noted twice on the right side about 7 days after each injection. The maintenance time for each procedure was about 1 month. The rhytides improved about 3 days after each injection and were maintained for about 4 months. No adverse effects were observed. This rare phenomenon could be due to the compensatory increased strength of the levator palpebrae superioris muscle and the anatomical structure of the patient’s right eyelid.
Pulling Strings: Otoplasty Complicated by Wound Dehiscence in the Setting of Prolonged Mask Wearing
Authors: Luther Lauren , Chrisos Haley A. , Ganor Oren
Published: August 2023

Improved understanding of the psychosocial effects of prominent ears has led to increased intervention in early school-aged children. Cartilage-sparing otoplasty procedures are commonly used in this population, given the effectiveness of sutures in remodeling the pliable pediatric ear. In addition to their efficacy, another advantage of these techniques is their low overall complication rates, with complications beyond 3 months being particularly uncommon. We present the clinical case of a 5-year-old female patient who experienced wound dehiscence 9 months after her cartilage-sparing otoplasty. Before experiencing her atypical complication, she had been wearing an ear-looped mask daily to comply with guidelines developed to reduce the transmission of SARS-CoV-2 in schools. The use of masks would previously not have been a concern in this age group, but given the longevity of the COVID-19 pandemic and the importance of masking as a public health tool, this needs to be a consideration for otoplasty patients going forward. Pressure and friction on an immature surgical scar impede healing and expose the patient to increased risk of complications. Therefore, we discuss options for decreasing exposure to COVID-19 and complying with local face-covering policies while avoiding the direct contact associated with traditional ear-looped masks. Additionally, we explore the role permanent suture material may have played in predisposing our patient to mask-related irritation.
How Important Are Dedicated Research Years and Global Health to Applicants in Plastic Surgery?
Authors: Reddy Narainsai K. , Applebaum Sarah A. , Wester James R. , Drolet Brian C. , Janis Jeffrey E. , Gosain Arun K.
Published: August 2023

Background:

Applicant preferences for required research and global surgery experiences during plastic surgery training have not been previously studied.

Methods:

An anonymous survey was sent to integrated plastic surgery applicants from consecutive residency application cycles (2018–2020). Research and global health experiences before residency were elicited, along with the interest to continue these activities. Data were analyzed using frequency distributions and chi-square test of independence.

Results:

Seventy-eight former plastic surgery applicants responded to the survey (15.7% response rate). Most participants (65%) viewed time for research as important when evaluating residency programs. Fewer respondents (10%) ranked programs with a required research year higher, whereas 47% ranked those programs lower and 43% did not factor it into their decision-making. Less than one-third of respondents (28%) reported prior global health experience, yet 44% viewed international opportunities as an important factor when ranking programs, and the majority (72%) stated plans to participate in global surgery during residency. Past experience on a global health trip predicted a strong preference for longer rotations (P = 0.003) and willingness to use vacation time to participate during residency (P < 0.001).

Conclusions:

Research was an important consideration in residency selection, but a few preferred a residency program with a dedicated research year. Although applicants had limited experience with global surgery, the majority intended to get involved during residency. Understanding factors that influence applicants’ interests in residency programs may better equip programs with information to create enriching experiences and attract the most qualified applicants.
Controversies regarding albumin therapy in cirrhosis
Authors: Trebicka Jonel , Garcia-Tsao Guadalupe
Published: August 2023

Albumin is the most abundant protein in the human body and is synthetized exclusively by the liver. Therefore, serum albumin levels are reduced in acute and/or chronic liver disease. In cirrhosis, low levels of albumin predict the outcome. In advanced cirrhosis, the quality of albumin is decreased due to high oxidative stress and a proinflammatory state. Therefore, the administration of i.v. albumin would seem to be of pathophysiological relevance and benefit. Yet, the questions that remain are who, when, how much, and how often. While albumin infusion is recommended after large-volume paracentesis, at diagnosis of spontaneous bacterial peritonitis, in acute kidney injury, and in hepatorenal syndrome, the amount and schedule of albumin to be administered require refinement, particularly given complications related to volume overload that have become increasingly apparent. Other indications for albumin such as infections other than spontaneous bacterial peritonitis, hyponatremia, HE, prevention of poor outcomes in hospitalized, and in outpatients with cirrhosis are still debated. The results of studies in these settings are either negative, controversial, or inconclusive. This sheds some doubts regarding the use of albumin as a “one size fits all” strategy. The indication and patient selection are crucial and not always intuitive. The amount and frequency also seem to play a role in the success or failure of albumin. This review will critically discuss the evidence and underline areas where there are indications for albumin use and others where evidence is still insufficient and will have to await the development/results of randomized controlled trials.
Hepatic venous outflow obstruction after adult living donor liver transplantation
Authors: Sambommatsu Yuzuru , Hirukawa Kazuya , Shimata Keita , Honda Masaki , Sakurai Yuto , Ishii Masatsugu , Ibuki Sho , Isono Kaori , Irie Tomoaki , Kawabata Seiichi , Hirao Hiroki , Sugawara Yasuhiko , Tamura Yoshitaka , Ikeda Osamu , Hirai Toshinori , Inomata Yukihiro , Morinaga Jun , Hibi Taizo
Published: August 2023

Hepatic venous outflow obstruction (HVOO) is a rare but critical vascular complication after adult living donor liver transplantation. We categorized HVOOs according to their morphology (anastomotic stenosis, kinking, and intrahepatic stenosis) and onset (early-onset < 3 mo vs. late-onset ≥ 3 mo). Overall, 16/324 (4.9%) patients developed HVOO between 2000 and 2020. Fifteen patients underwent interventional radiology. Of the 16 hepatic venous anastomoses within these 15 patients, 12 were anastomotic stenosis, 2 were kinking, and 2 were intrahepatic stenoses. All of the kinking and intrahepatic stenoses required stent placement, but most of the anastomotic stenoses (11/12, 92%) were successfully managed with balloon angioplasty, which avoided stent placement. Graft survival tended to be worse for patients with late-onset HVOO than early-onset HVOO (40% vs. 69.3% at 5 y, p = 0.162) despite successful interventional radiology. In conclusion, repeat balloon angioplasty can be considered for simple anastomotic stenosis, but stent placement is recommended for kinking or intrahepatic stenosis. Close follow-up is recommended in patients with late-onset HVOO even after successful treatment.
Dynamic Seeding versus Microinjection of Adipose-Derived Mesenchymal Stem Cells to Acellular Nerve Allograft Reconstructions
Authors: Bedar Meiwand , Pulos Nicholas A. , Shin Alexander Y.
Published: August 2023

Background:

Functional recovery after acellular nerve allograft (ANA) reconstruction remains inferior to that after autologous nerve grafting, but improved outcomes have been demonstrated with the addition of adipose-derived mesenchymal stem cells (MSCs). Controversy exists regarding the optimal cell-delivery method to enhance ANA reconstructions. The authors investigated the functional recovery of ANAs after dynamic seeding versus microinjection of MSCs.

Methods:

Forty Lewis rats underwent reconstruction of a 10-mm sciatic nerve defect. Animals were divided into 4 groups: reversed autograft, ANA alone, dynamically seeded ANA, or ANA injected with MSCs. During the survival period, ultrasound measurements of the tibialis anterior muscle cross-sectional area were performed. At 12 weeks, functional recovery was evaluated using measurements of ankle contracture, compound muscle action potential, maximum isometric tetanic force, muscle mass, histomorphometry, and immunofluorescence.

Results:

The dynamic seeding and microinjection groups demonstrated higher cross-sectional tibialis anterior muscle area recovery than autografts and ANAs alone at week 8 and weeks 4 and 8, respectively. The ankle contracture and compound muscle action potential amplitude recovery were superior in autografts and both seeding methods compared with ANAs alone. The microinjection group demonstrated significantly higher isometric tetanic force, muscle mass, and number of axons compared with ANAs alone. Both seeding methods showed higher CD34 densities compared with ANAs alone. No significant differences between dynamic seeding and microinjection were observed in functional or histologic outcomes.

Conclusions:

The addition of MSCs to ANAs demonstrated earlier motor regeneration compared with autografts and ANAs alone. Both seeding methods improved functional outcomes in the rat sciatic nerve defect model.
YOKENELLA REGENSBURGEI URINARY TRACT INFECTION IN AN IMMUNOCOMPETENT PATIENT: A CASE REPORT
Authors: V Annie Sheeba , Suji Thangamani , Jayanth Selvin Theodore , Sahni Rani Diana
Published: August 2023

Yokenella regensburgei, belonging to the order Enterobacterales, is a rare and emerging human pathogen reported to cause both superficial and invasive infections. The 13 case reports in literature worldwide highlight blood, bone and wound infections. To our knowledge this is the first case report of Yokenella regensburgei causing UTI in a 69-year old immunocompetent patient which was isolated in 2 separate specimens and identified using MALDI-TOF MS (bioMérieux, Version 3.2, France). It was found to be susceptible to most antimicrobials but resistant to penicillin, amoxicillin-clavulanate, cefoxitin, colistin and chromosomal inducible ampC resistance was demonstrated on disk approximation test and blaYOC-1 Class C beta-lactamase, beta lactamase superfamily and MBL fold metallo-hydrolase genes were found on whole genome sequencing.
Human kinesin-5 KIF11 drives the helical motion of anti-parallel and parallel microtubules around each other
Authors: Meißner Laura , Schüring Irene , Mitra Aniruddha , Diez Stefan
Published: August 2023

During mitosis, motor proteins and microtubule-associated protein organize the spindle apparatus by cross-linking and sliding microtubules. Kinesin-5 plays a vital role in spindle formation and maintenance, potentially inducing twist in the spindle fibers. The off-axis power stroke of kinesin-5 could generate this twist, but its implications in microtubule organization remain unclear. Here, we investigate 3D microtubule-microtubule sliding mediated by the human kinesin-5, KIF11, and found that the motor caused right-handed rotation of anti-parallel microtubules around each other. The effective sidestepping probability of KIF11 increased with reduced ATP concentration, indicating that forward and sideways stepping of the motor are not strictly coupled. Further, the microtubule-microtubule distance (motor extension) during sliding decreased with increasing sliding velocity. Intriguingly, parallel microtubules cross-linked by KIF11 orbit without forward motion, with nearly full extension. Altering the length of the neck linker increased the forward velocity and pitch of microtubules in anti-parallel overlaps. Taken together, we suggest that helical motion and orbiting of microtubules, driven by KIF11, enable flexible and context-dependent filament organization, as well as torque regulation within the mitotic spindle.
Time-deterministic cryo-optical microscopy
Authors: Yamanaka M. , Tsuji K. , Kumamoto Y. , Tamura S. , Miyamura W. , Kubo T. , Mizushima K. , Kono K. , Hirano H. , Sugiura K. , Fukushima S. , Kunimoto T. , Nishida K. , Mochizuki K. , Harada Y. , Smith N. I. , Heintzmann R. , Nagai T. , Tanaka H. , Fujita K.
Published: August 2023

We developed a technique to rapidly freeze biological systems during observation under an optical microscope, which allows for detailed optical observation at a precise time in the biological dynamics at high spatial resolution and quantifiability under low-temperature conditions. Our study further found that ion distributions and molecular conformations can be fixed in space and time, demonstrated by visualization of calcium waves rapid-frozen at an instant using fluorescent ion indicators. These results show that time-deterministic cryo-optical microscopy can suspend cellular dynamics while maintaining molecular and ionic states, allowing us to view cellular dynamics in a way that has not been possible before.

One-Sentence Summary

Rapid freezing of dynamic biological systems during optical observation presents time information to the fixed samples
Isolation and genomic characterization of the tick-borne relapsing fever spirochete,Borrelia turicatae, from ticks collected in a peridomestic setting of Camayeca, Mexico
Authors: Vázquez-Guerrero Edwin , Kneubehl Alexander R. , Pellegrini-Hernández Patricio , González-Quiroz José Luis , Domínguez-López María Lilia , Krishnavajhala Aparna , Santos Paulina Estrada-de los , Ibarra J. Antonio , Lopez Job E.
Published: August 2023

Surveillance studies were implemented in Sinaloa, Mexico to determine the circulation of tick-borne relapsing fever spirochetes. Argasid ticks were collected from a human dwelling in the village of Camayeca and spirochetes were isolated. Genomic analysis indicated thatBorrelia turicataeis a threat to those living in resource limited settings.

Article Summary Line

We report the collection of argasid ticks from a peridomestic setting in Mexico and the isolation ofBorrelia turicatae; increased surveillance efforts are needed on this overlooked vector-borne pathogen.
Mis-splicing Drives Loss of Function of p53E224DPoint Mutation
Authors: Lock Ian C. , Leisenring Nathan H. , Floyd Warren , Xu Eric S. , Luo Lixia , Ma Yan , Mansell Erin C. , Cardona Diana M. , Lee Chang-Lung , Kirsch David G.
Published: August 2023

Background

Tp53 is the most commonly mutated gene in cancer. Canonical Tp53 DNA damage response pathways are well characterized and classically thought to underlie the tumor suppressive effect of Tp53. Challenging this dogma, mouse models have revealed that p53 driven apoptosis and cell cycle arrest are dispensable for tumor suppression. Here, we investigated the inverse context of a p53 mutation predicted to drive expression of canonical targets, but is detected in human cancer.

Methods

We established a novel mouse model with a single base pair mutation (GAG>GAC, p53E221D) in the DNA-Binding domain that has wild-type function in screening assays, but is paradoxically found in human cancer in Li-Fraumeni syndrome. Using mouse p53E221Dand the analogous human p53E224Dmutant, we evaluated expression, transcriptional activation, and tumor suppression in vitro and in vivo.

Results

Expression of human p53E224Dfrom cDNA translated to a fully functional p53 protein. However, p53E221D/E221DRNA transcribed from the endogenous locus is mis-spliced resulting in nonsense mediated decay. Moreover, fibroblasts derived from p53E221D/E221Dmice do not express a detectable protein product. Mice homozygous for p53E221Dexhibited increased tumor penetrance and decreased life expectancy compared to p53 WT animals.

Conclusions

Mouse p53E221Dand human p53E224Dmutations lead to splice variation and a biologically relevant p53 loss of function in vitro and in vivo.
Macrophages form integrin-mediated adhesion rings to pinch off surface-bound objects for phagocytosis
Authors: Pal Kaushik , Kundu Subhankar , Wang Xuefeng
Published: August 2023

Macrophages engulf micron-sized objects including pathogens and cell debris by phagocytosis, serving a fundamental role in immune defense and homeostasis1, 2. Although the internalization process of suspended particles has been thoroughly investigated3, 4, it is incompletely understood how macrophages internalize surface-bound objects by overcoming the surface binding. Here, we prepared a force-sensing platform which visualizes cell-substrate adhesive force by fluorescence. Macrophages are tested on this platform with micron-sized objects (E. coli, microbeads and silver nanorods) immobilized. By co-imaging integrin-transmitted forces and corresponding structural proteins, we discovered that macrophages consistently form integrin-mediated adhesion structures on the surface to encircle and pinch off surface-bound objects. We termed these structures phagocytic adhesion rings (PAR) and showed that integrin tensions in PARs are resulted from local actin polymerization, but not from myosin II. We further demonstrated that the intensity of integrin tensions in PARs is correlated with the object surface-bound strength, and the integrin ligand strength (dictating the upper limit of integrin tensions) determines the phagocytosis efficiency. Collectively, this study revealed a new phagocytosis mechanism that macrophages form PARs to provide physical anchorage for local F-actin polymerization that pushes and lifts off surface-bound objects during phagocytosis.
SAMPLER: Empirical distribution representations for rapid analysis of whole slide tissue images
Authors: Mukashyaka Patience , Sheridan Todd B. , pour Ali Foroughi , Chuang Jeffrey H.
Published: August 2023

Deep learning has revolutionized digital pathology, allowing for automatic analysis of hematoxylin and eosin (H&E) stained whole slide images (WSIs) for diverse tasks. In such analyses, WSIs are typically broken into smaller images called tiles, and a neural network backbone encodes each tile in a feature space. Many recent works have applied attention based deep learning models to aggregate tile-level features into a slide-level representation, which is then used for slide-level prediction tasks. However, training attention models is computationally intensive, necessitating hyperparameter optimization and specialized training procedures. Here, we propose SAMPLER, a fully statistical approach to generate efficient and informative WSI representations by encoding the empirical cumulative distribution functions (CDFs) of multiscale tile features. We demonstrate that SAMPLER-based classifiers are as accurate or better than state-of-the-art fully deep learning attention models for classification tasks including distinction of: subtypes of breast carcinoma (BRCA: AUC=0.911 ± 0.029); subtypes of non-small cell lung carcinoma (NSCLC: AUC=0.940±0.018); and subtypes of renal cell carcinoma (RCC: AUC=0.987±0.006). A major advantage of the SAMPLER representation is that predictive models are >100X faster compared to attention models. Histopathological review confirms that SAMPLER-identified high attention tiles contain tumor morphological features specific to the tumor type, while low attention tiles contain fibrous stroma, blood, or tissue folding artifacts. We further apply SAMPLER concepts to improve the design of attention-based neural networks, yielding a context aware multi-head attention model with increased accuracy for subtype classification within BRCA and RCC (BRCA: AUC=0.921±0.027, and RCC: AUC=0.988±0.010). Finally, we provide theoretical results identifying sufficient conditions for which SAMPLER is optimal. SAMPLER is a fast and effective approach for analyzing WSIs, with greatly improved scalability over attention methods to benefit digital pathology analysis.
Genetic differentiation at extreme latitudes in the socially plastic sweat beeHalictus rubicundus
Authors: Michels Bas , Beekman Mariska M. , Field Jeremy , Gruber Jodie , Pannebakker Bart A. , Savill Charlotte , Boulton Rebecca A.
Published: August 2023

The sweat beeHalictus rubicundusis an important pollinator with a large latitudinal range and many potential barriers to gene flow. Alongside typical physical barriers, including mountain ranges and oceans, the climate may also impose restrictions on gene flow in this species. The climate influences voltinism and sociality inH. rubicundus, which is bivoltine and can nest socially at lower latitudes but can be univoltine and solitary in the north of its range and at higher altitudes where the climate is cooler. Variation in voltinism due to the climate may result in differences in phenology between populations across this species’ geographical range. Differences in phenology could limit gene flow, rendering populations at extreme latitudes genetically isolated and potentially more vulnerable to environmental stressors. A previous study found that the Irish Sea restricts gene flow in this species, but there was no evidence that differences in phenology had a similar effect as there was no genetic differentiation betweenH. rubicunduspopulations on mainland Britain. Here we extend the previous study to consider populations ofH. rubicundusat extreme northern and southern latitudes in the UK. Using 12 microsatellite markers for genotyping, we found that bees from a population in the far north of Scotland were genetically differentiated from bees collected in Cornwall in the south-west of England. In contrast, bees collected across the Irish Sea in Northern Ireland showed genetic overlap with both the Scottish and Cornish bees. Our results suggest that when populations at extreme latitudes are considered, phenology and the climate may act alongside physical barriers such as the Scottish Highlands and the Irish Sea to restrict gene flow inH. rubicundus. We discuss the implications of our results for local adaptation in the face of rapidly changing selection pressures which are likely under climate change.
Transformation of valence signaling in a striatopallidal circuit
Authors: Lee Donghyung , Lau Nathan , Liu Lillian , Root Cory M
Published: August 2023

The ways in which sensory stimuli acquire motivational valence through association with other stimuli is one of the simplest forms of learning. Though we have identified many brain nuclei that play various roles in reward processing, a significant gap remains in understanding how valence encoding transforms through the layers of sensory processing. To address this gap, we carried out a comparative investigation of the anteromedial olfactory tubercle (OT), and the ventral pallidum (VP) - 2 connected nuclei of the basal ganglia which have both been implicated in reward processing. First, using anterograde and retrograde tracing, we show that both D1 and D2 neurons of the anteromedial OT project primarily to the VP and minimally elsewhere. Using 2-photon calcium imaging, we then investigated how the identity of the odor and reward contingency of the odor are differently encoded by neurons in either structure during a classical conditioning paradigm. We find that VP neurons robustly encode reward contingency, but not identity, in low-dimensional space. In contrast, the OT neurons primarily encode odor identity in high-dimensional space. Although D1 OT neurons showed larger responses to rewarded odors than other odors, consistent with prior findings, we interpret this as identity encoding with enhanced contrast. Finally, using a novel conditioning paradigm that decouples reward contingency and licking vigor, we show that both features are encoded by non-overlapping VP neurons. These results provide a novel framework for the striatopallidal circuit in which a high-dimensional encoding of stimulus identity is collapsed onto a low-dimensional encoding of motivational valence.
Specific configurations of electrical synapses filter sensory information to drive choices in behavior
Authors: Almoril-Porras Agustin , Calvo Ana C. , Niu Longgang , Beagan Jonathan , Hawk Josh D. , Aljobeh Ahmad , Wisdom Elias M. , Ren Ivy , Díaz-García Malcom , Wang Zhao-Wen , Colón-Ramos Daniel A.
Published: August 2023

Synaptic configurations in precisely wired circuits underpin how sensory information is processed by the nervous system, and the emerging animal behavior. This is best understood for chemical synapses, but far less is known about how electrical synaptic configurations modulate,in vivoand in specific neurons, sensory information processing and context-specific behaviors. We discovered that INX-1, a gap junction protein that forms electrical synapses, is required to deploy context-specific behavioral strategies duringC. elegansthermotaxis behavior. INX-1 couples two bilaterally symmetric interneurons, and this configuration is required for the integration of sensory information during migration of animals across temperature gradients. Ininx-1mutants, uncoupled interneurons display increased excitability and responses to subthreshold temperature stimuli, resulting in abnormally longer run durations and context-irrelevant tracking of isotherms. Our study uncovers a conserved configuration of electrical synapses that, by increasing neuronal capacitance, enables differential processing of sensory information and the deployment of context-specific behavioral strategies.

One-Sentence Summary

Coupling of interneurons by electrical synapses reduces membrane resistance and filters sensory inputs to guide sensory-dependent behavioral choices.
Investigating tumor-associated macrophages and their polarization in colorectal cancer using Boolean implication networks
Authors: Dadlani Ekta , Dash Tirtharaj , Sahoo Debashis
Published: August 2023

Tumor-associated Macrophages (or TAMs) are amongst the most common cells that play a significant role in the initiation and progression of colorectal cancer (CRC). [Ghosh et al., 2023] have built a Boolean-logic dependent model to propose a set of gene signatures capable of identifying macrophage polarization states. The signature, called the Signature of Macrophage Reactivity and Tolerance (SMaRT), comprises of 338 human genes (equivalently, 298 mouse genes). The SMaRT signature was constructed using datasets that were not specialized towards any particular disease. To specifically investigate macrophage polarization in CRC, in this paper, we (a) perform a comprehensive analysis of the SMaRT signature on single-cell human and mouse colorectal cancer RNA-seq datasets and (b) adopt transfer learning to construct a “refined” SMaRT signature that specifically characterizes TAM polarization in the CRC tumor microenvironment. Towards validation of our refined gene signature, we use: (a) 5 RNA-seq datasets derived from single-cell human datasets; and (b) 5 large-cohort microarray datasets from humans. Furthermore, we propose the translational potential of our refined gene signature while investigating microsatellite stability and CpG island methylator phenotype (CIMP) in colorectal cancer. Overall, our refined gene signature and its extensive validation provide a path for its adoption in clinical practice in diagnosing colorectal cancer and associated attributes.

Availability and Implementation

The data, codes, and software packages used in our research are linked and shared publicly athttps://github.com/tirtharajdash/TAMs-CRC.
Data-driven signal analysis of sensory cortical processing using high-resolution fMRI across different studies
Authors: Plagwitz Lucas , Choi Sangcheon , Yu Xin , Segelcke Daniel , Pogatzki-Zahn Esther , Varghese Julian , Faber Cornelius , Pradier Bruno
Published: August 2023

The analysis of large data sets within and across preclinical studies has always posed a particular challenge in terms of data volume and method heterogeneity between studies. Recent developments in machine learning (ML) and artificial intelligence (AI) allow to address these challenges in complex macro- and microscopic data sets. Because of their complex data structure, functional magnetic resonance imaging (fMRI) measurements are perfectly suited to develop such ML/AI frameworks for data-driven analyses. These approaches have the potential to reveal patterns, including temporal kinetics, in blood-oxygen-level-dependent (BOLD) time series with a reduced workload. However, the typically poor signal-to-noise ratio (SNR) and low temporal resolution of fMRI time series have so far hampered such advances. Therefore, we used line scanning fMRI measurements with high SNR and high spatio-temporal resolution obtained from three independent studies and two imaging centers with heterogeneous study protocols. Unbiased time series clustering techniques were applied for the analysis of somatosensory information processing during electrical paw and optogenetic stimulation. Depending on the similarity formulation, our workflow revealed multiple patterns in BOLD time series. It produced consistent outcomes across different studies and study protocols, demonstrating the generalizability of the data-driven method for cross-study analyzes. Further, we introduce a statistical analysis that is entirely based on cluster distribution. Using this method, we can reproduce previous findings including differences in temporal BOLD characteristics between two stimulation modalities. Our data-driven approach proves high sensitivity, robustness, reproducibility, and generalizability and further quickly provides highly detailed insight into characteristics of BOLD time series. Therefore, it holds great potential for further applications in fMRI data including whole-brain task and resting-state fMRI, which can support fMRI routines. Furthermore, the analytic framework can be used for datasets that have a time-dependent data structure to integrate study results and create robust and generalizable datasets, despite different study protocols.
Tight junction membrane proteins regulate the mechanical resistance of the apical junctional complex
Authors: Nguyen Thanh Phuong , Otani Tetsuhisa , Tsutsumi Motosuke , Fujiwara Sachiko , Nemoto Tomomi , Fujimori Toshihiko , Furuse Mikio
Published: August 2023

Epithelia must be able to resist mechanical force to preserve tissue integrity. While intercellular junctions are known to be important for the mechanical resistance of epithelia, the roles of tight junctions (TJs) remain to be established. We previously demonstrated that epithelial cells devoid of the TJ membrane proteins claudins and JAM-A completely lack TJs and exhibit focal breakages of their apical junctions. Here, we demonstrate that apical junctions undergo spontaneous fracture when claudin/JAM-A-deficient cells are exposed to mechanical stress. The junction fracture was accompanied by actin disorganization, and actin polymerization was required for apical junction integrity in the claudin/JAM-A-deficient cells. Further deletion of CAR resulted in the disruption of ZO-1 molecule ordering at cell junctions, accompanied by severe defects in apical junction integrity. These results demonstrate that TJ membrane proteins regulate the mechanical resistance of the apical junctional complex in epithelial cells.

Tight junction membrane proteins claudins, JAM, and CAR coordinately regulate the nanometer-scale organization of ZO-1 molecules, and are required for the mechanical resistance of apical junctions in epithelial cells.
Human Intelligence and the Connectome are Driven by Structural Brain Network Control
Authors: Anderson Evan D. , Varshney Lav R. , Hemmatian Babak , Robles-Granda Pablo D. , Nayak Anuj Keshava , Wilcox Ramsey R. , Zwilling Christopher E. , Kim Been , Barbey Aron K.
Published: August 2023

Research in network neuroscience demonstrates that human intelligence is shaped by the structural brain connectome, which enables a globally coordinated and dynamic architecture for general intelligence. Building on this perspective, the network neuroscience theory proposes that intelligence arises from system-wide network dynamics and the capacity to flexibly transition between network states. According to this view, network flexibility is made possible by network controllers that move the system into specific network states, enabling solutions to familiar problems by accessing nearby, easy-to-reach network states and adapting to novel situations by engaging distant, difficult-to-reach network states. Although this framework predicts that general intelligence depends on network controllability, the specific cortical regions that serve as network controllers and the nature of their control operations remain to be established. We therefore conducted a comprehensive investigation of the relationship between regional measures of network controllability and general intelligence within a sample of 275 healthy young adults using structural and diffusion-weighted MRI data. Our findings revealed significant associations between intelligence and network controllers located within the frontal, temporal and parietal cortex. Furthermore, we discovered that these controllers collectively enable access to both easy- and difficult-to-reach network states, aligning with the predictions made by the network neuroscience framework. Additionally, our research demonstrated that the identified network controllers are primarily localized within the left hemisphere and do not reside within regions or connections that possess the highest capacity for structural control in general. This discovery suggests that the identified regions may facilitate specialized control operations and motivates further exploration of the network topology and dynamics underlying intelligence in the human brain.

This study examines the relationship between regional measures of network controllability and general intelligence within a sample of 275 healthy young adults using structural and diffusion-weighted MRI data. We report that individual differences in general intelligence are associated average and modal controllability in specific left-hemisphere cortical regions, and further show that controller regions associated with intelligence are distinct from regions with the highest, centrality, controllability, or communication. These findings reveal a significant structural role for individual regions in controlling the trajectory of the connectome, advancing our understanding of the nature and mechanisms of network controllability in general intelligence.
Unique T cell signatures associated with reducedChlamydia trachomatisreinfection in a highly exposed cohort
Authors: Yount Kacy S , Chen Chi-Jane , Kollipara Avinash , Liu Chuwen , Mokashi Neha V , Zheng Xiaojing , Bagwell C Bruce , Poston Taylor B , Wiesenfeld Harold C , Hillier Sharon L , O’Connell Catherine M , Stanley Natalie , Darville Toni
Published: August 2023

Chlamydia trachomatis(CT) is the most common bacterial sexually transmitted infection globally. Understanding natural immunity to CT will inform vaccine design. This study aimed to profile immune cells and associated functional features in CT-infected women, and determine immune profiles associated with reduced risk of ascended endometrial CT infection and CT reinfection. PBMCs from CT-exposed women were profiled by mass cytometry and random forest models identified key features that distinguish outcomes. CT+ participants exhibited higher frequencies of CD4+ Th2, Th17, and Th17 DN CD4 T effector memory (TEM) cells than uninfected participants with decreased expression of T cell activation and differentiation markers. No significant differences were detected between women with or without endometrial CT infection. Participants who remained follow-up negative (FU-) showed higher frequencies of CD4 T central memory (TCM) Th1, Th17, Th1/17, and Th17 DN but reduced CD4 TEM Th2 cells than FU+ participants. Expression of markers associated with central memory and Th17 lineage were increased on T cell subsets among FU- participants. These data indicate that peripheral T cells exhibit distinct features associated with resistance to CT reinfection. The highly plastic Th17 lineage appears to contribute to protection. Addressing these immune nuances could promote efficacy of CT vaccines.

GRAPHICAL ABSTRACT
Membrane molecule bouncer enables follicle fertilization in a viviparous teleost:Poecilia reticulata(guppy)
Authors: Yoshida Junki , Tajika Yuki , Uchida Kazuko , Kuwahara Makoto , Sano Kaori , Suzuki Takayuki , Hondo Eiichi , Iida Atsuo
Published: August 2023

Fertilization is a fundamental mechanism of sexual reproduction. Generally, oocytes are ovulated from the ovarian follicles and contact the sperm outside the ovarian medulla. Unlike this, follicle fertilization which means the egg contact with sperm in the ovarian medulla without ovulation is known in the viviparous teleost species belonging to the Poeciliidae. In this study, we focused on a viviparous teleost species,Poecilia reticulata(guppy). Our sperm tracking assay indicated that the sperm reached the immature oocytes with a germinal vesicle, and the fertilized immature oocytes were presumed to contribute to littermates. The binding between immature oocytes and sperm is a specific trait in the guppy, which was not observed inDanio rerio(zebrafish) orOryzias latipes(medaka). The loss- and gain-of-function assays indicated that bouncer plays a critical role in immature oocyte-to-sperm binding. This fertilization trait in immature oocytes may provide certain advantages for females with respect to nutrition or other gestation costs. Our findings shed light on the unique reproductive strategies of guppy and contribute to our understanding of the diverse reproductive mechanisms in vertebrates.

Summary statement

Unlike general vertebrates, guppy’s oocyte fertilizes with sperm in the ovarian medulla at the immature stages. The distinctive trait depends on the Ly6/uPAR protein bouncer.
m6A mRNA Methylation Regulates Early Pancreatic β-Cell Differentiation
Authors: Kahraman Sevim , De Jesus Dario F , Wei Jiangbo , Brown Natalie K. , Zou Zhongyu , Hu Jiang , He Chuan , Kulkarni Rohit N
Published: August 2023

N6-methyladenosine (m6A) is the most abundant chemical modification in mRNA, and plays important roles in human and mouse embryonic stem cell pluripotency, maintenance, and differentiation. We have recently reported, for the first time, the role of m6A in the postnatal control of β-cell function in physiological states and in Type 1 and 2 Diabetes. However, the precise mechanisms by which m6A acts to regulate the development of human and mouse β-cells are unexplored. Here, we show that the m6A landscape is dynamic during human pancreas development, and that METTL14, one of the m6A writer complex proteins, is essential for the early differentiation of both human and mouse β-cells.
Metabolic reprogramming duringCandida albicansplanktonic-biofilm transition is modulated by theZCF15andZCF26paralogs
Authors: Rai Laxmi Shanker , Chauvel Murielle , Sanchez Hiram , van Wijlick Lasse , Maufrais Corinne , Cokelaer Thomas , Sertour Natacha , Legrand Mélanie , Andes David R , Bachellier-Bassi Sophie , d’Enfert Christophe
Published: August 2023

Candida albicansis a commensal of the human microbiota that can form biofilms on implanted medical devices. These biofilms are tolerant to antifungals and to the host immune system. To identify novel genes modulatingC. albicansbiofilm formation, we performed a large-scale screen with 2454C. albicansdoxycycline-dependent overexpression strains and identified 16 genes whose overexpression significantly hampered biofilm formation. Among those, overexpression of theZCF15andZCF26paralogs that encode transcription factors and have orthologs only in biofilm-forming species of theCandidaclade, caused impaired biofilm formation bothin vitroandin vivo. Interestingly, overexpression ofZCF15specifically impeded biofilm formation without any defect in hyphal growth. Transcript profiling, transcription factor binding, and phenotypic microarray analyses conducted upon overexpression ofZCF15andZCF26demonstrated their direct role in reprogramming cellular metabolism by regulating glycolytic cycle and tricarboxylic acid cycle genes. Taken together, this study has identified a new set of biofilm regulators, includingZCF15andZCF26,that appear to control biofilm development through their specific role in metabolic remodeling.
A force-sensitive mutation reveals a spindle assembly checkpoint-independent role for dynein in anaphase progression
Authors: Salvador-Garcia David , Jin Li , Hensley Andrew , Gölcük Mert , Gallaud Emmanuel , Chaaban Sami , Port Fillip , Vagnoni Alessio , Planelles-Herrero Vicente José , McClintock Mark A. , Derivery Emmanuel , Carter Andrew P. , Giet Régis , Gür Mert , Yildiz Ahmet , Bullock Simon L.
Published: August 2023

The cytoplasmic dynein-1 (dynein) motor organizes cells by shaping microtubule networks and moving a large variety of cargoes along them. However, dynein’s diverse roles complicatein vivostudies of its functions significantly. To address this issue, we have used gene editing to generate a series of missense mutations inDrosophilaDynein heavy chain (Dhc). We find that mutations associated with human neurological disease cause a range of defects in larval and adult flies, including impaired cargo trafficking in neurons. We also describe a novel mutation in the microtubule-binding domain (MTBD) of Dhc that, remarkably, causes metaphase arrest of mitotic spindles in the embryo but does not impair other dynein-dependent processes. We demonstrate that the mitotic arrest is independent of dynein’s well-established roles in silencing the spindle assembly checkpoint.In vitroreconstitution and optical trapping assays reveal that the mutation only impairs the performance of dynein under load.In silicoall-atom molecular dynamics simulations show that this effect correlates with increased flexibility of the MTBD, as well as an altered orientation of the stalk domain, with respect to the microtubule. Collectively, our data point to a novel role of dynein in anaphase progression that depends on the motor operating in a specific load regime. More broadly, our work illustrates how cytoskeletal transport processes can be dissectedin vivoby manipulating mechanical properties of motors.
Hemispheric asymmetries in auditory cortex reflect discriminative responses to temporal details or summary statistics of stationary sounds
Authors: Berto Martina , Reisinger Patrick , Ricciardi Emiliano , Weisz Nathan , Bottari Davide
Published: August 2023

The processing of stationary sounds relies on both local features and compact representations. As local information is compressed into summary statistics, abstract representations emerge. Whether the brain is endowed with distinct neural architectures overseeing such computations is unknown.

In this magnetoencephalography (MEG) study, we employed a validated protocol to localize cortical correlates of local and summary representations, exposing participants to triplets of synthetic sound textures systematically varying for either local details or summary statistics. Sounds also varied for their sound duration, specifically short (40ms) or long (478ms). Results revealed clear distinct activation patterns for local features and summary statistics changes. Such activations diverged in magnitude, spatiotemporal distribution, and hemispheric lateralization. For short sounds, a change in local features, compared to summary statistics, predominantly activated the right hemisphere. Conversely, for long sounds, a change in summary statistics elicited higher activation than a change in local features in both hemispheres.

Specifically, while the right auditory cortex was responding more to changes in local features or summary statistics depending on sound duration (short or long, respectively), the left frontal lobe was selectively engaged in processing a change in summary statistics at a long sound duration. These findings provide insights into the neural mechanisms underlying the computation of local and summary acoustic information and highlight the involvement of distinct cortical pathways and hemispheric lateralization in auditory processing at different temporal resolutions.

Significant Statement

We revealed hemispheric specializations for auditory computations at high (local) and low (summary statistics) temporal resolutions. The right hemisphere was engaged for both computations, while the left hemisphere responded more to summary statistics changes. These findings highlight the multifaceted functions of the right hemisphere in capturing acoustic properties of stationary sounds and the left hemisphere’s involvement in processing abstract representations.
FAM210A mediates an inter-organelle crosstalk essential for protein synthesis and muscle growth in mouse
Authors: Chen Jingjuan , Yue Feng , Kim Kun Ho , Zhu Peipei , Qiu Jiamin , Tao W. Andy , Kuang Shihuan
Published: August 2023

Mitochondria are not only essential for energy production in eukaryocytes but also a key regulator of intracellular signaling. Here, we report an unappreciated role of mitochondria in regulating cytosolic protein translation in skeletal muscle cells (myofibers). We show that the expression of mitochondrial protein FAM210A (Family With Sequence Similarity 210 Member A) is positively associated with muscle mass in mice and humans. Muscle-specificMyl1Cre-drivenFam210aknockout (Fam210aMKO) in mice reduces mitochondrial density and function, leading to progressive muscle atrophy and premature death. Metabolomic and biochemical analyses reveal thatFam210aMKOreverses the oxidative TCA cycle towards the reductive direction, resulting in acetyl-CoA accumulation and hyperacetylation of cytosolic proteins. Specifically, hyperacetylation of several ribosomal proteins leads to disassembly of ribosomes and translational defects. Transplantation ofFam210aMKOmitochondria into wildtype myoblasts is sufficient to elevate protein acetylation in recipient cells. These findings reveal a novel crosstalk between the mitochondrion and ribosome mediated by FAM210A.
Conserved regulatory motifs in the juxtamembrane domain and kinase N-lobe revealed through deep mutational scanning of the MET receptor tyrosine kinase domain
Authors: Estevam Gabriella O. , Linossi Edmond M. , Macdonald Christian B. , Espinoza Carla A. , Michaud Jennifer M. , Coyote-Maestas Willow , Collisson Eric A. , Jura Natalia , Fraser James S.
Published: August 2023

MET is a receptor tyrosine kinase (RTK) responsible for initiating signaling pathways involved in development and wound repair. MET activation relies on ligand binding to the extracellular receptor, which prompts dimerization, intracellular phosphorylation, and recruitment of associated signaling proteins. Mutations, which are predominantly observed clinically in the intracellular juxtamembrane and kinase domains, can disrupt typical MET regulatory mechanisms. Understanding how juxtamembrane variants, such as exon 14 skipping (METΔEx14), and rare kinase domain mutations can increase signaling, often leading to cancer, remains a challenge. Here, we perform a parallel deep mutational scan (DMS) of the MET intracellular kinase domain in two fusion protein backgrounds: wild type and METΔEx14. Our comparative approach has revealed a critical hydrophobic interaction between a juxtamembrane segment and the kinase ⍺C-helix, pointing to potential differences in regulatory mechanisms between MET and other RTKs. Additionally, we have uncovered a β5 motif that acts as a structural pivot for the kinase domain in MET and other TAM family of kinases. We also describe a number of previously unknown activating mutations, aiding the effort to annotate driver, passenger, and drug resistance mutations in the MET kinase domain.