bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-term Outcomes After Gender-Affirming Surgery
Authors: Park Rachel H. , Liu Yi-Ting , Samuel Ankhita , Gurganus Margot , Gampper Thomas J. , Corbett Sean T. , Shahane Amit , Stranix John T.
Published: September 2022

Background

Gender dysphoria is a condition that often leads to significant patient morbidity and mortality. Although gender-affirming surgery (GAS) has been offered for more than half a century with clear significant short-term improvement in patient well-being, few studies have evaluated the long-term durability of these outcomes.

Methods

Chart review identified 97 patients who were seen for gender dysphoria at a tertiary care center from 1970 to 1990 with comprehensive preoperative evaluations. These evaluations were used to generate a matched follow-up survey regarding their GAS, appearance, and mental/social health for standardized outcome measures. Of 97 patients, 15 agreed to participate in the phone interview and survey. Preoperative and postoperative body congruency score, mental health status, surgical outcomes, and patient satisfaction were compared.

Results

Both transmasculine and transfeminine groups were more satisfied with their body postoperatively with significantly less dysphoria. Body congruency score for chest, body hair, and voice improved significantly in 40 years' postoperative settings, with average scores ranging from 84.2 to 96.2. Body congruency scores for genitals ranged from 67.5 to 79 with free flap phalloplasty showing highest scores. Long-term overall body congruency score was 89.6. Improved mental health outcomes persisted following surgery with significantly reduced suicidal ideation and reported resolution of any mental health comorbidity secondary to gender dysphoria.

Conclusion

Gender-affirming surgery is a durable treatment that improves overall patient well-being. High patient satisfaction, improved dysphoria, and reduced mental health comorbidities persist decades after GAS without any reported patient regret.
Augmented Reality–Assisted Design of Local Flaps
Authors: Kyriazidis Ioannis , Berner Juan Enrique , Jones Christopher David , Shokrollahi Kayvan , Benson Alex
Published: September 2022

Augmented reality (AR) is a new and promising technology that has been incorporated into several aspects of our everyday life, including surgery. Examples of its application throughout various fields of surgery, although most of them are in experimental stage, have already been demonstrated and published. In this article, we describe the utilization of AR to design effectively and accurately surgical flap markings just with the help of an AR-compatible mobile phone and a low-cost application. We believe that, due to its ease of use, AR will play a pivotal role to the education and the training in the field of plastic surgery and burns, and other surgical specialties alike.
Comparison of the Results of Suture and Resorbable Plate-Screw Fixation in Craniosynostosis
Authors: Sibar Serhat , Karasu Oğuzhan , Erol Gökberk , Findikçioğlu Kemal , Börcek Alp Özgün
Published: September 2022

Background

Although many fixation methods are used alone or in combination for craniosynostosis, only few studies have compared the effectiveness and long-term results of these methods.

Method

In this study, patients in whom suture or resorbable plate-screw system was used for fixation were evaluated in terms of postoperative results and complications. The data of patients who underwent surgery for craniosynostosis between 2002 and 2019 were retrospectively reviewed and evaluated.

Results

A total of 70 patients, 41 in the suture group and 29 in the resorbable plate-screw group, were included in the study. Whitaker classification was used for head shape evaluation, and anthropometric head circumference measurements were performed in all patients in the preoperative and postoperative periods. In the postoperative period, all patients were compared in terms of the operation time, transfusion requirement, discharge, follow-up period, and complications according to the chosen fixation method.

The mean age, postoperative complication rates, anthropometric head circumference measurements, and Whitaker scores of both groups were found to be statistically similar. Although the resorbable plate-screw group had a longer follow-up period, the operation time was longer in the suture group. Furthermore, the suture group had lower transfusion requirement and earlier discharge from the hospital than the resorbable plate-screw group.

Conclusions

If fixation with suture is chosen in suitable patients, in addition to the low patient cost, this method can be safely applied in centers with limited logistical possibilities, because of the results and complication rates being similar to fixation with resorbable plate-screws.
Identification of Unequal Flow-Carrying Capabilities of Choke Vessels in Rat Abdominal Flaps
Authors: Xu Heng , Zhu Zhu , Chen Jun , Xiao Dongchao , Pan Jiadong , Wang Xin , Li Hua , Ng Sally , Zhang Yixin
Published: September 2022

Background

Although the angiosome concept is a well-accepted theory, unexpected necrosis suggests that other factors can influence the flap survival. Our study uses the rat model to explore the flow capacity of the choke vessels across 2 angiosomes.

Methods

The medioventral line of Sprague-Dawley rats' abdominal flap was equally divided into 4 sections, which were preserved in 7 different groups (n = 6/group): A, no dissection; B to D, preserve the inferior 1/4, 2/4, and 3/4 sections; E to G, preserve the superior 1/4, 2/4, and 3/4 sections. The ratio (%) of the survival area of the distal/proximal territory was calculated. Indocyanine green, lead-oxide gel imaging, hematoxylin and eosin, and CD31 histology tests were performed.

Results

Compared with 96.0 ± 1.4% flap survival in group A, groups B, C, and D had distal territory flap loss (34.8% ± 4.1%, 65.0% ± 3.7%, and 94.3% ± 3.1% respectively). Group E lost the majority of the distal territory (3.5% ± 2.4%), whereas groups F and G (15.5% ± 3.8% and 79.2% ± 3.3%, respectively) had larger flap survival. Except for groups A and D, each of the other 2 groups showed statistically significant results (P < 0.001). Indocyanine green indicated no blood flow at the superior 1/4 part. Lead-oxide gel and histology showed that the choke vessels residing along the medioventral line had no significant difference.

Conclusions

Choke vessels do not carry blood flow equally. Two categories of choke vessels—“resting” and “active”—are proposed. The “active” form has variable flow carrying capabilities when the flap is harvested in different designs.
An Alternative Location for Fixation of Subcondylar Fractures With 2 Resorbable Plates
Authors: Hao Xing , Lv Kun
Published: September 2022

Background:

Mandibular subcondylar fractures can be fixed with 2 titanium plates or 2 resorbable plates. However, when a wider resorbable plate is used, there might be insufficient space on subcondylar region. The authors have tested the back of the condyle as an alternative location for the wide resorbable plate.

Methods:

The fractured condyle was accessed through the preauricular approach. The first resorbable plate (4 hole plate, extended; 2 mm Inion OTPSTM) was contoured around the posterior edge of the mandibular ramus. The upper and lower parts of the very resorbable plate were twisted into 2 different planes. The upper part was adapted and then fixed on the back of the condylar neck. And the lower part was fixed on the lateral surface of the posterior edge of the mandibular ramus. The second plate (4 hole plate; 2 mm Inion OTPSTM) was put below the mandibular notch as usual.

Results and Discussion:

Postoperative computed tomography confirmed a stable anatomical reduction of condyle. One-year follow-up showed good fracture healing. The authors believe that the back of the condyle is particularly suitable for wider resorbable plate. And this alternative site on the back of the condyle is also feasible in cases where the conventional site is not available.
Incidence of Internal Carotid Artery Stenosis in Oral Squamous Cell Carcinoma Patients After Neck Dissection
Authors: Gao Minghua , Hu Yongjie , Yin Xuelai
Published: September 2022

Objectives:

To determine the incidence of progressive internal carotid artery stenosis (ICAS) by head and neck contrast-enhanced computed tomography (CT) in 45 patients who underwent neck dissection for oral squamous cell carcinoma (OSCC).

Patients and Methods:

The study included 45 patients who underwent head and neck contrast-enhanced CT before and after surgery for OSCC by the Hu Yongjie team at the Department of Oral and Maxillofacial-Head & Neck Oncology of Shanghai Ninth People’s Hospital in 2016 and were followed up for 5 years.

Results:

Comparison of the current CT with previously obtained head and neck contrast-enhanced CT images revealed progressive ICAS in 3 patients with a mean age of 50.0 years. All 3 patients were male, and their OSCC sites were the tongue in 2 patients and the buccal in 1 patient. Tumor resection and neck dissection were performed for all 3 patients. Two patients underwent radiotherapy. In all 3 patients, the ICAS had occurred on the same side as the tumors.

Conclusions:

The results of this study suggest that neck dissection with cervical sheath removal might increase the incidence of ICAS, but this result may need the support of a larger sample size study.
A Functional and Neuroanatomical Model of Dehumanization
Authors: Mendez Mario F.
Published: September 2022

The dehumanization of others is a major scourge of mankind; however, despite its significance, physicians have little understanding of the neurobiological mechanisms for this behavior. We can learn much about dehumanization from its brain–behavior localization and its manifestations in people with brain disorders. Dehumanization as an act of denying to others human qualities includes two major forms. Animalistic dehumanization (also called infrahumanization) results from increased inhibition of prepotent tendencies for emotional feelings and empathy for others. The mechanism may be increased activity in the inferior frontal gyrus. In contrast, mechanistic dehumanization results from a loss of perception of basic human nature and decreased mind-attribution. The mechanism may be hypofunction of a mentalization network centered in the ventromedial prefrontal cortex and adjacent subgenual anterior cingulate cortex. Whereas developmental factors may promote animalistic dehumanization, brain disorders, such as frontotemporal dementia, primarily promote mechanistic dehumanization. The consideration of these two processes as distinct, with different neurobiological origins, could help guide efforts to mitigate expression of this behavior.
Adherence to and experiences of K–12 students in modified and standard home quarantine during the SARS-CoV-2 pandemic in Missouri
Authors: Worrell Mary Claire , Malone Sara , Dawson Patrick , Fritz Stephanie A. , Thomas Ebony , Peeler Bre , Rains Catherine , Tinker Sarah C. , Neatherlin John C. , Barrios Lisa , Mooney Jon , Towns Katie , Newland Jason , Salzer Johanna S.
Published: September 2022

Background

In November 2020, during the SARS-CoV-2 pandemic, Missouri allowed local public health jurisdictions the option to implement a modified quarantine policy allowing kindergarten through 12 (K-12) students with low-risk exposures to continue in-person learning. We assessed adherence to quarantine among participants in modified quarantine and standard home quarantine and the psychosocial impacts of quarantine on students and families.

Methods

In January-March 2021, as part of an investigation of in-school transmission of SARS-CoV-2, parents of 586 participating K-12 students identified as a close contact with a person with SARS-CoV-2 were sent a survey to assess their activities and psychosocial impacts to the child and family.

Results

Among the 227 (39%) survey respondents, 26 (11%) participated in modified quarantine and 201 (89%) participated in standard home quarantine. Forty-six percent of students in modified quarantine and 72% of students in standard home quarantine reported abstaining from non-school activities during quarantine. Parents of 17 (65%) students in modified quarantine and 80 (40%) in standard home quarantine reported low or neutral levels of stress in their children. Parents of students in standard home quarantine described greater stress, negative impacts to family functioning, and interruptions to educational opportunities for students.

Conclusions

Students in modified quarantine reported lower adherence to quarantine recommendations but lower daily impact and stressors than those in standard home quarantine. Because in-school transmission of SARS-CoV-2 has been shown to be low when layered prevention strategies are in place regardless of the use of modified or standard home quarantine, this modified quarantine approach provides a reasonable option for balancing the needs of students and families with SARS-CoV-2 prevention measures.
Paradoxical Effects of Depression on Psoriatic Arthritis Outcomes in a Combined Psoriasis-Psoriatic Arthritis Center
Authors: Haberman Rebecca H. , Um Seungha , Catron Sydney , Chen Alan , Lydon Eileen , Attur Malavika , Neimann Andrea L. , Reddy Soumya , Troxel Andrea , Adhikari Samrachana , Scher Jose U.
Published: September 2022

Psoriatic arthritis (PsA) is a chronic, complex, inflammatory arthritis that, when left untreated, can lead to erosions, deformities and decrease in quality of life. PsA is known to be associated with multiple comorbidities, including cardiovascular, metabolic and mental health syndromes, all of which can increase its overall morbidity and mortality. Here we describe a cohort of patients with PsA from an urban, tertiary care, and followed at a combined rheumatology-dermatology center. Depression was reported in 22.8% of the population, anxiety in 18%, and attention deficit hyperactivity disorder in 4%. Depression was more common in female participants (p<.001). At baseline, individuals with PsA and concomitant depression had similar tender and swollen joint counts and RAPID3 compared to those without depression, and had lower body surface area affected by psoriasis (p=.04). At year one, all patients had improvement in clinical outcomes. However, patients with depression had a significantly higher tender joint count compared to those without depression (p=.001), despite similar swollen joint count and body surface area. These observations underscore the importance of addressing depression and psychological distress as part of PsA treatment outcomes and points towards the need to address residual pain through co-adjuvant approaches.
Microtubule-mediated GLUT4 trafficking is disrupted in insulin resistant skeletal muscle
Authors: Knudsen Jonas R. , Persson Kaspar W. , Henriquez-Olguin Carlos , Li Zhencheng , Leo Nicolas Di , Raun Steffen H. , Hingst Janne R. , Trouillon Raphaël , Wohlwend Martin , Wojtaszewski Jørgen F. P. , Gijs Martin A. M. , Jensen Thomas E.
Published: September 2022

Microtubules serve as tracks for long-range intracellular trafficking of glucose transporter 4 (GLUT4), but the role of this process in skeletal muscle and insulin resistance is unclear. Here, we used fixed and live-cell imaging to study microtubule-based GLUT4 trafficking in human and mouse muscle fibers and L6 rat muscle cells. We found GLUT4 localized along and on the microtubules in mouse and human muscle fibers. Pharmacological microtubule disruption using Nocodazole (Noco) prevented long-range GLUT4 trafficking and depleted GLUT4-enriched structures at microtubule nucleation sites in a fully reversible manner. Using a perfused muscle-on-a-chip system to enable real-time glucose uptake measurements in isolated mouse skeletal muscle fibers, we observed that Noco maximally disrupted the microtubule network after 5 min without affecting insulin-stimulated glucose uptake. In contrast, a 2h Noco treatment markedly decreased insulin responsiveness of glucose uptake. Insulin resistance in mouse muscle fibers induced either in vitro by C2 ceramides or in vivo by diet-induced obesity, impaired microtubule-based GLUT4 trafficking. In L6 muscle cells, pharmacological activation of the microtubule motor protein kinesin-1 increased basal and insulin-stimulated GLUT4 translocation, whereas shRNA-mediated knockdown of the kinesin-1 protein encoding gene Kif5B reduced insulin-stimulated GLUT4 translocation. Thus, in adult skeletal muscle fibers, the microtubule network is essential for intramyocellular GLUT4 movement, likely functioning to maintain an insulin-responsive cell-surface recruitable GLUT4 pool via kinesin-1 mediated trafficking.
Social problems and brain structure development following childhood mild traumatic brain injury
Authors: Dégeilh Fanny , Soest Tilmann von , Ferschmann Lia , Beer Joanne C. , Gaubert Malo , Koerte Inga K. , Tamnes Christian K.
Published: September 2022

Childhood mild traumatic brain injury (mTBI) is associated with elevated risk of developing social problems, which may be underpinned by changes in the structural developmental trajectory of the social brain, a network of cortical regions supporting social cognition and behavior. However, limited sample sizes and cross-sectional designs generally used in neuroimaging studies of pediatric TBI have prevented explorations of this hypothesis. This longitudinal retrospective study examined the development of parent-reported social problems and cortical thickness in social brain regions following childhood mTBI using data from the large population-based Adolescent Brain Cognitive Development (ABCD) Study. Two-group latent change score models revealed different developmental trajectories from ages 10 to 12 years in social problems between children with (n=345) and without (n=7,089) mTBI. Children with mTBI showed higher levels of social problems than controls at age 10. Then, social problems decreased over 2 years, but still remained higher than in controls in which they stayed stable. Both groups showed similar decreases in social brain cortical thickness between ages 10 and 12 years. Further studies providing detailed information on the injury mechanism and acute symptoms are needed to better understand individual differences in social impairment and brain development in pediatric TBI.
Prognostic value of 8q gain in relation to BAP1 and SF3B1 mutated uveal melanoma
Authors: Nguyen Josephine Q.N. , Drabarek Wojtek , Vaarwater Jolanda , Yavuzyigitoglu Serdar , Verdijk Robert M. , Paridaens Dion , Naus Nicole C. , de Klein Annelies , Brosens Erwin , Kiliç Emine
Published: September 2022

Unstructured abstract

Chromosome 8q gain is associated with poor prognosis. Here, we show that the predictive value of chromosome 8q gain depends on the mutation status and is true for BAP1 but not for SF3B1-mutated tumors.
Bacillus subtilis remains translationally active after CRISPRi-mediated replication initiation arrest
Authors: Muñoz-Gutierrez Vanessa , Cornejo Fabián A. , Schmidt Katja , Frese Christian K. , Halte Manuel , Erhardt Marc , Elsholz Alexander K.W. , Turgay Kürşad , Charpentier Emmanuelle
Published: September 2022

Initiation of bacterial DNA replication takes place at the origin of replication, a region characterized by the presence of multiple DnaA boxes that serve as the binding sites for the master initiator protein DnaA. The absence or failure of DNA replication can result in bacterial cell growth arrest or death. Here, we aimed to uncover the physiological and molecular consequences of stopping replication in the model bacterium Bacillus subtilis. For this purpose, DNA replication was blocked using a CRISPRi approach specifically targeting DnaA boxes 6 and 7, which are essential for replication initiation. We characterized the phenotype of these cells and analyzed the overall changes in the proteome using quantitative mass spectrometry. Cells with arrested replication were elongating and not dividing but showed no evidence of DNA damage response. Moreover, these cells did not cease translation over time. This study sets the ground for future research on non-replicating but translationally active B. subtilis, which might be a valuable tool for biotechnological applications.

Importance

Even though bacteria are constantly replicating under laboratory conditions, natural environments expose them to various stresses like lack of nutrients, high salinity, and pH changes, which can keep them in non-replicating states. Non-replicating states can allow bacteria to become less sensitive or tolerant to antibiotics (persisters), remain inactive in specific niches for an extended period (dormancy), and adapt to some hostile ecosystems. Non-replicating states have been studied due to the possibility of repurposing energy to produce additional metabolites or proteins. Using CRISPRi targeting bacterial replication initiation sequences, we successfully arrested the replication of B. subtilis. We observed that non-replicating cells continued growing but not dividing, and the initial arrest did not induce global stress conditions such as SOS or stringent response. Notably, these cells continued their metabolic activity and translation. This study provides comprehensive insights into the physiological response of replication initiation blockage in B. subtilis.
Carcinoma associated mesenchymal stem cells promote ovarian cancer metastasis by increasing tumor heterogeneity through direct mitochondrial transfer
Authors: Pressimone Catherine , Frisbie Leonard , Dyer Emma , Baruwal Roja , Croix Claudette St. , Watkins Simon , Calderone Michael , Gorecki Grace , Javed Zaineb , Atiya Huda I , Hempel Nadine , Pearson Alexander , Coffman Lan
Published: September 2022

Ovarian cancer is characterized by early, diffuse metastatic spread with most women presenting with extensive abdominal metastasis at the time of diagnosis. Prior work demonstrated carcinoma-associated mesenchymal stem cells (CA-MSCs) enhance ovarian cancer metastasis through a process of direct cellular interaction and formation of heterocellular CA-MSC and tumor cell complexes. In this study, we demonstrated that CA-MSCs enhance metastasis by increasing tumor cell heterogeneity through mitochondrial donation. We showed that CA-MSCs directly interacted with ovarian cancer cells via tunneling nanotubules (TNTs), and CA-MSCs used these TNTs to transfer live mitochondria to adjacent ovarian cancer cells. This mitochondrial donation preferentially occurred with ovarian cancer cells that had the lowest mitochondrial mass, as quantified using live, actively respiring mitochondrial labeling. These ‘mito poor’ cancer cells demonstrated decreased proliferation, increased sensitivity to chemotherapy, and decreased oxidative phosphorylation compared to ‘mito rich’ cancer cells. CA-MSCs rescued the phenotypes of mito poor cancer cells, restoring their proliferative capacity, increasing chemotherapy resistance, and increasing oxidative phosphorylation. We validated these findings in a fully autologous system using CA-MSCs and cancer cells derived from the same patient to prevent confounding effects of cellular response to foreign organelle/DNA. Using a knockdown of the mitochondrial motor protein, MIRO1, in CA-MSCs, we demonstrated that mitochondrial transfer is necessary for the CA-MSC-mediated rescue of ‘mito poor’ cancer cells. Mitochondria of CA-MSC origin persisted in tumor cells over multiple passages. Importantly, CA-MSC mitochondrial donation occurred in vivo, significantly enhanced tumor cell heterogeneity and decreased survival in an orthotopic ovarian cancer mouse model. Collectively, this work identified CA-MSC mitochondrial transfer as a critical mediator of ovarian cancer cell survival, heterogeneity, and metastasis, and blocking CA-MSC mitochondrial transfer represents a unique therapeutic target in ovarian cancer.
Experimental Parameters-Based Monte-Carlo Simulation of Single-Molecule Localization Microscopy of Nuclear Pore Complex to Evaluate Clustering Algorithms
Authors: Yeo Wei-Hong , Zhang Yang , Neely Amy E. , Bao Xiaomin , Sun Cheng , Zhang Hao F.
Published: September 2022

Single-molecule localization microscopy (SMLM) enables the detailed visualization of nuclear pore complexes (NPC) in vitro with sub-20 nm resolution. However, it is challenging to translate the localized coordinates in SMLM images to NPC functions because different algorithms to cluster localizations as individual NPCs can be biased without ground truth for validation. We developed a Monte-Carlo simulation to generate synthetic SMLM images of NPC and used the simulated NPC images as the ground truth to evaluate the performance of six clustering algorithms. We identified HDBSCAN as the optimal clustering algorithm for NPC counting and sizing. Furthermore, we compared the clustering results between the experimental and synthetic data for NUP133, a subunit in the NPC, and found them to be in good agreement.
Massively-parallel Microbial mRNA Sequencing (M3-Seq) reveals heterogeneous behaviors in bacteria at single-cell resolution
Authors: Wang Bruce , Lin Aaron E. , Yuan Jiayi , Koch Matthias D. , Adamson Britt , Wingreen Ned S. , Gitai Zemer
Published: September 2022

Bacterial populations are highly adaptive. They can respond to stress and survive in shifting environments. How the behaviors of individual bacteria vary during stress, however, is poorly understood. To identify and characterize rare bacterial subpopulations, technologies for single-cell transcriptional profiling have been developed. Existing approaches, though, are all limited in some technical capacity (e.g., number of cells or transcripts that can be profiled). Due in part to these limitations, few conditions have yet been studied with these tools. Here, we developMassively-parallelMicrobialmRNA sequencing (M3-Seq), a single-cell RNA-sequencing platform for bacteria that pairs combinatorial cell indexing withpost hocrRNA depletion. We show that M3-Seq can profile hundreds of thousands of bacterial cells from different species under a range of conditions in single experiments. We then apply M3-Seq to reveal rare populations, insights into bet hedging strategies during stress responses, and host responses to phage infection.
A chromosome-assigned Mongolian gerbil genome with sequenced centromeres provides evidence of a new chromosome
Authors: Brekke Thomas D. , Papadopulos Alexander S. T. , Julià Eva , Fornas Oscar , Fu Beiyuan , Yang Fengtang , de la Fuente Roberto , Page Jesus , Baril Tobias , Hayward Alexander , Mulley John F.
Published: September 2022

Chromosome-scale genome assemblies based on ultra-long read sequencing technologies are able to illuminate previously intractable aspects of genome biology such as fine-scale centromere structure and large-scale variation in genome features such as heterochromatin, GC content, recombination rate, and gene content. We present here a new chromosome-scale genome of the Mongolian gerbil (Meriones unguiculatus) which includes the complete sequence of all centromeres. Gerbil centromeres are composed of four different repeats of length 6pb, 37bp, 127bp, or 1747bp which occur in simple alternating arrays and span 1-6Mb. Gerbil genomes have both an extensive set of GC-rich genes and chromosomes strikingly enriched for constitutive heterochromatin. We sought to determine if there was a link between these two phenomena and found that the two heterochromatic chromosomes of the Mongolian gerbil have distinct underpinnings: Chromosome 5 has a large block of intra-arm heterochromatin as the result of a massive expansion of centromeric repeats, while chromosome 13 is comprised of extremely large (>150kb) repeated sequences. In addition to characterizing centromeres, our results demonstrate the importance of including karyotypic features such as chromosome number and the locations of centromeres in the interpretation of genome sequence data, and highlight novel patterns involved in the evolution of chromosomes.
Efficient estimation of time-dependent functional connectivity using Structural Connectivity constraints
Authors: Hernandez Larzabal Hernan , Araya David , Gonzalez Rodriguez Lazara Liset , Roman Claudio , Trujillo-Barreto Nelson , Guevara Pamela , El-Deredy Wael
Published: September 2022

Multivariate autoregressive models [MAR] allows estimating effective brain connectivity by considering both power and phase fluctuations of the signals involved. A MAR models brain activity in one region as a linear combination of past activations in all other regions. A Hidden Markov model, HMM, whose states’ emisions are drawn from state-specific MARs, can then be used to model fast switching of effective brain connectivity over time. However, the large number of MAR parameters, impede the accurate and efficient estimation of such models from neuroimaging timeseries with limited length.

We propose a new model for inferring time-dependent effective brain connectivity by using a sparse MAR parameterisation to model the states’ emisions of a Hidden Semi-Markov Model, HsMM-MAR-AC. The sparse MAR model parameters are restricted by Anatomical Connectivity information in two ways: direct effective connectivity between two regions is only considered if the corresponding structural link/connection exists; and the time-lag associated with each direct connection is computed based on the average fibre length between the two regions, such that only one lag per connection is estimated.

We simulated ground truth time-dependent brain connectivity states by generating time-series of 4 to 10 minutes sampled at 5ms, from switching Resting State Networks with a reference structural connectivity, and evaluated the accuracy of the new model in recovering the simulated Brain connectivity States against different levels of connectivity thresholding above and below the reference.

We show that even when restricting the MAR to half of the reference connections, the model was able to recover the number of brain states, the associated connectivity features and their dynamics, with as little data as 4 mins. More relaxed structural connectivity thresholds required longer data to estimate the model accurately, and became computationally unfeasible without anatomical restrictions.

HsMM-MAR-AC offers an efficient algorithm for estimating time-depend Effective Connectivity (tdEC) from neuroimaging data, that exploits the advantages of MAR without identifiability problems, excessive demand on data collection, or unnecessary computational complexity.
Thalamic regulation of a visual critical period and motor behavior
Authors: Hageter John , Starkey Jacob , Horstick Eric J
Published: September 2022

During the visual critical period, sensory experience refines the structure and function of visual circuits. The basis of this plasticity was long thought to be limited to cortical circuits, yet recently described thalamic ocular dominance plasticity challenges this dogma and demonstrates greater complexity underlying visual plasticity. Yet how visual experience modulates responses of thalamic neurons or how the thalamus modulates CP timing is incompletely understood. Using a novel larval zebrafish, thalamus-centric ocular dominance model, we show functional changes in the thalamus and a role of inhibitory signaling to establish critical period timing using a combination of functional imaging, optogenetics, and pharmacology. Moreover, hemisphere-specific functional changes in genetically defined thalamic neurons correlate with changes in visuomotor behavior, establishing a role of thalamic plasticity in modulating motor performance. Together, our work demonstrates that visual plasticity is more broadly conserved and shows that visual experience leads to neuron-level functional changes in the thalamus that require inhibitory signaling to establish critical period timing.
A conserved ribosomal protein has entirely dissimilar structures in different organisms
Authors: Schierholz Léon , Brown Charlotte R. , Helena-Bueno Karla , Uversky Vladimir N. , Hirt Robert P. , Barandun Jonas , Melnikov Sergey V.
Published: September 2022

Ribosomes from different species can markedly differ in their composition by including dozens of ribosomal proteins that are unique to specific lineages but absent in others. However, it remains unknown how ribosomes acquire and specialize new proteins throughout evolution. Here, to help answer this question, we describe the evolution of the ribosomal protein msL1/msL2 that was recently found in ribosomes from the parasitic microorganism clade, microsporidia. We first show that this protein has a conserved location in the ribosome but entirely dissimilar structures in different organisms: in each of the analyzed species, msL1/msL2 exhibits an altered secondary structure, an inverted orientation of the N- and C-termini on the ribosomal binding surface, and a completely transformed three-dimensional fold. We then show that this evolutionary fold switching is likely caused by changes in the msL1/msL2-binding site in the ribosome; specifically, by variations in microsporidian rRNA. These observations allow us to infer an evolutionary scenario in which a small, positively-charged,de novo-born unfolded protein was first captured by rRNA to become part of the ribosome and subsequently underwent complete fold switching to optimize its binding to its evolving ribosomal binding site. Overall, our work provides a striking example of how a protein can switch its fold in the context of a complex biological assembly while retaining its specificity for its molecular partner. This finding will help us better understand the origin and evolution of new protein components of complex molecular assemblies – thereby enhancing our ability to engineer biological molecules, identify protein homologs, and peer into the history of life on Earth.
Repetitive mild traumatic brain injury impairs resting state fMRI connectivity and alters protein profile signaling networks
Authors: Ravi Sakthivel , Criado-Marrero Marangelie , Barroso Daylin , Braga Isadora M , Bolen Mackenzie , Rubinovich Uriel , Hery Gabriela P. , Grudny Matteo M , Koren John , Prokop Stefan , Febo Marcelo , Abisambra Jose Francisco
Published: September 2022

Repetitive mild traumatic brain injury (rmTBI) is a leading and severe threat to cognition that often goes undiagnosed. A major challenge in developing diagnostics and treatments for the consequences of rmTBI is the fundamental knowledge gaps that explain how rmTBI promotes brain dysfunction. It is both critical and urgent to understand the neuropathological and functional consequences of rmTBI to develop effective therapeutic strategies. In this study, we sought to define the extent of altered brain functional connectivity (FC) and expression of neuropathological markers after rmTBI. We performed two rmTBI (2x 0.6□J impacts 24□h apart) in male and female C57BL/6J wild-type (WT) (~2.5-3mo) mice using closed head injury model of engineered rotational acceleration (CHIMERA) or sham procedures. At 5-6 days post-injury (dpi), we measured changes in brain volume and FC using T2-weighted images, resting-state functional MRI (rsfMRI), and graph theory analyses. We used diffusion tensor imaging (DTI) to assess microstructural changes in white matter tracts. In addition, at 7dpi, we measured changes in Iba1 and GFAP to determine the extent of gliosis. The expression of disease-associated protein markers in grey and white matter regions were evaluated using the NanoString-GeoMx digital spatial protein profiling (DSP) platform. The rsfMRI data revealed aberrant changes in connectivity such as node clustering coefficient, global and local efficiency, participation coefficient, eigenvector centrality, and betweenness centrality in thalamus and other key brain regions that process visual, auditory, and somatosensory information. In addition, DTI revealed significantly decreased fractional anisotropy (FA) and axial diffusivity in the optic tract. Also, mean, radial, and axial diffusivity (L1) were significantly increased in the hippocampus. DSP revealed that phospho-serine 199 tau (pS199) as well as glial markers such as GFAP, cathepsin-D, and Iba1 were significantly increased in the optic tract. In thalamic nuclei, the neuroinflammatory marker GPNMB was increased significantly, and the cell proliferation marker Ki-67 was decreased in the rmTBI group. Our data suggest that rmTBI significantly alters brain functional connectivity and causes a profound inflammatory response in gray matter regions, beyond chronic white matter damage.
Mesenchymal stem cell suppresses the efficacy of CAR-T toward killing lymphoma cells by modulating the microenvironment through stanniocalcin-1
Authors: Zhang Rui , Liu Qingxi , Zhou Sa , He Hongpeng , Zhao Mingfeng , Ma Wenjian
Published: September 2022

Stem cells play critical roles both in the development of cancer and therapy resistance. Although mesenchymal stem cells (MSCs) can actively migrate to tumor sites, their impact on CAR-T immunotherapy has been little addressed. Using an in vitro cell co-culture model including lymphoma cells and macrophages, here we report that the CAR-T cell mediated cytotoxicity was significantly inhibited in the presence of MSCs. MSC caused an increase of CD4+ T cells and Treg cells but decrease of CD8+ T cells. In addition, MSCs stimulated the expression of indoleamine 2,3-dioxygenase (IDO) and programmed cell death-ligand 1 (PD-L1) that contribute to the immune-suppressive function of tumor. Moreover, MSCs suppressed key components of NLRP3 inflammasome by modulating mitochondrial ROS release. Interestingly, all these suppressive events hindering CAR-T efficacy could be abrogated if the STC1 gene, which encodes the glycoprotein hormone staniocalcin-1, was knockdown in MSC. Using xenograft mice, we confirmed that CAR-T function could also be inhibited by MSC in vivo and STC1 played a critical role. These data revealed a novel function of MSC and staniocalcin-1 in suppressing CAR-T efficacy, which should be considered in cancer therapy and may also have potential applications in controlling the toxicity arising from excessive immune response.
Alternative proteoforms and proteoform-dependent assemblies in humans and plants
Authors: McWhite Claire D. , Sae-Lee Wisath , Yuan Yaning , Mallam Anna L. , Gort-Freitas Nicolas A. , Ramundo Silvia , Onishi Masayuki , Marcotte Edward M.
Published: September 2022

Variability of proteins at the sequence level creates an enormous potential for proteome complexity. Exploring the depths and limits of this complexity is an ongoing goal in biology. Here, we systematically survey human and plant high-throughput bottom-up native proteomics data for protein truncation variants, where substantial regions of the full-length protein are missing from an observed protein product. In humans, Arabidopsis, and the green alga Chlamydomonas, approximately one percent of observed proteins show a short form, which we can assign by comparison to RNA isoforms as either likely deriving from transcript-directed processes or limited proteolysis. While some detected protein fragments align with known splice forms and protein cleavage events, multiple examples are previously undescribed, such as our observation of fibrocystin proteolysis and nuclear translocation in a green alga. We find that truncations occur almost entirely between structured protein domains, even when short forms are derived from transcript variants. Intriguingly, multiple endogenous protein truncations of phase-separating translational proteins resemble cleaved proteoforms produced by enteroviruses during infection. Some truncated proteins are also observed in both humans and plants, suggesting that they date to the last eukaryotic common ancestor. Finally, we describe novel proteoform-specific protein complexes, where loss of a domain may accompany complex formation.
Assembly mechanism of the AIM2 inflammasome sensor revealed by single-molecule analysis
Authors: Sharma Meenakshi , de Alba Eva
Published: September 2022

Pathogenic dsDNA prompts AIM2 (Absent In Melanoma 2) assembly leading to the formation of the inflammasome, a multimeric complex that triggers the inflammatory response. The recognition of foreign dsDNA involves AIM2 self-assembly concomitant with dsDNA binding. However, we lack mechanistic and kinetic information on the formation and propagation of the assembly, which can shed light on innate immunity’s time response and specificity. Using correlative optical traps and fluorescence microscopy, we determine here the association and dissociation rates of the AIM2-DNA complex at the single-molecule level. We identify distinct mechanisms for oligomer growth via the binding of incoming AIM2 molecules to adjacent dsDNA or direct interaction with bound AIM2 assemblies, thus resembling primary and secondary nucleation processes. Through these mechanisms, AIM2 oligomers increase at least fourfold their size in seconds. Finally, our data indicate that single AIM2 molecules do not diffuse/scan along the DNA, suggesting that oligomerization depends on stochastic encounters with DNA and/or DNA-bound AIM2 molecules.
Transcription factor TFII-I fine tunes innate properties of B lymphocytes
Authors: Singh Amit , Kaileh Mary , De Supriyo , Mazan-Mamczarz Krystyna , Bayarsaihan Dashzeveg , Sen Ranjan , Roy Ananda L
Published: September 2022

The ubiquitously expressed transcription factor TFII-I is a multifunctional protein with pleiotropic roles in gene regulation. TFII-I associated polymorphisms are implicated in Sjögren’s syndrome and Lupus in humans and, germline deletion of the Gtf2i gene in mice leads to embryonic lethality. Here we report a unique role for TFII-I in homeostasis of innate properties of B lymphocytes. Loss of Gtf2i in murine B lineage cells leads to a change in transcriptome and chromatin landscape, which resembles myeloid-like features and coincides with enhanced sensitivity to LPS induced transcription. TFII-I deficient B cells also show increased switching to IgG3, a phenotype associated with inflammation. These results demonstrate a role for TFII-I in maintaining immune homeostasis and provide clues for GTF2I polymorphisms associated with B cell dominated autoimmune diseases in humans.
Multi-modal brain magnetic resonance imaging database covering marmosets with a wide age range
Authors: Hata Junichi , Nakae Ken , Tsukada Hiromichi , Woodward Alexander , Haga Yawara , Iida Mayu , Uematsu Akiko , Seki Fumiko , Ichinohe Noritaka , Gong Rui , Kaneko Takaaki , Yoshimaru Daisuke , Watakabe Akiya , Abe Hiroshi , Tani Toshiki , Skibbe Henrik , Maeda Masahide , Papazian Frederic , Hagiya Kei , Kishi Noriyuki , Shimogori Tomomi , Yamamori Tetsuo , Okano Hirotaka James , Okano Hideyuki
Published: September 2022

Magnetic resonance imaging (MRI) is a noninvasive neuroimaging method beneficial for the identification of normal developmental and aging processes and data sharing. Marmosets have a relatively shorter life expectancy (approximately 10 years) than other primates, including, humans because they grow and age faster. Hence, the common marmoset model is effective in aging research. The current study investigated the aging process of the marmoset brain and provided an open MRI database on marmosets with a wide age range. The Brain/MINDS Marmoset Brain MRI Dataset contains brain MRI information on 216 marmosets aged between 1 and 10 years. During its release date, it is the largest public dataset worldwide. Further, it comprises multi contrast MRI images. In addition, 91 of 216 animals have corresponding ex vivo high-resolution MRI datasets. Our MRI database, which is available at the Brain/MINDS Data portal might help understand the effects of different factors, such as age, sex, body size, and fixation, on the brain. Moreover, it can contribute to and accelerate brain science studies worldwide.
Profiling Dynamic Patterns of Single-cell Motility
Authors: Maity Debonil , Sivakumar Nikita , Kamat Pratik , Zamponi Nahuel , Min Chanhong , Du Wenxuan , Jayatilaka Hasini , Johnston Adrian , Starich Bartholomew , Agrawal Anshika , Riley Deanna , Venturutti Leandro , Melnick Ari , Cerchietti Leandro , Walston Jeremy , Phillip Jude M.
Published: September 2022

Cell motility plays an essential role in many biological processes as cells move and interact within their local microenvironments. Current methods for quantifying cell motility typically involve tracking individual cells over time, but the results are often presented as averaged values across cell populations. While informative, these ensemble approaches have limitations in assessing cellular heterogeneity and identifying generalizable patterns of single-cell behaviors, at baseline and in response to perturbations. In this study, we introduce CaMI, a computational framework designed to leverage the single-cell nature of motility data. CaMI identifies and classifies distinct spatio-temporal behaviors of individual cells, enabling robust classification of single-cell motility patterns in a large dataset (n=74,253 cells). This framework allows quantification of spatial and temporal heterogeneities, determination of single-cell motility behaviors across various biological conditions, and provides a visualization scheme for direct interpretation of dynamic cell behaviors. Importantly, CaMI reveals insights that conventional cell motility analyses may overlook, showcasing its utility in uncovering robust biological insights. Together, we present a multivariate framework to classify emergent patterns of single-cell motility, emphasizing the critical role of cellular heterogeneity in shaping cell behaviors across populations.

Teaser

A computational framework to identify and classify single-cell motility patterns and phenotypic heterogeneity across biological conditions.
Classification of patients with osteoarthritis through clusters of comorbidities using 633,330 individuals from Spain
Authors: Pineda-Moncusí Marta , Dernie Francesco , Dell’Isola Andrea , Kamps Anne , Runhaar Jos , Swain Subhashisa , Zhang Weiya , Englund Martin , Pitsillidou Irene , Strauss Victoria Y , Robinson Danielle E , Prieto-Alhambra Daniel , Khalid Sara
Published: September 2022

Objectives

To explore clustering of comorbidities among patients with a new diagnosis of osteoarthritis (OA) and estimate the 10-year mortality risk for each identified cluster.

Methods

This is a population-based cohort study of individuals with first incident diagnosis of OA of the hip, knee, ankle/foot, wrist/hand, or ‘unspecified’ site between 2006 and 2020, using SIDIAP (a primary care database representative from Catalonia, Spain). At the time of OA diagnosis, conditions associated with OA in the literature that were found in ≥1% of the individuals (n=35) were fitted into two cluster algorithms, K-means and latent class analysis (LCA). Models were assessed using a range of internal and external evaluation procedures. Mortality risk of the obtained clusters was assessed by survival analysis using Cox proportional hazards.

Results

We identified 633,330 patients with a diagnosis of OA. Our proposed best solution used LCA to identify four clusters: ‘Low-morbidity (relatively low number of comorbidities), ‘Back/neck pain plus mental health’, ‘Metabolic syndrome’ and ‘Multimorbidity’ (higher prevalence of all study comorbidities). Compared to the ‘Low-morbidity, the ‘Multimorbidity’ cluster had the highest risk of 10-year mortality (adjusted HR: 2.19 [95%CI: 2.15-2.23]), followed by ‘Metabolic syndrome’ (adjusted HR: 1.24 [95%CI: 1.22-1.27]]) and ‘Back/neck pain plus mental health’ (adjusted HR: 1.12 [95%CI: 1.09-1.15]).

Conclusion

Patients with a new diagnosis of OA can be clustered into groups based on their comorbidity profile, with significant differences in 10-year mortality risk. Further research is required to understand the interplay between OA and particular comorbidity groups, and the clinical significance of such results.

Key Messages

Patients with newly diagnosed osteoarthritis can by classified into different clusters by their comorbidity patterns.

Such classification can help identify ‘high-risk’ patients who require more intense attention from healthcare providers.

The main patient sub-groups were ‘Low-morbidity’, ‘Back/neck pain plus mental health’, ‘Metabolic syndrome’ and ‘Multimorbidity’.