bluuebunny/crossref_metadata_2025 huggingface dataset:
The Transoral Alar Batten (TAB) Graft: A Functional Rhinoplasty Technique for the Orthognathic Jaw Surgery Patient
Authors: Garg Ravi K. , Vance Dylan T. , O’Connor Michaela K.
Published: March 2023

Many patients seeking orthognathic jaw surgery also experience nasal obstruction. Currently transoral functional rhinoplasty techniques include septoplasty and inferior turbinate reduction, which are performed through the mouth following maxillary downfracture. Although powerful, these interventions do not treat dynamic nasal sidewall collapse. Here we describe a novel transoral alar batten (TAB) graft. Using the maxillary vestibular approach, septal cartilage is harvested and delivered from the maxillary vestibule into the nasal alar-sidewall junction through a small tunnel. This procedure is simple, versatile, and carries minimal morbidity, enabling the orthognathic jaw surgeon to support the nasal sidewall through a minimal access approach and improve the patient’s nasal function and airway.
“Structure and Mechanical Performance Biomimetic Costal Cartilage Models for Ear Framework Handcraft Simulation.”
Authors: Wang Di , Lin Lin , Yang Qinghua , Song Yupeng , Zhou Jiayu , Zhang He , Yang Yang , Pan Bo , Jiang Haiyue
Published: March 2023

Ear framework handcraft simulation using costal cartilage models is crucially important for ear reconstruction surgery education. Fabricating proper models mechanically and structurally comparable to their native counterparts is an unmet challenge. Herein, the authors developed structure and mechanical performance bio-mimetic costal cartilage models used for practicing and simulating handcraft of ear framework. High-tensile silicone and three-dimensional techniques were utilized to fabricate bio-mimetic models. The models well replicated the three-dimensional structure of human costal cartilage. Proved by comprehensive mechanical tests, high-tensile silicone models had similar stiffness, hardness, and suture retention ability to their native counterparts, which was distinctly superior to commonly used materials for costal cartilage simulation. This kind of model satisfied surgeons and contributed to outstanding ear frameworks. The recreated models were used in ear framework handcrafting workshops. Novices’ surgical simulation performance with different models was compared and analyzed. People who used high-tensile silicone models enjoy greater progress and confidence after training. Using high-tensile silicone costal cartilage models is an excellent choice for practicing and simulating the fabrication of ear frameworks manually. They benefit practitioners and students much in practicing handcraft ear frameworks and surgical skill gains.
“Efficacy and safety of expanded polytetrafluoroethylene implantation in the correction of long-term posttraumatic enophthalmos”
Authors: Zhou Sizheng , Jiang Taoran , Zhong Yehong , Yu Zheyuan , Duan Huichuan , Li Dong , Xu Liang , Yuan Jie , Wei Min
Published: March 2023

Long-term enophthalmos is a common orbital fracture sequela. Various autografts and alloplastic materials have been studied in post-traumatic enophthalmos repair. However, the expanded polytetrafluoroethylene (ePTFE) implantation in late enophthalmos repair has scarcely been reported. Herein, we report novel use of ePTFE for late post-traumatic enophthalmos (PTE) repair. This retrospective study included patients with post-traumatic long-term enophthalmos who underwent hand-carved ePTFE intraorbital implantation for enophthalmos correction. Computed tomography data were collected preoperatively and at follow-up. The volume of ePTFE, the degree of proptosis (DP), and enophthalmos were measured. Postoperative and preoperative DP and enophthalmos were compared using paired t-test. The correlation between ePTFE volume and DP increment was established using linear regression. Complications were identified via chart review. Results showed that from 2014 to 2021, 32 patients were included, with a mean follow-up of 19.59 months. The mean volume of implanted ePTFE was 2.39 ± 0.89 ml. After surgery, the DP of the affected globe significantly improved from 12.75 ± 2.12 mm to 15.06 ± 2.50 mm (p<0.0001). A significant linear correlation was found between ePTFE volume and DP increment (p<0.0001). Enophthalmos were substantially ameliorated from 3.35 ± 1.89 mm to 1.09 ± 2.07 mm (p<0.0001). Twenty-five (78.23%) patients had postoperative enophthalmos less than 2 mm. Infection and implant dislocation were not observed. The authors concluded that ePTFE intraorbital implantation exhibited long-term efficacy and safety for late PTE repair. Thus, the ePTFE method is an effective and predictable alternative.
Prognostic Factors for Speech Outcome among Patients with Submucous Cleft Palate Managed by Furlow Palatoplasty or Posterior Pharyngeal flap
Authors: Zhang Bei , Shi Bing , Zheng Qian , Li Jingtao
Published: March 2023

Background:

Submucous cleft palate (SMCP) is a particular subtype of cleft deformity with the optimal surgical timing and technique still under debate. This study aimed to identify potential prognostic factors for the speech outcome of patients with SMCP and provide evidence for further management strategy optimization.

Methods:

We reviewed patients with nonsyndromic SMCP who received either Furlow palatoplasty (FP) or posterior pharyngeal flap (PPF) between 2008 and 2021 in a tertiary hospital-based cleft center. Both univariate and multivariate logistic regression models were employed to screen preoperative variables including cleft type (overt or occult), age at surgery, mobility of velum and pharyngeal wall, velopharyngeal closure ratio and pattern. Receiver operating characteristic curve was utilized to determine the cut-off value of the significant predictors for subgroup comparison.

Results:

A total of 131 patients were enrolled, with 92 receiving FP and 39 receiving PPF. Age at operation and cleft type were identified with significant impacts on FP outcome. Patients operated before 9.5 years demonstrated significantly higher velopharyngeal competence (VPC) rate than those operated after. The speech outcome among patients with occult SMCP was significantly worse than overt cases after FP treatment. No preoperative variable was found as correlated with PPF outcome. PPF yield higher VPC rate than FP among patients operated above 9.5 years.

Conclusions:

The prognosis of FP treated SMCP patients is sensitive to age at surgery and cleft type. PPF may be considered for aged patients in settings with limited access to multiple surgeries, especially when occult SMCP is diagnosed.
No long-term effect of past Pneumocystis jirovecii pneumonia on pulmonary function in people with HIV
Authors: Oomen Patrick G.A. , Bronsveld Inez , Hoepelman Andy I.M. , van Welzen Berend J. , Mudrikova Tania
Published: March 2023

Objective:

To assess the impact of past Pneumocystis jirovecii pneumonia (PJP) on the pulmonary diffusion capacity in people with HIV (PWH) with a history of advanced immunodeficiency.

Design:

Prospective cross-sectional study.

Methods:

Adult PWH with past PJP >1 year ago were included as the study group. The control group consisted of PWH with a nadir CD4+ lymphocyte count <200 cells/mm3, matched by age, sex, smoking status and time since HIV diagnosis. All PWH completed a pulmonary function test (PFT) consisting of pre-bronchodilation spirometry, body plethysmography and single-breath carbon monoxide transfer factor (TLCO) measurement. TLCO, diffusion impairment (defined as a TLCO Z-score <−1.645), total lung capacity (TLC) and forced expiratory volume in one second/forced vital capacity (FEV1/FVC) Z-scores were assessed. Multivariable regression analyses were conducted with Z-scores and odds of diffusion impairment as outcomes.

Results:

PFTs of 102 participants were analyzed, 51 of whom had past PJP with a median of 10 years since PJP. Mean TLCO Z-score and diffusion impairment rate did not differ significantly between groups (P = 0.790; P = 0.650). Past PJP was not independently associated with TLCO Z-score [β = 0.14; 95% confidence interval (CI) −0.30–0.57], diffusion impairment (odds ratio 1.00; 95% CI 0.36–2.75) nor TLC or FEV1/FVC Z-scores, whereas current (vs. never) smoking was associated with more diffusion impairment and lower TLCO Z-scores.

Conclusion:

In our study, past PJP was not associated with long-term diffusion impairment. Our findings suggest that smoking plays a more important role in persistent pulmonary function impairment whereas PJP-related changes seem to be reversible.
Improved Breast 2D SWE Algorithm to Eliminate False-Negative Cases
Authors: Barr Richard G. , Engel Aaron , Kim Su , Tran Phuong , De Silvestri Annalisa
Published: March 2023

Objectives

Two-dimensional shear wave elastography (SWE) has been limited in breast lesion characterization due to false-negative results from artifacts. The aim of this study was to evaluate an updated Food and Drug Administration–approved breast 2D-SWE algorithm and compare with the standard algorithm (SA).

Materials and Methods

This prospective, single-center study was approved by our local institutional review board and Health Insurance Portability and Accountability Act compliant. From April 25, 2019 to May 2, 2022, raw shear wave data were saved on patients having screening or diagnostic breast ultrasound on a Siemens Sequoia US. After removing duplicate images and those without biopsy diagnosis or stability over 2 years, there were 298 patients with 394 lesions with biopsy-proven pathology or >2-year follow-up. Raw data were processed using the SA and a new algorithm (NA). Five-millimeter regions of interest were placed in the highest stiffness in the lesion or adjacent 3 mm on the SA. Stiffness values (shear wave speed, max) in this location from both algorithms were recorded. Statistics were calculated for comparing the 2 algorithms.

Results

The mean patient age was 56.3 ± 16.1 years (range, 21–93 years). The mean benign lesion size was 10.7 ± 8.0 mm (range, 2–46 mm), whereas the mean malignant lesion size was 14.9 ± 7.8 mm (range, 4–36 mm). There were 201 benign (>2-year follow-up) and 193 biopsied lesions (65 benign; 128 malignant). The mean maximum stiffness for benign lesions was 2.37 m/s (SD 1.26 m/s) for SA and 3.51 m/s (SD 2.05 m/s) for NA. For malignant lesions, the mean maximum stiffness was 4.73 m/s (SD, 1.71 m/s) for SA and 8.45 m/s (SD, 1.42 m/s) for NA. The area under the receiver operating characteristic curve was 0.87 SA and 0.95 NA when using the optimal cutoff value. Using a threshold value of 5.0 m/s for NA and comparing to SA, the sensitivity increased from 0.45 to 1.00 and the specificity decreased from 0.94 to 0.81; the positive predictive value was 0.72, the negative predictive value was 1.00, and the negative likelihood ratio was 0.00.

Conclusions

Using a new breast SWE algorithm significantly improves the sensitivity of the technique with a small decrease in specificity, virtually eliminating the “soft” cancer artifact. The new 2D-SWE algorithm significantly increases the sensitivity and negative predictive value in characterizing breast lesions as benign or malignant and allows for downgrading all BI-RADS 4 lesions.
Infants With Trigonocephaly Treated With Fronto-Orbital Remodelling and Endocortical Positioning of Resorbable Plates—A Retrospective Cohort Study Including 101 Patients
Authors: Zittel Sven , Ristow Oliver , Moratin Julius , Rückschloß Thomas , Hoffmann Jürgen , El Damaty Ahmed , Freudlsperger Christian , Engel Michael
Published: March 2023

Purpose:

Fronto-orbital remodeling is the gold standard for surgical treatment of metopic synostosis in many craniofacial centers. For fixation, resorbable materials are widely used. Because of swelling during resorption, the positioning of the plates can be relevant. Therefore, the goal of this study was to investigate whether there are limitations to endocortical positioning of resorbable plates.

Methods:

In this retrospective study, all patients with metopic craniosynostosis resulting in trigonocephaly, who were treated with a standardized fronto-orbital remodeling and endocortical positioning of resorbable plates, between February 2012 and December 2019 were included. The endpoint of this study was the postoperative complications that can be attributed to the material used.

Results:

A total of 101 patients, who were treated at our unit, could be included with a male predominance, 81 (80.2%) boys versus 20 (19.8%) girls. Surgery was performed at a median age of 9 months (±2.56). No complications were seen related to resorbable plates. All patients of our study population were categorized as Whitaker classification I and II.

Conclusion:

This study shows that the risk level in using endocortical resorbable plates positioned on the inner surface of the bone is low. From an aesthetic point of view, we could not detect any disadvantage.
Stackelberg evolutionary game theory: how to manage evolving systems
Authors: Stein Alexander , Salvioli Monica , Garjani Hasti , Dubbeldam Johan , Viossat Yannick , Brown Joel S. , Staňková Kateřina
Published: March 2023

Stackelberg evolutionary game (SEG) theory combines classical and evolutionary game theory to frame interactions between a rational leader and evolving followers. In some of these interactions, the leader wants to preserve the evolving system (e.g. fisheries management), while in others, they try to drive the system to extinction (e.g. pest control). Often the worst strategy for the leader is to adopt a constant aggressive strategy (e.g. overfishing in fisheries management or maximum tolerable dose in cancer treatment). Taking into account the ecological dynamics typically leads to better outcomes for the leader and corresponds to the Nash equilibria in game-theoretic terms. However, the leader’s most profitable strategy is to anticipate and steer the eco-evolutionary dynamics, leading to the Stackelberg equilibrium of the game. We show how our results have the potential to help in fields where humans try to bring an evolutionary system into the desired outcome, such as, among others, fisheries management, pest management and cancer treatment. Finally, we discuss limitations and opportunities for applying SEGs to improve the management of evolving biological systems.

This article is part of the theme issue ‘Half a century of evolutionary games: a synthesis of theory, application and future directions’.
Evolutionary game theory and the adaptive dynamics approach: adaptation where individuals interact
Authors: Avila Piret , Mullon Charles
Published: March 2023

Evolutionary game theory and the adaptive dynamics approach have made invaluable contributions to understanding how gradual evolution leads to adaptation when individuals interact. Here, we review some of the basic tools that have come out of these contributions to model the evolution of quantitative traits in complex populations. We collect together mathematical expressions that describe directional and disruptive selection in class- and group-structured populations in terms of individual fitness, with the aims of bridging different models and interpreting selection. In particular, our review of disruptive selection suggests there are two main paths that can lead to diversity: (i) when individual fitness increases more than linearly with trait expression; (ii) when trait expression simultaneously increases the probability that an individual is in a certain context (e.g. a given age, sex, habitat, size or social environment) and fitness in that context. We provide various examples of these and more broadly argue that population structure lays the ground for the emergence of polymorphism with unique characteristics. Beyond this, we hope that the descriptions of selection we present here help see the tight links among fundamental branches of evolutionary biology, from life history to social evolution through evolutionary ecology, and thus favour further their integration.

This article is part of the theme issue ‘Half a century of evolutionary games: a synthesis of theory, application and future directions’.
Hermaphroditic origins of anisogamy
Authors: Henshaw Jonathan M. , Bittlingmaier Markus , Schärer Lukas
Published: March 2023

Anisogamy—the size dimorphism of gametes—is the defining difference between the male and female sexual strategies. Game-theoretic thinking led to the first convincing explanation for the evolutionary origins of anisogamy in the 1970s. Since then, formal game-theoretic models have continued to refine our understanding of when and why anisogamy should evolve. Such models typically presume that the earliest anisogamous organisms had separate sexes. However, in most taxa, there is no empirical evidence to support this assumption. Here, we present a model of the coevolution of gamete size and sex allocation, which allows for anisogamy to emerge alongside either hermaphroditism or separate sexes. We show that hermaphroditic anisogamy can evolve directly from isogamous ancestors when the average size of spawning groups is small and fertilization is relatively efficient. Sex allocation under hermaphroditism becomes increasingly female-biased as group size decreases and the degree of anisogamy increases. When spawning groups are very small, our model also predicts the existence of complex isogamous organisms in which individuals allocate resources equally to two large gamete types. We discuss common, but potentially unwarranted, assumptions in the literature that could be relaxed in future models.

This article is part of the theme issue ‘Half a century of evolutionary games: a synthesis of theory, application and future directions’.
Nocardioides okcheonensis sp. nov., isolated from riverside soil
Authors: Kim Ju Hee , Ham You Ju , Kim Seung Bum
Published: March 2023

An actinobacterial strain designated MMS20-HV4-12T, displaying a high hydrolytic potential for various substrates, was isolated from a riverside soil sample and characterized by polyphasic taxonomic analysis. Growth occurred at 10–37 °C (optimum, 30°C), with NaCl concentrations of 0–4 % (optimum, 0 %) and at pH 7–9 (optimum, pH 8). MMS20-HV4-12T was catalase-positive, oxidase-negative, rod-shaped and formed creamy white-coloured colonies. Based on the results of 16S rRNA gene sequence analysis, MMS20-HV4-12T was found to be mostly related to the type strains of

Nocardioides alpinus

(98.3 % sequence similarity),

Nocardioides furvisabuli

(98.1 %) and

Nocardioides zeicaulis

(98.0 %). MMS20-HV4-12T showed optimal growth on Reaoner's 2A agar, forming white-coloured colonies. The diagnostic polar lipid profile consisted of diphosphatidylglycerol, phosphatidylglycerol and phosphatidylinositol, the major fatty acids were iso-C16 : 0, C17 : 1 ω8c and 10-methyl-C17 : 0, the major isoprenoid quinone was MK-8(H4), the diagnostic cell-wall sugar was galactose, and the cell-wall diamino acid was ll-diaminopimelic acid. The genome of MMS20-HV4-12T was 4.47 Mbp in size with a G+C content of 72.9 mol%. The genome based analysis indicated low relatedness between MMS20-HV4-12T and all compared species of

Nocardioides

, as the highest digital DNA–DNA hybridization and the orthologous average nucleotide identity values were 26.8 and 83.8% respectively. Based on genotypic, phenotypic and phylogenomic characterization, MMS20-HV4-12T evidently represents a novel species of genus

Nocardioides

, for which the name Nocardioides okcheonensis sp. nov. (type strain=MMS20-HV4-12T=KCTC 49651T=LMG 32360T) is proposed.
Integration of Mendelian randomisation and systems biology models to identify novel blood-based biomarkers for stroke
Authors: Islam Tania , Rahman Md Rezanur , Khan Asaduzzaman , Moni Mohammad Ali
Published: March 2023

Stroke is the second largest cause of mortality in the world. Genome-wide association studies (GWAS) have identified some genetic variants associated with stroke risk, but their putative functional causal genes are unknown. Hence, we aimed to identify putative functional causal gene biomarkers of stroke risk. We used a summary-based Mendelian randomisation (SMR) approach to identify the pleiotropic associations of genetically regulated traits (i.e., gene expression and DNA methylation) with stroke risk. Using SMR approach, we integrated cis- expression quantitative loci (cis-eQTLs) and cis-methylation quantitative loci (cis-mQTLs) data with GWAS summary statistics of stroke. We also utilised heterogeneity in dependent instruments (HEIDI) test to distinguish pleiotropy from linkage from the observed associations identified through SMR analysis. Our integrative SMR analyses and HEIDI test revealed 45 candidate biomarker genes (FDR< 0.05;PHEIDI>0.01) that were pleiotropically or potentially causally associated with stroke risk. Of those candidate biomarker genes, 10 genes (HTRA1, PMF1, FBN2, C9orf84, COL4A1, BAG4, NEK6, SH2B3, SH3PXD2A, ACAD10) were differentially expressed in genome-wide blood transcriptomics data from stroke and healthy individuals (FDR<0.05). Functional enrichment analysis of the identified candidate biomarker genes revealed gene ontologies and pathways involved in stroke, including “cell aging”, “metal ion binding” and “oxidative damage”. Based on the evidence of genetically regulated expression of genes through SMR and directly measured expression of genes in blood, our integrative analysis suggests ten genes as blood biomarkers of stroke risk. Furthermore, our study provides a better understanding of the influence of DNA methylation on the expression of genes linked to stroke risk.
Volumetric and microstructural abnormalities of the amygdala in focal epilepsy with varied levels of SUDEP risk
Authors: Legouhy Antoine , Allen Luke A. , Vos Sjoerd B. , Oliveira Joana F. A. , Kassinopoulos Michalis , Winston Gavin P. , Duncan John S. , Ogren Jennifer A. , Scott Catherine , Kumar Rajesh , Lhatoo Samden D. , Thom Maria , Lemieux Louis , Harper Ronald M. , Zhang Hui , Diehl Beate
Published: March 2023

Although the mechanisms of sudden unexpected death in epilepsy (SUDEP) are not yet well understood, generalised- or focal-to-bilateral tonic-clonic seizures (TCS) are a major risk factor. Previous studies highlighted alterations in structures linked to cardio-respiratory regulation; one structure, the amygdala, was enlarged in people at high risk of SUDEP and those who subsequently died. We investigated volume changes and the microstructure of the amygdala in people with epilepsy at varied risk for SUDEP since that structure can play a key role in triggering apnea and mediating blood pressure.

The study included 53 healthy subjects and 143 patients with epilepsy, the latter separated into two groups according to whether TCS occur in years before scan. We used amygdala volumetry, derived from structural MRI, and tissue microstructure, derived from diffusion MRI, to identify differences between the groups. The diffusion metrics were obtained by fitting diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) models. The analyses were performed at the whole amygdala level and at the scale of amygdaloid nuclei.

Patients with epilepsy showed larger amygdala volumes and lower neurite density indices (NDI) than healthy subjects; the left amygdala volumes were especially enhanced. Microstructural changes, reflected by NDI differences, were more prominent on the left side and localized in the lateral, basal, central, accessory basal and paralaminar amygdala nuclei; basolateral NDI lowering appeared bilaterally. No significant microstructural differences appeared between epilepsy patients with and without current TCS.

The central amygdala nuclei, with prominent interactions from surrounding nuclei of that structure, project to cardiovascular regions and respiratory phase switching areas of the parabrachial pons, as well as to the periaqueductal gray. Consequently, they have the potential to modify blood pressure and heart rate, and induce sustained apnea or apneusis. The findings here suggest that lowered NDI, indicative of reduced dendritic density, could reflect an impaired structural organization influencing descending inputs that modulate vital respiratory timing and drive sites and areas critical for blood pressure control.
Low-frequency repetitive transcranial magnetic stimulation in patients with motor deficits after brain tumor resection: a randomised, double-blind, sham-controlled trial
Authors: Engelhardt Melina , Schneider Heike , Reuther Jan , Grittner Ulrike , Vajkoczy Peter , Picht Thomas , Rosenstock Tizian
Published: March 2023

Structured abstract

Background

Surgical resection of motor eloquent tumors poses the risk of causing postoperative motor deficits which leads to reduced quality of life in these patients. Currently, rehabilitative procedures are limited with physical therapy being the main treatment option.

Objective

The present study investigated the efficacy of repetitive navigated transcranial magnetic stimulation (rTMS) for treatment of motor deficits after supratentorial tumor resection.

Methods

This randomised, double-blind, sham-controlled trial recruited patients with a worsening of upper extremity motor function after tumor resection. They were randomly assigned to receive rTMS treatment (1Hz, 110% RMT, 15 minutes, 7 days) or sham stimulation to the motor cortex contralateral to the injury followed by physical therapy. Motor and neurological function as well as quality of life were assessed directly after the intervention, one month and three months postoperatively.

Results

Thirty patients were recruited for this study. There was no significant difference between both groups in the primary outcome, the Fugl Meyer score three months postoperatively (Group difference [95%-CI]: 5.05 [-16.0; 26.1]; p=0.631). Patients in the rTMS group presented with better hand motor function (BMRC scores) one month postoperatively. Additionally, a subgroup of patients with motor eloquent ischemia showed lower NIHSS scores at all timepoints.

Conclusion

Low-frequency rTMS facilitated the recovery process stimulated hand muscles, but with limited generalization to other functional deficits. Long-term motor deficits were not impacted by rTMS. Due to the reduced life expectancy in this patient group a shortened recovery duration of functional deficits can still be of high clinical significance.
Characteristics of parkrun That Encourage New Participants to Return
Authors: Gilburn Andre S.
Published: March 2023

Physical activity is essential to combating the obesity epidemic. parkrun organise free weekly 5km events. Previous studies have identified characteristics of people that act as barriers to new registrants engaging in and returning to events. The current study identifies characteristics of parkrun events that are associated with the return rate of new participants. The return rate of adult first-time participants to parkrun was determined for all events in Scotland over a 1-year period between 2/2019 and 1/2020. A GLMM was used to determine factors associated with whether they returned to parkrun. Return rates were higher for smaller events and events with more other first-time participants. Older participants and male participants were more likely to return. Those that finished in a relatively slow time were disproportionately less likely to return. Events with routes that run alongside freshwater had higher return rates for women. New participants at parkrun are more likely to return if they attended a smaller event suggesting that parkrun should continue to create new events to make parkrun more efficient at retaining new participants. New participants also returned more readily if they attended an event with a high proportion of other adult new participants so specific recruitment events could be advertised to encourage new participants to attend their first event together. New events could be prioritised in proximity to those events that currently experience the highest attendances.
Mechanistic convergence of depression and suicidality on astrocyte fatty acid metabolism
Authors: Fitzgerald Eamon , O’Toole Nicholas , Pokhvisneva Irina , Turecki Gustavo , Nagy Corina , Meaney Michael J
Published: March 2023

Genome-wide association studies (GWAS) show conceptual promise to identify novel mechanisms of major depressive disorder (MDD), but have not yet achieved this potential. One explanation is that MDD risk acts through complex expression networks, and GWAS-identified genes represent important components of these networks but in isolation are insufficient for their functional annotation. In this study, we aimed to identify and characterize the expression networks through which GWAS-identified MDD risk genes operate. We generated and characterized seeded co-expression networks of 252 MDD risk genes over 11 brain regions. We used principal component regression and Mendelian randomization to identify a relation between the networks of two such genes (FADS1andZKSCAN8) and suicidal ideation. These networks were primarily expressed in astrocytes, enriched for functions related to fatty acid metabolism, and could define MDD-altered astrocyte states. We then identifiedFGFR3toEPHA4signaling as a putative downstream effector of these astrocyte states on synaptic function. Finally through transcriptomic and genetic analyses, we identify PPARA as a putative therapeutic target of these mechanisms in MDD. Our study defines a tractable pathway to translate genetic findings into therapeutically actionable mechanisms.
Fate-mapping lymphocyte clones and their progenies from induced antigen-signals identifies temporospatial behaviours of T cells mediating tolerance
Authors: Takahashi Munetomo , So Tsz Y. , Williamson Kate , Hosseini Zhaleh , Kania Katarzyna , Ruhle Michelle , Mann Tiffeney , Schujis Martijn J. , Coupland Paul , Naisbitt Dean , Halim Timotheus Y.F. , Lyons Paul A. , Lio Pietro , Okkenhaug Klaus , Adams David J. , Smith Ken G.C. , Jodrell Duncan I. , Chapman Michael A. , Thaventhiran James E. D.
Published: March 2023

Tissue homeostasis is maintained by the behaviours of lymphocyte clones responding to antigenic triggers in the face of pathogen, environmental, and developmental challenges. Current methodologies for tracking the behaviour of specific lymphocytes identify clones of a defined antigen-receptor—antigen binding affinity. However, lymphocytes can receive antigenic signals from undefined or endogenous antigens, and the strength of each signal, even for the same lymphocyte, varies with accessory signalling, across tissues and across time. We present a novel fate-mapping mouse, that, by tracking lymphocyte clones and their progenies from induced antigen signals, overcomes these hurdles and provides novel insights into the maintenance of tissue homeostasis. We demonstrate the systems use by investigating the maintenance of localised T cell tolerance in tumour immunity. In a murine tumour model, our system reveals how Tregs differentiate to a reversible, tolerance inducing state within the tumour, and recirculate, while CD8+ T cells failing to recirculate, differentiate to an increasingly exhausted, tolerant state in the tumour. These contrasting T cell behaviours provide means by which immunity can tolerate a particular anatomical niche while maintaining systemic clonal protection. Our system can thus explore lymphocyte behaviours that cannot be tracked by previous methods and will therefore provide novel insights into the fundamental mechanisms underlying immunity’s role in tissue homeostasis.
Muscle of obese insulin-resistant humans exhibits losses in proteostasis and attenuated proteome dynamics that are improved by exercise training
Authors: Srisawat Kanchana , Stead Connor A , Hesketh Katie , Pogson Mark , Strauss Juliette A. , Cocks Matt , Siekmann Ivo , Phillips Stuart M. , Lisboa Paulo J. , Shepherd Sam , Burniston Jatin G
Published: March 2023

We examined muscle proteostasis in obese insulin-resistant (OIR) individuals to determine whether endurance exercise could positively influence proteome dynamics in this population. Male OIR (n = 3) and lean, healthy controls (LHC; n = 4) were recruited and underwent a 14-d measurement protocol of daily deuterium oxide (D2O) consumption and serial biopsies of vastus lateralis muscle. The OIR group then completed 10-weeks of high-intensity interval training (HIIT), encompassing 3 sessions per week of cycle ergometer exercise with 1 min intervals at 100 % maximum aerobic power (Wmax) interspersed by 1 min recovery periods. The number of intervals per session progressed from 4 to 8, and during weeks 8-10 the 14-d measurement protocol was repeated. The abundance and turnover rates of 880 and 301 proteins, respectively, were measured. OIR and LHC muscle exhibited 352 differences (p< 0.05, false discovery rate (p< 0.05) differences in protein turnover. OIR muscle was enriched with markers of metabolic stress, protein misfolding and components of the ubiquitin-proteasome system, and the turnover rate of many of these proteins was less compared to LHC muscle. HIIT altered the abundance of 53 proteins and increased the turnover rate of 22 proteins (p< 0.05) in OIR muscle and tended to restore proteostasis, evidenced by increasing muscle protein turnover rates and normalizing proteasome composition in OIR participants. In conclusion, obesity and insulin resistance are associated with compromised muscle proteostasis, which can be partially restored by endurance exercise.
Production of isotopically enriched high molecular weight hyaluronic acid and characterization by solid-state NMR
Authors: Rampratap Pushpa , Lasorsa Alessia , Perrone Barbara , van der Wel Patrick C.A. , Walvoort Marthe T.C.
Published: March 2023

Hyaluronic acid (HA) is a naturally occurring polysaccharide that is abundant in the extracellular matrix (ECM) of all vertebrate cells. HA-based hydrogels have attracted great interest for biomedical applications due to their high viscoelasticity and biocompatibility. In both ECM and hydrogel applications, high molecular weight (HMW)-HA can absorb a large amount of water to yield matrices with a high level of structural integrity. To understand the molecular underpinnings of structural and functional properties of HA-containing hydrogels, few techniques are available. Nuclear magnetic resonance (NMR) spectroscopy is a powerful tool for such studies, e.g.13C NMR measurements can reveal the structural and dynamical features of (HMW) HA. However, a major obstacle to13C NMR is the low natural abundance of13C, necessitating the generation of HMW-HA that is enriched with13C isotopes. Here we present a convenient method to obtain13C- and15N-enriched HMW-HA in good yield fromStreptococcus equisubsp. zooepidemicus. The labeled HMW-HA has been characterized by solution and magic angle spinning (MAS) solid-state NMR spectroscopy, as well as other methods. These results will open new ways to study the structure and dynamics of HMW-HA-based hydrogels, and interactions of HMW-HA with proteins and other ECM components, using advanced NMR techniques.
Bamboozle: A bioinformatic tool for identification and quantification of intraspecific barcodes
Authors: Pinder Matthew I M , Andersson Björn , Rengefors Karin , Blossom Hannah , Svensson Marie , Töpel Mats
Published: March 2023

Evolutionary changes in populations of microbes, such as microalgae, cannot be traced using conventional metabarcoding loci as they lack intraspecific resolution. Consequently, selection and competition processes amongst strains of the same species cannot be resolved without elaborate isolation, culturing, and genotyping efforts. Bamboozle, a new bioinformatic tool introduced here, scans a species’ entire genome and identifies allele-rich barcodes that enable direct identification of different strains from a common population, and a single DNA sample, using amplicon sequencing. We demonstrate its usefulness by identifying hypervariable barcoding loci (<500 bp) from genomic data in two microalgal species, the diploid diatomSkeletonema marinoi, and the haploid chlorophyteChlamydomonas reinhardtii. Across the genomes, only 26 loci capable of resolving all available strains’ genotypes were identified, all of which are within protein-coding genes of variable metabolic function. Single nucleotide polymorphisms (SNPs) provided the most reliable genetic markers, and amongst 55 strains ofS. marinoi,three 500 bp loci contained, on average, 46 SNPs, 103 unique alleles, and displayed 100% heterozygosity. The prevalence of heterozygosity was identified as a novel opportunity to improve strain quantification and detect false positive artefacts during denoising of amplicon sequences. Finally, we illustrate how metabarcoding of a single genetic locus can be used to track strain abundances of 58 strains ofS. marinoiin an artificial selection experiment. As future genomics datasets become available and DNA sequencing technologies develop, Bamboozle has flexible user settings enabling optimal barcodes to be designed for other species and applications.
Gene coexpression analysis identifies genes associated with chlorophyll content and relative water content in pearl millet
Authors: Shinde Harshraj , Dudhate Ambika , Sathe Atul , Paserkar Neha , Wagh Sopan G. , Kadam Ulhas S.
Published: March 2023

Pearl millet is a significant crop tolerant to abiotic stresses and is a staple food of arid regions. However, its underlying mechanisms of stress tolerance is not fully understood. Plant survival is regulated by the ability to perceive a stress signal and induce appropriate physiological changes. Here, we screened for genes regulating physiological changes such as chlorophyll content (CC) and relative water content (RWC) in response to abiotic stress. Using ‘weighted gene co-expression network analysis’ (WGCNA) and clustering associated changes in physiological traits,i.e., CC and RWC with gene expression. A group of genes showing correlation with traits was identified as modules, and different color names were used to denote a particular module. In WGCNA, the darkgreen module (7082 genes) showed a significant positive correlation with CC, and the black (1393 genes) module was negatively correlated with CC and RWC. Analysis of the module positively correlated with CC highlighted ribosome synthesis and plant hormone signaling as the most significant pathways.Potassium transporter 8andmonothiol glutaredoxinwere reported as the topmost hub genes in the darkgreen module. InClustanalysis, 2987 genes were found to display a correlation with increasing CC and RWC. Further, the pathway analysis of these clusters identified ribosome and thermogenesis as positive regulators of RWC and CC, respectively. Our study provides novel insights into the molecular mechanisms regulating CC and RWC in pearl millet.
Autophagy functions in lung macrophages and dendritic cells to suppress TH17 responses and neutrophil accumulation during allergic airway inflammation
Authors: Dubey Neha , Woodson Reilly , McKee Samuel R. , Rosen Anne L. , Rivera-Espinal Nicole , Kreamalmeyer Darren , Kau Andrew L. , Stallings Christina L.
Published: March 2023

Asthma affects nearly 260 million people worldwide, where severe asthma cases represent the most difficult to treat due to corticosteroid insensitivity. Severe asthma is associated with higher levels of TH17 and TH1 responses, accompanied by neutrophil dominated inflammation. Better understanding of the immune responses to airway allergens that promote or protect against severe asthma is critical for identifying ways to treat these patients. Single nucleotide polymorphisms in theATG5gene, which encodes for a protein required for the cellular recycling process of autophagy, has been associated with higher risk for developing severe asthma. However, the exact role for ATG5 during allergic inflammation and whether other autophagy proteins are involved remains elusive. Using genetic tools to dissect the roles for ATG5 in innate immune cells in house dust mite (HDM)-challenged mice, we have identified a specific role for ATG5 in CD11c+lung macrophages and dendritic cells for suppressing TH17 responses and neutrophil accumulation. We found that this role for ATG5 in CD11c+cells to regulate neutrophil accumulation during allergic airway inflammation also required other autophagy proteins but did not involve regulation of inflammasome, despite higher levels of IL-1β and Caspase 1 in the lungs of mice lacking autophagy in innate immune cells. Our data support a role for autophagy in CD11c+lung macrophages and dendritic cells to promote an immune response to airway allergens that is associated with less severe asthma by suppressing TH17 responses and neutrophil accumulation in the lung.
Popcorn haploids identified by Navajo phenotype and ploidy level
Authors: da Silva Jean Paulo Aparecido , Viana José Marcelo Soriano , Dias Kaio Olimpio das Graças , Silva Jéssica Coutinho , Tupper Vivian Torres Bandeira , Clarindo Wellington Ronildo
Published: March 2023

For popcorn, obtaining and identifying haploids are still challenging steps. We aimed to induce and screen haploids in popcorn using the Navajo phenotype, seedling vigor and ploidy level. We used the Krasnodar Haploid Inducer (KHI) in crosses with 20 popcorn source germplasms and five maize controls. The field trial design was completely randomized, with three replications. We assessed the efficacy of induction and of identification of haploids based on haploidy induction rate (HIR) and false positive and negative rates (FPR and FNR). Additionally, we also measured the penetrance of the Navajo marker gene (R1-nj). All putative haploids classified byR1-njwere germinated together with a diploid sample and evaluated for false positives and negatives based on vigor. Seedlings from 14 females were submitted to flow cytometry to determine the ploidy level. The HIR and penetrance were analyzed by fitting a generalized linear model with a logit link function. The HIR of the KHI, adjusted by cytometry, ranged from 0.0 to 1.2%, with a mean of 0.34%. The average FPR from screening based on the Navajo phenotype were 26.2% and 76.4%, by the vigor and ploidy, respectively. The FNR was zero. The penetrance ofR1-njranged from 30.8 to 98.6%. The average number of seeds per ear in temperate germplasm (76) was lower than that obtained in tropical germplasm (98). There is induction of haploids in germplasm of tropical and temperate origin. We recommend the selection of haploids associating the Navajo phenotype with a direct method of confirming the ploidy level, such as flow cytometry. We also show that haploid screening based on Navajo phenotype and seedling vigor reduces misclassification. The origin and genetic background of the source germplasm influence theR1-njpenetrance. Because the known inducers are maize, developing doubled-haploid technology for popcorn hybrid breeding requires overcoming the unilateral cross-incompatibility.
Structural context of homomeric interactions in the lg domain of the MPZ (P0) myelin adhesion protein and relation to Charcot-Marie-Tooth disease phenotype variants
Authors: Ptak Christopher P. , Peterson Tabitha A. , Hopkins Jesse B. , Ahern Christopher A. , Shy Michael E. , Piper Robert C.
Published: March 2023

Mutations in Myelin Protein Zero (MPZ) account for 5% of Charcot-Marie-Tooth cases and can cause demyelinating or axonal phenotypes, reflecting the diverse roles of MPZ in Schwann cells. MPZ holds the apposing membranes of the myelin sheath together, with the adhesion role fulfilled by the extracellular lmmunoglobulin-like domain (lgMPZ), which can oligomerize. Current knowledge for how the lgMPZmight form oligomeric assemblies involving 3 weakly-interacting interfaces has been extrapolated from a protein crystal structure in which individual rat lgMPZsubunits are packed together under artificial conditions. These interfaces include one that organizes the lgMPZinto tetramers, a ‘dimer’ interface that could link tetramers together, and a third hydrophobic interface that could mediate binding to lipid bilayers or the same hydrophobic surface on another lgMPZdomain. There are at present no data confirming whether the proposed lgMPZinterfaces actually mediate oligomerization in solution, whether they are required for the adhesion activity of MPZ, whether they are important for myelination, or whether their loss results in disease. We performed NMR and SAXS analysis of wild-type lgMPZas well as mutant forms with amino-acid substitutions designed to interrupt its presumptive oligomerization interfaces. Here, we confirm the interface that mediates lgMPZtetramerization, but find that dimerization is mediated by a distinct interface that has yet to be identified. We next correlated CMT phenotypes to subregions within lgMPZtetramers. Axonal late-onset disease phenotypes (CMT2l/J) map to surface residues of lgMPZproximal to the transmembrane domain. Early-onset demyelinating disease phenotypes (CMT1B/Dejerine-Sottas syndrome) map to two groups: one is described by variants that disrupt the stability of the lg-fold itself and are largely located within the core of the lg domain; whereas another describes a surface on the distal outer surface of lgMPZtetramers. Computational docking studies predict that this latter disease-relevant subregion may mediate dimerization of lgMPZtetramers.
A double-hit of social and economic stress in mice precipitates changes in decision-making strategies
Authors: Durand-de Cuttoli Romain , Martínez-Rivera Freddyson J. , Li Long , Minier-Toribio Angélica , Dong Zhe , Cai Denise J. , Russo Scott J. , Nestler Eric J. , Sweis Brian M.
Published: March 2023

Economic stress can serve as a “second-hit” for those who already accumulated a history of adverse life experiences. How one recovers from a setback is a core feature of resilience but is seldom captured in animal studies. We challenged mice in a novel two-hit stress model by exposing animals to chronic social defeat stress (first-hit) and then testing how mice adapt to reward scarcity on a neuroeconomic task (second-hit). Mice were tested longitudinally across months on the Restaurant Row task during which mice foraged daily for their sole source of food while on a limited time budget. An abrupt transition into a reward-scarce environment on this task elicits an economic crisis, precipitating a massive drop in food intake and body weight to which mice must respond in order to survive. We found that mice with a history of social defeat mounted a robust behavioral response to this economic challenge. This recovery was achieved through a complex redistribution of how time was allocated among competing opportunities via multiple valuation algorithms. Interestingly, we found that mice with a history of social defeat displayed changes in the development of decision-making policies during the recovery process important for not only ensuring food security necessary for survival but also prioritizing subjective value. These findings indicate that an individual’s capacity to “bounce back” from economic stress depends on one’s prior history of stress and can affect multiple aspects of subjective well-being, highlighting a motivational balance that may be altered in stress-related disorders such as depression.

In Brief

Durand-de Cuttoli et al. found that after chronic social defeat stress, when mice were subsequently challenged on a neuroeconomic foraging task, an economic stressor can serve as a “second hit” and reveal changes in the development of complex decision-making strategies important for maintaining the balance between food security and subjective well-being.