bluuebunny/crossref_metadata_2025 huggingface dataset:
Patient Perceptions and Experiences With Maggot Debridement Therapy for Managing Chronic Wounds
Authors: Babiarczyk Beata , Tobiczyk Joanna
Published: April 2024

PURPOSE:

The purpose of this study was to describe patient experiences and satisfaction with use of maggot debridement therapy (MDT) for hard-to-heal wounds.

DESIGN:

Descriptive, cross-sectional study.

SUBJECTS AND SETTING:

The sample comprised 60 participants, 60% were male (n = 36). Their mean age was 62.9 (SD = 20) years. Almost half of participants had lower extremity wounds (n = 26; 43.3%), diabetic foot ulcers (n = 18; 30%), and pressure injuries (n = 9; 15%). Most received maggot therapy via biobags (n = 36; 60%).

METHODS:

Participants completed a questionnaire designed for purposes of the study that queried demographic and pertinent clinical characteristics, current health status including current topical therapies, and duration of their chronic wound. Nine items queried emotional responses prior to MDT, the amount and method of the maggot therapy, discomfort experienced during therapy, and sources of information regarding this treatment.

RESULTS:

Emotional responses before starting MDT included disgust (n = 30, 50%), anxiety (n = 26, 43.3%), doubts about its effectiveness (n =20, 33.3%), and disbelief (n = 11, 18.3%). Approximately one-third of participants reported feelings of biting, itching, and fear of the maggots. Despite these feelings, a majority (n = 38, 63.3%) indicated that they were pleased with treatment outcome and willing to undergo additional MDT if needed.

CONCLUSIONS:

While a majority of participants with nonhealing chronic wounds reported negative emotions association with MDT, more than half indicated that they were pleased with the outcome of treatment and willing to undergo repeat treatment if indicated.
Unexpected increase in structural integrity caused by thermally induced dwarfism in large benthic foraminifera
Authors: Titelboim Danna , Rothwell Nikita J. , Lord Oliver T. , Harniman Robert L. , Melbourne Leanne A. , Schmidt Daniela N.
Published: April 2024

Climate change is predicted to negatively impact calcification and change the structural integrity of biogenic carbonates, influencing their protective function. We assess the impacts of warming on the morphology and crystallography of
Amphistegina lobifera
, an abundant benthic foraminifera species in shallow environments. Specimens from a thermally disturbed field area, mimicking future warming, are about 50% smaller compared with a control location. Differences in the position of the ν1 Raman mode of shells between the sites, which serves as a proxy for Mg content and calcification temperature, indicate that calcification is negatively impacted when temperatures are below the thermal range facilitating calcification. To test the impact of thermal stress on the Young's modulus of calcite which contributes to structural integrity, we quantify elasticity changes in large benthic foraminifera by applying atomic force microscopy to a different genus,
Operculina ammonoides
, cultured under optimal and high temperatures. Building on these observations of size and the sensitivity analysis for temperature-induced change in elasticity, we used finite element analysis to show that structural integrity is increased with reduced size and is largely insensitive to calcite elasticity. Our results indicate that warming-induced dwarfism creates shells that are more resistant to fracture because they are smaller.
New fossil of
Gaoloufangchaeta
advances the origin of Errantia (Annelida) to the early Cambrian
Authors: Yang Xiaoyu , Aguado M. Teresa , Helm Conrad , Zhang Zhiqian , Bleidorn Christoph
Published: April 2024

Molecular clock estimates suggest the origin of Annelida dates back to the Ediacaran period, which is in discordance with the first appearance of this taxon in the early Cambrian, as evidenced by the fossil records of stem-group and basally branching crown-group annelids. Using new material from the early Cambrian Guanshan biota (Cambrian Series 2, Stage 4), we re-interpret
Gaoloufangchaeta bifurcus
Zhao, Li & Selden, 2023, as the earliest known errantian annelid.
Gaoloufangchaeta
has a prominent anterior end bearing three pairs of putatively sensory appendages and a pair of anterior eyes; a muscular eversible pharynx with papillae is identified. The presence of enlarged parapodia with acicula-like structures and long capillary chaetae suggests a pelagic lifestyle for this taxon. Our phylogenetic analyses recover
Gaoloufangchaeta
within the Phyllodocida (Pleistoannelida, Errantia), extending the origin of Errantia back to the early Cambrian. Our data are in line with the hypothesis that Annelida diverged before the Cambrian and indicate both morphological and ecological diversification of annelids in the early Cambrian.
A pseudo-analytic generalization of the memoryless property for continuous random variables and its use in pricing contingent claims
Authors: Carr Peter , Cirillo Pasquale
Published: April 2024

We explore an extension of the memoryless property for continuous random variables by using the concept of pseudo-sum. Subsequently, we demonstrate the practicality of this approach through two financial applications in which pseudo-sums characterize the values of arbitrage-free contingent claims. Moreover, we are able to establish new interesting connections between different probability distributions.
Advancing multimodal medical image fusion: an adaptive image decomposition approach based on multilevel Guided filtering
Authors: Moghtaderi Shiva , Einlou Mokarrameh , Wahid Khan A. , Lukong Kiven Erique
Published: April 2024

With the rapid development of medical imaging methods, multimodal medical image fusion techniques have caught the interest of researchers. The aim is to preserve information from diverse sensors using various models to generate a single informative image. The main challenge is to derive a trade-off between the spatial and spectral qualities of the resulting fused image and the computing efficiency. This article proposes a fast and reliable method for medical image fusion depending on multilevel Guided edge-preserving filtering (MLGEPF) decomposition rule. First, each multimodal medical image was divided into three sublayer categories using an MLGEPF decomposition scheme: small-scale component, large-scale component and background component. Secondly, two fusion strategies—pulse-coupled neural network based on the structure tensor and maximum based—are applied to combine the three types of layers, based on the layers' various properties. The three different types of fused sublayers are combined to create the fused image at the end. A total of 40 pairs of brain images from four separate categories of medical conditions were tested in experiments. The pair of images includes various case studies including magnetic resonance imaging (MRI) , TITc, single-photon emission computed tomography (SPECT) and positron emission tomography (PET). We included qualitative analysis to demonstrate that the visual contrast between the structure and the surrounding tissue is increased in our proposed method. To further enhance the visual comparison, we asked a group of observers to compare our method’s outputs with other methods and score them. Overall, our proposed fusion scheme increased the visual contrast and received positive subjective review. Moreover, objective assessment indicators for each category of medical conditions are also included. Our method achieves a high evaluation outcome on feature mutual information (FMI), the sum of correlation of differences (SCD), Qabf and Qy indexes. This implies that our fusion algorithm has better performance in information preservation and efficient structural and visual transferring.
Mothers’ knowledge and practices towards oral hygiene of their children aged 5-9 years old: a cross-sectional study in Dhaka
Authors: Tamannur Tahazid , Das Sadhan Kumar , Nesa Arifatun , Nahar Foijun , Nowshin Nadia , Binty Tasnim Haque , Shakil Shafiul Azam , Kundu Shuvojit Kumar , Siddik Md Abu Bakkar , Rafsun Shafkat Mahmud , Habiba Umme , Farhana Zaki , Sultana Hafiza , Kamil Anton Abdulbasah , Rahman Mohammad Meshbahur
Published: April 2024

Background

Healthy oral hygiene is crucial for overall health and well-being. Parents’ dental care knowledge and practice affect their children’s oral health. Thus, this study assessed the oral hygiene knowledge and practice in mothers of children aged 5-9 years.

Methods

This cross-sectional study was conducted from 1 January to 31 December 2022 in Dhaka, Bangladesh. Mothers’ oral hygiene knowledge and practices were assessed through a semi-structured questionnaire. Statistical analysis including the Mann–Whitney U test and Kruskal– Wallis one-way ANOVA test were performed to show average knowledge and practice variations among different socio-demographics of mothers.

Results

Out of 400 samples, the mean age of mothers was 30.94±5.15 years where majority were in Muslim faith (97%), housewife (86.8%) and came from nuclear family (68.0%). The prevalence of good knowledge was 41.2%, following 21.5% had moderately average, 18.8% had average and 18.5% mothers had poor knowledge respectively on their children’s oral hygiene. On the other hand, 45.5% mothers had good practice, following 19.5% had average practice, 18.8% had moderately average and 16.2% had poor practice behavior. Mothers’ knowledge levels were significantly (p<0.05) associated with age, education, family size, and monthly income. On the other hand, educational status and income was significantly (p<0.05) associated with mothers’ oral hygiene practices. Non-parametric analysis revealed that the average knowledge level was significantly (p<0.05) higher with respect to higher age group, educational attainment, currently working status, and whose family income was high. On the other hand, oral hygiene practice level was significantly (p<0.05) higher among mother having higher education and higher family income. Mothers’ knowledge was significantly (p<0.05) and positively correlated with the practice behavior obtained by Pearson correlation coefficient.

Conclusions

The revealed that the knowledge and practices of mothers directly influence the oral hygiene behavior of children. Mothers with sound knowledge tend to exhibit positive practices concerning their children’s oral hygiene. These findings underscore the importance of taking necessary actions to enhance both the knowledge and practices related to oral hygiene among mothers, thereby ensuring the well-being of their children.
CELEBRIMBOR: Pangenomes from metagenomes
Authors: Hellewell Joel , Horsfield Samuel T. , von Wachsmann Johanna , Gurbich Tatiana , Finn Robert D. , Iqbal Zamin , Roberts Leah W. , Lees John A.
Published: April 2024

Metagenome Assembled Genomes (MAGs) are often incomplete, with sequences missing due to errors in assembly or low coverage. Incomplete MAGs present a particular challenge for identification of shared genes within a microbial population, known as core genes, as a core gene missing in only a few assemblies will result in it being mischaracterized at a lower frequency. Here, we present CELEBRIMBOR, a snakemake pangenome analysis pipeline which uses a measure of genome completeness to automatically adjust the frequency threshold at which core genes are identified, enabling accurate core gene identification in MAGs.

Availability and implementation

CELEBRIMBOR is published under open source Apache 2.0 licence athttps://github.com/bacpop/CELEBRIMBORand is available as a Docker container. Supplementary material is available in the online version of the article.
Reconstructing bat antiviral immunity using epithelial organoids
Authors: Kellner Max J. , Zelger Patrick , Monteil Vanessa , Pei Gang , Onji Masahiro , Nayak Komal , Zilbauer Matthias , Balkema-Buschmann Anne , Dorhoi Anca , Mirazimi Ali , Penninger Josef M.
Published: April 2024

Bats are remarkably resilient to viruses with pandemic potential. To resolve largely unknown molecular mechanisms governing their exceptional antiviral immunity, we established an organoid platform to model the entire respiratory airway and intestinal epithelium of the important viral reservoir speciesRousettus aegyptiacus(Egyptian fruit bat). These bat organoids exhibit an unexpected diversity of cell types and support replication of highly pathogenic zoonotic viruses including Marburg virus (MARV) and MERS-Coronavirus. Following virus infection, bat organoids unleash a strong interferon response, uniquely regulated through virus-dependent and virus-independent mechanisms. By contrast, MARV infected human organoids fail to induce an antiviral gene response and express pro-inflammatory cytokines after interferon stimulation, revealing important molecular differences between bats and humans with implications for lethal Marburg virus infections in primates. These data provide the most comprehensive organoid platform in bats to decode species-specific differences and uncover fundamental principles of bat disease resilience to emerging viruses with pandemic potential.
Strength of Activation and Temporal Dynamics of BioLuminescent-Optogenetics in Response to Systemic Injections of the Luciferin
Authors: Murphy Emily F. , Means Aniya , Li Chen , Baez Hector , Gomez-Ramirez Manuel
Published: April 2024

BioLuminescent OptoGenetics (“BL-OG”) is a chemogenetic method that can evoke optogenetic reactions in the brain non-invasively. In BL-OG, an enzyme that catalyzes a light producing reaction (i.e., a luciferase) is tethered to an optogenetic element that is activated in response to bioluminescent light. Bioluminescence is generated by injecting a chemical substrate (luciferin, e.g., h-Coelenterazine; h-CTZ) that is catalyzed by the luciferase. By directly injecting the luciferin into the brain, we showed that bioluminescent light is proportional to spiking activity, and this relationship scales as a function of luciferin dosage. Here, we build on these previous observations by characterizing the temporal dynamics and dose response curves of BL-OG effects to intravenous (IV) injections of the luciferin. We imaged bioluminescence through a thinned skull of mice running on a wheel, while delivering h-CTZ via the tail vein with different dosage concentrations and injection rates. The data reveal a systematic relationship between strength of bioluminescence and h-CTZ dosage, with higher concentration generating stronger bioluminescence. We also found that bioluminescent activity occurs rapidly (< 60 seconds after IV injection) regardless of concentration dosage. However, as expected, the onset time of bioluminescence is delayed as the injection rate decreases. Notably, the strength and time decay of bioluminescence is invariant to the injection rate of h-CTZ. Taken together, these data show that BL-OG effects are highly consistent across injection parameters of h-CTZ, highlighting the reliability of BL-OG as a non-invasive neuromodulation method.
Deep Brain Stimulation of Nucleus Basalis of Meynert improves learning in rat model of dementia
Authors: Kumbhare Deepak , Rajagopal Megan , Toms Jamie , Freelin Anne , Weistroffer George , McComb Nicholas , Karnam Sindhu , Azghadi Adel , Murnane Kevin S. , Baron Mark S. , Holloway Kathryn L.
Published: April 2024

Background

Deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM) has been preliminarily investigated as a potential treatment for dementia. The degeneration of NBM cholinergic neurons is a pathological feature of many forms of dementia. Although stimulation of the NBM has been demonstrated to improve learning, the ideal parameters for NBM stimulation have not been elucidated. This study assesses the differential effects of varying stimulation patterns and duration on learning in a dementia rat model.

Methods

192-IgG-saporin (or vehicle) was injected into the NBM to produce dementia in rats. Next, all rats underwent unilateral implantation of a DBS electrode in the NBM. The experimental groups consisted of i-normal, ii-untreated demented, and iii-demented rats receiving NBM DBS. The stimulation paradigms included testing different modes (tonic and burst) and durations (1-hr, 5-hrs, and 24-hrs/day) over 10 daily sessions. Memory was assessed pre- and post-stimulation using two established learning paradigms: novel object recognition (NOR) and auditory operant chamber learning.

Results

Both normal and stimulated rats demonstrated improved performance in NOR and auditory learning as compared to the unstimulated demented group. The burst stimulation groups performed better than the tonic stimulated group. Increasing the daily stimulation duration to 24-hr did not further improve cognitive performance in an auditory recognition task and degraded the results on a NOR task as compared with 5-hr.

Conclusion

The present findings suggest that naturalistic NBM burst DBS may offer a potential effective therapy for treating dementia and suggests potential strategies for the reevaluation of current human NBM stimulation paradigms.
Inhibition of PAK2 in endothelial cells suppresses tumor angiogenesis and promotes immune sensitization through CXCL10
Authors: Corriveau Jeanne , Monot Pascale , Delisle Chantal , Goyette Marie-Anne , Gasse Camille , El Bakkouri Yassine , Hoang Trang , Côté Jean-François , Gratton Jean-Philippe
Published: April 2024

Tumor angiogenesis is induced by the secretion of pro-angiogenic factors and results in a disorganized tumor vasculature. The p21-activated kinase 2 (PAK2) is involved in endothelial cell (EC) migration, an essential step of angiogenesis. However, the involvement of PAK2 in tumor angiogenesis remains ill-defined. Here, we show that, during orthotopic tumor growth, the specific deletion of PAK2 in ECs reduces tumor size and angiogenesis. In addition, endothelial-specific loss of PAK2 was found to normalize the remaining tumor blood vessels, favoring innate immune cells infiltration. Importantly, we uncovered a role for PAK2 in regulating chemokine expression, notably CXCL10. Secretion of CXCL10 from ECs is enhanced following PAK2 depletion and its expression is essential for the inhibitory effects of PAK2 silencing on EC spouting. Furthermore, neutralization of CXCL10 in mice reversed the effects induced by the deletion of PAK2 on tumor vasculature and immune composition of tumors. Together, our findings identify endothelial PAK2 as a potential target to reduce tumor angiogenesis and reprogram ECs to promote immune cell infiltration within tumors through the expression of CXCL10.
TopDIA: A Software Tool for Top-Down Data-Independent Acquisition Proteomics
Authors: Basharat Abdul Rehman , Xiong Xingzhao , Xu Tian , Zang Yong , Sun Liangliang , Liu Xiaowen
Published: April 2024

Top-down mass spectrometry is widely used for proteoform identification, characterization, and quantification owing to its ability to analyze intact proteoforms. In the last decade, top-down proteomics has been dominated by top-down data-dependent acquisition mass spectrometry (TD-DDA-MS), and top-down data-independent acquisition mass spectrometry (TD-DIA-MS) has not been well studied. While TD-DIA-MS produces complex multiplexed tandem mass spectrometry (MS/MS) spectra, which are challenging to confidently identify, it selects more precursor ions for MS/MS analysis and has the potential to increase proteoform identifications compared with TD-DDA-MS. Here we present TopDIA, the first software tool for proteoform identification by TD-DIA-MS. It generates demultiplexed pseudo MS/MS spectra from TD-DIA-MS data and then searches the pseudo MS/MS spectra against a protein sequence database for proteoform identification. We compared the performance of TD-DDA-MS and TD-DIA-MS usingEscherichia coliK-12 MG1655 cells and demonstrated that TD-DIA-MS with TopDIA increased proteoform and protein identifications compared with TD-DDA-MS.
Chronic hyperactivation of midbrain dopamine neurons causes preferential dopamine neuron degeneration
Authors: Rademacher Katerina , Doric Zak , Haddad Dominik , Mamaligas Aphroditi , Liao Szu-Chi , Creed Rose B. , Kano Kohei , Chatterton Zac , Fu Yuhong , Garcia Joseph H. , Vance Victoria , Sei Yoshitaka , Kreitzer Anatol , Halliday Glenda M , Nelson Alexandra B. , Margolis Elyssa B. , Nakamura Ken
Published: April 2024

Parkinson’s disease (PD) is characterized by the death of substantia nigra (SNc) dopamine (DA) neurons, but the pathophysiological mechanisms that precede and drive their death remain unknown. The activity of DA neurons is likely altered in PD, but we understand little about if or how chronic changes in activity may contribute to degeneration. To address this question, we developed a chemogenetic (DREADD) mouse model to chronically increase DA neuron activity, and confirmed this increase usingex vivoelectrophysiology. Chronic hyperactivation of DA neurons resulted in prolonged increases in locomotor activity during the light cycle and decreases during the dark cycle, consistent with chronic changes in DA release and circadian disturbances. We also observed early, preferential degeneration of SNc projections, recapitulating the PD hallmarks of selective vulnerability of SNc axons and the comparative resilience of ventral tegmental area axons. This was followed by eventual loss of midbrain DA neurons. Continuous DREADD activation resulted in a sustained increase in baseline calcium levels, supporting an important role for increased calcium in the neurodegeneration process. Finally, spatial transcriptomics from DREADD mice examining midbrain DA neurons and striatal targets, and cross-validation with human patient samples, provided insights into potential mechanisms of hyperactivity-induced toxicity and PD. Our results thus reveal the preferential vulnerability of SNc DA neurons to increased neural activity, and support a potential role for increased neural activity in driving degeneration in PD.
Simulation-based dosimetry of transcranial and intranasal photobiomodulation of the human brain: the roles of wavelength, power density and skin colour
Authors: Van Lankveld Hannah , Mai Anh Q. , Lim Lew , Hosseinkhah Nazanin , Cassano Paolo , Jean Chen J.
Published: April 2024

Photobiomodulation (PBM) is a novel technique that is actively studied for neuromodulation. However, despite the many in vivo studies, the stimulation protocols for PBM vary amongst studies, and the current understanding of neuromodulation via PBM is limited in terms of the extent of light penetration into the brain and its dosage dependence. Moreover, as near-infrared light can be absorbed by melanin in the skin, skin tone is a highly relevant but under-studied variable of interest. In this study, to address these gaps, we use Monte Carlo simulations (with MCX) of a single laser source for transcranial (tPBM) and intranasal (iPBM, nostril position) irradiated on a healthy human brain model. We investigate wavelengths of 670, 810 and 1064 nm in combination with light (“Caucasian”), medium (“Asian”) and dark (“African”) skin tones. Our simulations show that a maximum of 15% of the incidental energy for tPBM and 1% for iPBM reaches the cortex from the light source at the skin level. The rostral dorsal prefrontal cortex in tPBM and the ventromedial prefrontal cortex for iPBM accumulates the highest highest light energy, respectively for both wavelengths. Specifically, the 810 nm wavelength for tPBM and 1064 nm wavelength for iPBM produced the highest energy accumulation. Optical power density was found to be linearly correlated with energy. Moreover, we show that “Caucasian” skin allows the accumulation of higher light energy than other two skin colours. This study is the first to account for skin colour as a PBM dosing consideration, and provides evidence for hypothesis generation in in vivo studies of PBM.
Structure-function coupling and decoupling during movie-watching and resting-state: Novel insights bridging EEG and structural imaging
Authors: Subramani Venkatesh , Lioi Giulia , Jerbi Karim , Farrugia Nicolas
Published: April 2024

The intricate structural and functional architecture of the brain enables a wide range of cognitive processes ranging from perception and action to higher-order abstract thinking. Despite important progress, the relationship between the brain’s structural and functional properties is not yet fully established. In particular, the way the brain’s anatomy shapes its electrophysiological dynamics remains elusive. The electroencephalography (EEG) activity recorded during naturalistic tasks is thought to exhibit patterns of coupling with the underlying brain structure that vary as a function of behavior. Yet these patterns have not yet been sufficiently quantified. We address this gap by jointly examining individual Diffusion-Weighted Imaging (DWI) scans and continuous EEG recorded during video-watching and resting state, using a Graph Signal Processing (GSP) framework. By decomposing the structural graph into Eigenmodes and expressing the EEG activity as an extension of anatomy, GSP provides a way to quantify the structure-function coupling. We elucidate how the structure shapes function during naturalistic tasks such as movie-watching and how this association is modulated by tasks. We quantify the coupling relationship in a region-, time-, frequency-resolved manner. First of all, our findings indicate that the EEG activity in the sensorimotor cortex is strongly coupled with brain structure, while the activity in higher-order systems is less constrained by anatomy, i.e., shows more flexibility. In addition, we found that watching videos was associated with stronger structure-function coupling in the sensorimotor cortex, as compared to resting-state data. Second, time-resolved analysis revealed that the unimodal systems undergo minimal temporal fluctuation in structure-function association, and the transmodal system displays highest temporal fluctuations, with the exception of PCC seeing low fluctuations. Lastly, our frequency-resolved analysis revealed a consistent topography across different EEG rhythms, suggesting a similar relationship with the anatomical structure across frequency bands. Together, this unprecedented characterization of the link between structure and function using continuous EEG during naturalistic behavior underscores the role of anatomy in shaping ongoing cognitive processes. Taken together, by combining the temporal and spectral resolution of EEG and the methodological advantages of GSP, our work sheds new light onto the anatomo-functional organization of the brain.
Virus-like particle (VLP)-based vaccine targeting tau phosphorylated at Ser396/Ser404 (PHF1) site outperforms phosphorylated S199/S202 (AT8) site in reducing tau pathology and restoring cognitive deficits in the rTg4510 mouse model of tauopathy
Authors: Hulse Jonathan , Maphis Nicole , Peabody Julianne , Chackerian Bryce , Bhaskar Kiran
Published: April 2024

Tauopathies, including Alzheimer’s disease (AD) and Frontotemporal Dementia (FTD), are histopathologically defined by the aggregation of hyperphosphorylated pathological tau (pTau) as neurofibrillary tangles in the brain. Site-specific phosphorylation of tau occurs early in the disease process and correlates with progressive cognitive decline, thus serving as targetable pathological epitopes for immunotherapeutic development. Previously, we developed a vaccine (Qβ-pT181) displaying phosphorylated Thr181 tau peptides on the surface of a Qβ bacteriophage virus-like particle (VLP) that induced robust antibody responses, cleared pathological tau, and rescued memory deficits in a transgenic mouse model of tauopathy. Here we report the characterization and comparison of two additional Qβ VLP-based vaccines targeting the dual phosphorylation sites Ser199/Ser202 (Qβ-AT8) and Ser396/Ser404 (Qβ-PHF1). Both Qβ-AT8 and Qβ-PHF1 vaccines elicited high-titer antibody responses against their pTau epitopes. However, only Qβ-PHF1 rescued cognitive deficits, reduced soluble and insoluble pathological tau, and reactive microgliosis in a 4-month rTg4510 model of FTD. Both sera from Qβ-AT8 and Qβ-PHF1 vaccinated mice were specifically reactive to tau pathology in human AD post-mortem brain sections. These studies further support the use of VLP-based immunotherapies to target pTau in AD and related tauopathies and provide potential insight into the clinical efficacy of various pTau epitopes in the development of immunotherapeutics.
Peroxidasin is associated with a mesenchymal-like transcriptional phenotype and promotes invasion in metastatic melanoma
Authors: Smith-Díaz Carlos C , Kumar Abhishek , Das Andrew , Pace Paul , Chitcholtan Kenny , Magon Nicholas J , Hossain Sultana Hossain Mehbuba , Eccles Michael R , Winterbourn Christine C , Paumann-Page Martina
Published: April 2024

Cutaneous melanoma is a highly invasive, heterogeneous and treatment resistant cancer. It’s ability to dynamically shift between transcriptional states or phenotypes results in an adaptive cell plasticity that may drive cancer cell invasion or the development of therapy resistance. The expression of peroxidasin (PXDN), an extracellular matrix peroxidase, has been proposed to be associated with the invasive metastatic melanoma phenotype. We have confirmed this association by analysing the transcriptomes of 70 metastatic melanoma cell lines with variable levels of PXDN expression. This analysis highlighted a strong association between high PXDN expression and the undifferentiated invasive melanoma phenotype. To assess the functional role of PXDN in melanoma invasion, we performed a knockout of PXDN in a highly invasive cell line (NZM40). PXDN knockout decreased the invasive potential by ∼50% and decreased the expression of epithelial-mesenchymal transition and invasive marker genes as determined by RNAseq and substantiated by proteomics analysis. Bioinformatics analysis of differentially expressed genes following PXDN knockout highlighted decreases in genes linked to extracellular matrix formation, organisation and degradation as well as signalling pathways such as the WNT pathway. This study provides compelling evidence that PXDN plays a functional role in melanoma invasion by promoting an invasive, mesenchymal-like transcriptional phenotype.

Research Highlights

PXDN expression is strongly associated with the invasive melanoma phenotype. Knockout of PXDN decreased invasion and expression of EMT marker genes concomitant with vast transcriptional changes relevant to many aspects of melanoma biology.
Fmo5 plays a sex-specific role in goblet cell maturation and mucus barrier formation
Authors: Schaller Megan L. , Sykes Madeline M. , Mecano Joy , Solanki Sumeet , Huang Wesley , Rebernick Ryan J. , Beydoun Safa , Wang Emily , Bugarin-Lapuz Amara , Shah Yatrik M. , Leiser Scott F.
Published: April 2024

Background and Aims

The intestine plays a key role in metabolism, nutrient and water absorption, and provides both physical and immunological defense against dietary and luminal antigens. The protective mucosal lining in the intestine is a critical component of intestinal barrier that when compromised, can lead to increased permeability, a defining characteristic of inflammatory bowel disease (IBD), among other intestinal diseases. Here, we define a new role for the flavin-containing monooxygenase (FMO) family of enzymes in maintaining a healthy intestinal epithelium.

Methods

UsingCaenorhabditis eleganswe measure intestinal barrier function, actin expression, and intestinal damage response. In mice, we utilize an intestine-specific, tamoxifen- inducible knockout model of the mammalian homolog ofCefmo-2, Fmo5, and assess histology, mucus barrier thickness, and goblet cell physiology. We also treat mice with the ER chaperone Tauroursodeoxycholic acid (TUDCA).

Results

In nematodes, we findCefmo-2is necessary and sufficient for intestinal barrier function, intestinal actin expression, and is induced by intestinal damage. In mice, we find striking changes to the intestine within two weeks following Fmo5 disruption. Alterations include sex-dependent changes in colon epithelial histology, goblet cell localization, and mucus barrier formation. These changes are significantly more severe in female mice, mirroring differences observed in IBD patients. Furthermore, we find increased protein folding stress in Fmo5 knockout animals and successfully rescue the severe female phenotype with addition of a chemical ER chaperone.

Conclusions

Together, our results identify a highly conserved and novel role for Fmo5 in the mammalian intestine and support a key role for Fmo5 in maintenance of ER/protein homeostasis and proper mucus barrier formation.
Translational control of microglial inflammatory and neurodegenerative responses
Authors: Bermudez Sara , Choi Jung-Hyun , Vogel Jacob W. , Kim Sung-Hoon , Mahmood Niaz , Zhu Vivian Yuchan , Cozachenco Danielle , Yaqubi Moein , Zhou Linqiao , Stratton Jo Ann , Hansson Oskar , Healy Luke , Aguilar-Valles Argel , Sonenberg Nahum
Published: April 2024

In Alzheimer’s Disease (AD), activation of the mechanistic target of rapamycin (mTOR) pathway is essential for microglia neuroprotective roles, but it is unclear which mTOR effectors promote these neuroprotective functions. The mTOR complex 1 (mTORC1) inactivates the translation suppressors eukaryotic translation Initiation Factor 4E (eIF4E)-Binding Proteins (4E-BP) to promote mRNA translation. We show that 4E-BP1 inactivation is impaired in microglia under AD-relevant conditions. Depleting 4E-BPs in microglia increases mitochondrial metabolism, suppresses the pro-inflammatory profile, and mitigates amyloid-induced apoptosis. Furthermore, in the cerebrospinal fluid of patients with amyloid pathology, there was a positive association between microglia activation and neurodegeneration, which increases along 4E-BP1 levels. Thus, we propose the engagement mTORC1-4E-BP1 axis as a neuroprotective mechanism and a therapeutic target or biomarker for microglia modulation in AD.
Parameterizing Pantherinae: de novo mutation rate estimates from Panthera and Neofelis pedigrees
Authors: Armstrong Ellie E , Carey Sarah B. , Harkess Alex , Zenato Lazzari Gabriele , Solari Katherine A , Maldonado Jesus E. , Fleischer Robert C. , Aziz Neel , Walsh Pattie , Koepfli Klaus-Peter , Eizirik Eduardo , Petrov Dmitri A. , Campana Michael
Published: April 2024

Estimates of de novo mutation rates are essential for phylogenetic and demographic analyses, but their inference has previously been impeded by high error rates in sequence data and uncertainty in the fossil record. Here, we directly estimate de novo germline mutation rates for all extant members of Panthera, as well as the closely related outgroup Neofelis nebulosa, using pedigrees. We use a previously validated pipeline (RatesTools) to calculate mutation rate for each species and subsequently explore the impacts of the novel rates on historic effective population size estimates in each of these charismatic felids of conservation concern. Importantly, we find that the choice of reference genome, the data type and coverage, and the individual all impact estimates of the mutation rate. Despite these stochastic effects, we inferred that base pair mutation rates for all species fell between 0.5 and 1.4e-08 per generation per base pair (mean 0.81e-08 +/- 0.35-08 across Pantherinae). Our results provide a cautionary view on inter-species mutation rate comparisons, given the error associated with the reference genome choice and sequencing depth of coverage of the individuals.
Overfeeding does not increase energy expenditure or energy excretion in mice
Authors: Ranea-Robles Pablo , Lund Camilla , Lund Jens , Kleinert Maximilian , Clemmensen Christoffer
Published: April 2024

To curb the obesity epidemic, it is imperative that we improve our understanding of the mechanisms controlling fat mass and body weight regulation. While great progress has been made in mapping the biological feedback forces opposing weight loss, the mechanisms countering weight gain remain less well defined. Here, we integrate a mouse model of intragastric overfeeding with a comprehensive evaluation of the regulatory aspects of energy balance, encompassing food intake, energy expenditure, and fecal energy excretion. To evaluate the role of adipose tissue thermogenesis in the homeostatic protection against overfeeding-induced weight gain, we exposed uncoupling protein 1 (UCP1) knockout (KO) mice to overfeeding. Our results confirm that 7 days of 150% overfeeding induces ∼11% weight gain and triggers a potent and prolonged reduction in voluntary food intake that drives body weight back to baseline following overfeeding. Overfeeding has no effects on energy expenditure, consistent with the observation that mice lacking UCP1 are not compromised in their ability to defend against overfeeding-induced weight gain. These data emphasize that whole-body energy expenditure and adipose thermogenesis are not key contributors to protection against overfeeding in mice. Lastly, we show that fecal energy excretion decreases in response to overfeeding, primarily driven by a reduction in fecal output rather than in fecal caloric content. In conclusion, these results challenge the prevailing notion that adaptive thermogenesis contributes to the defense against weight gain induced by overfeeding. Instead, the protection against enforced weight gain in mice is primarily linked to a profound reduction in food intake.
PIEZO1 and PIEZO2 Blade domains are differentially required for channel localization and function
Authors: Sarrió-Ferrández Sergio , Selva Espe , Taberner Francisco J
Published: April 2024

PIEZO1 and PIEZO2 are critical force-gated ion channels, detecting and transducing mechanical forces into ionic currents in many eukaryotic cell types, serving essential physiological roles. CryoEM and structure-function studies have revealed that three PIEZO monomers assemble as a 3-blade propeller, highlighting essential structural aspects for channel function. One of the most prominent features in PIEZO architecture is the Blade, a large membrane embedded domain that comprises 36 transmembrane fragments organized in 9 THU (Transmembrane Helix Units). Despite its suggested role in force transduction, the contribution of the Blade domain in channel physiology remains unclear. By systematically generating different truncated versions of PIEZO1 and PIEZO2, lacking parts of the Blade, we show the intact PIEZO1 Blade is essential for proper localization and function. Conversely, our results indicate the PIEZO2 Distal Blade segments (THU1-3) are dispensable for normal mechanical sensitivity. However, it plays a central role in channel stability and localization, containing a region that mediates the intracellular retention of a chimeric membrane protein. Our study indicates that, in addition to their biophysical properties, PIEZO1 and PIEZO2 also differ in the regulation of their localization, adding a new layer of control on PIEZO2 activity.
Neurological Research in 47 Asian Countries
Authors: Hassan Waseem , Zafar Mehreen
Published: April 2024

Neurology research in the Asian region has seen significant growth and development over the past decade, yet comprehensive analyses of its progress remain scarce. This study aims to address this gap by providing a detailed examination of neurology research in 47 Asian countries from 2013 to 2022. Data was extracted from the Scopus database, encompassing scholarly output, citations, and citation impact metrics. Findings reveal a total of 128,306 research documents published with 1,725,678 total citations, demonstrating a commendable level of research activity. However, disparities exist among countries, with China, Japan, and Australia emerging as leading contributors in terms of both quantity and citation impact. Despite this, a substantial number of countries and universities have published fewer than 100 papers, indicating room for improvement and the need for targeted capacity-building efforts.
Formerly degenerate seventh zinc finger domain from transcription factor ZNF711 rehabilitated by experimental NMR structure
Authors: Rua Antonio J. , Alexandrescu Andrei T.
Published: April 2024

Domain Z7 of nuclear transcription factor ZNF711 has the consensus last metal-ligand H23 found in odd-numbered zinc-fingers of this protein replaced by a phenylalanine. Ever since the discovery of ZNF711 it has been thought that Z7 is probably non-functional because of the H23F substitution. The presence of H26 three positions downstream prompted us to examine if this histidine could substitute as the last metal ligand. The Z7 domain adopts a stable tertiary structure upon metal binding. The NMR structure of Zn2+-bound Z7 shows the classical ββα-fold of CCHH zinc fingers. Mutagenesis and pH titration experiments indicate that H26 is not involved in metal binding and that Z7 has a tridentate metal-binding site comprised of only residues C3, C6, and H19. By contrast, an F23H mutation that introduces a histidine in the consensus position forms a tetradentate ligand. The structure of the WT Z7 is stable causing restricted ring-flipping of phenyalanines 10 and 23. Dynamics are increased with either the H26A or F23H substitutions and aromatic ring rotation is no longer hindered in the two mutants. The mutations have only small effects on theKdvalues for Zn2+and Co2+and retain the high thermal stability of the WT domain above 80 °C. Like two previously reported designed zinc fingers with the last ligand replaced by water, the WT Z7 domain is catalytically active, hydrolyzing 4-nitophenyl acetate. We discuss the implications of naturally occurring tridentate zinc fingers for cancer mutations and drug targeting of notoriously undruggable transcription factors. Our findings that Z7 can fold with only a subset of three metal ligands suggests the recent view that most everything about protein structure can be predicted through homology modeling might be premature for at least the resilient and versatile zinc-finger motif.
Classification and functional characterization of regulators of intracellular STING trafficking identified by genome-wide optical pooled screening
Authors: Gentili Matteo , Carlson Rebecca J. , Liu Bingxu , Hellier Quentin , Andrews Jocelyn , Qin Yue , Blainey Paul C. , Hacohen Nir
Published: April 2024

STING is an innate immune sensor that traffics across many cellular compartments to carry out its function of detecting cyclic di-nucleotides and triggering defense processes. Mutations in factors that regulate this process are often linked to STING-dependent human inflammatory disorders. To systematically identify factors involved in STING trafficking, we performed a genome-wide optical pooled screen and examined the impact of genetic perturbations on intracellular STING localization. Based on subcellular imaging of STING protein and trafficking markers in 45 million cells perturbed with sgRNAs, we defined 464 clusters of gene perturbations with similar cellular phenotypes. A higher-dimensional focused optical pooled screen on 262 perturbed genes which assayed 11 imaging channels identified 73 finer phenotypic clusters. In a cluster containing USE1, a protein that mediates Golgi to ER transport, we found a gene of unknown function, C19orf25. Consistent with the known role of USE1, loss of C19orf25 enhanced STING signaling. Other clusters contained subunits of the HOPS, GARP and RIC1-RGP1 complexes. We show that HOPS deficiency delayed STING degradation and consequently increased signaling. Similarly, GARP/RIC1-RGP1 loss increased STING signaling by delaying STING exit from the Golgi. Our findings demonstrate that genome-wide genotype-phenotype maps based on high-content cell imaging outperform other screening approaches, and provide a community resource for mining for factors that impact STING trafficking as well as other cellular processes observable in our dataset.
Long-term tree population growth can predict woody encroachment patterns
Authors: Shriver Robert K. , Pletcher Elise , Biondi Franco , Urza Alexandra K. , Weisberg Peter J.
Published: April 2024

Recent increases of woody plant density in dryland ecosystems around the world are often attributed to land use changes such as increased livestock grazing and fire suppression, or to climatic trends driven by increasing atmospheric carbon dioxide1,2. While such changes have undoubtedly impacted ecosystem structure and function, the evidence linking them to woody encroachment is mixed and demographic processes underlying changes in woody plant abundance require further consideration3. After examining tree age structures from woodlands across the interior western USA using demographic models, we find little evidence of widespread increases in per-capita tree establishment rates following 19thcentury Euro-American settlement. Woodlands dominated by young trees have often been cited as evidence of woody encroachment driven by a number of anthropogenic processes, but we demonstrate they can also be accurately predicted by a null model including only steady long-term tree population growth. Contrary to common interpretations, we show that tree establishment rates in the last century have mostly declined, rather than increased, and in fact they are currently at their lowest rates since at least 1600 CE.
In humans, insulo-striate structural connectivity is largely biased toward either striosome-like or matrix-like striatal compartments
Authors: Funk AT , Hassan AAO , Waugh JL
Published: April 2024

The insula is an integral component of sensory, motor, limbic, and executive functions, and insular dysfunction is associated with numerous human neuropsychiatric disorders. Insular afferents project widely, but insulo-striate projections are especially numerous. The targets of these insulo-striate projections are organized into tissue compartments, the striosome and matrix. These striatal compartments have distinct embryologic origins, afferent and efferent connectivity, dopamine pharmacology, and susceptibility to injury. Striosome and matrix appear to occupy separate sets of cortico-striato-thalamo-cortical loops, so a bias in insulo-striate projections towards one compartment may also embed an insular subregion in distinct regulatory and functional networks. Compartment-specific mapping of insulo-striate structural connectivity is sparse; the insular subregions are largely unmapped for compartment-specific projections.

In 100 healthy adults, we utilized probabilistic diffusion tractography to map and quantify structural connectivity between 19 structurally-defined insular subregions and each striatal compartment. Insulo-striate streamlines that reached striosome-like and matrix-like voxels were concentrated in distinct insular zones (striosome: rostro- and caudoventral; matrix: caudodorsal) and followed different paths to reach the striatum. Though tractography was generated independently in each hemisphere, the spatial distribution and relative bias of striosome-like and matrix-like streamlines were highly similar in the left and right insula. 16 insular subregions were significantly biased towards one compartment: seven toward striosome-like voxels and nine toward matrix-like voxels. Striosome-favoring bundles had significantly higher streamline density, especially from rostroventral insular subregions. The biases in insulo-striate structural connectivity we identified mirrored the compartment-specific biases identified in prior studies that utilized injected tract tracers, cytoarchitecture, or functional MRI. Segregating insulo-striate structural connectivity through either striosome or matrix may be an anatomic substrate for functional specialization among the insular subregions.