bluuebunny/crossref_metadata_2025 huggingface dataset:
Three montages for Transcranial Electric Stimulation in predicting the early post-surgery outcome of the facial nerve functioning
Authors: Izzo Mikael Gian Andrea , Sebastiano Davide Rossi , Catanzaro Valentina , Melillo Ylenia , Togni Ramona , Visani Elisa , Falco Jacopo , Casali Cecilia , Gemma Marco , Ferroli Paolo , Gallone Annamaria , Daniele Cazzato , Devigili Grazia , Alverà Sara , Lanteri Paola
Published: March 2024

Objective

We assessed the Transcranial Electrical Stimulation (TES)-induced Corticobulbar-Motor Evoked Potentials (Cb-MEPs) evoked from Orbicularis Oculi (Oc) and Orbicularis Oris (Or) muscles with FCC5h/FCC6h-Mz, C3/C4-Cz and C5/C6/-Cz stimulation, during IntraOperative NeuroMonitoring (IONM) in 30 patients who underwent skull-base surgery.

Methods

before (T0) and after (T1) the surgery, we compared the peak-to-peak amplitudes of Cb-MEPs obtained from TES with C3/C4-Cz, C5/C6-Cz and FCC5h/FCC6h-Mz. Then, we compared the response category (present, absent and peripheral) related to different montages. Finally, we classified the Cb-MEPs data from each patient for concordance with clinical outcome and we assessed the diagnostic measures for Cb-MEPs data obtained from FCC5h/FCC6h-Mz, C3/C4-Cz and C5/C6-Cz TES stimulation.

Results

Both at T0 and T1, FCC5h/FCC6h-Mz stimulation evoked larger Cb-MEPs than C3/C4-Cz, less peripheral responses from direct activation of facial nerve than C5/C6-Cz. FCC5h/FCC6h-Mz stimulation showed the best accuracy and specificity of Cb-MEPs for clinical outcomes.

Conclusions

FCC5h/FCC6h-Mz stimulation showed the best performances for monitoring the facial nerve functioning, maintaining excellent diagnostic measures even at low stimulus voltages.Significance:We demonstrated that FCC5h/FCC6h-Mz TES montage for Cb-MEPs in IONM has good accuracy in predicting the post-surgery outcome of facial nerve functioning.

Highlights

At low voltage, FCC5h/FCC6h-Mz stimulation evoked larger Cb-MEPs than C3/C4-Cz

At low voltage, FCC5h/FCC6h-Mz stimulation induced less peripheral responses by direct activation of facial nerve than C5/C6-Cz

FCC5h/FCC6h-Mz stimulation is safe and increases the accuracy and the specificity of Cb-MEPs with respect to facial nerve outcome
Identification of established and novel extracellular matrix components in glioblastoma as targets for angiogenesis and prognosis
Authors: Barbosa Lucas Cunha , Machado Gabriel Cardoso , Heringer Manoela , Ferrer Valéria Pereira
Published: March 2024

Glioblastomas (GBM) are aggressive tumors known for their heterogeneity, rapid proliferation, treatment resistance, and extensive vasculature. Angiogenesis, the formation of new vessels, involves endothelial cell (EC) migration and proliferation. Various extracellular matrix (ECM) molecules regulate EC survival, migration, and proliferation. Culturing human brain EC (HBMEC) on GBM-derived ECM revealed a decrease in EC numbers compared to controls. Throughin silicoanalysis, we explored ECM gene expression differences between GBM and brain normal glia cells and the impact of GBM microenvironment on EC ECM transcripts. ECM molecules such as collagen alpha chains (COL4A1,COL4A2, p < 0.0001); laminin alpha (LAMA4), beta (LAMB2), and gamma (LAMC1) chains (p < 0.0005); neurocan (NCAN), brevican (BCAN) and versican (VCAN) (p < 0.0005); hyaluronan synthase (HAS) 2 and metalloprotease (MMP) 2 (p < 0.005); MMP inhibitors (TIMP1-4, p < 0.0005), transforming growth factor beta-1 (TGFB1) and integrin alpha (ITGA3/5) (p < 0.05) and beta (ITGB1, p < 0.0005) chains showed increased expression in GBM. Additionally, GBM-influenced EC exhibited elevated expression ofCOL5A3,COL6A1,COL22A1andCOL27A1(p < 0.01);LAMA1,LAMB1(p < 0.001); fibulins (FBLN1/2, p < 0.01);MMP9,HAS1,ITGA3,TGFB1, and wingless-related integration site 9B (WNT9B) (p < 0.01) compared to normal EC. Some of these molecules:COL5A1/3,COL6A1,COL22/27A1,FBLN1/2,ITGA3/5,ITGB1andLAMA1/B1(p < 0.01);NCAN,HAS1,MMP2/9,TIMP1/2andTGFB1(p < 0.05) correlated with GBM patient survival. In conclusion, this study identified both established and novel ECM molecules regulating GBM angiogenesis, suggestingNCANandCOL27A1are new potential prognostic biomarkers for GBM.
Flexible-circuit-based 3-D aware modular optical brain imaging system for high-density measurements in natural settings
Authors: Xu Edward , Vanegas Morris , Mireles Miguel , Dementyev Artem , Yücel Meryem , Carp Stefan , Fang Qianqian
Published: March 2024

Significance

Functional near-infrared spectroscopy (fNIRS) presents an opportunity to study human brains in every-day activities and environments. However, achieving robust measurements under such dynamic condition remains a significant challenge.

Aim

The modular optical brain imaging (MOBI) system is designed to enhance optode-to-scalp coupling and provide real-time probe 3-D shape estimation to improve the use of fNIRS in everyday conditions.

Approach

The MOBI system utilizes a bendable and lightweight modular circuit-board design to enhance probe conformity to head surfaces and comfort for long-term wearability. Combined with automatic module connection recognition, the built-in orientation sensors on each module can be used to estimate optode 3-D positions in real-time to enable advanced tomographic data analysis and motion tracking.

Results

Optical characterization of the MOBI detector reports a noise equivalence power (NEP) of 8.9 and 7.3 pW/ Hz at 735 nm and 850 nm, respectively, with a dynamic range of 88 dB. The 3-D optode shape acquisition yields an average error of 4.2 mm across 25 optodes in a phantom test compared to positions acquired from a digitizer. Results for initialin vivovalidations, including a cuff occlusion and a finger-tapping test, are also provided.

Conclusions

To the best of our knowledge, the MOBI system is the first modular fNIRS system featuring fully flexible circuit boards. The self-organizing module sensor network and automatic 3-D optode position acquisition, combined with lightweight modules (18 g/module) and ergonomic designs, would greatly aid emerging explorations of brain function in naturalistic settings.
RACIAL AND ETHNIC DIFFERENCES IN LONG-TERM CARDIOVASCULAR MORTALITY AMONG WOMEN AND MEN FROM THE CAC CONSORTIUM
Authors: Rosenblatt Shmuel , Blaha Michael J. , Blankstein Ron , Yeboah-Kordieh Yvette , Nasir Khurram , Lin Fay , Berman Daniel S. , Miedema Michael D. , Whelton Seamus P. , Rumberger John , Budoff Matthew J. , Leipsic Jonathon , Shaw Leslee J.
Published: March 2024

Background

Despite an increasingly diverse population, knowledge regarding racial and ethnic disparities is limited among women and men undergoing atherosclerotic cardiovascular (ASCVD) screening. Our aim was to compare CV mortality by ASCVD risk and coronary artery calcium (CAC) scores among Black and Hispanic women and men compared to other participants.

Design and Methods

From the CAC Consortium, 42,964 participants with self-reported race and ethnicity were followed for a median of 11.7 years. Multivariable Cox proportional hazards regression models were used to estimate CV mortality, with separate analyses by sex.

Results

One-third of enrollees were women; 977 self-reported as Black, 1,349 as Hispanic, 1,621 as Asian, and 740 as American Indian/Native Alaskan/Hawaiian or other; the remainder were white. Black women and men had higher ASCVD risk and CAC scores yielding the highest CV mortality compared to other participants. Among Black women and men with a 0 CAC or ASCVD risk score <5%, hazard ratios (HRs) were 6-9-fold higher than that of other women and men. In men with CAC scores ≥100, Black men (HR: 4.2,p<0.001) had the highest CV mortality compared to all other men. A similar high-risk pattern was noted for Black women with CAC scores ≥100 (p<0.001), even when adjusting for the ASCVD risk score. Overall, Hispanics had an elevated CV mortality, higher than others but less than that of Black participants. Patterns of intermediate risk were notable for Hispanic men with a CAC score of 0 (HR=3.6, p=0.006) and ≥100 (HR=2.3, p=0.03).

Conclusions

The disproportionately high and excess CV mortality among Black women and men represents significant barriers to reducing the burden of ASCVD through effective screening using ASCVD risk and CAC scores.
Nanopore sequencing with unique molecular identifiers enables accurate mutation analysis and haplotyping in the complex Lipoprotein(a) KIV-2 VNTR
Authors: Amstler Stephan , Streiter Gertraud , Pfurtscheller Cathrin , Forer Lukas , Di Maio Silvia , Weissensteiner Hansi , Paulweber Bernhard , Schönherr Sebastian , Kronenberg Florian , Coassin Stefan
Published: March 2024

Background

Repetitive genome regions, such as variable number of tandem repeats (VNTR) or short tandem repeats (STR), are major constituents of the uncharted dark genome and evade conventional sequencing approaches. The protein-codingLPAkringle IV type-2 (KIV-2) VNTR (5.6 kb per unit, 1-40 units per allele) is a medically highly relevant example with a particularly intricate structure, multiple haplotypes, intragenic homologies and an intra-VNTR STR. It is the primary regulator of plasma lipoprotein(a) [Lp(a)] concentrations, an important cardiovascular risk factor. However, despite Lp(a) variance is mostly genetically determined, Lp(a) concentrations vary widely between individuals and ancestries. This VNTR region hides multiple causal variants and functional haplotypes.

Methods

We evaluated the performance of amplicon-based nanopore sequencing with unique molecular identifiers (UMI-ONT-Seq) for SNP detection, haplotype mapping, VNTR unit consensus sequence generation and copy number estimation via coverage-corrected haplotypes quantification in the KIV-2 VNTR. We used 15 human samples and low-level mixtures (0.5% to 5%) of KIV-2 plasmids as a validation set. We then applied UMI-ONT-Seq to extract KIV-2 VNTR haplotypes in 48 multi-ancestry 1000-Genome samples and analyzed at scale a poorly characterized STR within the KIV-2 VNTR.

Results

UMI-ONT-Seq detected KIV-2 SNPs down to 1% variant level with high sensitivity, specificity and precision (0.977±0.018; 1.000±0.0005; 0.993±0.02) and accurately retrieved the full-length haplotype of each VNTR unit. Human variant levels were highly correlated with next-generation sequencing (R2=0.983) without bias across the whole variant level range. Six reads per UMI produced sequences of each KIV-2 unit with Q40-quality. The KIV-2 repeat number determined by coverage-corrected unique haplotype counting was in close agreement with droplet digital PCR (ddPCR), with 70% of the samples falling even within the narrow confidence interval of ddPCR. We then analyzed 62,679 intra-KIV-2 STR sequences and identified ancestry-specific STR patterns. Finally, we characterized the KIV-2 haplotype patterns across multiple ancestries.

Conclusions

UMI-ONT-Seq accurately retrieves the SNP haplotype and precisely quantifies the VNTR copy number of each repeat unit of the complex KIV-2 VNTR region across multiple ancestries. This study utilizes the KIV-2 VNTR, presenting a novel and potent tool for comprehensive characterization of medically relevant complex genome regions at scale.
The community of Marine Alveolate parasites in the Atlantic inflow to the Arctic Ocean is structured by season, depth and water mass
Authors: Egge Elianne , Vaulot Daniel , Larsen Aud , Edvardsen Bente
Published: March 2024

The marine alveolates (MALVs) are a highly diverse group of parasitic dinoflagellates, which may regulate populations of a wide range of hosts, including other dinoflagellates, copepods and fish eggs. Knowledge on their distribution and ecological role is still limited, as they are difficult to study with morphological methods. In this work, we describe the taxonomic composition, seasonal- and depth distribution of MALVs in the Arctic Ocean west and north of Svalbard, based on metabarcoding data from five cruises. We recovered amplicon sequence variants (ASVs) representing all major groups previously described from environmental sequencing studies (Dino-Groups I-V), with Dino-Groups I and II being the most diverse. The community was structured by season, depth, and water mass. In the epipelagic zone, the taxonomic composition varied strongly by season, however there was also a difference between Arctic and Atlantic water masses in winter. The spring and summer epipelagic communities were characterized by a few dominating ASVs, which were present in low proportions during winter and in mesopelagic summer samples, suggesting that they proliferate under certain conditions, e.g., when specific hosts are abundant. The mesopelagic samples were more similar across sampling months, and may harbor parasites of deep-dwelling organisms, little affected by season.
Element accumulation in the tracheal and bronchial cartilages of monkeys
Authors: Azuma Cho , Oishi Takao , Tohno Yoshiyuki , Ke Lining , Zhao Xiao-zhen , Minami Takeshi , Horii-Hayashi Noriko , Inoue Koichi
Published: March 2024

Compositional changes in the tracheal and bronchial cartilages can affect respiratory ventilation and lung function. We aimed to elucidate element accumulation in the tracheal and bronchial cartilages of monkeys and divided it into four sites: tracheal, tracheal bifurcation, left bronchial, and right bronchial cartilages. The elemental content was analyzed using inductively coupled plasma atomic emission spectrometry.

The average calcium content was two to three times higher in the tracheal cartilage than in the other three cartilages. The trends of phosphorus and zinc were similar to those of calcium. The average calcium, phosphorus, and zinc contents were the highest in the tracheal cartilage and decreased in the following order: the left bronchial, right bronchial, and tracheal bifurcation cartilages. These findings revealed that differences existed in element accumulation between different sites within the same airway cartilage and that calcium, phosphorus, and zinc accumulation mainly occurred in the tracheal cartilage.

A substantial direct correlation was observed between age and calcium content in the tracheal and bronchial cartilages and all such monkeys with high calcium content were > four years of age. These results suggest that calcium accumulation occurs in the tracheal and bronchial cartilages after reaching a certain age.

An extremely substantial direct correlation was observed between calcium and phosphorus contents in the tracheal and bronchial cartilages. This finding is similar to the previously published calcium and phosphorus correlations in several other cartilages, suggesting that the calcium and phosphorus contents of cartilage exist in a certain ratio.
Juvenile Atlantic Sturgeon Survival and Movement in Proximity to an Active Cutterhead Suction Dredge
Authors: Balazik Matthew , Clarke Douglas
Published: March 2024

During 2019 and 2020, 268 (30-71cm fork length) juvenile Atlantic Sturgeon were captured and released in proximity to an active cutterhead suction dredge among three sites in the James River, Virginia. Of these captures, 30 were implanted with acoustic tags and telemetry was used to track their movements. Three juveniles telemetry tagged prior to this project were also detected moving within dredge operations. Cumulatively, tagged juveniles made at least 125 passes of the dredging operations with no evidence of detrimental impact in terms of survival and all were detected following the cessation of dredging. Juveniles were captured, presumed feeding, around 100m from the dredge in areas that could easily be avoided if the dredge created a stressful environment. No significant differences in catch-per-unit-effort were found when trawl catch was compared to a reference location or when monitoring gill netting catch 100m down current of a dredge over a month-long period at one of the sites. These results suggest a finding of very low risk of entrainment, migratory blockage or avoidance within 100m of an active cutterhead suction dredge by juvenile Atlantic Sturgeon.
Intermittent protein restriction elevates food intake and plasma ghrelin in male mice
Authors: Volcko K.L , Taghipourbibalan H. , McCutcheon J.E.
Published: March 2024

Low-protein diets affect body weight, body composition, food intake, and food preferences in mice. Furthermore, single periods of protein restriction can have lasting effects on these parameters. We sought to examine the effect of multiple, short, bouts of protein restriction, relative to long-term maintenance on either a control (NR) or protein-restricted (PR) diet. We found that male mice experiencing intermittent protein restriction (IPR) were indistinguishable from NR mice in terms of body weight and composition, but had food intake and plasma ghrelin as high as mice on PR diet, even when they were returned to control diet. This was not found in female mice. The results of this experiment highlight the importance of diet history on food intake and ghrelin levels in male mice, and the difference in how PR diet might affect male and female mice.
Metformin treatment results in distinctive skeletal muscle mitochondrial remodeling in rats with different intrinsic aerobic capacities
Authors: Bubak Matthew P. , Davidyan Arik , O’Reilly Colleen L. , Mondal Samim A. , Keast Jordan , Doidge Stephen M. , Borowik Agnieszka K. , Taylor Michael E. , Volovičeva Evelina , Kinter Michael T. , Britton Steven L. , Koch Lauren G. , Stout Michael B. , Lewis Tommy L. , Miller Benjamin F.
Published: March 2024

The rationale for the use of metformin as a treatment to slow aging was largely based on data collected from metabolically unhealthy individuals. For healthspan extension metformin will also be used in periods of good health. To understand potential context specificity of metformin treatment on skeletal muscle, we used a rat model (HCR/LCR) with a divide in intrinsic aerobic capacity. Outcomes of metformin treatment differed based on baseline intrinsic mitochondrial function, oxidative capacity of the muscle (gastroc vs soleus), and the mitochondrial population (IMF vs SS). Metformin caused lower ADP-stimulated respiration in LCRs, with less of a change in HCRs. However, a washout of metformin resulted in an unexpected doubling of respiratory capacity in HCRs. These improvements in respiratory capacity were accompanied by mitochondrial remodeling that included increases in protein synthesis and changes in morphology. Our findings raise questions about whether the positive findings of metformin treatment are broadly applicable.
Exposure to live saprophyticLeptospirabefore challenge with a pathogenic serovar prevents severe leptospirosis and promotes kidney homeostasis
Authors: Kundu Suman , Shetty Advait , Gomes-Solecki Maria
Published: March 2024

Previous studies demonstrated thatLeptospira biflexa, a saprophytic species, triggers innate immune responses in the host during early infection. This raised the question of whether these responses could suppress a subsequent challenge with pathogenicLeptospira. We inoculated C3H/HeJ mice with a single or a double dose ofL. biflexabefore challenge with a pathogenic serovar,L. interrogansserovar Copenhageni FioCruz (LIC). Pre-challenge exposure toL. biflexadid not prevent LIC dissemination and colonization of the kidney. However, it rescued weight loss and mouse survival thereby mitigating disease severity. Unexpectedly, there was correlation between rescue of overall health (weight gain, higher survival, lower kidney fibrosis marker ColA1) and higher shedding of LIC in urine. This stood in contrast to theL. biflexaunexposed LIC challenged control. Immune responses were dominated by increased frequency of effector T helper (CD4+) cells in spleen, as well as significant increases in serologic IgG2a. Our findings suggest that exposure to live saprophyticLeptospiraprimes the host to develop Th1 biased immune responses that prevent severe disease induced by a subsequent challenge with a pathogenic species. Thus, mice exposed to live saprophyticLeptospirabefore facing a pathogenic serovar may withstand infection with far better outcomes. Furthermore, a status of homeostasis may have been reached after kidney colonization that helps LIC complete its enzootic cycle.

Significance

Previous evidence of host innate immunity induced by live saprophyticLeptospirain mice led us to posit that these responses might mitigate leptospirosis severity upon a subsequent challenge with a pathogenic serovar. In this study, we validated our hypothesis. This is important for development of novel strategies to control leptospirosis and for understanding the epidemiologic risk factors of this and other infectious diseases transmitted by direct contact between pathogen and host. Unexpectedly, these studies also show that there is a correlation between kidney health afterL. interrogansinfection (less fibrosis marker ColA1) and higher shedding of this spirochete in urine. This suggests that a status of homeostasis may be reached after kidney colonization byL. interrogansthat helps the spirochete fulfill its enzootic cycle.
Decentralizing genetic testing for biodiversity monitoring and biosurveillance with the Nucleic Acid Barcode Identification Tool (NABIT) and Molecular Development Kit (MDK)
Authors: Holmes HR , Winters M , Fang C , Fotouhi G , Mercader J , Fox DA , Bunje PME , Dehgan A
Published: March 2024

The escalating threats to biodiversity, public health, and food security posed by emerging infectious diseases and illegal wildlife trafficking requires novel approaches to biosurveillance. This paper introduces two innovations developed to address these multifaceted challenges: the Nucleic Acid Barcode Identification Tool (NABIT) and the Molecular Development Kit (MDK).

The NABIT is a handheld, battery-powered device that enables genetic tests to be performed at the point of contact by non-technical users, creating a critical bridge between centralized laboratories and the field by reducing barriers to accessible and routine genetic testing. Verification testing and validation results for the NABIT and the lyophilized assays used with it demonstrate key performance parameters, including sample preparation, detection sensitivity, and stability of field-ready assays after 17 months without refrigeration.

The MDK complements the NABIT by providing a framework for third-party development and deployment of field-ready genetic assays. Similar to software development kits (SDKs), the MDK offers documentation, software tools, and NABIT hardware to accelerate the development of new assays, enabling early detection strategies and minimizing future losses. Crucially, the MDK empowers scientists worldwide to contribute to a new ecosystem for wildlife genetics and biosurveillance by developing their own field-ready tests for the NABIT.

In summary, the NABIT and MDK present the potential for a paradigm shift in biosurveillance, ecosystem monitoring, and biodiversity conservation, enabling decentralized genetic testing, early disease detection, and rapid response to protect sensitive ecosystems, public health, and food security.
Metabolic Vulnerabilities of Temozolomide-Resistant Glioblastoma Cells: Implications for Targeted Therapies and Overcoming Chemoresistance
Authors: Amereh Meitham , Seyfoori Amir , Shojaei Shahla , Lane Sarah , Zhao Tian , Shokrollahi Mahdieh , Lum Julian , Walter Patrick , Akbari Mohsen
Published: March 2024

Chemoresistance is a major clinical challenge in the management of glioblastoma (GB), making it difficult to achieve long-term success with traditional treatments. Therefore, there is a need for the development of novel drugs. We explored the metabolic vulnerabilities of temozolomide (TMZ)-resistant GB and their potential implications for targeted therapies. In monolayer and tumoroid cultures, we found elevated reliance on oxidative phosphorylation in TMZ-resistant cells. Notably, iron reduction in TMZ-resistant cells reduced viability and proliferation, upregulated hypoxia-inducible factor 1-α (Hif1-α) expression, induced autophagy, inhibited autophagic flux, and increased reactive oxygen species (ROS) generation, indicating the significance of iron in metabolic vulnerabilities of these cells. Hypoxic cells showed acquired resistance to iron chelation compared to their normoxic state, suggesting an adaptive mechanism associated to hypoxia. Viability, size, and invasion were reduced in TMZ-resistant tumoroids. Additionally, we reported IC50 for the combination of TMZ with a range of DFO and DFP, making the combination therapy a promising drug candidate to improve therapeutic treatments.

Teaser

Combining iron reduction and chemotherapy in drug-resistant glioblastoma cells enhances therapeutic outcomes.
Do seabirds dream of artificial lights? Understanding light preferences of Procellariiformes
Authors: Atchoi Elizabeth , Mitkus Mindaugas , Machado Biana , Medeiros Valter , Garcia Sofia , Juliano Manuela , Bried Joël , Rodríguez Airam
Published: March 2024

Seabirds, and particularly fledglings of burrow-nesting species, are greatly impacted by light pollution. During their inaugural flights from colony to sea, fledglings become grounded after encountering artificial light. Such groundings, or fallout events, affect many fledglings each year. To mitigate this light induced mortality, rescue programs have been implemented for decades in many locations worldwide. Despite the notoriety of fallouts, the contributing behavioural and biological factors remain mostly unknown. How do the mechanisms of light attraction and light avoidance interact or how do they manifest in different groups (e.g., age, personality, populations), or light pollution levels, remain open questions. We tested behavioural preferences of Cory’s shearwaterCalonectris borealisfledglings, rescued after being grounded in urban areas, and of breeding adults, for contrasting light sources. Fledglings and adults were exposed to one of the three treatments in an experimental y-maze set-up: white light versus no-light, blue versus red light, and a control with no-light on each arm of the y-maze. Both age groups have shown preferences for the no-light arms and the red light arm. The preference for longer wavelengths and darker environments, along with slower responses by fledglings, suggest that close range light pollution appears to cause disorientation in seabirds. Our study helps to clarify the behavioural components of fallouts and provides further evidence on the disruptive effects of nocturnal artificial light on sensitive species.
Gut Microbiome-Driven Metabolites Influence Skin Pigmentation in TYRP1 Mutant Oujiang Color Common Carp
Authors: Mandal Roland Nathan , Ke Jing , Kanika Nusrat Hasan , Hou Xin , Zhang Zhiyi , Zhang Penghui , Chen Huifan , Zeng Chunxiao , Chen Xiaowen , Wang Jun , Wang Chenghui
Published: March 2024

The gut microbiome is one of the major regulators of the gut-skin axis and is partly regulated by host genetics. In the present study, using comparative high-throughput omics data on CRISPR/Cas9-mediatedTYRP1mutant and wild-color common carp populations, we quantified the proportion of inter-individual variation in the skin transcriptome and blood metabolome by genetic architecture and gut microbiomes. We found 525 differential metabolites (DMs) and 45 differential gut microbial genera inTYRP1mutant fishes relative to the wild type. Through interaction analysis and causal mediation analyses, we revealed that the TYRP1-mutant derived genetic background may exert an inflammatory Acinetobacter - Leukotrience-C4 and – Spermine metabolic pathway under the regulation of an anti-inflammatory cardio-vascular genetic network underlying the upregulating expression ofCOMT,PLG,C2,C3,F10,TDO2,MHC1, andSERPINF2gene for evolving unusual coffee-like color phenotype. This unique network appears to underlie the “coffee-like” color phenotype. We propose that theCOMT-mediated causal effect of the unusual gut microbiome on the atypical skin gene expression patterns through the gut-skin metabolic pathway.

Article Summary

R.N. Mandal et al. report on the causal effect of gut microbiome-driven metabolites on the expression pattern of regulatory genes underlying an unusual color phenotype. It suggests that TYRP1 Mutation may rise an unusual inflammatory gut microbiome-skin metabolic pathway that may be balanced by an anti-inflammatory cardio-vascular genetic network leading to unique coloration in Oujiang Color Common Carp.
FACS-Sortable Triple Emulsion Picoreactors for Screening Reactions in Biphasic Environments
Authors: Thompson Samuel , Zhang Yanrong , Yang Zijian , Nichols Lisa A. , Fordyce Polly M.
Published: March 2024

Biphasic environments can enable successful chemical reactions where any single solvent results in poor substrate solubility or poor catalyst reactivity. For screening biphasic reactions at high-throughput, a platform based on microfluidic double emulsions could use widely available FACS (Fluorescence Activated Cell Sorting) machines to screen millions of picoliter reactors in a few hours. However, encapsulating biphasic reactions within double emulsions to form FACS-sortable droplet picoreactors requires optimized solvent phases and surfactants to produce triple emulsion droplets that are stable over multi-hour assays and compatible with desired reaction conditions. This work demonstrates such FACS-sortable triple emulsion picoreactors with a fluorocarbon shell and biphasic octanol-in-water core. First, surfactants were screened to stabilize octanol-in-water emulsions for the picoreactor core. With these optimized conditions, stable triple emulsion picoreactors were produced (>70% of droplets survived to 24 hours), and the ability to produce protein in the biphasic core was demonstrated via cell-free protein synthesis. Finally, triple emulsion picoreactors were sorted based on fluorescence using commercial FACS sorters at >100 Hz with 75-80% of droplets recovered. These triple emulsion picoreactors have potential for future screening bead-encoded catalyst libraries, including enzymes such as lipases for biofuel production.
Age-related behavioral resilience in smartphone touchscreen interaction dynamics
Authors: Ceolini Enea , Ridderinkhof K. Richard , Ghosh Arko
Published: March 2024

We experience a life that is full of ups and downs. The ability to bounce back after adverse life events such as the loss of a loved one or serious illness declines with age, and such isolated events can even trigger accelerated aging. How humans respond to common day-to-day perturbations is less clear. Here, we infer the aging status from smartphone behavior by using a decision tree regression model trained to accurately estimate the chronological age based on the dynamics of touchscreen interactions. Individuals (N = 280, 21 to 83 years of age) expressed smartphone behavior that appeared younger on certain days and older on other days through the observation period that lasted up to ∼4 years. We captured the essence of these fluctuations by leveraging the mathematical concept of critical transitions and tipping points in complex systems. In most individuals, we find one or more alternative stable aging states separated by tipping points. The older the individual, the lower the resilience to forces that push the behavior across the tipping point into an older state. Traditional accounts of aging based on sparse longitudinal data spanning decades suggest a gradual behavioral decline with age. Taken together with our current results, we propose that the gradual age-related changes are interleaved with more complex dynamics at shorter timescales where the same individual may navigate distinct behavioral aging states from one day to the next. Real-world behavioral data modeled as a complex system can transform how we view and study aging.
EHR-ML: A generalisable pipeline for reproducible clinical outcomes using electronic health records
Authors: Ramakrishnaiah Yashpal , Macesic Nenad , Webb Geoffrey I. , Peleg Anton Y. , Tyagi Sonika
Published: March 2024

The healthcare landscape is experiencing a transformation with the integration of Artificial Intelligence (AI) into traditional analytic workflows. However, this advancement encounters challenges due to variations in clinical practices, resulting in a crisis of generalisability. Addressing this issue, our proposed solution, EHR-ML, offers an open-source pipeline designed to empower researchers and clinicians. By leveraging institutional Electronic Health Record (EHR) data, EHR-ML facilitates predictive modelling, enabling the generation of clinical insights. EHR-ML stands out for its comprehensive analysis suite, guiding researchers through optimal study design, and its built-in flexibility allowing for construction of robust, customisable models. Notably, EHR-ML integrates a dedicated two-layered ensemble model utilising feature representation learning. Additionally, it includes a feature engineering mechanism to handle intricate temporal signals from physiological measurements. By seamlessly integrating with our quality assurance pipelines, this utility leverages its data standardization and anomaly handling capabilities.

Benchmarking analyses demonstrate EHR-ML’s efficacy, particularly in predicting outcomes like inpatient mortality and the Intensive Care Unit (ICU) Length of Stay (LOS). Models built with EHR-ML outperformed conventional methods, showcasing its generalisability and versatility even in challenging scenarios such as high class-imbalance.

We believe EHR-ML is a critical step towards democratising predictive modelling in health-care, enabling rapid hypothesis testing and facilitating the generation of biomedical knowledge. Widespread adoption of tools like EHR-ML will unlock the true potential of AI in healthcare, ultimately leading to improved patient care.
Investigating the Relationship Between Rare Genetic Variants and Fibrosis in Pediatric Nonalcoholic Fatty Liver Disease
Authors: Wattacheril Julia , Kleinstein Sarah E. , Shea Patrick R. , Wilson Laura A. , Subramanian G. Mani , Myers Robert P. , Lefkowitch Jay , Behling Cynthia , Xanthakos Stavra A. , Goldstein David B. ,   the NASH Clinical Research Network
Published: March 2024

Background and Aims

Nonalcoholic Fatty Liver Disease (NAFLD) is a complex human disease. Common genetic variation in the patatin-like phospholipase domain containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2) genes have been associated with an increased risk of developing NAFLD, nonalcoholic steatohepatitis (NASH), and fibrosis in adults. The role of rare genetic variants in the development and progression of NAFLD in children is not well known. We aimed to explore the role of rare genetic variants in pediatric patients with advanced fibrosis.

Methods

Whole exome sequencing data was generated for 229 pediatric patients diagnosed with NAFLD recruited from the NASH Clinical Research Network (NASH CRN). Case-control single variant and gene-based collapsing analyses were used to test for rare variants that were enriched or depleted within the pediatric NAFLD cohort specifically for advanced fibrosis (cases) versus those without fibrosis (controls) or six other histologic characteristics. Exome data from non-NAFLD population controls were also used for additional analyses. All results were adjusted for multiple testing using a Bonferroni correction.

Results

No genome-wide significant associations were found between rare variation and presence of advanced fibrosis or NASH, nor the severity of steatosis, inflammation, or hepatocellular ballooning. Significantly, no enrichment of rare variants inPNPLA3orTM6SF2was observed across phenotypes.

Conclusion

In a cohort of children with histologically proven NAFLD, no genome-wide significant associations were found between rare genetic variation and advanced fibrosis or six other histologic features. Of particular interest was the lack of association with genes of interest in adults:PNPLA3andTM6SF2,though limitations in sample size may reduce the ability to detect associations, particularly with rare variation.
Enhanced 40 and 80 Hz Auditory Steady State Responses in Idiopathic Tinnitus
Authors: Ghasemahmad Zahra , Mahmoudian Saeid , Gavazzi Daniel , Jalaei Shohreh , Farahani Saeid
Published: March 2024

Objectives: This study aimed to investigate changes in auditory processing using auditory steady state response (ASSR) in patients with idiopathic tinnitus. Method: 19 tinnitus patients and 23 control subjects without tinnitus were examined with multiple ASSR. Three modulation frequencies of 20, 40, and 80HZ were tested and the steady state responses were compared between tinnitus and control group. Further, the thresholds in ipsi- and contralateral side to ear with tinnitus sensation were compared. Results: Our findings showed no significant difference in ASSR thresholds in ipsi- and contralateral side to ear with tinnitus. However, we observed enhanced ASSRs at 40 and 80Hz modulation in patients with Idiopathic tinnitus compared to no-tinnitus control subjects. Conclusions: The results of this study suggest possible sensory deficits along higher order auditory regions in patients with idiopathic tinnitus. Further, our data indicates a bilateral involvement of auditory pathway in these regions in patients with lateralized tinnitus.
Revised Mechanism of Hydroxyurea Induced Cell Cycle Arrest and an Improved Alternative
Authors: Shaw Alisa E. , Whitted Jackson E. , Mihelich Mattias N. , Reitman Hannah J. , Timmerman Adam J. , Schauer Grant D.
Published: March 2024

Replication stress describes various types of endogenous and exogenous challenges to DNA replication in S-phase. Stress during this critical process results in helicase-polymerase decoupling at replication forks, triggering the S-phase checkpoint, which orchestrates global replication fork stalling and delayed entry into G2. The replication stressor most often used to induce the checkpoint response is hydroxyurea (HU), a chemotherapeutic agent. The primary mechanism of S-phase checkpoint activation by HU has thus far been considered to be a reduction of dNTP synthesis by inhibition of ribonucleotide reductase (RNR), leading to helicase-polymerase decoupling and subsequent activation of the checkpoint, mediated by the replisome associated effector kinase Mrc1. In contrast, we observe that HU causes cell cycle arrest in budding yeast independent of both the Mrc1-mediated replication checkpoint response and the Psk1-Mrc1 oxidative signaling pathway. We demonstrate a direct relationship between HU incubation and reactive oxygen species (ROS) production in yeast nuclei. We further observe that ROS strongly inhibits thein vitropolymerase activity of replicative polymerases (Pols), Pol α, Pol δ, and Pol ε, causing polymerase complex dissociation and subsequent loss of DNA substrate binding, likely through oxidation of their integral iron sulfur Fe-S clusters. Finally, we present “RNR-deg,” a genetically engineered alternative to HU in yeast with greatly increased specificity of RNR inhibition, allowing researchers to achieve fast, nontoxic, and more readily reversible checkpoint activation compared to HU, avoiding harmful ROS generation and associated downstream cellular effects that may confound interpretation of results.
Intrahost evolution leading to distinct lineages in the upper and lower respiratory tracts during SARS-CoV-2 prolonged infection
Authors: El Moussaoui Majdouline , Bontems Sebastien , Meex Cecile , Hayette Marie-Pierre , Lejeune Marie , Hong Samuel L. , Dellicour Simon , Moutschen Michel , Cambisano Nadine , Renotte Nathalie , Bours Vincent , Darcis Gilles , Artesi Maria , Durkin Keith
Published: March 2024

Accumulating evidence points to persistent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in immunocompromised individuals as a source of genetically divergent, novel lineages, generally characterised by increased transmissibility and immune escape. While intrahost evolutionary dynamics of the virus in chronically infected patients have been previously reported, existing knowledge is primarily based on samples obtained from the nasopharyngeal compartment. In this study, we investigate the intrahost evolution and genetic diversity that accumulated during a prolonged SARS-CoV-2 infection with the Omicron sublineage BF.7, estimated to have persisted for over one year in an immunosuppressed patient. Based on the sequencing of eight viral genomes collected from the patient at six time points, we identified 86 intrahost single-nucleotide variants (iSNVs), two indels, and a 362 bp deletion. Our analysis revealed distinct viral genotypes in the nasopharyngeal (NP), endotracheal aspirate (ETA), and bronchoalveolar (BAL) samples. Notably, while significant divergence was observed between NP and BAL samples, most of the iSNVs found in ETA samples were also detected in NP or BAL samples. This suggests that NP samples may not offer a comprehensive representation of the overall intrahost viral diversity. Nonsynonymous mutations were most frequent in the spike and envelope genes, along with loss-of-function mutations in ORF8, generated by a frameshift mutation and a large deletion detected in the BAL and NP samples, respectively. Using long-range PCR on SARS-CoV-2 samples sequenced as part of routine surveillance, we validated that similar deletions causing ORF8 loss of function can be carried by SARS-CoV-2 during acute infection. Our findings not only demonstrate that the Omicron sublineage BF.7 can further diverge from its already exceptionally mutated state but also highlight that patients chronically infected with SARS-CoV-2 can develop genetically specific viral populations across distinct anatomical compartments. This provides novel insights into the intricate nature of viral diversity and evolution dynamics in persistent infections.
Nasopharyngeal metatranscriptomics reveals host-pathogen signatures of pediatric sinusitis
Authors: AbuMazen Nooran , Chu Vivian , Hunjan Manjot , Lobb Briallen , Lee Sojin , Kurs-Lasky Marcia , Williams John V. , MacDonald William , Johnson Monika , Hirota Jeremy A. , Shaikh Nader , Doxey Andrew C.
Published: March 2024

Acute sinusitis (AS) is the fifth leading cause of antibiotic prescriptions in children. Distinguishing bacterial AS from common viral upper respiratory infections in children is crucial to prevent unnecessary antibiotic use but is challenging with current diagnostic methods. Despite its speed and cost, untargeted RNA sequencing of clinical samples from children with suspected AS has the potential to overcome several limitations of other methods. However, the utility of sequencing-based approaches in analysis of AS has not been fully explored. Here, we performed RNA-seq of nasopharyngeal samples from 221 children with clinically diagnosed AS to characterize their pathogen and host-response profiles. Results from RNA-seq were compared with those obtained using culture for three common bacterial pathogens and qRT-PCR for 12 respiratory viruses. Metatranscriptomic pathogen detection showed high concordance with culture or qRT-PCR, showing 87%/81% sensitivity (sens) / specificity (spec) for detecting bacteria, and 86%/92% (sens/spec) for viruses, respectively. We also detected an additional 22 pathogens not tested for in the clinical panel, and identified plausible pathogens in 11/19 (58%) of cases where no organism was detected by culture or qRT-PCR. We assembled genomes of 205 viruses across the samples including novel strains of coronaviruses, respiratory syncytial virus (RSV), and enterovirus D68. By analyzing host gene expression, we identified host-response signatures that distinguished bacterial and viral infections and correlated with pathogen abundance. Ultimately, our study demonstrates the potential of untargeted metatranscriptomics for in depth analysis of the etiology of AS, comprehensive host-response profiling, and using these together to work towards optimized patient care.

One Sentence Summary

RNA-sequencing of nasopharyngeal samples enables pathogen-detection and host-response profiling in pediatric acute sinusitis.
The seroprevalence of SARS-CoV-2-specific antibodies in Australian children: a cross sectional study
Authors: Koirala Archana , McRae Jocelynne , Britton Philip N , Downes Marnie , Prasad Shayal A , Nicholson Suellen , Winkler Noni E , O’Sullivan Matthew V N , Gondalwala Fatima , Castellano Cecile , Carey Emma , Hendry Alexandra , Crawford Nigel , Wadia Ushma , Richmond Peter , Marshall Helen S , Clark Julia E , Francis Joshua R , Carr Jeremy , Bartlett Adam , McMullan Brendan , Skowno Justin , Hannah Donald , Davidson Andrew , von Ungern-Sternberg Britta S , Lee-Archer Paul , Burgoyne Laura L , Waugh Edith B , Carlin John B , Naing Zin , Kerly Nicole , McMinn Alissa , Hunter Guillian , Heath Christine , D’Angelo Natascha , Finucane Carolyn , Francis Laura A , Dougherty Sonia , Rawlinson William , Karapanagiotidis Theo , Cain Natalie , Brizuela Rianne , Blyth Christopher C , Wood Nicholas , Macartney Kristine
Published: March 2024

Background

Following reduction of public health and social measures concurrent with SARS-CoV-2 Omicron emergence in late 2021 in Australia, COVID-19 case notification rates rose rapidly. As rates of direct viral testing and reporting dropped, true infection rates were most likely to be underestimated.

Objective

To better understand infection rates and immunity in this population, we aimed to estimate SARS-CoV-2 seroprevalence in Australians aged 0-19 years.

Methods

We conducted a national cross sectional serosurvey from June 1, 2022, to August 31, 2022, in children aged 0-19 years undergoing an anesthetic procedure at eight tertiary pediatric hospitals. Parents or guardians of children and adolescents under 18 years provided written consent and participants aged 18-19 years provided their own consent. Participant questionnaires were administered, and blood samples tested using the Roche Elecsys Anti-SARS-CoV-2 total spike and nucleocapsid antibody assays. S and N seroprevalence adjusted for geographic and socioeconomic imbalances in the participant sample compared to the Australian population was estimated using multilevel regression and poststratification within a Bayesian framework.

Results

Blood was collected from 2,046 participants (median age: 6.6 years). Adjusted seroprevalence of spike-antibody was 92.1 % (95% credible interval (CrI) 91.0-93.3%) and nucleocapsid-antibody was 67.0% (95% CrI 64.6-69.3). In unvaccinated children spike and nucleocapsid antibody seroprevalences were 84.2% (95% CrI 81.9-86.5) and 67.1% (95%CrI 64.0-69.8), respectively. Seroprevalence increased with age but was similar across geographic distribution and socioeconomic quintiles.

Conclusion

Most Australian children and adolescents aged 0-19 years, across all jurisdictions were infected with SARS-CoV-2 by August 2022, suggesting rapid and uniform spread across the population in a very short time period. High seropositivity in unvaccinated children informed COVID-19 vaccine recommendations in Australia.

Funding

Australian Government Department of Health and Aged Care.