bluuebunny/crossref_metadata_2025 huggingface dataset:
Direct synthesis, characterization,
in vitro
and
in silico
studies of simple chalcones as potential antimicrobial and antileishmanial agents
Authors: ur Rashid Haroon , Khan Sherwali , Irum  , Khan Asad , Ahmad Nasir , Shah Tanzeel , Khan Khalid
Published: June 2024

Chalcone represents a vital biosynthetic scaffold owing to its numerous therapeutic effects. The present study was intended to synthesize 17 chalcone derivatives (
3a
–
q
) by direct coupling of substituted acetophenones and benzaldehyde. The target chalcones were characterized by spectroscopic analyses followed by their
in vitro
antimicrobial, and antileishmanial investigations with reference to standard drugs. The majority of the chalcones displayed good to excellent biological activities. Chalcone
3q
(1000 µg ml
−1
) exhibited the most potent antibacterial effect with its zone of inhibition values of 30, 33 and 34 mm versus
Staphylococcus aureus
,
Escherichia coli
and
Pseudomonas aeruginosa
respectively. The results also confirmed chalcone
3q
to be the most potent versus
Leishmania major
with the lowest IC
50
value of 0.59 ± 0.12 µg ml
−1
. Chalcone
3i
(500 µg ml
−1
) was noticed to be the most potent antifungal agent with its zone of inhibition being 29 mm against
Candida albicans
. Computational studies of chalcones
3i
and
3q
supported the preliminary
in vivo
results. The existence of the amino moiety and bromine atom on ring-A and methoxy moieties on ring-B caused better biological effects of the chalcones. In brief, the investigations reveal that chalcones (
3i
and
3q
) can be employed as building blocks to discover novel antimicrobial agents.
Using photovoice to engage students in a non-major microbiology course
Authors: Kelly Bridget G.
Published: June 2024

In the past decade, it has become increasingly difficult to engage and encourage critical thinking and deeper learning in students who participate in higher education, particularly in non-major subjects. Photovoice is a participatory action research methodology that has been used in community-based research in many different areas including social science, health science and education. In this study, photovoice was used as a pedagogical tool in a third-year BSc Bioscience non-major microbiology module at Dundalk Institute of Technology. In order to ascertain if photovoice was an effective way of engaging these students, a qualitative descriptive methodological approach, in the form of a focus group, was employed. Six of the 13 students who took the module participated in the focus group, reporting a positive experience overall of using photovoice. Further analysis of the focus group data resulted in the overarching theme of choice, with creativity and critical thinking and research skills as sub-themes to emerge. These findings suggest that photovoice is an effective way to engage students in microbiology as a non-major subject. However, as it was a small sample size, future research would need to use a larger cohort of students to provide further evidence of using photovoice as a pedagogical engagement tool for non-major subjects.
Environmental sampling for the detection of capripox viruses and peste des petits ruminants virus in households and livestock markets in Northern Nigeria
Authors: Brown Emma , Ehizibolo David , Dogonyaro Banenat , Wungak Yiltawe , Oyekan Olumuyiwa , Adedeji Adeyinka , Ijeoma Sandra , Atai Rebecca , Oguche Moses , Samson Mark , Rosso Fabrizio , Ludi Anna B , Limon Georgina , Shaw Andrew E , Colenutt Claire , Gubbins Simon
Published: June 2024

Multiple transboundary animal diseases (TADs) circulate in Northern Nigeria, where livestock keeping is a common practice and contributes to both physical and socioeconomic wellbeing of a large proportion of the population. Environmental samples, collected on a monthly basis from five households, one transhumance site and one livestock market in Northern Nigeria between March and October 2021 were tested using real-time PCR for the presence of common TADs in the region. Of the samples tested 2.4% of samples (n=11) were positive for peste de petit ruminants virus (PPRV) RNA and 1.3% of samples (n=6) were positive for capripox virus DNA. A capripox differentiation assay showed that these samples were positive for sheep pox virus (SPPV) (n=2), goat pox virus (GTPV) (n=2) and lumpy skin disease virus (LSDV) (n=2).
The results of this study demonstrate that environmental sampling is a valuable approach to TAD surveillance in areas with limited veterinary resources. Collection of environmental swabs requires little technical knowledge, enabling widespread application of this sampling method. The detection of multiple viruses from a single set of samples highlights the effective nature of environmental sampling in determining the presence of TADs within a region.
Actin isovariant ACT2-mediated cellular auxin homeostasis regulates lateral root organogenesis inArabidopsis thaliana
Authors: Hanzawa Aya , Rahman Arifa Ahamed , Rahman Abidur
Published: June 2024

Lateral root (LR) organogenesis is regulated by cellular flux of auxin within pericycle cells, which depends on the membrane distribution and polar localization of auxin carrier proteins. The correct distribution of auxin carrier proteins relies on the intracellular trafficking of these proteins aided by filamentous actin as a track. However, the precise role of actin in lateral root development is still elusive. Here, using vegetative class actin isovariant mutants, we revealed that loss of actin isovariant ACT8 led to an increase in lateral root formation. The distribution of auxin within pericycle cells was altered inact8mutant, primarily due to the altered distribution of AUX1 and PIN7. Interestingly, incorporation ofact2mutant inact8background (act2act8) effectively nullified the LR phenotype observed inact8mutant, indicating that ACT2 plays an important role in LR development. To explore further, we investigated the possibility that theact8mutant’s LR phenotype and cellular auxin distribution resulted from ACT2 overexpression. Consistent with the idea, enhanced lateral root formation, altered AUX1, PIN7 expression and auxin distribution in pericycle cells were observed in ACT2 overexpression lines. Collectively, these results suggest that actin isovariant ACT2 but not ACT8 plays a pivotal role in regulating source to sink auxin distribution during lateral root organogenesis.
Spectrally Resolved Single Molecule Orientation Imaging Reveals Direct Correspondence between Polarity and Order Experienced by Nile Red in Supported Lipid Bilayer Membrane
Authors: Sarkar Aranyak , Mitra Jyotsna Bhatt , Sharma Veerendra K. , Namboodiri Vinu , Kumbhakar Manoj
Published: June 2024

Molecular level interaction among lipids, cholesterol and water dictates nanoscale membrane organization of lipid bilayers into liquid ordered (Lo) and liquid disordered (Ld) phases, characterized by different polarity and order. Generally, solvatochromic dyes easily discriminate polarity difference between Lo and Ld phases, whereas molecular flippers and rotors show distinct photophysics depending on membrane order. In spite of progress in single molecule spectral imaging and single molecule orientation mapping, still direct experimental proof linking polarity with order sensed by the same probe eludes us. Here, we demonstrate spectrally resolved single molecule orientation localization microscopy to connect nanoscopic localization of probe on bilayer membrane with its emission spectra, three-dimensional dipole orientation and rotational constraint offered by the local microenvironment and highlights the beautiful correspondence between polarity and order. This technique has the potential to addres nanoscale heterogeneity and dynamics, especially in biology as well as material sciences.

TOC GRAPHICS
Localization of Proteins Involved in the Biogenesis of the Photosynthetic Apparatus to Thylakoid Subdomains in Arabidopsis
Authors: Chotewutmontri Prakitchai , Barkan Alice
Published: June 2024

Thylakoid membranes in chloroplasts and cyanobacteria harbor the multisubunit protein complexes that catalyze the light reactions of photosynthesis. In plant chloroplasts, the thylakoid membrane system comprises a highly organized network with several subcompartments that differ in composition and morphology: grana stacks, unstacked stromal lamellae, and grana margins at the interface between stacked and unstacked regions. The localization of components of the photosynthetic apparatus among these subcompartments has been well characterized. However, less is known about the localization of proteins involved in the biogenesis and repair of the photosynthetic apparatus, the partitioning of proteins between two recently resolved components of the traditional margin fraction (refined margins and curvature), and the effects of light on these features. In this study, we analyzed the partitioning of numerous thylakoid biogenesis and repair factors among grana, curvature, refined margin, and stromal lamellae fractions of Arabidopsis thylakoid membranes, comparing the results from illuminated and dark-adapted plants. Several proteins previously shown to localize to a margin fraction partitioned in varying ways among the resolved curvature and refined margin fractions. For example, the ALB3 insertase and FtsH protease involved in photosystem II (PSII) repair were concentrated in the refined margin fraction, whereas TAT translocon subunits and proteins involved in early steps in photosystem assembly were concentrated in the curvature fraction. By contrast, two photosystem assembly factors that facilitate late assembly steps were depleted from the curvature fraction. The enrichment of the PSII subunit OE23/PsbP in the curvature fraction set it apart from other PSII subunits, supporting the previous conjecture that OE23/PsbP assists in PSII biogenesis and/or repair. The PSII assembly factor PAM68 partitioned differently among thylakoid fractions from dark-adapted plants and illuminated plants, and was the only analyzed protein to convincingly do so. These results demonstrate an unanticipated spatial heterogeneity of photosystem biogenesis and repair functions in thylakoid membranes, and reveal the curvature fraction to be a focal point of early photosystem biogenesis.
Joint Moment–Angle/Velocity Relations in the Hip, Knee, and Ankle: A Meta-Visualization of Datasets
Authors: Chen Ziyu , Franklin David W
Published: June 2024

Joint moment is a prominent kinetic property in biomechanical investigations, whose pattern and magnitude unravel the characteristics of musculoskeletal motion and muscle biomechanics. Nonetheless, the relations of joint moment with joint angle and velocity are complicated, and it is often unclear how the kinetic capacity of each joint varies in different configurations. With common techniques in systematic review, we collected a total of 985 passive, isometric and isokinetic joint moment datasets from literature and visualized the major joint moment–angle and moment–velocity relations in the hip, knee, and angle. The findings contribute to the understanding and analysis of musculoskeletal mechanics, as well as providing reference regarding the experimental design for future moment measurement.
Personality homophily drives female friendships in a feral ungulate
Authors: Bhattacharjee Debottam , Flay Kate J , McElligott Alan G
Published: June 2024

Friendships, exhibited by both humans and non-human animals, have considerable adaptive benefits. In humans, similarity or homophily in personality is considered a proximate mechanism driving friendships, yet little is known about the behavioural ′decision rules′ underlying animal friendships. Some empirical research suggests that animal friendships can be driven by personality homophily. However, these studies are restricted to non-human primates, limiting our understanding of the mechanisms of friendships. We investigated a feral population of water buffalo (Bubalus bubalis) to determine whether homophily in personality drives friendships in this ′non-model′ social species in free-ranging environmental conditions. We conducted observations on females (n=30) and assessed their friendships and personalities. Close spatial proximity served as a behavioural indicator of friendship, validated by affiliative body contact. An objective ′bottom-up′ method revealed three personality traits –social tension,vigilance, andgeneral dominance. We found that females with comparatively lower personality differences in social tension and general dominance traits exhibited significantly higher close spatial associations. We did not find an effect of kinship on close spatial associations. Our findings show that friendships in buffalo can form based on personality homophily, a decision rule attributed predominantly to primates. We discuss these findings in light of buffalo socioecology but emphasise their implications in the broader evolutionary context of animal personalities and friendships.
Use of the EsoGuard®Molecular Biomarker Test in Non-Endoscopic Detection of Barrett’s Esophagus among High-Risk Individuals in a Screening Population
Authors: Shaheen Nicholas J. , Othman Mohamed O. , Taunk Jawar , Chang Kenneth J. , Jaganmohan Sathya , Yachimski Patrick S. , Fang John C. , Spataro Joseph S. , Verma Suman , Lee Victoria T. , deGuzman Brian J. , Aklog Lishan
Published: June 2024

Background and Aims

Barrett’s Esophagus (BE) is the precursor to esophageal adenocarcinoma (EAC). We aimed to assess performance, safety, and tolerability of the EsoGuard (EG) assay on samples collected non-endoscopically with the EsoCheck (EC) device (EG/EC) for BE detection in the intended-use population, meeting American College of Gastroenterology (ACG) guideline criteria (chronic gastroesophageal reflux disease (GERD) and 3+ additional risk factors).

Methods

We performed a prospective, multicenter study (NCT04293458) to assess EG performance (primary endpoint) on cells collected with EC, for detection of BE and EAC using esophagogastroduodenoscopy (EGD) and biopsies as the comparator. Twenty-four sites across the U.S. and Spain participated. EC safety and usability were assessed as secondary endpoints.

Results

180 male subjects aged >50 years with chronic GERD met eligibility criteria, of which 163 (90.6%) had EGD and successful EC administration. Mean age was 60.5yrs, 34.4% were obese, 56.7% had tobacco history, and 3.9% had a 1stdegree relative with BE or EAC. Of 122 samples analyzed, 93 contributed to the primary endpoint analysis. About 9% of subjects in the Primary Analysis Population had BE on EGD, none with dysplasia. Sensitivity of EG for BE was 87.5% (95% CI 47.4-99.7), specificity was 81.2% (95% CI 71.2-88.8), positive predictive value was 30.4% (95% CI 13.2-52.9), and negative predictive value was 98.6% (95% CI 92.3-99.96). Mild esophageal abrasions were observed in 1.5%; no serious adverse events were reported.

Conclusions

EG/EC appears effective for BE screening. This approach provides a safe, accurate, and well-tolerated non-endoscopic alternative in high-risk patients.
Cognitive Outcomes of the At-Home Brain Balance Program
Authors: Jackson Rebecca , Meng Yue
Published: June 2024

Accessibility to developmental interventions for children and adolescents could be increased through virtual, at-home delivery of home-based training programs incorporating technology. Virtual childhood training programs and their effects on cognitive outcomes in children and adolescents with developmental delays have not been well studied. To that end, this study examined the effects of the virtual at-home Brain Balance®(BB) program on the cognitive task performance of children and adolescents with baseline developmental and attentional difficulties (aged 4-17 years). The at-home BB program is delivered through: (1) a computer-based format utilizing multimodal program activities previously studied in-center (multisensory stimulation with gross motor, coordination, balance, and timing activities, along with nutritional recommendations); and (2) the BB app (visual motor, auditory and visual processing, and rhythm and timing training) — creating a comprehensive program experience delivered remotely. Cognitive performance was measured by six online cognitive assessments from Creyos Health before and after 3 months of participation in the at-home BB program (N = 316) or in-center BB program (N = 4,232), compared to controls. Results showed that overall cognitive assessment scores (including attention, response inhibition, and working memory) improved after participation in either the at-home or the in-center program, compared to controls. Importantly, significant improvements over the controls were observed for two tasks, Double Trouble and Feature Match, in both programs. Further, two analyses support that the effects on cognitive performance from either delivery format, in-center or at home, are comparable in magnitude. This research: (1) presents new findings demonstrating improved cognitive performance after 3 months of the at-home BB program; (2) replicates previous findings of cognitive improvements after 3 months of the in-center BB program; and (3) suggests that the cognitive effects of virtual at-home BB training are similar to those observed for in-center BB training. Overall, the results demonstrate the effectiveness of the at-home BB program in improving cognitive functioning in pediatric populations with preexisting developmental and attentional difficulties. With virtual delivery and ease of use, at-home programs have the potential to increase access to much-needed developmental and cognitive support, ultimately reaching populations that may otherwise lack easy access to high-quality, evidence-based developmental programs.
Unveiling the Longitudinal Journey: Three-Year Follow-up of Women with MINOCA and INOCA in a Specialized Heart Centre
Authors: Théberge Emilie T. , Burden Elizabeth , Leung Katrina , Parvand Mahraz , Prodan-Bhalla Natasha , Humphries Karin H. , Sedlak Tara L.
Published: June 2024

Background

Myocardial infarction with no obstructive coronary arteries (MINOCA) and ischemia with no obstructive coronary arteries (INOCA), are female predominant conditions, with a lack of clinical trials guiding medical management for the common underlying vasomotor etiologies. Long-term outcomes of (M)INOCA patients following attendance at a women’s heart center (WHC) are lacking.

Methods

Women diagnosed with MINOCA (n=51) or INOCA (n=112) were prospectively followed for 3 years at the Vancouver WHC. Baseline characteristics, diagnoses, chest pain type, major adverse cardiac events, hospital encounters, medications, and Seattle Angina Questionnaire (SAQ) responses were compared between baseline and 3 years. Chi-squared tests were used to compare categorical variables, with Students’ t-tests for continuous variables.

Results

MINOCA patients had significantly more non-exertional chest pain and diagnoses of vasospasm than INOCA patients, who had more exertional chest pain and diagnoses of coronary microvascular dysfunction. Following baseline, both groups had significant reductions in cardiovascular emergency room visits, with INOCA patients also experiencing fewer cardiovascular hospitalizations. At 3 years, the most commonly prescribed medications were calcium channel blockers, long-acting nitrates and beta blockers, with MINOCA having more acetylsalicylic acid and INOCA more short-acting nitrates and ranolazine prescriptions. Both groups observed significant improvements in SAQ scores, with greater improvements observed in INOCA patients. Patients with depression or prescribed ranolazine at 3 years had worse SAQ scores at baseline.

Conclusions

Three-year outcomes of (M)INOCA patients indicate that the WHC’s comprehensive care model effectively improves diagnostic clarity, reduces hospital encounters, optimizes medication management, and improves self-reported patient well-being.
Brain dopamine responses to ultra-processed milkshakes are highly variable and not significantly related to adiposity in humans
Authors: Darcey Valerie L. , Guo Juen , Chi Meible , Chung Stephanie T. , Courville Amber B. , Gallagher Isabelle , Herscovitch Peter , Joseph Paule V. , Howard Rebecca , LaNoire Melissa , Milley Lauren , Schick Alex , Stagliano Michael , Turner Sara , Urbanski Nicholas , Yang Shanna , Zhai Nan , Zhou Megan S. , Hall Kevin D.
Published: June 2024

Ultra-processed foods high in fat and sugar may be addictive, in part, due to their purported ability to induce an exaggerated postingestive brain dopamine response akin to drugs of abuse. Using standard [11C]raclopride positron emission tomography (PET) displacement methods used to measure brain dopamine responses to addictive drugs, we measured postingestive striatal dopamine responses to an ultra-processed milkshake high in fat and sugar in 50 young, healthy adults over a wide body mass index range (BMI 20-45 kg/m2). Surprisingly, milkshake consumption did not result in significant postingestive dopamine response in the striatum (p=0.62) nor any striatal subregion (p>0.33) and the highly variable interindividual responses were not significantly related to adiposity (BMI:r=0.076,p=0.51; %body fat:r=0.16,p=0.28). Thus, postingestive striatal dopamine responses to an ultra-processed milkshake were likely substantially smaller than many addictive drugs and below the limits of detection using standard PET methods.

ClinicalTrials.gov Identifier:NCT03648892
Tolerant mothers: aggression does not explain solitary living in the bush Karoo rat
Authors: Makuya L. , Pillay N. , Sangweni S.P. , Schradin C.
Published: June 2024

Many mammal species are thought to adopt solitary living due to mothers becoming intolerant of their adult offspring as well as social intolerance between adults. However, field studies on how solitary mammals interact are rare. Here we show that solitary living can occur without social intolerance. Over three years, we recorded interactions between free living bush Karoo rats (Otomys unisulcatus) and conducted dyadic encounter experiments between kin and non-kin female neighbours, both in a neutral test arena and in field intruder experiments. Social interactions were rare (N=230 in N=2062 observations), and, when observed, were aggressive in only 34% of the cases. In dyadic encounters, mothers interacted amicably with young offspring. Aggression between mothers and offspring was almost absent. This mother-offspring relationship remained amicable even after the offspring had dispersed. Aggression between neighbouring adult females was low in neutral arena tests, independent of kinship and season. However, in the field, females reacted more aggressively towards non-kin than kin intruders, especially during the breeding season. Tolerance between mothers and adult offspring indicates that aggression is not the mechanism leading to natal dispersal and solitary living. We found a solitary social system characterised by social tolerance, suggesting that dispersal in combination with a lack of social attraction rather than aggression can lead to solitary living.
Integration of ATAC and RNA-sequencing identifies chromatin and transcriptomic signatures in classical and non-classical zebrafish osteoblasts and indicates mechanisms ofentpd5aregulation
Authors: Petratou Kleio , Stehling Martin , Müller Ferenc , Schulte-Merker Stefan
Published: June 2024

Two types of osteoblasts are required to assemble the zebrafish embryonic skeleton: classical osteoblasts homologous to the mammalian cell, and notochord sheath cells, which serve as non-classical osteoblasts. The geneentpd5ais critically required for ossification via both types of osteoblasts. Despite the indispensability of zebrafish models in vertebrate research, the genetic regulation of bone formation, as well as mechanisms of transcriptional control ofentpd5a, remain largely unknown. Here, using a newly generated transgenic line, we isolate classical and non-classical osteoblasts from zebrafish embryos and performed both ATAC-seq and RNA-seq. We analysed results independently and integratively to understand those chromatin dynamics and accompanying transcriptomic changes that occur in different skeletal cell types. We show that although Dlx family factors are playing important roles in classical osteoblast regulation, Hox family factors are involved in governing spinal ossification via non-classical osteoblasts. We further present a resource-driven analysis of theentpd5apromoter, experimentally validating the ATAC-seq dataset and proposing mechanisms of regulating the complexentpd5aexpression pattern during zebrafish osteogenesis. Our results thus provide a necessary comprehensive resource for the field of bone development and indicate spatio-temporally regulated promoter/enhancer interactions taking place in theentpd5alocus.
Sex-steroid hormones relate to cerebellar structure and functional connectivity across adulthood
Authors: Magalhães Thamires N. C. , Hicks Tracey H. , Jackson T. Bryan , Ballard Hannah K. , Herrejon Ivan A. , Bernard Jessica A.
Published: June 2024

Aging involves complex biological changes that affect disease susceptibility and aging trajectories. Although females typically live longer than males, they have a higher susceptibility to diseases like Alzheimer’s, speculated to be influenced by menopause, and reduced ovarian hormone production. Understanding sex-specific differences is crucial for personalized medical interventions and gender equality in health. Our study aims to elucidate sex differences in regional cerebellar structure and connectivity during normal aging by investigating both structural and functional connectivity variations, with a focus on investigating these differences in the context of sex-steroid hormones. The study included 138 participants (mean age = 57(13.3) years, age range = 35-86 years, 54% women). The cohort was divided into three groups: 38 early middle-aged individuals (EMA) (mean age = 41(4.7) years), 48 late middle-aged individuals (LMA) (mean age = 58(4) years), and 42 older adults (OA) (mean age = 72(6.3) years). All participants underwent MRI scans, and saliva samples were collected for sex-steroid hormone quantification (17β-estradiol (E), progesterone (P), and testosterone (T)). We found less connectivity in females between Lobule I-IV and the cuneus, and greater connectivity in females between Crus I, Crus II, and the precuneus with increased age. Higher 17β-estradiol levels were linked to greater connectivity in Crus I and Crus II cerebellar subregions. Analyzing all participants together, testosterone was associated with both higher and lower connectivity in Lobule I-IV and Crus I, respectively, while higher progesterone levels were linked to lower connectivity in females. Structural differences were observed, with EMA males having larger volumes compared to LMA and OA groups, particularly in the right I-IV, right Crus I, right V, and right VI. EMA females showed higher volumes in the right lobules V and VI. These results highlight the significant role of sex hormones in modulating cerebellar connectivity and structure across adulthood, emphasizing the need to consider sex and hormonal status in neuroimaging studies to better understand age-related cognitive decline and neurological disorders.
Single-nucleus RNA sequencing reveals enduring signatures of acute stress and chronic exercise in striatal microglia
Authors: Connolly Meghan G. , Johnson Zachary V. , Chu Lynna , Johnson Nicholas D. , Buhr Trevor J. , McNeill Elizabeth M. , Clark Peter J. , Rhodes Justin S.
Published: June 2024

Acute stress has enduring effects on the brain and motivated behavior across species. For example, acute stress produces persisting decreases in voluntary physical activity as well as molecular changes in the striatum, a brain region that regulates voluntary physical activity and other motivated behaviors. Microglia, the primary immune cells of the central nervous system, are positioned at the interface between neural responses to stress and neural coordination of voluntary activity in that they respond to stress, sense molecular changes in the striatum, and modulate neuronal activity. However, the role of striatal microglia in stress-induced long-term suppression of voluntary activity is unknown. Here we employ single nucleus RNA-sequencing to investigate how stress and exercise impact the biology of microglia in the striatum. We find that striatal microglia display altered activation profiles six weeks after an acute stressor. Furthermore, we show that access to a running wheel is associated with an additional and distinct microglial activation profile characterized by upregulation of genes related to complement components and phagocytosis pathways. Lastly, we find that distinct gene sets show expression changes associated with general access to a running wheel versus variation in running levels. Taken together, our results deepen our understanding of the diverse molecular states that striatal microglia assume in response to stress and exercise and suggest that microglia exhibit a broader range of functional states than previously thought.
TurboID-mediated surface protein biotinylation to inhibit the growth ofStaphylococcus aureus
Authors: Qian Lijuan , He Yuxin , Lian Wenzhe , Ji Zhiyuan , Tian Ziming , Wang Chuyun , Cao Chen , Shern Tyler , Stedman Teagan , Sun Yujun
Published: June 2024

Staphylococcus aureus(S. aureus) infection is major cause of nosocomial infections. Antibiotic treatment forS. aureusremains the primary solution for managingS. aureusinfections, which, however, increases the risk of antibiotic resistance. To broaden the resolutions onS. aureusinfection, here we report TurboID-mediated protein proximity technologies to inhibit the growth ofS. aureus. To achieve this goal, we utilized synthetic biology techniques to create a fusion protein named N-AgrD-TurboID (Agr-ID). The N-AgrD domain includes auto-inducer peptide (AIP) which combined to the surface AgrC protein onS. aureus. As such, TurboID then catalyzed the production of biotinoyl-5’-AMP anhydride, triggering the biotinylation of surface proteins onS. aureus25923 which were visualized by using fluorescence microscopy after incubating with Alexa Fluor 647-conjugated streptavidin. The biotinylation of surface protein onS. aureus25923,S. aureus43300, andS. aureus6538 (MRSA) also resulted in growth inhibition and impaired colonization. Moreover, the biotinylation on surface protein further inhibited virulence protein production inS. aureus25923, as indicated by reduced apoptosis of HEK 293T cells after treatment withS. aureus25923 lysates. Overall, our work reveals that the biotinylation of surface proteins can inhibit the growth and toxicity ofS. aureus25923,S. aureus43300, andS. aureus6538 (MRSA), indicating therapeutic potential in clinical treatment.
Synchronized Temporal-spatial Analysis via Microscopy and Phoshoproteomics (STAMP) of Quiescence
Authors: Aziz-Zanjani Mohammad Ovais , Turn Rachel E. , Xu Lucy Artemis , Jackson Peter K.
Published: June 2024

Tightly coordinated cell cycle regulation is essential for homeostasis. G0, or quiescence, is especially crucial for cells to respond to extracellular stimuli. Little is known about the mechanisms that establish the G0program, though the primary cilium (a key signaling hub formed only in G0) is the most widely recognized marker. The study of ciliogenesis is challenging due to its small size, relative to the cell body. To address this gap in our understanding, we developed STAMP (Spatio-Temporal Analysis via Microscopy and Proteomics) to temporally map the changes in cellular landscape occurring in G0and ciliogenesis. Using synchronized RPE cells, we used fixed and live cell imaging combined with phosphoproteomics to uncover new signals and order them in these processes, which also allows further, more targeted, analyses (e.g., using genetic and pharmacological perturbations). We propose that STAMP is broadly applicable for studying temporal-spatial signaling processes and the underlying mechanisms in various biological contexts and cell types.
Highly Sequence-specific, Timing-controllable m6A Demethylation by Modulating RNA-binding Affinity of m6A Erasers
Authors: Otonari Kenko , Asami Yuri , Ogata Kosuke , Ishihama Yasushi , Futaki Shiroh , Imanishi Miki
Published: June 2024

In recent years, significant progress has been made in developing tools that consist of programmable RNA binding proteins and m6A-erasers to selectively demethylate m6A at specific sites. Especially, timing-controllable demethylation tools using stimulus-inducible dimerization show promise in understanding the impact of individual m6A modifications on dynamic physiological processes. However, a critical issue with these technologies is the possible off-target effects, wherein wild-type m6A-erasers constituting the tools may decrease methylation levels at sites other than the intended target m6A. In this study, we addressed this issue by reducing the intrinsic RNA-binding ability of m6A-erasers to prevent off-target effects and by fusing with PUF RNA-binding protein to provide recognition ability of arbitrary RNA sequences. Taking advantage of the reduced RNA-binding ability of the m6A-erasers themselves, we employed a rapamycin-based switching system in the linker connecting the PUF and m6A-eraser domains. The resulting m6A-erasers exhibited superior precision in demethylating targeted sites while minimizing off-target effects, presenting a novel approach for precise temporal control over m6A modification dynamics.
The role of sex hormones in severe mental illness: a genetic exploration
Authors: Veeneman R. R. , Verweij K. J. H. , Sommer I. E. C. , Treur J. L. , Vermeulen J. M.
Published: June 2024

Introduction

Despite advances in psychotherapies and pharmacological treatments, the burden of severe mental illness (SMI) remains high. Prominent sex differences exist in SMI, with increasing evidence pointing towards a pivotal role for sex hormones. Elucidation of these hormonal influences is crucial to tailor sex-specific prevention and treatment.

Methods

To investigate potential shared genetics and bi-directional causal effects between sex hormone traits and SMI, we computed genetic correlations using linkage disequilibrium score regression and bi-directional summary-level Mendelian Randomization (MR). A range of sensitivity methods was applied and potential mediators were investigated using multivariable MR. Sex-stratified data from genome-wide association studies (GWAS)s were used, further stratified on menopausal status when available. The main analysis focused on depressive disorder (N women=23,618 and N men=17,336), bipolar disorder (N women=26,573 and N men=22,381), schizophrenia (N women=54,513 and N men=68,287) as SMIs, and oestrogen (N women=229,966 and N men=206,927) and testosterone (N women=230,454 and N men=194,453) as the primary sex hormone traits. Exploratory analyses included other sex hormone traits (progesterone, sex hormone-binding globulin, prolactin, age of menarche, age of menopause). Potential mediators examined included levels of cortisol and CRP, smoking initiation, alcohol dependence, alcohol intake, BMI and body fat distribution. Only individuals of European ancestry were included.

Results

We found a widespread pattern of significant genetic correlations between oestrogen/testosterone levels and depressive disorder/schizophrenia, in both positive and negative directions in both sexes (ranging between -0.22 and 0.13). There was no significant genetic correlation for bipolar disorder. In the MR analyses, evidence for causal effects was largely lacking; however, there was consistent evidence for a causal, increasing effect of testosterone levels on schizophrenia risk in men, completely mediated by CRP. Conversely, there was evidence for a causal, increasing effect of liability to schizophrenia on testosterone levels in both sexes.

Conclusion

This study offers new insights into the complex aetiology of SMI by comprehensively mapping genetic associations with sex hormone traits, emphasizing the need to further investigate sex hormones’ impact on SMI using larger and more precisely phenotyped samples to identify individuals particularly vulnerable to hormonal disturbances.
Empowering Radiologists with ChatGPT-4o: Comparative Evaluation of Large Language Models and Radiologists in Cardiac Cases
Authors: Cesur Turay , Gunes Yasin Celal , Camur Eren , Dağlı Mustafa
Published: June 2024

Purpose

This study evaluated the diagnostic accuracy and differential diagnosis capabilities of 12 Large Language Models (LLMs), one cardiac radiologist, and three general radiologists in cardiac radiology. The impact of ChatGPT-4o assistance on radiologist performance was also investigated.

Materials and Methods

We collected publicly available 80 “Cardiac Case of the Month’’ from the Society of Thoracic Radiology website. LLMs and Radiologist-III were provided with text-based information, whereas other radiologists visually assessed the cases with and without ChatGPT-4o assistance. Diagnostic accuracy and differential diagnosis scores (DDx Score) were analyzed using the chi-square, Kruskal-Wallis, Wilcoxon, McNemar, and Mann-Whitney U tests.

Results

The unassisted diagnostic accuracy of the cardiac radiologist was 72.5%, General Radiologist-I was 53.8%, and General Radiologist-II was 51.3%. With ChatGPT-4o, the accuracy improved to 78.8%, 70.0%, and 63.8%, respectively. The improvements for General Radiologists-I and II were statistically significant (P≤0.006). All radiologists’ DDx scores improved significantly with ChatGPT-4o assistance (P≤0.05). Remarkably, Radiologist-I’s GPT-4o-assisted diagnostic accuracy and DDx Score were not significantly different from the Cardiac Radiologist’s unassisted performance (P>0.05).

Among the LLMs, Claude 3.5 Sonnet and Claude 3 Opus had the highest accuracy (81.3%), followed by Claude 3 Sonnet (70.0%). Regarding the DDx Score, Claude 3 Opus outperformed all models and Radiologist-III (P<0.05). The accuracy of the general radiologist-III significantly improved from 48.8% to 63.8% with GPT4o-assistance (P<0.001).

Conclusion

ChatGPT-4o may enhance the diagnostic performance of general radiologists for cardiac imaging, suggesting its potential as a valuable diagnostic support tool. Further research is required to assess its clinical integration.
Reactogenicity Differences between COVID-19 Vaccines: A Pro-spective Observational Study in the United States and Canada
Authors: Rousculp Matthew D. , Hollis Kelly , Ziemiecki Ryan , Odom Dawn , Marchese Anthony M. , Montazeri Mitra , Odak Shardul , Jackson Laurin , Beyhaghi Hadi , Toback Seth
Published: June 2024

Participants in studies investigating COVID-19 vaccines commonly report reactogenicity events, and concerns about side effects may lead to reluctance to receive updated COVID-19 vaccinations. A real-world, post hoc analysis, observational 2019nCoV-406 study, was conducted to examine reactogenicity within the first 2 days after vaccination with either a protein-based vaccine (NVX-CoV2373) or an mRNA vaccine (BNT162b2 or mRNA-1273) in individuals who previously completed a primary series. Propensity score adjustments were conducted to address potential confounding. The analysis included 1130 participants who received a post–primary series dose of NVX-CoV2373 (n = 303) or an mRNA vaccine (n = 827) during the study period. Within the first 2 days after vaccination, solicited systemic reactogenicity events (adjusted) were reported in 60.5% of participants who received NVX-CoV2373 compared with 84.3% of participants who received an mRNA vaccine; moreover, 33.9% and 61.4%, respectively, reported ≥3 systemic reactogenicity symptoms. The adjusted mean (95% CI) number of systemic symptoms was 1.8 (1.6–2.0) and 3.2 (3.0–3.4), respectively. Local reactogenicity events (adjusted) were reported in 73.4% and 91.7% of participants who received NVX-CoV2373 and mRNA vaccines, respectively; the adjusted mean (95% CI) number of local symptoms was 1.5 (1.33–1.61) and 2.4 (2.31–2.52), respectively. These results support the use of adjuvanted, protein-based NVX-CoV2373 as an immunization option with low reactogenicity.
IMPROVE-IT2: Implementing non-invasive circulating tumor DNA analysis to optimize the operative and postoperative treatment for patients with colorectal cancer – Intervention Trial 2: Statistical analysis plan
Authors: Gotschalck Kåre Andersson , Heide-Jørgensen Uffe , Iversen Lene Hjerrild , Andersen Claus Lindbjerg
Published: June 2024

Background

Surveillance after curative intended surgery and adjuvant chemotherapy for localized colorectal cancer (CRC) aim at detecting recurrence sufficiently early to allow efficient treatment. Minimally invasive blood-based analysis of circulating tumor DNA (ctDNA) has the potential to identify patients with microscopic residual disease early after surgery and adjuvant chemotherapy for CRC, with a median lead time of 9 months compared to standard-of-care CT-based surveillance. The IMPROVE-IT2 study is a randomized controlled trial investigating the effect of ctDNA-guided surveillance compared to standard-of-care CT-based surveillance in high-risk stage II and stage III CRC patients after curative intended surgery and adjuvant chemotherapy. The primary trial endpoint is the fraction of recurrence patients receiving curative intended surgery or local metastasis directed treatment within 3 years after primary surgery for CRC. Secondary endpoints include time-to-clinical-recurrence, overall survival, quality-of-life, and quality-adjusted life-years cost-effectiveness.

Objective

To outline a pre-determined statistical analysis plan (SAP) before patients have completed the first year of follow-up after primary surgery.

Methods

The SAP describes the IMPROVE-IT2 study design and endpoints, the randomization procedure, sample size estimation, and the specific statistical procedures and methods for analyzing efficacy outcomes. Health economics and quality of life analyses are not included in this SAP but will be analyzed separately. The SAP outlines the planned primary analyses, subgroup analyses, and a range of specific sensitivity analyses. To avoid bias, the final analyses of the IMPROVE-IT2 trial will adhere to the SAP. The SAP was approved after end of recruitment and before completion of the first 12 months of follow-up after primary surgery.

Trial Registration

Clinicaltrials.govNCT04084249, registered in April 2019.
Suboptimal dietary patterns are associated with accelerated biological aging in young adulthood: a twin study
Authors: Ravi Suvi , Kankaanpää Anna , Bogl Leonie H. , Heikkinen Aino , Pietiläinen Kirsi H. , Kaprio Jaakko , Ollikainen Miina , Sillanpää Elina
Published: June 2024

Background & aims

Suboptimal diets increase morbidity and mortality risk. Epigenetic clocks are algorithms that can assess health and lifespan, even at a young age, before clinical manifestations of diseases. We investigated the association between dietary patterns and biological aging in young adult twins.

Methods

The data were drawn from the population-based FinnTwin12 study and consisted of twins aged 21–25 years (n=826). Food and beverage intakes were assessed using a food frequency questionnaire. Biological aging was estimated using the epigenetic clocks GrimAge and DunedinPACE. Latent class analysis was used to identify dietary patterns. The association between dietary patterns and biological aging was assessed using linear regression modeling at the individual level, followed by within–twin pair analyses to account for genetic liabilities and shared familial confounders.

Results

Six dietary patterns were identified: 1) High fast food, low fruits and vegetables (F&V), 2) Plant-based, 3) Health-conscious, 4) Western with infrequent fish, 5) Western with regular fish, and 6) Balanced average. At the individual level, GrimAge acceleration was slower in the Plant-based, Health-conscious, and Balanced-average patterns compared to the High fast food, low F&V, and faster in the Western with infrequent fish pattern compared to the Balanced average, regardless of sex, nonalcoholic energy intake, smoking, and alcohol consumption. After further adjustment for BMI and sports participation, the strengths of the associations modestly decreased; however, the difference between the Balanced-average and High fast food, low F&V patterns remained significant. The pace of aging (DunedinPACE) was slower in the Plant-based pattern compared to the High fast food, low F&V and the Western with infrequent fish patterns after adjustment for sex, nonalcoholic energy intake, smoking, and alcohol. The effect sizes were attenuated and reached a non-significant level when BMI and sports participation were added to the model. Most of the associations were replicated in the within-pair analyses among all twin pairs and among dizygotic twin pairs, but the effect sizes tended to be smaller among monozygotic twin pairs. This suggests that genetics, but not a shared environment, may partially explain the observed associations between diet and biological aging.

Conclusion

Diets high in fast food, processed red meat, and sugar-sweetened beverages and low in fruits and vegetables are associated with accelerated biological aging in young adulthood. The clustering effect of lifestyle factors and genetic confounders should be considered when interpreting the findings.
Feasibility to virtually generate T2 fat-saturated breast MRI by convolutional neural networks
Authors: Liebert Andrzej , Hadler Dominique , Ehring Chris , Schreiter Hannes , Brock Luise , Kapsner Lorenz A. , Eberle Jessica , Erber Ramona , Emons Julius , Laun Frederik B. , Uder Michael , Wenkel Evelyn , Ohlmeyer Sabine , Bickelhaupt Sebastian
Published: June 2024

Background

Breast magnetic resonance imaging (MRI) protocols often include T2-weighted fat-saturated (T2w-FS) sequences, which are vital for tissue characterization but significantly increase scan time.

Purpose

This study aims to evaluate whether a 2D-U-Net neural network can generate virtual T2w-FS images from routine multiparametric breast MRI sequences.

Materials and Methods

This IRB approved, retrospective study included n=914 breast MRI examinations performed between January 2017 and June 2020. The dataset was divided into training (n=665), validation (n=74), and test sets (n=175). The U-Net was trained on T1-weighted (T1w), diffusion-weighted imaging (DWI), and dynamic contrast-enhanced (DCE) sequences to generate virtual T2w-FS images (VirtuT2). Quantitative metrics and a qualitative multi-reader assessment by two radiologists were used to evaluate the VirtuT2 images.

Results

VirtuT2 images demonstrated high structural similarity (SSIM=0.87) and peak signal-to-noise ratio (PSNR=24.90) compared to original T2w-FS images. High level of the frequency error norm (HFNE=0.87) indicates strong blurring presence in the VirtuT2 images, which was also confirmed in qualitative reading. Radiologists correctly identified VirtuT2 images with 92.3% and 94.2% accuracy, respectively. No significant difference in diagnostic image quality (DIQ) was noted for one reader (p=0.21), while the other reported significantly lower DIQ for VirtuT2 (p<=0.001). Moderate inter-reader agreement was observed for edema detection on T2w-FS images (ƙ=0.43), decreasing to fair on VirtuT2 images (ƙ=0.36).

Conclusion

The 2D-U-Net can technically generate virtual T2w-FS images with high similarity to real T2w-FS images, though blurring remains a limitation. Further investigation of other architectures and using larger datasets are needed to improve clinical applicability.

Summary Statement

Virtual T2-weighted fat-saturated images can be generated from routine breast MRI sequences using convolutional neural networks, showing high structural similarity but with notable blurring, necessitating further refinement for clinical use.

Key Results

Images with T2w-FS characteristics can be virtually generated from T1w and DWI images using deep learning

Image blurring occurring in the VirtuT2 image limit clinical use for the current moment

Further investigation of different architectures and with larger datasets are necessary in the future to improve the VirtuT2 performance.