bluuebunny/crossref_metadata_2025 huggingface dataset:
Do Chosen Learning Strategies Predict Academic Performance in First-Year DPT Anatomy Students?
Authors: Moulton Joy , Vecchiarelli Craig , Cheng M. Samuel
Published: December 2023

Introduction.

The purpose of this study was to identify predictors of anatomy final course grades from first-year physical therapist students' characteristics and chosen learning strategies, as indicated on the Motivated Strategies for Learning Questionnaire (MSLQ). Identifying factors that contribute to success in content intensive classes may aid in coaching successful learning strategies as students transition from undergraduate coursework to Doctor of Physical Therapy (DPT) programs.

Review of Literature.

Previous studies show that first-year graduate students use ineffective learning strategies that are insufficient for graduate-level study. The MSLQ correlates with academic performance at several educational levels. To date, only one study has examined the correlation of MSLQ with physical therapist students' academic performance for an anatomy course.

Subjects.

Thirty-nine first-year physical therapist students participated in the study (27 from a hybrid program, 12 from a traditional program).

Methods.

This study analyzed MSLQ scores for the total instrument, each domain, and each subscale using regression analyses to determine predictors of final anatomy grades.

Results.

The subscales of Self-Efficacy and Test Anxiety had significant predictive value for anatomy grades (R2= 0.455,F= 5.203,P= .029). Test Anxiety had an inverse relationship to anatomy grades, meaning lower test anxiety scores correlated with higher anatomy grades. The combination of Self-Efficacy, Test Anxiety, and Critical Thinking subscales resulted in a significant prediction of anatomy grades (R2= 0.603,F= 6.659,P= .014).

Discussion and Conclusion.

This study found moderate correlations between MSLQ Motivation subscales and final grades in DPT anatomy classes. Self-Efficacy and Test Anxiety subscales had the strongest correlations and were significantly predictive of anatomy grades. Faculty may benefit from using inventories like the MSLQ for first-year physical therapist students to identify motivational characteristics associated with success and to remediate students' learning strategies to prevent academic failure.
The Phenomenology of Visual and Other Nonauditory Hallucinations in Affective and Nonaffective Psychosis
Authors: Toh Wei Lin , Thomas Neil , Rossell Susan Lee
Published: December 2023

Nonauditory hallucinations in psychosis have not received as much attention relative to voice-hearing experiences. The current paper aimed to document the characteristics of these hallucinations in affective and nonaffective psychosis. Participants were selected from a primary voice-hearing sample, who had endorsed visual, tactile, or olfactory hallucinations (N = 55–75). A comprehensive, semistructured phenomenological interview was conducted, followed by mixed methods analysis. Visual hallucinations typically occurred daily, for a few minutes per episode, within one's direct line of sight; persons and/or animals were most commonly seen, with low controllability and mostly engendered negative affective outcomes. Tactile and olfactory hallucinations were endorsed by 46.8% and 39.0% of participants, respectively. The affective psychosis group (n = 33) reported significantly greater awareness and lower functional impairment relative to the nonaffective psychosis group (n = 42). Qualitative thematic analysis revealed notable themes and subthemes across each of these hallucinations modes. Further phenomenological investigations should be carried out in lesser known hallucination modalities, assisted by the development of appropriate assessment tools.
Integrated Endoscopic Craniosynostosis Surgery and Cranial Orthosis Program
Authors: Ravi Subhashree , Aziz Waseem , AlOlama Mohammed , Stenger Charl , AlSaadawi Ghaith , Baldrighi Carla , Ahmed Anwar , Mendonca Derek
Published: December 2023

Introduction:

Craniosynostosis results from premature fusion of the cranial sutures. There has been a continuous evolution of surgical correction techniques from an extensive open procedure to the minimally invasive technique.

Aims and Objectives:

This novel surgical technique has never been previously done in the UAE and this article documents the experience of the first team to endoscopically correct craniosynostosis with planning, surgical techniques, and customized helmet therapy.

Methods:

A retrospective case series of 16 nonsyndromic craniosynostosis patients with unicoronal (6), sagittal (5), bicoronal (1), frontosphenoidal (2), and metopic craniosynostoses (2) was corrected endoscopically and followed up with customized cranial helmet. Preoperative and postoperative photography, along with anthropometric measurements were taken.

Results:

The mean age of all patients at the time of surgery was 101 (90–117) days, mean duration of surgery was 70 minutes (38–129), mean blood loss was 120 mL (100–150), and mean duration of hospital stay 4 days (4–5). No complications and mortality were reported. Mean number of helmets was 2 (1–3). Cranial index improved in all patients with sagittal and bicoronal craniosynostosis. Close cooperation with the orthotist ensured timely helmet therapy and accurate laser scanning documentation in head molding.

Conclusions:

This case series has demonstrated that endoscopically craniosynostosis correction is safe, effective, and reliable and is the first reported series from the Middle East. The authors believe that every patient with nonsyndromic single‑suture craniosynostosis should be offered endoscopic correction before the age of 6 months. The orthotist forms an important part of the Multi-disciplinary team, enabling successful outcomes.
Differences in the biochemical content and radical scavenging activity of propolis from different parts of aMeliponula ferrugineahive
Authors: Kegode Timothy M. , Mokaya Hosea O. , Chogo Solomon I. , Noiset Pierre , Vereecken Nicolas J. , Tamiru Amanuel , Subramanian Sevgan , Kiatoko Nkoba
Published: December 2023

Research on stingless bee products has increased in recent years, and of particular interest is propolis because of its biological activities such as antioxidant and antimicrobial. However, there is paucity of information regarding intra-hive variations in the biochemical composition and biofunctional properties of this propolis. In this study, we investigated the phytochemicals and radical scavenging activity (RSA) ofMeliponula ferrugineapropolis from 10 wooden hives (n= 49). The samples were collected from five different locations comprising the entrance, involucrum, pillars, pots and sealant. Principal component analysis showed that there is an intra-hive variation in phytochemical content and RSA. Phenolic content constituted the highest phytochemical content in all the locations. The sealant and entrance had the highest amounts of phytochemicals compared to the involucrum, pillars and pots. Further analysis of propolis extracts by gas chromatography-mass spectrometry revealed occurrence of different compounds such as monoterpenoids, hydrocarbons, triterpenoids and alkaloids. Hydrocarbons were common in all parts while monoterpenes and triterpenes were present in the entrance. The findings of our study indicates that there is an intra-hive variation in propolis ofM. ferrugineaand hence this information will provide further insight into better understanding of stingless bee propolis.
Stochastic power processing through logic operation of power packets
Authors: Mochiyama Shiu , Hikihara Takashi
Published: December 2023

This article presents an application of the recently proposed logic operation of power based on power packetization. In a power packet despatching system, the power supply can be considered as a sequence of power pulses, where the occurrence of pulses follows a probability that corresponds to the capacity of the power sources or power lines. In this study, we propose a processing scheme to reshape a stream of power packets from such stochastic sequences to satisfy the load demand. The proposed scheme is realized by extending the concept of stochastic computing to the power domain. We demonstrate the operation of the proposed scheme through experiments and numerical simulations by implementing it as a function of a power packet router, which forms a power packet despatching network. The stochastic framework proposed in this study provides a new design foundation for low-power distribution networks as an embodiment of the close connection between the cyber and physical components.
Intermediate observers based robust fault estimation for multi-agent systems under communication constraints via switching scheme
Authors: Quan Yue , Sun Ruopeng , Ding Shichuan , Guo Hai , Hu Fuzhi , Zhang Di , Fan Xiaoyu
Published: December 2023

This paper addresses the problem of robust fault estimation for multi-agent systems (MASs) under communication constraints. Taking into account the possible data packet loss (DPL) in the information interaction of each subsystem, MASs are remodelled as switching systems by introducing a variable sampling strategy. Then, using the local information among agents, a novel intermediate observer design method based on switching scheme is proposed to estimate faults of MASs. Combining Lyapunov’s criterion and linear matrix inequality, sufficient conditions for the intermediate observer to be exponentially stable and have
H
∞
performance against bounded disturbances and the DPL are given. Finally, some simulations are provided to verify the effectiveness of the proposed method.
Meltwater Pulse 1a drowned fringing reefs around Tahiti 15 000 years ago
Authors: Blanchon Paul , Chutcharavan Peter
Published: December 2023

Reconstruction of postglacial sea-level rise using reef cores recovered from Tahiti during IODP Expedition 310 showed that the first major acceleration, known as Meltwater Pulse 1a (MWP-1a), was a 12–22 m rise in 340 years starting at 14.65 ka BP. Although it was reported that the pulse did not drown Tahitian reefs, the subsequent discovery of a fringing reef at the base of several cores implies that its timing, magnitude and impact require revision. Here, we report facies and paleodepth data from this reef, revise sea level, and revisit reef response. We find its reef crest is dominated by surf-adapted corals to a depth of 2.5 m and show that it retreated upslope over an approximately 1000-year interval from 16 ka. Reef development then apparently ceased at 15 ka at −106 m and remained absent for approximately 600 years, before resuming at 14.4 ka further upslope at −93 m. This absence is consistent with reef drowning and requires that MWP-1a had a smaller magnitude of 13.8 ± 1.3 m, and may have started 300 years earlier than previously reported. It confirms MWP-1a was a global event, drowning reefs on Tahiti as well as those in other oceans.
Guar gum/poly ethylene glycol/graphene oxide environmentally friendly hybrid hydrogels for controlled release of boron micronutrient
Authors: Azeem Muhammad Khalid , Islam Atif , Khan Rafi Ullah , Rasool Atta , Anees Ur Rehman Qureshi Muhammad , Rizwan Muhammad , Shuib Raa Khimi , Rehman Abdul , Sadiqa Ayesha
Published: December 2023

The present study was aimed at synthesis of polymeric hydrogels for controlled boron (B) release, as B deficiency is a major factor that decreases crops yield. Thus, graphene oxide incorporated guar gum and poly (ethylene glycol) hydrogels were prepared using the Solution Casting method for boron release. 3-Glycidyloxypropyl trimethoxysilane (GLYMOL) was used as a cross-linker. Characterizations of hydrogels were carried out by Fourier Transform Infrared Spectroscopy (FTIR), Thermo-Gravimetric Analysis and Scanning Electron scope. The FTIR outcomes confirmed the existence of functional groups, bindings and development of hydrogel frameworks from incorporated components. The quantity of GLYMOL directly increased the thermal stability and water retention but decreased the swelling %. The maximum swelling for the hydrogel formulations was observed at pH 7. The addition of GLYMOL changed the diffusion from quasi-Fickcian to non-Fickcian diffusion. The maximum swelling quantities of 3822% and 3342% were exhibited by GPP (control) and GPP-8 in distilled water, respectively. Boron release was determined in distilled water and sandy soil by azomethine-H test using UV-Visible spectrophotometer while 85.11% and 73.65% boron was released from BGPP-16, respectively. In short, water retentive, water holding capacities, swelling performances, biodegradability and swelling/deswelling features would offer an ideal platform for boron release in sustained agricultural applications.
Spectral wear modelling of rubber friction on a hard substrate with large surface roughness
Authors: Tanaka H. , Yanagihara S. , Shiomi K. , Kuroda T. , Oku Y.
Published: December 2023

Soft-hard matter friction is a long-standing tribology problem that remains unclarified, requiring engineers to empirically predict the wear life. To clarify this issue, this study examines the transient running-in regime of rubber friction on a hard rough substrate and models the temporal wear progression using the spectrum curves of surface roughness for both materials. Performing a series of friction tests and three-dimensional surface-height measurements, the time-dependent behaviours of the power spectral densities (PSDs) are divided into two phases, namely the initial non-steady and long-term steady phases. The detailed spectral analyses of worn rubber surfaces in the initial phase lead to a blended PSD function between self-affine and

K

-correlation surface models, consisting of one variable (the Hurst exponent) that is saturated by the substrate self-affinity. Supported by the Greenwood–Williamson theory concerning rough contact mechanics, the volumetric estimate with the blended PSD function is used to assess the volume rate of wear debris in the steady phase, which is validated experimentally. These findings not only improve the wear predictions of soft materials from the initial measurements of worn surfaces but also help clarify the constrained multiscale mechanism of wear.
Over-eruption in marsupial carnivore teeth: compensation for a constraint
Authors: Jones Menna E.
Published: December 2023

Pronounced over-eruption of the canine teeth, causing the cervical enamel margin to extend beyond the alveolar bone and exposing the root, occurs with age and growth in Australian marsupial carnivores, much more than in eco-morphologically equivalent placental carnivores. Suppression of functional tooth replacement is characteristic of marsupials, where most placentals have the primitive diphyodont pattern of two generations of incisor, canine and premolar teeth. Canine and molar tooth dimensions of four species of marsupial carnivores (thylacine
Thylacinus cynocephalus
, Tasmanian devil
Sarcophilus harrisii
and two quolls
Dasyurus
spp
.
) and canine dimensions of seven eco-morphologically equivalent placental carnivore species were measured from museum specimens. Canine dimensions were measured in a time series on live wild-living individual devils and quolls. The canine teeth and to a lesser extent the molar teeth of marsupial carnivores continue to erupt through life, resulting in a net increase in tooth height and diameter, a phenomenon not evident in placental carnivores. Potential mechanisms causing over-eruption include tooth wear and gradual release of occlusal pressure as the individual grows. Over-eruption in marsupial carnivores may be a compensatory response for tooth size limits imposed by monophyodont tooth replacement, ensuring that animal's teeth are scaled to jaw size from juvenile to adulthood.
The faculty-to-faculty mentorship experience: a survey on challenges and recommendations for improvements
Authors: Sarabipour Sarvenaz , Niemi Natalie M. , Burgess Steven J. , Smith Christopher T. , Bisson Filho Alexandre W. , Ibrahim Ahmed , Clark Kelly
Published: December 2023

Faculty at research institutions play a central role in advancing knowledge and careers, as well as promoting the well-being of students and colleagues in research environments. Mentorship from experienced peers has been touted as critical for enabling these myriad roles to allow faculty development, career progression, and satisfaction. However, there is little information available on who supports faculty and best ways to structure a faculty mentorship programme for early- and mid-career academics. In the interest of advocating for increased and enhanced faculty mentoring and mentoring programmes, we surveyed faculty around the world to gather data on whether and how they receive mentoring. We received responses from 457 early- and mid-career faculty and found that a substantial portion of respondents either reported having no mentor or a lack of a formal mentoring scheme. Qualitative responses on the quality of mentorship revealed that the most common complaints regarding mentorship included lack of mentor availability, unsatisfactory commitment to mentorship, and non-specific or non-actionable advice. On these suggestions, we identify a need for training for faculty mentors as well as strategies for individual mentors, departments, and institutions for funding and design of more intentional and supportive mentorship programmes for early- and mid-career faculty.
Variation in personality shaped by evolutionary history, genotype and developmental plasticity in response to feeding modalities in the Arctic charr
Authors: Dellinger Marion , Steele Sarah E. , Sprockel Evert , Philip Joris , Pálsson Arnar , Benhaïm David
Published: December 2023

Animal personality has been shown to be influenced by both genetic and environmental factors and shaped by natural selection. Currently, little is known about mechanisms influencing the development of personality traits. This study examines the extent to which personality development is genetically influenced and/or environmentally responsive (plastic). We also investigated the role of evolutionary history, assessing whether personality traits could be canalized along a genetic and ecological divergence gradient. We tested the plastic potential of boldness in juveniles of five Icelandic Arctic charr morphs (
Salvelinus alpinus
), including two pairs of sympatric morphs, displaying various degrees of genetic and ecological divergence from the ancestral anadromous charr, split between treatments mimicking benthic versus pelagic feeding modalities. We show that differences in mean boldness are mostly affected by genetics. While the benthic treatment led to bolder individuals overall, the environmental effect was rather weak, suggesting that boldness lies under strong genetic influence with reduced plastic potential. Finally, we found hints of differences by morphs in boldness canalization through reduced variance and plasticity, and higher consistency in boldness within morphs. These findings provide new insights on how behavioural development may impact adaptive diversification.
Variant Mapping Application: Customize And Annotate Figures Of Voltage-Gated Sodium Channel
Authors: Wen Winnie , Mahadevan Arjun , Parrish R. Ryley , Dean Richard , Cutts Alison , Johnson JP
Published: December 2023

Voltage-gated sodium ion channels allow for the initiation and transmission of action potentials. There is a high interest in research and drug development to selectively target these ion channels to treat epilepsy and other disorders such as pain. Scientific literature and presentations often incorporate maps of these integral membrane proteins with markers indicating gene mutations to highlight genotype/phenotype correlations. There is a need for automated tools to create high quality figures with mutation (variant) locations displayed on these channel maps. This manuscript introduces a simple application to create visualization for mutations on alpha voltage-gated sodium channels, created using the D3.js library. The application allows for mapping of variant sequences, as well as important properties like the type of variant and the phenotypes linked to the variant. It also allows for customizability and the production of high-quality images for publication. This application and code base can further be extrapolated to other ion channels as well.
SARS-CoV-2 nsp15 preferentially degrades AU-rich dsRNA via its dsRNA nickase activity
Authors: Wang Xionglue , Zhu Bin
Published: December 2023

It has been proposed that coronavirus nsp15 mediates evasion of host cell double-stranded (ds) RNA sensors via its uracil-specific endoribonuclease activity. However, how nsp15 processes viral dsRNA, commonly considered as a genome replication intermediate, remains elusive. Previous research has mainly focused on short single-stranded RNA as substrates, and whether nsp15 prefers single-stranded or double-stranded RNA for cleavage is controversial. In the present work, we prepared numerous RNA substrates, including both long substrates mimicking the viral genome and short defined RNA, to clarify the substrate preference and cleavage pattern of SARS-CoV-2 nsp15. We demonstrated that SARS-CoV-2 nsp15 preferentially cleaved flexible pyrimidine nucleotides located in AU-rich areas and mismatch-containing areas in dsRNA via a nicking manner. The AU content and distribution in dsRNA along with the RNA length affected cleavage by SARS-CoV-2 nsp15. Because coronavirus genomes generally have a high AU content, our work supported the mechanism that coronaviruses evade the antiviral response mediated by host cell dsRNA sensors by using nsp15 dsRNA nickase to directly cleave dsRNA intermediates formed during genome replication and transcription.
Choline degradation inParacoccus denitrificans: identification of sources of formaldehyde
Authors: Parekh Trusha , Tsai Marcus , Spiro Stephen
Published: December 2023

Paracoccus denitrificansis a facultative methylotroph that can grow on methanol and methylamine as sole sources of carbon and energy. Both are oxidized to formaldehyde and then to formate, so growth on C1 substrates induces the expression of genes encoding enzymes required for the oxidation of formaldehyde and formate. This induction involves a histidine kinase response regulator pair (FlhSR) that is likely triggered by formaldehyde. Catabolism of some complex organic substrates (for example choline and L-proline betaine) also generates formaldehyde. Thus,flhSandflhRmutants that fail to induce expression of the formaldehyde catabolic enzymes cannot grow on methanol, methylamine and choline. Choline is oxidized to glycine via glycine betaine, dimethylglycine and sarcosine. By exploringflhSRgrowth phenotypes and the activities of a promoter and enzyme known to be up-regulated by formaldehyde, we identify the oxidative demethylations of glycine betaine, dimethylglycine and sarcosine as sources of formaldehyde. Growth on glycine betaine, dimethylglycine and sarcosine is accompanied by the production of up to three, two and one equivalents of formaldehyde, respectively. Genetic evidence implicates two orthologous monooxygenases in the oxidation of glycine betaine. Interestingly, one of these appears to be a bifunctional enzyme that also oxidizes L-proline betaine (stachydrine). We present preliminary evidence to suggest that growth on L-proline betaine induces expression of a formaldehyde dehydrogenase distinct from the enzyme induced during growth on other formaldehyde-generating substrates.

IMPORTANCE

The bacterial degradation of one carbon compounds (methanol and methylamine) and of some complex multi-carbon compounds (for example, choline) generates formaldehyde. Formaldehyde is toxic and must be removed, which can be done by oxidation to formate and then to carbon dioxide. These oxidations provide a source of energy, in some species the CO2thus generated can be assimilated into biomass. Using the Gram-negative bacteriumParacoccus denitrificansas the experimental model, we infer that oxidation of choline to glycine generates up to three equivalents of formaldehyde and we identify the three steps in the catabolic pathway that are responsible. Our work sheds further light on metabolic pathways that are likely important in a variety of environmental contexts.
Discovery of new endogenous viral elements in campoplegine wasps (Ichneumonidae, Campopleginae, Campoplex) suggests a widespread nudivirus domestication event
Authors: de Araujo Alexandra Cerqueira , Leobold Matthieu , Cariou Marie , dos Santos Bernardo Ferreira , Uzbekov Rustem , Ricciardi Renato , Scaramozzino Pierluigi , Lucchi Andrea , Musset Karine , Drezen Jean-Michel , Josse Thibaut , Huguet Elisabeth
Published: December 2023

Viral endogenization is a widespread phenomenon that generally results in non-functional viral elements. In parasitoid wasps, nudiviruses have been involved in three independent domestication events and play a key role in parasitism success. In Campopleginae (Ichneumonidae), endogenized ichnovirus presence is widespread, with the exception ofVenturia canescens(Ichneumonidae Campopleginae), which is known to harbour an endogenous nudivirus that enables the wasp to produce Virus-Like-Particles (VLPs). So far, in Campopleginae, the nudivirus endogenization event was an isolated case restricted toV. canescens.Using third generation sequencing technologies, microscopy and mass spectrometry, we described new cases of domesticated nudiviruses in campoplegine wasps of the genusCampoplex. We found endogenized viruses inCampoplexgenomes which belong to the Alphanudivrius genus and derive from the same endogenization event as the virus found inV. canescens,suggesting that this integration event could be much more widespread in Campopleginae than previously thought. These nudiviruses are organised in highly conserved clusters, but this organisation appears to have changed relatively to free viruses during the domestication process. We showed thatCampoplex capitatorproduces in its ovaries VLPs that are similar morphologically toV. canescensVLPs, with almost the same protein content, except for a strikingly different virulence proteins, a sign of different evolutionary paths taken to respond to distinct evolutive pressure. While ichnovirus remnants have been previously found inV. canescens, no trace of ichnovirus could be detected inCampoplexgenomes, meaning that the evolutionary history of viral integrations in Campopleginae is more complex than previously imagined.
The association of longitudinal diet and waist-to-hip ratio from midlife to old age with hippocampus connectivity and memory in old age: a cohort study
Authors: Jensen Daria EA , Ebmeier Klaus P. , Akbaraly Tasnime , Jansen Michelle G , Singh-Manoux Archana , Kivimäki Mika , Zsoldos Enikő , Klein-Flügge Miriam C , Suri Sana
Published: December 2023

Epidemiological studies suggest lifestyle factors may reduce the risk of dementia. However, few studies have examined the association of diet and waist-to-hip ratio with hippocampus connectivity. In the Whitehall II Imaging Sub-study, we examined longitudinal changes in diet quality in 512 participants and waist-to-hip ratio in 665 participants. Diet quality was measured using the Alternative Health Eating Index-2010 assessed three times across 11 years between ages 48 and 60 years, and waist-to-hip ratio five times over 21 years between ages 48 and 68 years. Brain imaging and cognitive tests were performed at age 70±5 years. We measured white matter using diffusion tensor imaging and hippocampal functional connectivity using resting-state functional magnetic resonance imaging. In addition to associations of diet and waist-to-hip ratio with brain imaging measures, we tested whether associations between diet, waist-to-hip ratio and cognitive performance were mediated by brain connectivity. We found better diet quality in midlife and improvements in diet over mid-to-late life were associated with higher hippocampal functional connectivity to the occipital lobe and cerebellum, and better white matter integrity as measured by higher fractional anisotropy and lower diffusivity. Higher waist-to-hip ratio in midlife was associated with higher mean and radial diffusivity and lower fractional anisotropy in several tracts including the inferior longitudinal fasciculus and cingulum. Associations between midlife waist-to-hip ratio, working memory and executive function were partially mediated by radial diffusivity. All associations were independent of age, sex, education, and physical activity. Our findings highlight the importance of maintaining a good diet and a healthy waist-to-hip ratio in midlife to maintain brain health in later life. Future interventional studies for the improvement of dietary and metabolic health should target midlife for the prevention of cognitive decline in old age.
Multifocal, multiphenotypic tumours arising from an MTOR mutation acquired in early embryogenesis
Authors: Pacyna Clarissa N. , Anandapadamanaban Madhanagopal , Loudon Kevin W. , Hay Iain M. , Perisic Olga , Li Ruoyan , Byrne Matthew , Allen Laura , Roberts Kirsty , Hooks Yvette , Warren Anne Y. , Stewart Grant D. , Clatworthy Menna R. , Teichmann Sarah A. , Behjati Sam , Campbell Peter J. , Williams Roger L. , Mitchell Thomas J.
Published: December 2023

Embryogenesis is a vulnerable time. Mutations in developmental cells can result in the wide dissemination of cells predisposed to disease within mature organs. We characterised the evolutionary history of four synchronous renal tumours from a 14-year-old girl, timing their shared origin to a multipotent embryonic cell committed to the right kidney, around 4 weeks post-conception. Their sharedMTORmutation, absent from normal tissues, enhances protein flexibility, which enables a FAT domain hinge to dramatically increase activity of mTORC1 and mTORC2. Developmental mutations, not usually detected in traditional genetic screening, have vital clinical importance in guiding prognosis, targeted treatment, and family screening decisions for paediatric tumours.
Genome-wide association study of delay discounting in Heterogenous Stock rats
Authors: Lara Montana Kay , Chitre Apurva S. , Chen Denghui , Johnson Benjamin B. , Nguyen Khai-Minh , Cohen Katarina A. , Muckadam Sakina A. , Lin Bonnie , Ziegler Shae , Beeson Angela , Sanches Thiago , Solberg Woods Leah C. , Polesskaya Oksana , Palmer Abraham A. , Mitchell Suzanne H.
Published: December 2023

Delay discounting refers to the behavioral tendency to devalue rewards as a function of their delay in receipt. Heightened delay discounting has been associated with substance use disorders, as well as multiple co-occurring psychopathologies. Genetic studies in humans and animal models have established that delay discounting is a heritable trait, but only a few specific genes have been associated with delay discounting. Here, we aimed to identify novel genetic loci associated with delay discounting through a genome-wide association study (GWAS) using Heterogenous Stock rats, a genetically diverse outbred population derived from eight inbred founder strains. We assessed delay discounting in 650 male and female rats using an adjusting amount procedure in which rats chose between smaller immediate sucrose rewards or a larger reward at variable delays. Preference switch points were calculated for each rat and both exponential and hyperbolic functions were fitted to these indifference points. Area under the curve (AUC) and the discounting parameterkof both functions were used as delay discounting measures. GWAS for AUC, exponentialk, and indifference points for a short delay identified significant loci on chromosomes 20 and 14. The geneSlc35f1,which encodes a member of the solute carrier family of nucleoside sugar transporters, was the only gene within the chromosome 20 locus. That locus also contained an eQTL forSlc35f1, suggesting that heritable differences in the expression of that gene might be responsible for the association with behavior. The geneAdgrl3, which encodes a member of the latrophilin family of G-protein coupled receptors, was the only gene within the chromosome 14 locus. These findings implicate novel genes in delay discounting and highlight the need for further exploration.
Organelle phenotyping and multi-dimensional microscopy identify C1q as a novel regulator of microglial function
Authors: Sakthivel Pooja S. , Scipioni Lorenzo , Karam Josh , Keulen Zahara , Blurton-Jones Mathew , Gratton Enrico , Anderson Aileen J.
Published: December 2023

Microglia, the immune cells of the central nervous system (CNS), are incredibly dynamic and heterogenous cells. While single cell RNA sequencing has become the conventional methodology for evaluating microglial state, transcriptomics do not provide insight into functional changes. Here, we propose a novel organelle phenotyping approach where we treat live human induced pluripotent stem cell-derived microglia (iMGL) with organelle dyes (mitochondria, lipids, lysosomes) and acquire data by live-cell spectral microscopy. Dimensionality reduction techniques and unbiased cluster identification allow for recognition of microglial subpopulations based in organelle function. We validate this methodology using lipopolysaccharide (LPS) and IL-10 treatment to polarize iMGL to an inflammatory” and “anti-inflammatory state, respectively, and then apply it to identify a novel regulator of iMGL function, complement protein C1q. C1q is traditionally known as the initiator of the complement cascade, but here we use organelle phenotyping to identify a role for C1q in regulating iMGL fatty acid storage and mitochondria membrane potential. Follow up evaluation of microglia with more traditional read outs of activation state confirm that C1q drives an increase in microglia pro-inflammatory cytokine production and migration, while suppressing microglial proliferation. These data together validate the use of a novel organelle phenotyping approach and enable better mechanism investigation of molecular regulators of microglial state, such as C1q.
Simulating BRAFV600E-MEK-ERK signalling dynamics in response to vertical inhibition treatment strategies
Authors: De Carli Alice , Kapelyukh Yury , Kursawe Jochen , Chaplain Mark A.J. , Wolf C. Roland , Hamis Sara
Published: December 2023

In vertical inhibition treatment strategies, multiple components of an intracellular pathway are simulta-neously inhibited. Vertical inhibition of the BRAFV600E-MEK-ERK signalling pathway is a standard of care for treating BRAFV600E-mutated melanoma where two targeted cancer drugs, a BRAFV600E-inhibitor, and a MEK-inhibitor, are administered in combination. Targeted therapies have been linked to early onsets of drug resistance, and thus treatment strategies of higher complexities and lower doses have been proposed as alternatives to current clinical strategies. However, finding optimal complex, low-dose treatment strategies is a challenge, as it is possible to design more treatment strategies than are feasibly testable in experimental settings.

To quantitatively address this challenge, we develop a mathematical model of BRAFV600E-MEK-ERK signalling dynamics in response to combinations of the BRAFV600E-inhibitor dabrafenib (DBF), the MEK-inhibitor trametinib (TMT), and the ERK-inhibitor SCH772984 (SCH). From a model of the BRAFV600E-MEK-ERK pathway, and a set of molecular-level drug-protein interactions, we extract a system of chemical reactions that is parameterized by in vitro data and converted to a system of ordinary differential equations (ODEs) using the law of mass action. The ODEs are solved numerically to produce simulations of how pathway-component concentrations change over time in response to different treatment strategies,i.e., inhibitor combinations and doses. The model can thus be used to limit the search space for effective treatment strategies that target the BRAFV600E-MEK-ERK pathway and warrant further experimental investigation. The results demonstrate that DBF and DBF-TMT-SCH therapies show marked sensitivity to BRAFV600E concentrations in silico, whilst TMT and SCH monotherapies do not.
ARID1AMutations Protect Follicular Lymphoma from FAS-dependent Immune Surveillance by Reducing RUNX3/ETS1-Driven FAS-Expression
Authors: Antoniolli Martina , Solovey Maria , Strobl Carolin Dorothea , Bararia Deepak , Keay William David , Hildebrand Johannes Adrian , Adolph Louisa , Heide Michael , Passerini Verena , Freyholdt Tabea , Wange Lucas , Enard Wolfgang , Thieme Susanne , Blum Helmut , Rudelius Martina , Mergner Julia , Ludwig Christina , Bultmann Sebastian , Schmidt-Supprian Marc , Leonhardt Heinrich , Subklewe Marion , von Bergwelt-Baildon Michael , Colomé-Tatché Maria , Weigert Oliver
Published: December 2023

The cell death receptor FAS and its ligand (FASLG) play crucial roles in the selection of B cells during the germinal center (GC) reaction. Failure to eliminate potentially harmful B cells via FAS can lead to lymphoproliferation and the development B cell malignancies. The classic form of follicular lymphoma (FL) is a prototypic GC-derived B cell malignancy, characterized by the t(14;18) (q32;q21)IGH::BCL2translocation and overexpression of antiapoptotic BCL2. Additional alterations were shown to be clinically relevant, including mutations inARID1A. ARID1A is part of the SWI/SNF nucleosome remodeling complex that regulates DNA accessibility (“openness”). However, the mechanism howARID1Amutations contribute to FL pathogenesis remains unclear.

We analyzed 151 FL biopsies of patients with advanced stage disease at initial diagnosis and found thatARID1Amutations were recurrent and mainly disruptive, with an overall frequency of 18%. Additionally, we observed thatARID1Amutant FL showed significantly lower FAS protein expression in the FL tumor cell population. Functional experiments in BCL2-translocated lymphoma cells demonstrated that ARID1A is directly involved in the regulation of FAS, and ARID1A loss leads to decreased FAS protein and gene expression. However, ARID1A loss did not affectFASpromotor openness. Instead, we identified and experimentally validated a previously unknown co-transcriptional complex consisting of RUNX3 and ETS1 that regulatesFASexpression, and ARID1A loss leads to reducedRUNX3promotor openness and gene expression. The reduced FAS levels induced by ARID1A loss rendered lymphoma cells resistant to both soluble and T cell membrane-anchored FASLG-induced apoptosis.

In summary, we have identified a functionally and clinically relevant mechanism how FL cells can escape FAS-dependent immune surveillance, which may also impact the efficacy of T cell-based therapies, including bispecific antibodies and CAR T cells.
Dynamic evolution of infarct volumes at MRI in ischemic stroke due to large vessel occlusion
Authors: Munsch Fanny , Planes David , Fukutomi Hikaru , Marnat Gaultier , Courret Thomas , Micard Emilien , Chen Bailiang , Seners Pierre , Dubos Johanna , Planche Vincent , Coupé Pierrick , Dousset Vincent , Lapergue Bertrand , Olivot Jean-Marc , Sibon Igor , Thiebaut de Schotten Michel , Tourdias Thomas
Published: December 2023

Background and Objectives

The typical infarct volume trajectories in stroke patients, categorized as slow or fast progressors, remain largely unknown. This study aimed to reveal the characteristic spatiotemporal evolutions of infarct volumes caused by large vessel occlusion (LVO) and show that such growth charts help anticipate clinical outcomes.

Methods

We conducted a secondary analysis from prospectively collected databases (FRAME, 2017– 2019; ETIS, 2015–2022). We selected acute MRI data from anterior LVO stroke patients with witnessed onset which were divided into training- and independent validation-datasets. In the training-dataset, using Gaussian mixture analysis, we classified the patients into three growth groups based on their rate of infarct growth (diffusion volume / time-to-imaging). Subsequently, we extrapolated pseudo-longitudinal models of infarct growth for each group and generated sequential frequency maps to highlight the spatial distribution of infarct growth. We used these charts to attribute a growth group to the independent patients from the validation-dataset. We compared their 3-month modified Rankin scale (mRS) with the predicted values based on a multivariable regression model from the training-dataset that used growth group as independent variable.

Results

We included 804 patients (median age, 73.0 years [IQR, 61.2-82.0 years]; 409 men). The training-dataset revealed non-supervised clustering into 11% (74/703) slow, 62% (437/703) intermediate, and 27% (192/703) fast progressors. Infarct volume evolutions were best fitted with a linear (r=0.809;P<.001), cubic (r=0.471;P<.001), and power (r=0.63;P<.001) functions for the slow, intermediate and fast progressors, respectively. Notably, the deep nuclei and insular cortex were rapidly affected in the intermediate and fast groups with further cortical involvement in the fast group. The variable “growth group” significantly predicted 3-month mRS (multivariate OR, 0.51; 95% CI: 0.37-0.72,P<.0001) in the training-dataset, yielding a mean AUC of 0.78 (95% CI: 0.66-0.88) in the independent validation-dataset.

Conclusions

We revealed spatiotemporal archetype dynamic evolutions following large vessel occlusion stroke according to three growth phenotypes called slow, intermediate and fast progressors, providing insight into anticipating clinical outcome. We expect this could help in designing neuroprotective trials aiming at modulating infarct growth prior EVT.
Hop stunt viroid infection alters host heterochromatin
Authors: Marquez-Molins Joan , Cheng Jinping , Corell-Sierra Julia , Juarez-Gonzalez Vasti Thamara , Villalba-Bermell Pascual , Annacondia Maria Luz , Gomez Gustavo , Martinez German
Published: December 2023

Viroids are pathogenic non-coding RNAs that completely rely on their host molecular machinery to accomplish their life cycle. Several interactions between viroids and their host molecular machinery have been identified, including an interference with epigenetic mechanisms such as DNA methylation. Despite this, whether viroids influence changes in other epigenetic marks such as histone modifications remained unknown. Epigenetic regulation is particularly important during pathogenesis processes because it might be a key regulator of the dynamism of the defense response. Here we have analyzed the changes taking place inCucumis sativusfacultative and constitutive heterochromatin during hop stunt viroid (HSVd) infection using chromatin immunoprecipitation (ChIP) of the two main heterochromatic marks: H3K9me2 and H3K27me3. We find that HSVd infection is associated with changes in both H3K27me3 and H3K9me2, with a tendency to decrease the levels of repressive epigenetic marks through infection progression. These epigenetic changes are connected to the transcriptional regulation of their expected targets, genes and transposable elements. Indeed, several genes related to the defense response are targets of both epigenetic marks. Our results highlight another host regulatory mechanism affected by viroid infection, providing further information about the complexity of the multiple layers of interactions between pathogens/viroids and hosts/plants.
The ubiquitin-conjugating enzyme UBE2D/eff maintains a youthful proteome and ensures protein quality control during aging
Authors: Hunt Liam C. , Nyamkondiwa Kudzai , Stephan Anna , Jiao Jianqin , Kavdia Kanisha , Pagala Vishwajeeth , Peng Junmin , Demontis Fabio
Published: December 2023

Ubiquitin-conjugating enzymes (E2s) are key for regulating protein function and turnover via ubiquitination but it remains undetermined which E2s maintain proteostasis during aging. Here, we find that E2s have diverse roles in handling a model aggregation-prone protein (huntingtin-polyQ) in theDrosophilaretina: while some E2s mediate aggregate assembly, UBE2D/effete (eff) and other E2s are required for huntingtin-polyQ degradation. UBE2D/eff is key for proteostasis also in skeletal muscle: eff protein levels decline with aging, and muscle-specific eff knockdown causes an accelerated buildup in insoluble poly-ubiquitinated proteins (which progressively accumulate with aging) and shortens lifespan. Transgenic expression of human UBE2D2, homologous to eff, partially rescues the lifespan and proteostasis deficits caused by muscle-specific effRNAiby re-establishing the physiological levels of effRNAi-regulated proteins, which include several regulators of proteostasis. Interestingly, UBE2D/eff knockdown in young age reproduces part of the proteomic changes that normally occur in old muscles, suggesting that the decrease in UBE2D/eff protein levels that occurs with aging contributes to reshaping the composition of the muscle proteome. Altogether, these findings indicate that UBE2D/eff is a key E2 ubiquitin-conjugating enzyme that ensures protein quality control and helps maintain a youthful proteome composition during aging.
Herpes Simplex Virus 1 (HSV-1) Uses the Rab6 Post-Golgi Secretory Pathway For Viral Egress
Authors: Bergeman Melissa H. , Velarde Kimberly , Glenn Honor L. , Hogue Ian B.
Published: December 2023

Herpes Simplex Virus 1 (HSV-1) is an alpha herpesvirus that infects a majority of the world population. The mechanisms and cellular host factors involved in the intracellular transport and exocytosis of HSV-1 particles are not fully understood. To elucidate these late steps in the replication cycle, we developed a live-cell fluorescence microscopy assay of HSV-1 virion intracellular trafficking and exocytosis. This method allows us to track individual virus particles, and identify the precise moment and location of particle exocytosis using a pH-sensitive reporter. We show that HSV-1 uses the host Rab6 post-Golgi secretory pathway during egress. The small GTPase, Rab6, binds to nascent secretory vesicles at thetrans-Golgi network and regulates vesicle trafficking and exocytosis at the plasma membrane. HSV-1 particles colocalize with Rab6a in the region of the Golgi, cotraffic with Rab6a to the cell periphery, and undergo exocytosis from Rab6a vesicles. Consistent with previous reports, we find that HSV-1 particles accumulate at preferential egress sites in infected cells. The Rab6a secretory pathway mediates this preferential/polarized egress, since Rab6a vesicles accumulate near the plasma membrane similarly in uninfected cells. These data suggest that, following particle envelopment, HSV-1 egress follows a pre-existing cellular secretory pathway to exit infected cells rather than novel, virus-induced mechanisms.

IMPORTANCE

HSV-1 infects a majority of people. It establishes a life-long latent infection, and occasionally reactivates, typically causing characteristic oral or genital lesions. Rarely in healthy natural hosts, but more commonly in zoonotic infections and in elderly, newborn, or immunocompromised patients, HSV-1 can cause severe herpes encephalitis. The precise cellular mechanisms used by HSV-1 remain an important area of research. In particular, the egress pathways that newly-assembled virus particles use to exit from infected cells are unclear. In this study, we used fluorescence microscopy to visualize individual virus particles exiting from cells, and found that HSV-1 particles use the pre-existing cellular secretory pathway, regulated by the cellular protein, Rab6.
The steroid hormone ADIOL promotes learning by reducing neural kynurenic acid levels
Authors: Lemieux George A. , Yoo Shinja , Lin Lin , Vohra Mihir , Ashrafi Kaveh
Published: December 2023

Reductions in brain kynurenic acid levels, a neuroinhibitory metabolite, improve cognitive function in diverse organisms. Thus, modulation of kynurenic acid levels is thought to have therapeutic potential in a range of brain disorders. Here we report that the steroid 5-androstene 3β, 17β-diol (ADIOL) reduces kynurenic acid levels and promotes associative learning inCaenorhabditis elegans. We identify the molecular mechanisms through which ADIOL links peripheral metabolic pathways to neural mechanisms of learning capacity. Moreover, we show that in aged animals, which normally experience rapid cognitive decline, ADIOL improves learning capacity. The molecular mechanisms that underlie the biosynthesis of ADIOL as well as those through which it promotes kynurenic acid reduction are conserved in mammals. Thus, rather than a minor intermediate in the production of sex steroids, ADIOL is an endogenous hormone that potently regulates learning capacity by causing reductions in neural kynurenic acid levels.