bluuebunny/crossref_metadata_2025 huggingface dataset:
Deciphering Structural Traits for Thermal and Kinetic Stability across Protein Family Evolution through Ancestral Sequence Reconstruction
Authors: Cea Pablo A , Pérez Myriam , Herrera Sixto M , Muñoz Sebastián M , Fuentes-Ugarte Nicolás , Coche-Miranda José , Maturana Pablo , Guixé Victoria , Castro-Fernandez Victor
Published: June 2024

Natural proteins are frequently marginally stable, and an increase in environmental temperature can easily lead to unfolding. As a result, protein engineering to improve protein stability is an area of intensive research. Nonetheless, since there is usually a high degree of structural homology between proteins from thermophilic organisms and their mesophilic counterparts, the identification of structural determinants for thermoadaptation is challenging. Moreover, in many cases, it has become clear that the success of stabilization strategies is often dependent on the evolutionary history of a protein family. In the last few years, the use of ancestral sequence reconstruction (ASR) as a tool for elucidation of the evolutionary history of functional traits of a protein family has gained strength. Here, we used ASR to trace the evolutionary pathways between mesophilic and thermophilic kinases that participate in the biosynthetic pathway of vitamin B1 in bacteria. By combining biophysics approaches, X-ray crystallography, and molecular dynamics simulations, we found that the thermal stability of these enzymes correlates with their kinetic stability, where the highest thermal/kinetic stability is given by an increase in small hydrophobic amino acids that allow a higher number of interatomic hydrophobic contacts, making this type of interaction the main support for stability in this protein architecture. The results highlight the potential benefits of using ASR to explore the evolutionary history of protein sequence and structure to identify traits responsible for the kinetic and thermal stability of any protein architecture.
The cochlear dose and the age at radiotherapy predict severe hearing loss after passive scattering proton therapy and cisplatin in children with medulloblastoma
Authors: Abu-Arja Mohammad H , Brown Austin L , Su Jack M , Okcu M Fatih , Lindsay Holly B , McGovern Susan L , McAleer Mary Frances , Grosshans David R , Chintagumpala Murali M , Paulino Arnold C
Published: June 2024

Background

Hearing loss (HL) is associated with worse neurocognitive outcomes among patients with medulloblastoma. We aimed to identify risk factors associated with severe HL and to evaluate the generalizability of a published HL calculator among patients treated with passive scattering proton therapy (PSPT) and cisplatin.

Methods

We identified patients aged 3–21 years who were treated at our centers between 2007 and 2022. Audiograms were graded using the International Society of Pediatric Oncology (SIOP) Boston scale. Time to grades 3–4 HL was evaluated using Kaplan–Meier and multivariable Cox models to estimate hazard ratios and 95% confidence intervals (CI).

Results

Seventy-nine patients were treated with PSPT at a median age of 7.5 years (range: 3.1–21.1). The mean cochlear dose (Dmc) (±SD) was 31.5 ± 8.5 Gy, and the cumulative cisplatin dose was 295 ± 50 mg/m2. Fifty-nine patients (75%) received amifostine. Patients completed a median of 9 audiograms (range: 4–22) with a median audiogram follow-up of 49 months (range: 6–177). Twenty-seven patients (34%) had grades 3–4 HL. In adjusted Cox models, only higher Dmc (HR = 1.12, 95% CI:1.06–1.18) was associated with grades 3–4 HL. The predicted 3-year incidence of grades 3–4 HL was 40.0% (95% CI: 21.3–66.3) and 66.7% (95% CI: 35.4–93.7) for children with Dmc ≥36 Gy and age at radiotherapy ≥7 and <7 years, respectively (P = .042). It was 8.9% (95% CI: 2.3–31.6) and 15.6% (95% CI: 5.3–41.1) for children with Dmc <36 Gy and age at radiotherapy ≥7 and <7 years, respectively (P = .78).

Conclusions

Children <7 years at radiotherapy with a Dmc ≥36 Gy are at higher risk for HL.
Oral Lipid Nanocrystal Amphotericin B (MAT2203) for the Treatment of Invasive Fungal Infections
Authors: Dalton Liam M , Kauffman Carol A , Miceli Marisa H
Published: June 2024

Amphotericin B (AmB) has broad fungicidal activity against many fungi, but the high incidence of adverse events, particularly nephrotoxicity, and the need for intravenous administration restrict its use for many patients. MAT2203, an investigational oral AmB formulation available under a compassionate use program, uses a lipid nanocrystal bilayer structure to deliver AmB with lower toxicity. We present a synopsis of clinical characteristics, treatment course, and outcomes for 5 patients who were treated with MAT2203. Outcomes were positive, with cure of infection noted in 4 patients and improvement in 1 patient who remains on therapy. MAT2203 was well tolerated with only modest gastrointestinal adverse effects. This new oral formulation might provide a safer treatment option for patients requiring extended courses of AmB.
Abstract Representations of Voices in Video Games
Authors: Medina-Gray Elizabeth
Published: June 2024

Elizabeth Medina-Gray aims to provide a framework from which to analyze the abstract representation of voice in video games. Her focus is on the use of sounds that accompany texted dialogue but that have no linguistic meaning or comprehensible words and phrases and where the sound has noticeable technologically mediated qualities. The purpose is to allow for an exploration of the spaces at the intersection of the human and the mechanical, and, to this end, Medina-Gray makes use of both social semiotics and musical analysis of the sounds to suggest that players will use imagination to uncover the human in such abstract representations.
Music and Motion in First-Person Virtual Reality Games
Authors: Mancey Kate
Published: June 2024

Kate Mancey uses the concepts of place illusion and plausibility illusion from the field of Psychology to highlight the role of music in virtual reality games. In particular, she is concerned with the perception of motion in music, a motion that, in the game’s world, is independent of any changes in the player’s head position. Using Half-Life: Alyx as an example, Mancey offers a methodology for analyzing motion in recorded sound and shows how music’s independence of motion allows the player to imagine the presence of other entities beyond what can be seen. Through this, she argues that music offers a life force for virtual worlds.
Video Games Live and the Gamification of the Orchestral Concert Experience
Authors: Hunt Elizabeth
Published: June 2024

Elizabeth Hunt’s chapter focuses on the long-running concert series Video Games Live (VGL), which raises issues of gamification for both the audience and the performers. Hunt argues that the VGL concerts subvert traditional concert codes by inciting the carnivalesque through gamification of the concert mechanics and through audience participation on stage. This is demonstrated through examination of the VGL performance of Space Invaders (Taito, 1978), Frogger (Konami, 1981), and Guitar Hero (Harmonix, 2005). It is through such features that the audience member becomes a voluntary and active coproducer of the concert; this form of “participatory spectatorship” helps to break down the boundary between high art and low art erected, in part, by the traditional rules of orchestral concerts.
Auditory Reality and Virtuality
Authors: Collins KC , Kapralos Bill
Published: June 2024

KC Collins and Bill Kapralos investigate advances in spatial audio rendering for video game sound and discuss the pros and cons of the technology within the framework of realism. The authors first provide an overview of human localization of real-world sound, attempts to emulate these real-world conditions in virtual reality and video game audio technology, and the problems encountered in doing so. They then turn to the psychology of hearing—in particular, the role of attention and focus in our sound perception, and the importance of using sound design for emotion and expression. Collins and Kapralos argue that, in using sound as a “tool of realism” in video games, the artistic power of sound is lost: the belief that technological advances in spatial audio’s emulation of the real world produces realism, or even hyperrealism, is misguided, and what often results is an anemic hyporealism that lacks the imagination both game and player require.
Unreal Performances
Authors: Cook James
Published: June 2024

James Cook’s chapter explores the growing phenomenon of the use of video game technologies and platforms to host “live” music concerts. Cook presents several brief case studies, each exploring the history or a particular dimension of musical performances within games. Thus, the chapter provides overviews of concerts in Second Life and Fortnite, as well as musical avatars such as Gorillaz and Hatsune Miku, and Cook’s own experience of recording historical performances in reconstructed VR settings. Throughout, Cook expounds the view that such musical performances are examples of metalepsis; the events are a recontextualization of liveness and provide a “liminal space between the virtual and real world” into and out of which performers and audiences step.
Perceived stress and influencing factors for the people at high risk to COVID-19 in centralized quarantine camps in Wenzhou, China
Authors: Zhou Yi-Wei , Zheng Jian-Yong , Shan Chun-Yan , Yang Hong-Sheng , Su Yi-Suo , Wang Deborah Baofeng , Ni Jian-Xiao , Lan Liu-Jie , Lian Xin-Ze , Zhou Zu-Mu
Published: June 2024

Background

This study was designed to assess stress levels and related factors during the coronavirus disease 2019 (COVID-19) epidemic among individuals in centralized quarantine camps in Wenzhou, China.

Methods

The survey was conducted using a questionnaire. The questionnaire included questions on sociodemographic characteristics, life events related to the COVID-19 and stressful situations, as well as Perceived Stress Scale-14. Participants included close contacts of patients with COVID-19 or at-risk individuals in quarantine camps. Multivariate logistic regression was used to analyze different factors affecting perceived stress.

Results

The prevalence of high stress among quarantine camp participants was 37.45%. Of the 881 respondents, 51.99% were concerned about the difficulty of controlling the epidemic, 46.20% were concerned about the health of themselves and their family members and 39.61% were concerned about not being able to leave their homes. Multivariate logistic regression analysis revealed statistically significant differences in the prevalence of stress among different groups for certain variables, including occupation, education level and knowledge of COVID-19 (all P < 0.05). Our study found that at-risk individuals and close contacts experienced high levels of stress in quarantine camps during the COVID-19 pandemic.

Conclusions

These findings suggest that centralized quarantine policies should be adapted and optimized to minimize negative psychological effects on quarantined individuals.
The Impact of Neuroanesthesia Fellowship Training and Anesthesiologist-Surgeon Dyad Volume on Patient Outcomes in Adult Spine Surgery: A Population-Based Study
Authors: Chui Jason , Ng Wai , Yang Victor , Duggal Neil
Published: June 2024

Introduction:

Extensive research has explored the impact of surgeons’ characteristics on patient outcomes; however, the influence of anesthesiologists remains understudied. We performed a population-based retrospective cohort study to investigate the impact of anesthesiologists’ characteristics on in-hospital morbidity after spine surgery.

Methods:

Adult patients who underwent spine surgery at the London Health Science Centre, Ontario, Canada between January 1, 2010 and June 30, 2023 were included in this study. Data was extracted from the local administrative database. Five anesthesiologists’ characteristics (neuroanesthesia fellowship and residency training backgrounds, surgeon familiarity, annual case volume, and sex) were examined as primary exposures. The primary outcome was composite in-hospital morbidity, encompassing 141 complications. Multivariable logistic regression was performed to assess the association between anesthesiologists’ characteristics and postoperative morbidity with adjustment of patients’ sex, Charlson Comorbidities Index, surgical complexity, and surgeon characteristics.

Results:

A total of 7692 spine surgeries were included in the analysis. Being a neuroanesthesia fellowship-trained anesthesiologist and high anesthesiologist-surgeon annual dyad volume were associated with reduction in in-hospital comorbidity; adjusted odds ratio (95% CI) of 0.58 (0.49-0.69; P<0.001) and 0.93 (0.91-0.95; P<0.001), respectively. Conversely, anesthesiologist annual case volume, characteristics of residency training and anesthesiologist sex showed only nuanced associations with outcomes.

Conclusions:

Neuroanesthesia fellowship training and high surgeon-anesthesiologist dyad familiarity was associated with a reduction in in-hospital morbidity following spine surgery. These findings underscore the superiority of structured fellowship education over case exposure experience alone, advocate for dedicated neuroanesthesia teams with high surgeon-anesthesiologist dyad volume and recognize neuroanesthesia as a crucial subspecialty in spine surgery.
Albumin Versus Balanced Crystalloid for the Early Resuscitation of Sepsis: An Open Parallel-Group Randomized Feasibility Trial. The ABC-Sepsis Trial
Authors: Gray Alasdair J. , Oatey Katherine , Grahamslaw Julia , Irvine Sîan , Cafferkey John , Kennel Titouan , Norrie John , Walsh Tim , Lone Nazir , Horner Daniel , Appelboam Andy , Hall Peter , Skipworth Richard J. E. , Bell Derek , Rooney Kevin , Shankar-Hari Manu , Corfield Alasdair R. ,   on behalf of the Albumin, Balanced, and Crystalloid-Sepsis (ABC-Sepsis) Investigators
Published: June 2024

Objectives:

International guidelines recommend IV crystalloid as the primary fluid for sepsis resuscitation, with 5% human albumin solution (HAS) as the second line. However, it is unclear which fluid has superior clinical effectiveness. We conducted a trial to assess the feasibility of delivering a randomized controlled trial comparing balanced crystalloid against 5% HAS as sole early resuscitation fluid in patients with sepsis presenting to hospital.

Design:

Multicenter, open, parallel-group randomized feasibility trial.

Setting:

Emergency departments (EDs) in 15 U.K. National Health Service (NHS) hospitals.

Patients:

Adult patients with sepsis and a National Early Warning Score 2 greater than or equal to five requiring IV fluids withing one hour of randomization.

Interventions:

IV fluid resuscitation with balanced crystalloid or 5% HAS for the first 6 hours following randomization.

Measurements and Main Results:

Primary feasibility outcomes were recruitment rate and 30-day mortality. We successfully recruited 301 participants over 12 months. Mean (sd) age was 69 years (± 16 yr), and 151 (50%) were male. From 1303 participants screened; 502 participants were potentially eligible and 300 randomized to receive trial intervention with greater than 95% of participants receiving the intervention. The median number of participants per site was 19 (range, 1–63). Thirty-day mortality was 17.9% (n = 53). Thirty-one participants died (21.1%) within 30 days in the 5% HAS arm, compared with 22 participants (14.8%) in the crystalloid arm (adjusted odds ratio, 1.50; 95% CIs, 0.84–2.83).

Conclusions:

Our results suggest it is feasible to recruit critically ill patients to a fluid resuscitation trial in U.K. EDs using 5% HAS as a primary resuscitation fluid. There was lower mortality in the balanced crystalloid arm. Given these findings, a definitive trial is likely to be deliverable, but the point estimates suggest such a trial would be unlikely to demonstrate a significant benefit from using 5% HAS as a primary resuscitation fluid in sepsis.
Sensory Stimulation and Robot-Assisted Arm Training After Stroke: A Randomized Controlled Trial
Authors: Egger Marion , Bergmann Jeannine , Krewer Carmen , Jahn Klaus , Müller Friedemann
Published: June 2024

Background and Purpose:

Functional recovery after stroke is often limited, despite various treatment methods such as robot-assisted therapy. Repetitive sensory stimulation (RSS) might be a promising add-on therapy that is thought to directly drive plasticity processes. First positive effects on sensorimotor function have been shown. However, clinical studies are scarce, and the effect of RSS combined with robot-assisted training has not been evaluated yet. Therefore, our objective was to investigate the feasibility and sensorimotor effects of RSS (compared to a control group receiving sham stimulation) followed by robot-assisted arm therapy.

Methods:

Forty participants in the subacute phase (4.4-23.9 weeks) after stroke with a moderate to severe arm paresis were randomized to RSS or control group. Participants received 12 sessions of (sham-) stimulation within 3 weeks. Stimulation of the fingertips and the robot-assisted therapy were each applied in 45-min sessions. Motor and sensory outcome assessments (e.g. Fugl-Meyer-Assessment, grip strength) were measured at baseline, post intervention and at a 3-week follow-up.

Results:

Participants in both groups improved their sensorimotor function from baseline to post and follow-up measurements, as illustrated by most motor and sensory outcome assessments. However, no significant group effects were found for any measures at any time (P > 0.058). Stimulations were well accepted, no safety issues arose.

Discussion and Conclusions:

Feasibility of robot-assisted therapy with preceding RSS in persons with moderate to severe paresis was demonstrated. However, RSS preceding robot-assisted training failed to show a preliminary effect compared to the control intervention. Participants might have been too severely affected to identify changes driven by the RSS, or these might have been diluted or more difficult to identify because of the additional robotic training and neurorehabilitation.

Video Abstract available

for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A478).
Visuospatial Skills Explain Differences in the Ability to Use Propulsion Biofeedback Post-stroke
Authors: Kettlety Sarah A. , Finley James M. , Leech Kristan A.
Published: June 2024

Background and Purpose:

Visual biofeedback can be used to help people post-stroke reduce biomechanical gait impairments. Using visual biofeedback engages an explicit, cognitively demanding motor learning process. Participants with better overall cognitive function are better able to use visual biofeedback to promote locomotor learning; however, which specific cognitive domains are responsible for this effect are unknown. We aimed to understand which cognitive domains were associated with performance during acquisition and immediate retention when using visual biofeedback to increase paretic propulsion in individuals post-stroke.

Methods:

Participants post-stroke completed cognitive testing, which provided scores for different cognitive domains, including executive function, immediate memory, visuospatial/constructional skills, language, attention, and delayed memory. Next, participants completed a single session of paretic propulsion biofeedback training, where we collected treadmill-walking data for 20 min with biofeedback and 2 min without biofeedback. We fit separate regression models to determine if cognitive domain scores, motor impairment (measured with the lower-extremity Fugl-Meyer), and gait speed could explain propulsion error and variability during biofeedback use and recall error during immediate retention.

Results:

Visuospatial/constructional skills and motor impairment best-explained propulsion error during biofeedback use (adjusted R2 = 0.56, P = 0.0008), and attention best-explained performance variability (adjusted R2 = 0.17, P = 0.048). Language skills best-explained recall error during immediate retention (adjusted R2 = 0.37, P = 0.02).

Discussion and Conclusions:

These results demonstrate that specific cognitive domain impairments explain variability in locomotor learning outcomes in individuals with chronic stroke. This suggests that with further investigation, specific cognitive impairment information may be useful to predict responsiveness to interventions and personalize training parameters to facilitate locomotor learning.
Smooth pursuit deficits impact dynamic visual acuity in macular degeneration
Authors: Shanidze Natela M. , Verghese Preeti
Published: June 2024

SIGNIFICANCE

Prior studies with large, highly visible targets report low smooth pursuit gains in individuals with macular degeneration (MD). We show that lower gains persist even when observers are pursuing a target that requires discrimination at the acuity limit. This low gain causes retinal slip, potentially leading to motion blur and target disappearance in the scotoma, which further compromise the visibility of moving object.

PURPOSE

In this study, we examine whether the characteristics of smooth pursuit (pursuit gain and placement of the fixational locus relative to the target) change when the task requires dynamic visual acuity.

METHODS

Using the scanning laser ophthalmoscope, we recorded smooth pursuit eye movements in 10 eyes of 6 MD participants and 7 eyes of 4 age-matched controls in response to leftward- or rightward-moving annular targets (O) that briefly (300 milliseconds) changed to a Landolt C at one of several time points during the pursuit trial. Participants were asked to pursue the target and indicate the direction of the C opening.

RESULTS

Individuals with MD had lower pursuit gains and fewer saccades during the C presentation than during the O, compared with their age-matched peers. Further, pursuit gain, but not the distance of the retinal pursuit locus from the target, predicted task performance in the MD group.

CONCLUSIONS

Our findings suggest that compromised pursuit gain in MD participants likely further compromises their dynamic visual acuity and thus ability to view moving targets.
Molecular Surrogate Subtypes of Ovarian and Peritoneal Low-grade Serous Carcinoma
Authors: Da-Anoy Annalyn , Kang Eun Young , Lee Cheng Han , Cheasley Dane , Llaurado Fernandez Marta , Carey Mark S. , Cameron Anna , Köbel Martin
Published: June 2024

Low-grade serous carcinoma (LGSC) is an uncommon histotype of ovarian carcinoma, accounting for ~3% of cases. There is evidence that survival of peritoneal LGSC (pLGSC) is longer than that of ovarian LGSC (oLGSC). Key molecular alterations of LGSC have been established, including loss of CDKN2A and PR expression, MAPK pathway alterations, and loss of USP9X expression. We hypothesized that LGSC could be subclassified into clinically applicable molecular subtypes by a few surrogate tests similar to endometrioid carcinomas using a hierarchical decision tree based on the strength of the prognostic associations of the individual alterations. Our study included 71 LGSCs. Immunohistochemistry for CDKN2A, ER, PR, NF1, and USP9X and sequencing for KRAS, NRAS, and BRAF were performed. Our data showed the co-occurrence of key molecular alterations, and despite suggestive trends, hierarchical molecular subtyping did not provide significantly different stratification of patients according to survival in this cohort. We confirmed that patients diagnosed with pLGSC have a longer survival than high-stage oLGSC, with the intriguing observation that normal CDKN2A and PR status were associated with excellent survival in pLGSC. Therefore, CDKN2A and PR status might aid in the classification of indeterminate implants, where abnormal findings favor pLGSC over noninvasive implants. Molecular subtypes should be further evaluated in larger cohorts for their prognostic and potentially predictive value.
Integrated 68Ga-FAPI-04 PET/MR in Pancreatic Cancer
Authors: Zhang Zeyu , Guo Shiwei , Cheng Chao , Cao Kai , Jiang Hui , Jin Gang , Zuo Changjing
Published: June 2024

Purpose

This study aimed to investigate the value of 68Ga-fibroblast activation protein inhibitor (FAPI) PET/MR semiquantitative parameters in the prediction of tumor response and resectability after neoadjuvant therapy in patients with pancreatic cancer.

Patients and Methods

This study was performed retrospectively in patients with borderline resectable or locally advanced pancreatic cancer who underwent 68Ga-FAPI PET/MRI from June 2020 to June 2022. The SUVmax, SUVmean, SUVpeak, uptake tumor volume (UTV), and total lesion FAP expression (TLF) of the primary tumor were recorded. The target-to-background ratios (TBRs) of the primary tumor to normal tissue muscle (TBRmuscle) and blood (TBRblood) were also calculated. In addition, the minimum apparent diffusion coefficient value of the tumor was measured. After 3–4 cycles of gemcitabine + nab-paclitaxel chemotherapy, patients were divided into responders and nonresponders groups according to RECIST criteria (v.1.1). They were also divided into resectable and unresectable groups according to the surgical outcome. The variables were compared separately between groups.

Results

A total of 18 patients who met the criteria were included in this study. The UTV and TLF were significantly higher in nonresponders than in responders (P < 0.05). The SUVmax, SUVmean, and TBRmuscle were significantly higher in unresectable patients than in resectable ones (P < 0.05). Receiver operating characteristic curve analysis identified UTV (area under the curve [AUC] = 0.840, P = 0.015) and TLF (AUC = 0.877, P = 0.007) as significant predictors for the response to gemcitabine + nab-paclitaxel chemotherapy, with cutoff values of 25.05 and 167.38, respectively. In addition, SUVmax (AUC = 0.838, P = 0.016), SUVmean (AUC = 0.812, P = 0.026), and TBRmuscle (AUC = 0.787, P = 0.041) were significant predictors of the resectability post-NCT, with cutoff values of 14.0, 6.0, and 13.9, respectively. According to logistic regression analysis, TLF was found to be significantly associated with tumor response (P = 0.032) and was an independent predictor of tumor response (P = 0.032). In addition, apparent diffusion coefficient value was an independent predictor of tumor resectability (P = 0.043).

Conclusions

This pilot study demonstrates the value of 68Ga-FAPI PET/MR for the prediction of tumor response and resectability after neoadjuvant therapy. It may aid in individualized patient management by guiding the treatment regimens.
On the calculation and use of effective single-particle energies: the example of the neutron 1d
3/2
–1d
5/2
splitting along
N
= 20 isotones
Authors: Somà V. , Duguet T.
Published: June 2024

The rich phenomenology of quantum many-body systems such as atomic nuclei is complex to interpret. Often, the behaviour (e.g. evolution with the number of constituents) of measurable/observable quantities such as binding or excitation energies can be best understood based on a simplified picture involving auxiliary quantities that are not observable, i.e. whose values vary with parameters that are internal to the theoretical construction (contrarily to measurable/observable quantities). While being useful, the simplified interpretation is thus theoretical-scheme dependent. This applies, in particular, to the so-called single-nucleon shell structure based on auxiliary effective single-particle energies (ESPEs). In this context, the present work aims at (i) recalling the way to compute ESPEs out of solutions of many-body Schrödinger’s equation, (ii) illustrating the use of ESPEs within the frame of state-of-the-art
ab initio
calculations to interpret the outcome of a recent nuclear experiment, and (iii) demonstrating the impact of several alterations on the computation of ESPEs. While the chosen alterations constitute approximations within the
ab initio
scheme, they are built-in when employing other theoretical constructs at play in nuclear physics. The present considerations are thus meant to empirically illustrate variations that can be expected between ESPEs computed within different (equally valid) theoretical schemes.

This article is part of the theme issue ‘The liminal position of Nuclear Physics: from hadrons to neutron stars’.
Nuclear clustering—manifestations of non-uniformity in nuclei
Authors: Uesaka T. , Itagaki N.
Published: June 2024

Well-developed

α

clusters are known to exist in light

N
=
Z

nuclei, and their properties are reasonably well described with modern nuclear structure theories. However, ‘modestly’ developed clusters in medium to heavy nuclei remain little understood, both theoretically and experimentally. Extension of the focus to include modestly developed clusters leads us to a concept of ‘generalized clusters’ and ‘cluster ubiquitousness’. The former includes clusters more weakly bound than an

α

cluster, such as deuteron, triton and

He

3

, and even clusters partially broken owing to nuclear medium effects. The latter means the existence of clusters in any nuclei, where cluster development was not previously discussed. Effects of the tensor and the spin–orbit interactions on the coexistence of clusters with independent nucleons are discussed using recent nuclear theoretical models. A mixture of the clusters with shell-like components plays an essential role in the synthesis of elements in the universe and the origin of life, together with an

α

decay. It is also pointed out that clustering in heavy nuclei may accelerate fission and fusion processes. Future experimental plans using cluster knockout reactions, which have the potential to extract information of ‘generalized clusters’ in a variety of nuclei including stable and unstable nuclei, are also discussed.

This article is part of the theme issue ‘The liminal position of Nuclear Physics: from hadrons to neutron stars’.
Hyperons in neutron stars: studies of hyperon spectroscopy and the hyperon–nucleon interaction with the K-long Facility
Authors: Zachariou N. , Fegan S. , Watts D. , Bashkanov M.
Published: June 2024

Elucidating the role of strange baryons (hyperons) in neutron stars requires detailed knowledge of hyperon–nucleon interactions in the light (u,d,s) quark sector. The structure of the hyperons and their excitation spectra also directly impact, and are an input to, models of big-bang nucleosynthesis. The upcoming K-long Facility will provide a much-needed intense and clean neutral strange meson beam, from which hyperons can be produced at rates where hyperon structure, hyperon–nucleon interactions and higher-order interactions can be studied with a new level of accuracy and for hitherto unreachable measurements. The new facility has the potential to address long-standing questions surrounding the strange sector of the strong force and its relevance to the structure of atomic nuclei, neutron stars and the cosmos at large.

This article is part of the theme issue ‘The liminal position of Nuclear Physics: from hadrons to neutron stars’.
Auxiliary field Quantum Monte Carlo for dilute neutrons on the lattice
Authors: Curry Ryan , Dissanayake Jayani , Gandolfi Stefano , Gezerlis Alexandros
Published: June 2024

We employ constrained path Auxiliary Field Quantum Monte Carlo (AFQMC) in the pursuit of studying physical nuclear systems using a lattice formalism. Since AFQMC has been widely used in the study of condensed-matter systems such as the Hubbard model, we benchmark our method against published results for both one- and two-dimensional Hubbard model calculations. We then turn our attention to cold atomic and nuclear systems. We use an onsite contact interaction that can be tuned in order to reproduce the known scattering length and effective range of a given interaction. Developing this machinery allows us to extend our calculations to study nuclear systems within a lattice formalism. We perform initial calculations for a range of nuclear systems from two- to few-body neutron systems.

This article is part of the theme issue ‘The liminal position of Nuclear Physics: from hadrons to neutron stars’.
Evolutionary ecology of dispersal in biodiverse spatially structured systems: what is old and what is new?
Authors: Fronhofer Emanuel A. , Bonte Dries , Bestion Elvire , Cote Julien , Deshpande Jhelam N. , Duncan Alison B. , Hovestadt Thomas , Kaltz Oliver , Keith Sally A. , Kokko Hanna , Legrand Delphine , Malusare Sarthak P. , Parmentier Thomas , Saade Camille , Schtickzelle Nicolas , Zilio Giacomo , Massol François
Published: June 2024

Dispersal is a well-recognized driver of ecological and evolutionary dynamics, and simultaneously an evolving trait. Dispersal evolution has traditionally been studied in single-species metapopulations so that it remains unclear how dispersal evolves in metacommunities and metafoodwebs, which are characterized by a multitude of species interactions. Since most natural systems are both species-rich and spatially structured, this knowledge gap should be bridged. Here, we discuss whether knowledge from dispersal evolutionary ecology established in single-species systems holds in metacommunities and metafoodwebs and we highlight generally valid and fundamental principles. Most biotic interactions form the backdrop to the ecological theatre for the evolutionary dispersal play because interactions mediate patterns of fitness expectations across space and time. While this allows for a simple transposition of certain known principles to a multispecies context, other drivers may require more complex transpositions, or might not be transferred. We discuss an important quantitative modulator of dispersal evolution—increased trait dimensionality of biodiverse meta-systems—and an additional driver: co-dispersal. We speculate that scale and selection pressure mismatches owing to co-dispersal, together with increased trait dimensionality, may lead to a slower and more ‘diffuse’ evolution in biodiverse meta-systems. Open questions and potential consequences in both ecological and evolutionary terms call for more investigation.

This article is part of the theme issue 'Diversity-dependence of dispersal: interspecific interactions determine spatial dynamics'.
Adaptive Wheel Exercise for Mouse Models of Parkinson’s Disease
Authors: Skelton Henry , Grogan Dayton , Kotlure Amrutha , Berglund Ken , Gutekunst Claire-Anne , Gross Robert
Published: June 2024

Exercise is widely studied as a therapy in mouse models of neurological disease. However, the established techniques for exercise in mice are not ideally suited toward motor deficient disease models, nor do they facilitate active measurement of neurophysiology with tethered assays. To address this, we developed an apparatus and technique for inducing exercise in mice without aversive stimuli, using a motorized wheel with closed-loop acceleration that tracks subject performance. We demonstrated the efficacy of this approach in the 6-hydroxydopamine mouse model of PD, including with single-unit electrophysiology. This approach should allow for exercise to be better studied as a dynamic, physiological intervention in neurological disease models.
Central nucleus of the amygdala to medial prefrontal cortex 5-HTergic neural circuit modulates the recovery of consciousness during sevoflurane anesthesia
Authors: Wang YuLing , Yang Yue , Wu YaXuan , Xu XiaoXia , Xu Qing , Zhang ZiWen , Di XuanYi , Zhang HongHai
Published: June 2024

General anesthesia, widely employed for its capacity to induce unconsciousness during surgical and diagnostic procedures, frequently results in postoperative recovery delays, a common complication. The precise mechanisms underpinning this delayed emergence from anesthesia remain not fully understood. Prior research has established a strong association between sleep-wake neural circuits and the anesthetic effects of general anesthetics, with serotonin (5-HT) playing a pivotal role in the regulation of anesthesia emergence. Extensive projections exist between the amygdala and the medial prefrontal cortex (mPFC). In this study, we utilized pharmacological, chemogenetic, and optogenetic techniques to explore the relationship between the 5-HT neural circuitry within the central amygdala (CeA)-mPFC pathway and the process of awakening from general anesthesia. Our findings reveal that modulating the 5-HT system in both the CeA and mPFC, via endogenous and exogenous means, can effectively reverse delayed emergence. This suggests that the 5-HT-ergic pathway within the CeA-mPFC circuit is instrumental in regulating the awakening process from sevoflurane anesthesia. These insights may inform future clinical interventions designed to prevent delayed emergence and reduce postoperative risks.
WT1 targeting multi-epitope vaccine design for glioblastoma multiforme using immuno-informatics approaches
Authors: Ahmed Tanvir
Published: June 2024

Glioblastoma multiforme (GBM) is a highly aggressive form of brain cancer classified as grade 4 glioma with a median survival rate of 12-14 months. Currently there is no cure and the conventional treatment outcomes are poor making it imperative to develop novel treatments. WT1, also known as Wilms’ Tumor 1, is a protein that is often found to be overexpressed in GBM and has minimal expression in normal tissues has become a promising target for immunotherapy for its oncogenicity and immunogenicity. This study aimed to develop a multi-epitope vaccine using immuno-informatics approaches that specifically targets the WT1 protein. The WT1 sequence was used to predict B and T cell epitopes which showed probable antigenic, non-allergic and non-toxic properties. Using suitable linker and adjuvants the vaccine construct (370 amino acids) was prepared which were then analyzed for solubility, physicochemical properties, molecular docking to show receptor interactions and molecular dynamics to show stability of the vaccine-receptor complexes. Subsequently, the vaccine sequence was back translated (1110 nucleotides), codon adaptation, pET-28a (+) vector in-silico cloning, and immune response simulations were performed. The designed vaccine lays groundwork for future in-vitro and in-vivo studies and potentially develop it into a novel treatment option for GBM patients.
Suppression of astrocyte BMP signaling improves fragile X syndrome molecular signatures and functional deficits
Authors: Deng James , Labarta-Bajo Lara , Brandebura Ashley N. , Kahn Samuel B. , Pinto Antonio F. M. , Diedrich Jolene K. , Allen Nicola J.
Published: June 2024

Fragile X syndrome (FXS) is a monogenic neurodevelopmental disorder with manifestations spanning molecular, neuroanatomical, and behavioral changes. Astrocytes contribute to FXS pathogenesis and show hundreds of dysregulated genes and proteins; targeting upstream pathways mediating astrocyte changes in FXS could therefore be a point of intervention. To address this, we focused on the bone morphogenetic protein (BMP) pathway, which is upregulated in FXS astrocytes. We generated a conditional KO (cKO) of Smad4 in astrocytes to suppress BMP signaling, and found this lessens audiogenic seizure severity in FXS mice. To ask how this occurs on a molecular level, we performedin vivotranscriptomic and proteomic profiling of cortical astrocytes, finding upregulation of metabolic pathways, and downregulation of secretory machinery and secreted proteins in FXS astrocytes, with these alterations no longer present when BMP signaling is suppressed. Functionally, astrocyte Smad4 cKO restores deficits in inhibitory synapses present in FXS auditory cortex. Thus, astrocytes contribute to FXS molecular and functional phenotypes, and targeting astrocytes can mitigate FXS symptoms.
Ecological factors alter how spatial overlap predicts viral infection dynamics in wild rodent populations
Authors: Mistrick Janine , Veitch Jasmine SM , Wearing Katherine E , Kitchen Shannon M , Clague Samuel , Du Stephanie , Michalska-Smith Matthew , Newman Brent C , Sironen Tarja , Cressler Clayton E , Hall Richard J , Budischak Sarah A , Forbes Kristian M , Craft Meggan E
Published: June 2024

Spatial overlap between animals in wildlife populations can have important implications for pathogen transmission. Ecological factors and animal demographic traits can influence animal space use and spatial overlap, but it is unclear how these interactions drive pathogen transmission. We experimentally manipulated wild bank vole populations via resource supplementation and anthelmintic treatment. Using network analysis, we investigated the relationship between spatial overlap and infection likelihood of an endemic zoonotic hantavirus, including how vole sex and reproductive status interact with spatial behaviour to affect infection likelihood. Spatial overlap in a previous month drove the likelihood of current hantavirus infection, and food supplementation and anthelmintic treatment altered the effects of spatial overlap on infection likelihood. Vole sex and reproductive status were important factors determining whether spatial overlap increased or decreased the likelihood of hantavirus infection and interacted with resource supplementation and anthelmintic treatment, generating different infection dynamics in each treatment. Our research provides rare empirical evidence linking previous spatial overlap to current infection status in wildlife populations, with implications for understanding disease dynamics and persistence as well as developing effective management efforts. We further highlight the importance of incorporating variation in ecological factors and host demography when studying pathogen transmission in wildlife systems.
Perfringolysin O pore-forming complexes are predominantly integral multiples of six subunits
Authors: Liu Meijun , Qin Xintao , Luo Menglin , Shen Yi , Wang Jiabin , Sun Jielin , Czajkowsky Daniel M. , Shao Zhifeng
Published: June 2024

Perfringolysin O is a well-studied bacterial cytolysin that forms large oligomeric pores with a wide range of sizes on membranes via a prepore intermediate. Here we examined the sizes of both PFO prepore and pore complexes electrophoretically using a multi-stack-gradient gel and found that, unexpectedly, there are only at most seven predominant sizes of either pores or prepores. Complexes extracted from each band exhibit contour lengths that are integral multiples of six subunits. High-resolution atomic force microscopy images of PFO pore complexes in supported bilayers also reveal a predominant hexameric-based stoichiometry. Thus, these results reveal a previously unknown structural hierarchy in PFO complexes, with larger complexes apparently built up from hexameric sub-complexes. We suggest that different inter-subunit interactions within and between the hexamers result in a likewise difference in the coordination of the prepore-to-pore transition within and between the hexamers, and is thus a critical feature of the allostery of this large multi-subunit complex.
Self-supervised machine learning methods for protein design improve sampling, but not the identification of high-fitness variants
Authors: Ertelt Moritz , Moretti Rocco , Meiler Jens , Schoeder Clara T.
Published: June 2024

Machine learning (ML) is changing the world of computational protein design, with data- driven methods surpassing biophysical-based methods in experimental success rates. However, they are most often reported as case studies, lack integration and standardization across platforms, and are therefore hard to objectively compare. In this study, we established a streamlined and diverse toolbox for methods that predict amino acid probabilities inside the Rosetta software framework that allows for the side-by-side comparison of these models. Subsequently, existing protein fitness landscapes were used to benchmark novel self- supervised machine learning methods in realistic protein design settings. We focused on the traditional problems of protein sequence design: sampling and scoring. A major finding of our study is that novel ML approaches are better at purging the sampling space from deleterious mutations. Nevertheless, scoring resulting mutations without model fine-tuning showed no clear improvement over scoring with Rosetta. This study fills an important gap in the field and allows for the first time a comprehensive head-to-head comparison of different ML and biophysical methods. We conclude that ML currently acts as a complement to, rather than a replacement for, biophysical methods in protein design.
Psychological Resilience as a Mediator Between Depression and Quality of Life in Relapsing-Remitting Multiple Sclerosis Patients
Authors: Broche-Pérez Yunier , Jiménez-Morales Rodneys M.
Published: June 2024

Depression represents a significant and prevalent challenge among individuals with multiple sclerosis (MS) substantially impacting their quality of life (QoL). This study explores the mediating role of psychological resilience in the relationship between depression and QoL in a sample of patients with multiple sclerosis (PwMS). This online cross-sectional study involves 179 Relapsing-Remitting Multiple Sclerosis (RRMS) patients. The PwMS completed three questionnaires: the Chicago Multiscale Depression Inventory, the Connor-Davidson Resilience Scale, and the Multiple Sclerosis Quality of Life (MSQOL-29). The results confirmed that higher levels of depression were associated with lower QoL in RRMS patients. However, the inclusion of psychological resilience as a mediator attenuated this direct effect, suggesting that resilience plays a crucial role in mitigating the negative impact of depression on QoL.
m6A methylation dynamically participates in the immune response againstVibrio anguillarumin half-smooth tongue sole (Cynoglossus semilaevis)
Authors: Tan Suxu , Wang Wenwen , Han Sen , Shi Kunpeng , Zang Shaoqing , Wu Zhendong , Sha Zhenxia
Published: June 2024

N6-methyladenosine (m6A) is the most prevalent RNA modification and a multifaceted regulator capable of affecting various aspects of mRNA metabolism, thereby playing important roles in numerous physiological processes. However, it is still unknown whether, when, and to what extent m6A modulation are implicated in the immune response of an economically important aquaculture fish, half-smooth tongue sole (Cynoglossus semilaevis). Herein, we systematically profiled and characterized the m6A epitranscriptome and transcriptome inC. semilaevisafter the infection ofVibrio anguillarum, a serious threat to the aquaculture industry. We demonstrated that m6A could be modulated as early as 4-hour post infection (hpi), and the overall intensity of m6A methylation was enhanced following infection. Both conservative and novel motifs were uncovered from the m6A modification sites. Furthermore, differentially m6A methylated genes (DMGs) and differentially expressed genes (DEGs) were identified, and functional enrichment revealed multiple immune-related pathways, especially the FoxO signaling pathway which showed significance in every comparison. Joint analysis highlighted the remarkedly dynamic role of m6A on gene expression, i.e. early on, m6A mainly prioritized the down-regulation of specific genes, and later, it switched gears to promote expression of another set of genes. Moreover, key immune-related genes, includingpdp1,rgs5l, andplk2b, were identified. To our limited knowledge, this is the first study comprehensively characterizing the global m6A atlas in aquaculture fish species. The presented results provide new insights into the dynamics of m6A modifications in the transcriptome of the half-smooth tongue sole following bacterial infection. Further studies are warranted to elucidate the functional significance of these changes and to understand how they affect specific biological processes.