bluuebunny/crossref_metadata_2025 huggingface dataset:
Micronutrient deficiency and supplements in schoolchildren and teenagers
Authors: Berger Mette M. , Shenkin Alan
Published: March 2024

Purpose of review

The essential micronutrients are corner stones in the functional and physical development. Early deficiency has life-long consequences. While awareness about iron deficiency is relatively high, it remains lower for other micronutrients. This review aims at reporting on recent data and attracting attention to the high prevalence of micronutrient deficiencies in school-age and adolescent individuals.

Recent findings

Iron deficiency anaemia remains highly prevalent worldwide and the most frequent deficiency but can be corrected with simple tools ranging from food fortification, nutritional intervention, and to supplements. The link between micronutrient (MN) deficiency and neurobehavioral disorders is increasingly established and is worrying even in Western countries. Paediatric individuals are prone to imbalanced diets and picky eating behaviour, and their diets may then become incomplete: the highest risk for deficiency is observed for iron, zinc and vitamin D.

There is not much new information, but rather confirmation of the importance of health policies. Well conducted randomized controlled trials confirm that deficiencies can be corrected efficiently including with food fortification, and result in clinical benefits. Individual complementation should be considered in children and adolescents with proven deficiency.
Selection of radionuclide(s) for targeted alpha therapy based on their nuclear decay properties
Authors: Ree Samantha M. , Greenwood Howard , Young Jennifer D. , Roberts Rachel , Livens Francis R. , Heath Scott L. , Sosabowski Jane K.
Published: March 2024

Targeted alpha therapy (TAT) is a promising form of oncology treatment utilising alpha-emitting radionuclides that can specifically accumulate at disease sites. The high energy and high linear energy transfer associated with alpha emissions causes localised damage at target sites whilst minimising that to surrounding healthy tissue. The lack of appropriate radionuclides has inhibited research in TAT. The identification of appropriate radionuclides should be primarily a function of the radionuclide’s nuclear decay properties, and not their biochemistry or economic factors since these last two factors can change; however, the nuclear decay properties are fixed to that nuclide. This study has defined and applied a criterion based on nuclear decay properties useful for TAT. This down-selection exercise concluded that the most appropriate radionuclides are: 149Tb, 211At/211Po, 212Pb/212Bi/212Po, 213Bi/213Po, 224Ra, 225Ra/225Ac/221Fr, 226Ac/226Th, 227Th/223Ra/219Rn, 229U, 230U/226Th, and 253Fm, the majority of which have previously been considered for TAT. 229U and 253Fm have been newly identified and could become new radionuclides of interest for TAT, depending on their decay chain progeny.
G protein-coupled receptor 146: new insights from genetics and model systems
Authors: Tharehalli Umesh , Rimbert Antoine
Published: March 2024

Purpose of review

Atherosclerotic cardiovascular diseases continue to be a significant global cause of death. Despite the availability of efficient treatments, there is an ongoing need for innovative strategies to lower lipid levels, especially for individuals experiencing refractory dyslipidemias or intolerable adverse effects. Based on human genetic findings and on mouse studies, the G protein-coupled receptor 146 (GPR146) emerges as a promising target against hypercholesterolemia and atherosclerosis. The present review aims at providing a thorough summary of the latest information acquired regarding GPR146, encompassing genetic evidence, functional insights, and its broader implications for cardiometabolic health.

Recent findings

Human genetic studies uncovered associations between GPR146 variants, plasma lipid levels and metabolic parameters. Additionally, GPR146's influence extends beyond lipid regulation, impacting adipocyte differentiation, lipolysis, and inflammation pathways. Despite GPR146's orphan status, ongoing efforts to deorphanize it, suggest a potential ligand with downstream effects involving Gαi coupling.

Here, we outline and deliberate on recent progress focused on: enhancing comprehension of the effects of inhibiting GPR146 in humans through genetic instruments, evaluating the extra-hepatic functions of GPR146, and discovering its natural ligand(s). Grasping these biological parameters and mechanisms is crucial in the exploration of GPR146 as a prospective therapeutic target.
Efficacy of modified Alvarado score combined with ultrasound in the diagnosis of acute appendicitis: a prospective analytical study
Authors: Sirpaili Santosh , Rajthala Lilamani , Banmala Sabin , Gautam Pratima , Ranabhat Sangita , Ghatani Sangita Raj , Shrestha Eruka
Published: March 2024

Background:

Appendicitis is the most common surgical emergency encountered in the emergency department, and diagnosis is difficult at times. Imaging and various clinical scoring are present to aid in the diagnosis. Ultrasound is an easily accessible modality and can accomplish more than a computed tomography (CT) scan at times. Modified Alvarado score (MAS) includes parameters that do not pose an extra financial burden to the patient. Combining both the imaging and clinical scoring systems, the authors decided to evaluate the combined MAS for the diagnosis of acute appendicitis.

Methods:

This is a prospective analytical study conducted in a tertiary hospital for one and a half years. Fifty-five patients with right lower quadrant pain were enroled, and evaluated along with an ultrasound. MAS and combined MAS were obtained, and the results of the histopathological examination were compared.

Results:

Out of 55 clinically diagnosed cases who underwent an emergency appendectomy, 27 were males and 28 were females. Of these, 50 cases had acute appendicitis as per histopathological examination. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of the MAS was 42%, 100%, 100%, 20.8%, 47.27%, respectively. The sensitivity, specificity, PPV, NPV and accuracy of the USG were 84%, 40%, 93.3%, 20%, and 80%, respectively. Combining both the scores, the Combined MAS had the sensitivity, specificity, PPV, NPV, and accuracy of 98.18%, 0%, 90.7%, 0%, and 89.09%, respectively.

Conclusion:

As the combination of USG has raised the sensitivity and diagnostic accuracy of the MAS, it can be an alternative to CT/MRI imaging for the diagnosis of acute appendicitis in resource-limited settings. This score requires further studies to validate with a larger sample size.
A Conference Designathon to Spark Innovation: Actionable Ideas to Enhance Sexually Transmitted Disease Control
Authors: Tucker Joseph D. , Chikwari Chido Dziva , Tang Weiming , Jarolimova Jana , Gravett Ronnie , Goense Cornelia J.D. , Matoga Mitch M. , Tan Rayner K. J. , Niaupari Steph , Morroni Chelsea , Van Der Pol Barbara
Published: March 2024

Background

Designathons can be used to enhance public health training and spur innovation. A designathon is a 3-stage participatory activity that includes preparation, intensive collaboration, and follow-up activities. We organized a designathon focused on developing actionable sexually transmitted disease (STD) control strategies and examined the content of ideas resulting from an STD designathon.

Methods

For this designathon, we created four groups: early career researchers, silver group (people with >10 years of experience), travelers (people from low- and middle-income countries and those who received a conference scholarship) and a community group. Each group developed its own plan to consult members, iteratively develop ideas, and aggregate insights. Each group developed STD control strategies that were presented. Cross-cutting themes across these ideas were identified.

Results

Designathon participants included a subset of conference participants. Cross-cutting themes from final ideas included cocreating STD interventions with end-users, using sex-positive framing, enhancing open access digital STD resources, and reducing STD stigma. Early career researchers presented a call for community ideas focusing on ending STD epidemics by increasing accessibility to STD care services among all populations. The silver group proposed digital innovations, including an AI-powered tool for testing and treatment and a social game to promote sex positivity. The traveler group conceptualized an information hub to support implementation of STD programs. Community members underscored the importance of a more human-centered approach to STD control, which reduces stigma and normalizes sex and sexual pleasure.

Conclusion

Sex positive campaigns and open access digital resources should be considered within STD programs. Implementation research studies are needed to evaluate these ideas
Biomarker Assessment of a High-Risk, Data-Driven Pediatric Sepsis Phenotype Characterized by Persistent Hypoxemia, Encephalopathy, and Shock
Authors: Atreya Mihir R. , Bennett Tellen D. , Geva Alon , Faustino E. Vincent S. , Rogerson Colin M. , Lutfi Riad , Cvijanovich Natalie Z. , Bigham Michael T. , Nowak Jeffrey , Schwarz Adam J. , Baines Torrey , Haileselassie Bereketeab , Thomas Neal J. , Luo Yuan , Sanchez-Pinto L. Nelson ,   for the Novel Data-Driven Sepsis Phenotypes in Children Study and the Genomics of Pediatric Septic Shock Investigators
Published: March 2024

OBJECTIVES:

Identification of children with sepsis-associated multiple organ dysfunction syndrome (MODS) at risk for poor outcomes remains a challenge. We sought to the determine reproducibility of the data-driven “persistent hypoxemia, encephalopathy, and shock” (PHES) phenotype and determine its association with inflammatory and endothelial biomarkers, as well as biomarker-based pediatric risk strata.

DESIGN:

We retrained and validated a random forest classifier using organ dysfunction subscores in the 2012–2018 electronic health record (EHR) dataset used to derive the PHES phenotype. We used this classifier to assign phenotype membership in a test set consisting of prospectively (2003–2023) enrolled pediatric septic shock patients. We compared profiles of the PERSEVERE family of biomarkers among those with and without the PHES phenotype and determined the association with established biomarker-based mortality and MODS risk strata.

SETTING:

Twenty-five PICUs across the United States.

PATIENTS:

EHR data from 15,246 critically ill patients with sepsis-associated MODS split into derivation and validation sets and 1,270 pediatric septic shock patients in the test set of whom 615 had complete biomarker data.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

The area under the receiver operator characteristic curve of the modified classifier to predict PHES phenotype membership was 0.91 (95% CI, 0.90–0.92) in the EHR validation set. In the test set, PHES phenotype membership was associated with both increased adjusted odds of complicated course (adjusted odds ratio [aOR] 4.1; 95% CI, 3.2–5.4) and 28-day mortality (aOR of 4.8; 95% CI, 3.11–7.25) after controlling for age, severity of illness, and immunocompromised status. Patients belonging to the PHES phenotype were characterized by greater degree of systemic inflammation and endothelial activation, and were more likely to be stratified as high risk based on PERSEVERE biomarkers predictive of death and persistent MODS.

CONCLUSIONS:

The PHES trajectory-based phenotype is reproducible, independently associated with poor clinical outcomes, and overlapped with higher risk strata based on prospectively validated biomarker approaches.
Effects of a Guided Neck-Specific Exercise Therapy on Recovery After a Whiplash
Authors: Muñoz Lazcano Pablo , Rojano Ortega Daniel , Fernández López Isidro
Published: March 2024

Objective

To analyze the effects on pain and disability recovery after a whiplash of a guided neck-specific exercise therapy, compared to a different or an unguided neck-specific exercise therapy.

Design

A literature search was conducted from inception to May 31, 2023, in three electronic databases: PubMed, ScienceDirect, and Web of Science. Eleven randomized controlled trials were included. Meta-analyses were performed with Review Manager software. The standardized mean difference with a 95% confidence interval was used to measure the effect sizes and only short-term time points were considered.

Results

Not all studies reported a significant decrease of pain and disability in the neck-specific exercise group compared to controls. However, meta-analyses demonstrated a significantly greater decrease in neck pain (standardized mean difference: −0.25; 95% confidence interval: [−0.38, −0.12]; P = 0.0002) and neck-disability index (standardized mean difference: −0.35; 95% confidence interval: [−0.54, −0.15]; P = 0.0005) in the neck-specific exercise group.

Conclusions

In addition to the benefits that a guided neck-specific exercise therapy has on motivation and program adherence, it provides greater benefits in pain and disability than a different or unguided neck-specific exercise therapy. Positive results are observed primarily with intervention periods of more than 6 wks and at least two sessions per week.

To Claim CME Credits

Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME

CME Objectives

Upon completion of this article, the reader should be able to: (1) Determine the impact that whiplash-associated disorders have on a patient’s life; (2) Identify and recognize the greater benefits of a supervised exercise therapy on recovery after a whiplash injury; and (3) Differentiate between the different exercise protocols conducted (types of exercises and duration) and incorporate therapy appropriately as part of an effective treatment plan.

Level

Advanced

Accreditation

The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Association of Academic Physiatrists designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.
Unusual Sites of Visceral Spread in Prostate Cancer: A Prostate-Specific Membrane Antigen–Based Theranostic Imaging Series
Authors: Aggarwal Piyush , Sood Ashwani , Kumar Rajender , Singh Harmandeep , Singh Harpreet , Bhatia Vikas , Mittal Bhagwant Rai
Published: March 2024

Prostate cancer commonly metastasizes to lymphatic and skeletal systems with lesser frequency to visceral organs; however, uncommon visceral sites have also been found and reported as case reports. We present a series of uncommon metastatic visceral spread in prostate cancer on prostate-specific membrane antigen–based diagnostic and posttherapeutic imaging modalities.
Application Value of 68Ga-FAPI PET/CT in the Evaluation of Myelofibrotic Diseases
Authors: Liu Ya , Li Xue , Jing Li , Guo Chunmei , Wan Zibei , Zhang Feiyu , Wu Pengqiang , Huang Zhanwen
Published: March 2024

Purpose

Fibroblast activation protein is highly expressed in neoplastic lesions and various fibrotic tissues, making it an attractive target for disease evaluation. 68Ga-labeled fibroblast activation protein inhibitor (FAPI), a new tumor interstitial imaging agent, holds promise for evaluating myelofibrosis. Therefore, this study aimed to use 68Ga-FAPI PET/CT for the noninvasive visualization and quantification of the extent of myelofibrosis.

Patients and Methods

This was a prospective clinical study involving 22 patients with myelofibrosis who underwent 68Ga-FAPI PET/CT. The uptake of 68Ga-FAPI was measured in their respective bone marrow and spleen, and the obtained imaging findings were compared with laboratory, cytogenetic, and histopathological data.

Results

68Ga-FAPI uptake in the bone marrow was significantly and positively correlated with the myelofibrosis grade (r > 0.8, P < 0.001). 68Ga-FAPI PET/CT showed visually negative results in patients with grades 0–1 myelofibrosis and positive in those with grades 2–3, but the level of involvement varied. 68Ga-FAPI PET/CT provides a noninvasive means of visualizing the extent of systemic bone marrow involvement and differentiation between the early and advanced stages of fibrosis.

Conclusions

68Ga-FAPI PET/CT shows promise as a method for visualizing and quantifying myelofibrosis, providing suitable sites for bone marrow biopsy. The extent of 68Ga-FAPI uptake by bone marrow increases with the progression of myelofibrosis, thus it is a simple and noninvasive measurement that can be used to evaluate the progression of myelofibrosis. Nevertheless, although 68Ga-FAPI PET/CT has demonstrated a potential value in prognostic assessment, further confirmation is needed.
68Ga-DOTA–Ibandronic Acid PET/CT in a Patient With Chemotherapy-Induced Salivary Gland Hypofunction
Authors: Liu Ya , Ding Haoyuan , Zhang Ting , Chen Yue , Huang Zhanwen
Published: March 2024

DOTA–ibandronic acid (IBA) is a novel precursor targeting bone metastasis. It can be radiolabeled with 68Ga for the diagnosis of bone metastases. However, extraosseous lesions can also show increased DOTA-IBA uptake. We report the 68Ga-DOTA-IBA PET/CT findings in a case with cholangiocarcinoma with multiple bone metastases. 68Ga-DOTA-IBA PET/CT revealed increased uptake of DOTA-IBA in bone metastases. Besides, symmetrical and diffuse increased DOTA-IBA uptake in bilateral salivary glands was observed. 99mTcO4
− salivary gland scintigraphy showed impaired salivary gland function.
Extravasation After [177Lu]Lu-HA-DOTATATE Therapy
Authors: de Vries-Huizing Daphne M. V. , Cheung Zing J. , Hendrikx Jeroen J. M. A. , Donswijk Maarten L. , Versleijen Michelle W. J.
Published: March 2024

Extravasation of the radiopharmaceutical during peptide receptor radionuclide therapy infusion is an unwanted infrequently reported event. We present the case of a 74-year old woman with a neuroendocrine tumor who was referred for peptide receptor radionuclide therapy. During intravenous infusion of 7.4 GBq [177Lu]Lu-HA-DOTATATE in the upper right arm, extravasation of the radiopharmaceutical occurred through a displaced intravenous catheter. Planar scintigraphy showed pooling of radioactivity in the right upper arm. After 24 hours, the swelling in the arm was decreased; however, erythema was increased. One week later, symptoms had disappeared, and the patient did not experience any complications during follow-up of 11 months.
Dominance of Tau Burden in Cortical Over Subcortical Regions Mediates Glymphatic Activity and Clinical Severity in PSP
Authors: Hsu Jung-Lung , Wei Yi-Chia , Hsiao Ing-Tsung , Lin Kun-Ju , Yen Tzu-Chen , Lu Chin-Song , Wang Han-Cheng , Leemans Alexander , Weng Yi-Hsin , Huang Kuo-Lun
Published: March 2024

Background

Progressive supranuclear palsy (PSP) is a tauopathy that involves subcortical regions but also extends to cortical areas. The clinical impact of different tau protein sites and their influence on glymphatic dysfunction have not been investigated.

Patients and Methods

Participants (n = 55; 65.6 ± 7.1 years; 29 women) with PSP (n = 32) and age-matched normal controls (NCs; n = 23) underwent 18F-Florzolotau tau PET, MRI, PSP Rating Scale (PSPRS), and Mini-Mental State Examination. Cerebellar gray matter (GM) and parametric estimation of reference signal intensity were used as references for tau burden measured by SUV ratios. Glymphatic activity was measured by diffusion tensor image analysis along the perivascular space (DTI-ALPS).

Results

Parametric estimation of reference signal intensity is a better reference than cerebellar GM to distinguish tau burden between PSP and NCs. PSP patients showed higher cortical and subcortical tau SUV ratios than NCs (P < 0.001 and <0.001). Cortical and subcortical tau deposition correlated with PSPRS, UPDRS, and Mini-Mental State Examination scores (all P’s < 0.05). Cortical tau deposition was further associated with the DTI-ALPS index and frontal-temporal-parietal GM atrophy. The DTI-ALPS indexes showed a significantly negative correlation with the PSPRS total scores (P < 0.01). Finally, parietal and occipital lobe tau depositions showed mediating effects between the DTI-ALPS index and PSPRS score.

Conclusions

Cortical tau deposition is associated with glymphatic dysfunction and plays a role in mediating glymphatic dysfunction and clinical severity. Our results provide a possible explanation for the worsening of clinical severity in patients with PSP.
177Lu-FAP-2286 Therapy in a Metastatic Bone Malignant Solitary Fibrous Tumor
Authors: Yang Hongyu , Liu Huipan , Li Hongmei , Zhang Yu , Chen Yue
Published: March 2024

A 57-year-old woman with a metastatic bone malignant solitary fibrous tumor received 177Lu-FAP-2286 therapy. After 1 treatment cycle, 68Ga-FAP-2286 PET/CT revealed remission of the lesions. Moreover, the patient did not report any adverse effects.
Variation in Defining Retention After Onabotulinum Toxin A for Overactive Bladder: A Systematic Review
Authors: Castaneda Peris R. , Chen Andrew , Kuhlmann Paige , Anger Jennifer T. , Eilber Karyn S.
Published: March 2024

Importance

Urinary retention is a common adverse effect after intravesical injection of onabotulinum toxin A (BTX) for overactive bladder (OAB). Reported retention rates range from 1.6% to more than 40%. This variation may be due to varying definitions of retention in the literature.

Objective

We aimed to assess the variation in definitions of urinary retention across studies of BTX for the treatment of OAB.

Study Design

We performed a systematic review of studies of BTX for OAB by querying MEDLINE and EMBASE according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We included original research studies on adults with overactive bladder treated with BTX and urinary retention reported as an outcome from January 2000 to December 2020.

Results

From 954 results, we identified 53 articles that met inclusion criteria. There were 6 definitions for urinary retention. The majority of studies (60.4%) reported initiating clean intermittent catheterization (CIC) as the metric for retention. Five (9.5%) studies provided no definition despite reporting retention as an adverse event. Twenty studies (37.7%) specified a postvoid residual volume (PVR) threshold for initiating CIC in asymptomatic patients; 19 (35.8%) specified a PVR threshold for CIC in symptomatic patients. The PVR thresholds ranged from 100 to 400 mL. Twenty-three studies (43.4%) did not address asymptomatic elevation of PVR, and 22 (41.5%) did not address how symptomatic patients were managed.

Conclusions

Urinary retention after BTX injection is inconsistently defined in the literature. Lack of standardization in reporting retention after intravesical BTX prevents accurate assessment of the risk of urinary retention and comparison of outcomes between studies.
Pilot Study of a Digital Behavioral Therapy for Overactive Bladder in Women
Authors: Sooknarine Celine , Farrell Sylvia , Sarma Susmita , Salameh Fadi , Burke Naomi , Staunton Brendan , Carr Emma , Sexton K. , Agnew Gerry , Downey Andrew , D'Arcy Francis , Cundiff Geoffrey W.
Published: March 2024

Importance

The burden and high prevalence of overactive bladder (OAB) underline the urgent need for effective treatment. This study provides an initial look at an alternative approach to behavioral therapy for overactive bladder (OAB) that is delivered as an app on a smartphone.

Objective

This study aimed to investigate feasibility, acceptability, and preliminary efficacy of a digital therapeutic for OAB.

Study Design

This was a multicentered prospective pilot study. We used a convenience sample (N = 30) from waiting lists of women referred for incontinence, excluding urinary tract infections, urinary retention, bladder pain syndrome, pelvic cancer, current pregnancy, kidney disease, dementia, stroke, and prior neuromodulation. The intervention, a smartphone app, provided an 8-week program with weekly modules combining evidence-based knowledge videos and skill-building exercises that incorporated behavioral therapy, cognitive behavioral therapy, pelvic muscle training, and general health information. Combined scores on the International Consultation on Incontinence Questionnaire was the primary outcome measure. Secondary outcomes included improvement in quality of life, based on International Consultation on Incontinence Questionnaire, a 72-hour urinary diary, and Patient Global Impression of Improvement. We evaluated usability with the Mobile Application Rating Scale. Statistical tests included Shapiro-Wilk tests and paired-sample t tests.

Results

Overall, 100% of participants reported a reduction in their OAB symptoms and 82% reported an improvement in quality of life. There was a significant improvement in diary parameters, including frequency (10.19–6.71 a day: SD, 1.25; P = 0.017) and incontinence (10–3.57: SD, 4.58). Participants rated the app highly on functionality, and 70% would recommend it. Patient Global Impression of Improvement improved for 69% of participants.

Conclusions

This study supports the application of a digital platform to over-come the real-world barriers for first-line treatment for OAB and offers information to inform further evaluation of the safety and efficacy of the NUIG OAB App.
Beta bursts in the parkinsonian cortico-basal ganglia network form spatially discrete ensembles
Authors: Grennan Isaac , Mallet Nicolas , Magill Peter J. , Cagnan Hayriye , Sharott Andrew
Published: March 2024

Defining spatial synchronization of pathological beta oscillations is important, given that many theories linking them to parkinsonian symptoms propose a reduction in the dimensionality of the coding space within and/or across cortico-basal ganglia structures. Such spatial synchronization could arise from a single process, with widespread entrainment of neurons to the same oscillation. Alternatively, the partially segregated structure of cortico-basal ganglia loops could provide a substrate for multiple ensembles that are independently synchronized at beta frequencies. Addressing this question requires an analytical approach that identifiesgroupsof signals with a statistical tendency for beta synchronisation, which is unachievable using standard pairwise measures. Here, we utilized such an approach on multichannel recordings of background unit activity (BUA) in the external globus pallidus (GP) and subthalamic nucleus (STN) in parkinsonian rats. We employed an adapted version of a principle and independent component analysis-based method commonly used to define assemblies of single neurons (i.e., neurons that are synchronized over short timescales). This analysis enabled us to define whether changes in the power of beta oscillations in local ensembles of neurons (i.e., the BUA recorded from single contacts) consistently covaried over time, forming a “beta ensemble”. Multiple beta ensembles were often present in single recordings and could span brain structures. Membership of a beta ensemble predicted significantly higher levels of short latency (<5ms) synchrony in the raw BUA signal and phase synchronization with cortical beta oscillations, suggesting that they comprised clusters of neurons that are functionally connected at multiple levels, despite sometimes being non-contiguous in space. Overall, these findings suggest that beta oscillations do not comprise a single synchronization process, but rather multiple independent activities that can bind both spatially contiguous and non-contiguous pools of neurons within and across structures. As previously proposed, such ensembles provide a substrate for beta oscillations to constrain the coding space of cortico-basal ganglia circuits.
zIncubascope: long-term quantitative imaging of multi-cellular assemblies inside an incubator
Authors: Jana Anirban , Mekhlieri Naveen , Boyreau Adeline , Bazin Aymerick , Pujol Nadège , Alessandri Kevin , Recher Gaëlle , Nassoy Pierre , Badon Amaury
Published: March 2024

Recent advances in bioengineering have made it possible to develop increasingly complex biological systems to recapitulate organ functions as closely as possiblein vitro. Monitoring the assembly and growth of multi-cellular aggregates, micro-tissues or organoids and extracting quantitative information is a crucial but challenging task required to decipher the underlying morphogenetic mechanisms. We present here an imaging platform designed to be accommodated inside an incubator which provides high-throughput monitoring of cell assemblies over days and weeks. We exemplify the capabilities of our system by investigating human induced pluripotent stem cells (hiPSCs) enclosed in spherical capsules, hiPSCs in tubular capsules and yeast cells in spherical capsules. Combined with a customized pipeline of image analysis, our solution provides insight into the impact of confinement on the morphogenesis of these self-organized systems.
The neural dynamics of positive and negative expectations of pain
Authors: Wittkamp Christoph A. , Wolf Maren-Isabel , Rose Michael
Published: March 2024

Pain is heavily modulated by expectations. Whereas the integration of expectations with sensory information has been examined in some detail, little is known about how positive and negative expectations are generated and their neural dynamics from generation over anticipation to the integration with sensory information. The present preregistered study employed a novel paradigm to induce positive and negative expectations on a trial-by-trial basis and examined the neural mechanisms using combined EEG-fMRI measurements (n=50). We observed substantially different neural representations between the anticipatory and the actual pain period. In the anticipation phase i.e., before the nociceptive input, the insular cortex, dorsolateral prefrontal cortex (DLPFC), and anterior cingulate cortex (ACC) showed increased activity for directed expectations regardless of their valence. Interestingly, a differentiation between positive and negative expectations within the majority of areas only occurred after the arrival of nociceptive information. FMRI-informed EEG analyses could reliably track the temporal sequence of processing showing an early effect in the DLPFC, followed by the anterior insula and late effects in the ACC. The observed effects indicate the involvement of different expectation-related subprocesses, including the transformation of visual information into a value signal that is maintained and differentiated according to its valence only during stimulus processing.
De Novo TranscriptomeAnalysis Reveals Novel Insights into Secondary Metabolite Biosynthesis inTylophora indica(Burm. f) Merrill
Authors: Gupta Anamika , Singh Deeksha , Ranjan Rajiv
Published: March 2024

Tylophora indicahas been widely recognized for its therapeutic properties in traditional Indian medicine. Although its bioactive compounds are used extensively to treat a wide range of ailments, a comprehensive understanding of their genetic basis remains limited. In this study, we conducted a transcriptomic analysis ofT indicaleaf and root using the Illumina platform. High-quality RNA was isolated, and cDNA libraries were constructed for sequencing, generating4.67 GB and5.51 GB of data for leaf and root samples, respectively. 72,795 unigenes and 24,470 coding sequences (CDS) were predicted based on de novo assembly of reads, revealing a complex transcriptome landscape. Functional annotation and pathway analysis revealed biological processes and pathways associated withT indica. Based on the Gene Ontology (GO) mapping, the CDS was categorized into biological processes, cellular components, and molecular functions. An analysis of pathways using the KEGG database revealed involvement in critical metabolic pathways. Furthermore, SSRs contributed to the understanding of genetic diversity by identifying simple sequence repeats. In addition, differential gene expression analysis identified genes involved in secondary metabolite synthesis, among other physiological processes. The qRT-PCR validation of selected genes confirmed their differential expression profiles, with roots exhibiting higher expression than leaves. In this study, transcriptomics is conducted for the first time forT indica, which may be useful for future molecular research. The detailed findings help us understandT indica’sbiology, which can be used in biotechnology, and they also show how important it is to protect this species because it is used in medicine.
The Molecular Basis for Hydrodynamic Properties of PEGylated Human Serum Albumin
Authors: Fleming Patrick J. , Correia John J. , Fleming Karen G.
Published: March 2024

Polyethylene glycol conjugation provides a protective modification that enhances the pharmacokinetics and solubility of proteins for therapeutic use. A knowledge of the structural ensemble of these PEGylated proteins is necessary to understand the molecular details that contribute to their hydrodynamic and colligative properties. Because of the large size and dynamic flexibility of pharmaceutically important PEGylated proteins, the determination of structure is challenging. Here we demonstrate that structural ensembles, generated by coarse-grained simulations, can be analyzed with HullRad and used to predict sedimentation coefficients and concentration dependent hydrodynamic and diffusion nonideality coefficients of PEGylated proteins. A knowledge of these properties enhances the ability to design and analyze new modified protein therapeutics.

STATEMENT OF SIGNIFICANCE

Proteins constitute a growing class of biotherapeutics. Chemical modification(s) with inert polymers are known to enhance the serum half-life and formulation of these biological therapeutics but the effects of modification on protein-protein interactions in solution have been difficult to predict. Here we describe methods for predicting the molecular basis for the hydrodynamic properties of polymer conjugated proteins that determine their solution behavior.
Introducing CHiDO – a No Code Genomic Prediction Software implementation for the Characterization & Integration of Driven Omics
Authors: González Francisco , García-Abadillo Julián , Jarquín Diego
Published: March 2024

Climate change represents a significant challenge to global food security by altering environmental conditions critical to crop growth. Plant breeders can play a key role in mitigating these challenges by developing more resilient crop varieties; however, these efforts require significant investments in resources and time. In response, it is imperative to use current technologies that assimilate large biological and environmental datasets into predictive models to accelerate the research, development, and release of new improved varieties. Leveraging large and diverse data sets can improve the characterization of phenotypic responses due to environmental stimuli and genomic pulses. A better characterization of these signals holds the potential to enhance our ability to predict trait performance under changes in weather and/or soil conditions with high precision. This paper introduces CHiDO, an easy-to-use, no-code platform designed to integrate diverse omics datasets and effectively model their interactions. With its flexibility to integrate and process data sets, CHiDO’s intuitive interface allows users to explore historical data, formulate hypotheses, and optimize data collection strategies for future scenarios. The platform’s mission emphasizes global accessibility, democratizing statistical solutions for situations where professional ability in data processing and data analysis is not available.

Core ideas

The authors developed CHiDO, a platform for breeders to build predictive models integrating multi-omics data.

CHiDO is a no-code tool that leverages the reaction norm model proposed by Jarquin et al. (2014).

The platform aims to increase access to predictive analytics lowering relevant technical and financial barriers.
A model of task-level human stepping regulation yields semistable walking
Authors: Patil Navendu S. , Dingwell Jonathan B. , Cusumano Joseph P.
Published: March 2024

A simple lateral dynamic walker, with swing leg dynamics and three adjustable input parameters, is used to study how motor regulation affects frontal plane stepping. Motivated by experimental observations and phenomenological models, we imposed task-level multiobjective regulation targeting the walker’s optimal lateral foot placement at each step. The regulator prioritizes achieving step width and lateral body position goals to varying degrees by choosing a mixture parameter. Our model thus integrates a lateralmechanical template, which captures fundamental mechanics of frontal-plane walking, with a lateralmotor regulation template, an empirically verified model of how humans manipulate lateral foot placements in a goal-directed manner. The model captures experimentally observed stepping fluctuation statistics and demonstrates how linear empirical models of stepping dynamics can emerge from first-principles nonlinear mechanics. We find that task-level regulation gives rise to a goal equivalent manifold in the system’s extended state space of mechanical states and inputs, a subset of which contains a continuum of period-1 gaits forming asemistableset: perturbations off of any of its gaits result in transients that return to the set, though typically to different gaits.
Maximum Likelihood Inference of Time-scaled Cell Lineage Trees with Mixed-type Missing Data
Authors: Mai Uyen , Chu Gillian , Raphael Benjamin J.
Published: March 2024

Recent dynamic lineage tracing technologies combine CRISPR-based genome editing with single-cell sequencing to track cell divisions during development. A key computational problem in dynamic lineage tracing is to infer a cell lineage tree from the measured CRISPR-induced mutations. Three features of dynamic lineage tracing data distinguish this problem from standard phylogenetic tree inference. First, the CRISPR-editing process modifies a genomic location exactly once. Thisnon-modifiableproperty is not well described by the time-reversible models commonly used in phylogenetics. Second, as a consequence of non-modifiability, the number of mutations per time unit decreases over time. Third, CRISPR-based genome-editing and single-cell sequencing results in high rates of both heritable and non-heritable (dropout) missing data. To model these features, we introduce the Probabilistic Mixed-type Missing (PMM) model. We describe an algorithm, LAML (Lineage Analysis via Maximum Likelihood), to search for the maximum likelihood (ML) tree under the PMM model. LAML combines an Expectation Maximization (EM) algorithm with a heuristic tree search to jointly estimate tree topology, branch lengths and missing data parameters. We derive a closed-form solution for the M-step in the case of no heritable missing data, and a block coordinate ascent approach in the general case which is more efficient than the standard General Time Reversible (GTR) phylogenetic model. On simulated data, LAML infers more accurate tree topologies and branch lengths than existing methods, with greater advantages on datasets with higher ratios of heritable to non-heritable missing data. We show that LAML provides unbiasedtime-scaledestimates of branch lengths. In contrast, we demonstrate that maximum parsimony methods for lineage tracing data not only underestimate branch lengths, but also yield branch lengths which are not proportional to time, due to the nonlinear decay in the number of mutations on branches further from the root. On lineage tracing data from a mouse model of lung adenocarcinoma, we show that LAML infers phylogenetic distances that are more concordant with gene expression data compared to distances derived from maximum parsimony. The LAML tree topology is more plausible than existing published trees, with fewer total cell migrations between distant metastases and fewer reseeding events where cells migrate back to the primary tumor. Crucially, we identify three distinct time epochs of metastasis progression, which includes a burst of metastasis events to various anatomical sites during a single month.

Software

https://github.com/raphael-group/LAML

Data availability

https://github.com/raphael-group/laml-experiments
T cell polarization and NFAT translocation are stiffness-dependent and are differentially regulated by Piezo1 and Orai1
Authors: Zhao Renping , Zhang Jingnan , Schwarz Eva C. , del Campo Aránzazu , Hoth Markus , Qu Bin
Published: March 2024

Effective T cell responses against tumor cells require diverse effector functions including polarization towards tumor cells to form immunological synapses and nuclear factor of activated T-cells (NFAT)-dependent gene transcription. While the role of tumor cell softening has been associated with malignancy, stemness, and metastasis, potentially contributing to immune evasion, its impact on cellular processes in T cells is not well understood. Here, we show that both T cell polarization and NFAT nuclear translocation are modulated by target stiffness in a Ca2+ dependent manner. Using both anti-CD3 antibody-functionalized substrates with varying stiffness as surrogates for target cells or softened tumor cells, we found that both, reorientation of microtubule organizing center (MTOC) towards the tumor cells, a hallmark for T cell polarization, and NFAT translocation were impaired on softer hydrogels or following contact with softer cancer cells. The amplitudes of intracellular Ca2+ signals were dependent on stiffness, and removal of extracellular Ca2+ inhibited stiffness-dependent T cell responsiveness. While stiffness-dependent Ca2+ signaling was crucial for both, T cell polarization and NFAT translocation, Ca2+ influx through Piezo1, a mechanosensitive ion channel, mediated stiffness-dependent MTOC reorientation but not NFAT translocation. In contrast, Ca2+ influx through store-operated Orai channels mediated NFAT translocation but not MTOC reorientation. Our results demonstrate that tumor cell stiffness directly influences T cell functionality through distinct Ca2+ influx pathways, revealing cell softening as an essential mechanism employed by malignant cells to evade immune surveillance.
The activation ofChlamydomonas reinhardtiialpha amylase 2 by glutamine requires its N-terminal ACT domain
Authors: Scholtysek Lisa , Poetsch Ansgar , Hofmann Eckhard , Hemschemeier Anja
Published: March 2024

The coordination of assimilation pathways for all the elements that make up cellular components is a vital task for every organism. Integrating the assimilation and use of carbon (C) and nitrogen (N) is of particular importance because of the high cellular abundance of these elements. Starch is one of the most important storage polymers of photosynthetic organisms, and a complex regulatory network ensures that biosynthesis and degradation of starch are coordinated with photosynthetic activity and growth. Here, we analyzed three starch metabolism enzymes ofChlamydomonas reinhardtiithat we captured by a cyclic guanosine monophosphate-(cGMP-) affinity chromatography approach, namely soluble starch synthase STA3, starch branching enzyme SBE1 and α-amylase AMA2. While none of the recombinant enzymes was directly affected by the presence of cGMP or other nucleotides, suggesting an indirect binding to cGMP, AMA2 activity was stimulated in the presence of L-glutamine (Gln). This activating effect required the enzyme’s N-terminal aspartate kinase–chorismate mutase– tyrA (ACT) domain. Gln is the first N assimilation product and not only a central compound for the biosynthesis of N-containing molecules, but also a recognized signaling molecule for the N status. Our observation suggests that AMA2 might be a means to coordinate N- and C metabolism at the enzymatic level, increasing the liberation of C-skeletons from starch when high Gln levels signal an abundance of assimilated N.
The strength of sexual signals predicts same-sex paring in termites
Authors: Mizumoto Nobuaki , Lee Sang-Bin , Chouvenc Thomas
Published: March 2024

Same-sex sexual behavior (SSB) is an enigma in behavioral ecology as it does not result in reproduction. Proximately, the evolution of sexual signals is critical for the evolution of SSB in a sex-specific manner. For signal receivers, the loss of sexual signals leads to smaller phenotypic sex differences, leading to frequent accidental SSB between receivers. Alternatively, for senders, sexual signals could help locate another sender, enhancing intentional SSB as in heterosexual pairing. Here, we demonstrate this link between sex pheromone signaling and the frequency of same-sex pairing in twoCoptotermestermites that use the same chemical as sex pheromones but in different quantities. In termites, mating pairs engage in tandem runs, where a male follows a female with sex pheromones. We found that female-female tandems were more stable inC. formosanus,whose females produce more pheromones, while the male-male interactions were more frequent inC. gestroi, whose females produce fewer pheromones. Thus, stronger pheromones lead to sender-sender SSB, while weaker pheromones lead to receiver-receiver SSB. In both species, same-sex tandems were less stable than heterosexual tandems, contrasting withReticulitermes, another termite group that shows frequent same-sex tandems. The proximate mechanism of SSB is diverse, reflecting the heterosexual context.
Supramolecular complexes of GCAP1: towards the development of effective biologics for inherited retinal dystrophies
Authors: Biasi A. , Marino V. , Dal Cortivo G. , Dell’Orco D.
Published: March 2024

Guanylate Cyclase Activating Protein 1 (GCAP1) is a neuronal Ca2+-sensor protein expressed in photoreceptors where it regulates the enzymatic activity of retinal Guanylate Cyclase 1 (GC1) in a Ca2+-dependent manner. Recently, over 20 missense mutations inGUCA1A(encoding for GCAP1) have been associated with inherited autosomal dominant retinal diseases, namely cone dystrophy (COD) and cone-rod dystrophy (CORD). Since GCAP1 is known to be a functional dimer, COD/CORD patients present a heterogeneous pool of GCAP1 assemblies constituted by wild-type and mutated homodimers and heterodimers. Here, we present an integratedin silicoand biochemical investigation on the effects of the E111V substitution, associated with a severe form of CORD, on GCAP1 homo- and hetero-dimerization. Despite inducing a constitutive activation of GC1 due to impaired Ca2+-binding in the high-affinity EF-hand 3 motif, the E111V substitution did not affect either the homo- or the hetero dimerization process as clearly highlighted by aSEC and molecular docking experiments. Indeed, both variants exhibited micromolar monomer-dimer equilibrium constants in the presence of both Mg2+and Ca2++, indicating that at physiological cellular concentrations both variants are predominantly monomers under Ca2+-loaded and, to a lesser extent, Mg2+-loaded conditions. Molecular docking and dynamics simulations confirmed chromatographic results highlighting slight alterations in free energy of binding involving the pathogenic E111V variant in the Ca2+-bound state and increased mobility over time affecting the Ca2+-coordinating EF3 motif. In addition, to evaluate possible therapeutic approaches, the regulation of the catalytic activity of GC1 by WT and E111V-GCAP1 was studied in the presence of retinal degeneration protein 3 (RD3), an α-helical protein that strongly inhibits GC1, and a RD3-derived peptide (RD3ppt) which encompasses a region of RD3 that is essential for its inhibitory activity. GC1 activity assays in the presence of RD3ppt suggest that the enzymatic activity is partially inhibited by the peptide at low micromolar concentrations when GCAP1 variants are present. The incomplete shut down of GC1 by RD3 could be explained by the interaction occurring between RD3 and GCAP1, known to form a complex with GC1 in the endoplasmic reticulum. This fundamental interaction was here investigated spectroscopically andin silico, unveiling major structural rearrangements upon complex formation. Interestingly, the full RD3 protein was able to better modulate GC1 activity and restore the abnormal cGMP production induced by the pathogenic E111V-GCAP1 variant to a physiological level.