bluuebunny/crossref_metadata_2025 huggingface dataset:
The physiological and clinical-behavioral effects of HRV biofeedback in adolescents with autism: a pilot randomized controlled trial
Authors: Thoen Anoushka , Alaerts Kaat , Prinsen Jellina , Steyaert Jean , Van Damme Tine
Published: June 2023

Background

Adolescents with autism present lower levels of cardiac vagal modulation in comparison to typically developing peers. These lower values are also associated with psychosocial and behavioral problems. Heart Rate Variability Biofeedback (HRVB) was therefore suggested as an interesting avenue for further exploration since it focusses on the up-regulation of cardiac vagal modulation and has demonstrated positive effects on mental health outcomes. However, scarce evidence was present regarding the effectiveness of HRVB in this population. It was hypothesized that HRVB would increase the level of cardiac vagal modulation in adolescents with autism which would result in positive effects on physiological outcome measures and psychosocial parameters. Furthermore, it was hypothesized that a home-based, non-supervised HRVB training would be feasible in this population.

Methods

A single-blind, randomized sham-controlled pilot trial was used. During the initial single-blind phase, adolescents with autism performed supervised HRVB (n=24) or a sham training (n=20) for five weeks with one guided session per week and home-based practice (20 min) on the remaining days. In the subsequent follow-up period of five weeks, half of the adolescents of each group received HRVB training at home, in a non-supervised manner, whereas the other subset did not practice during that period. A combination of physiological, cortisol and behavioral data was collected during standardized stress-provoking assessments before (T0) and after each training period (T1 and T2).

Results

Supervised HRVB resulted in a late increase in cardiac vagal modulation in adolescents with autism. Heart rate increased and cortisol decreased significantly immediately after the supervised HRVB training, but none of these effects remained after the follow-up period of five weeks. None of the outcome measures on psychosocial functioning and self-reported stress revealed a significant change following the supervised HRVB training. The home-based HRVB training was feasible in this population but with a significant decrease in compliance rate. However, adolescents reported significantly lower symptoms of stress after this training period, regardless of the prior training (sham or HRVB).

Conclusion

HRVB is feasible and effective in adolescents with autism as demonstrated by late-emerging increases in cardiac vagal modulation and less self-reported symptoms of stress. Researchers are encouraged to replicate this study with a larger sample size and to further explore the possible working mechanisms of HRVB.
The Use of the Integrated Cognitive Assessment (ICA) to Improve the Efficiency of Primary Care Referrals to Memory Services in the Accelerating Dementia Pathway Technologies (ADePT) Study
Authors: Modarres Mohammad Hadi , Kalafatis Chris , Apostolou Panos , Tabet Naji , Khaligh-Razavi Seyed-Mahdi
Published: June 2023

Background

Current primary care cognitive assessment tools are either crude or time-consuming instruments that can only detect cognitive impairment when it is well established. This leads to unnecessary or late referrals to memory services, by which time the disease may have already progressed into more severe stages.

Due to the COVID-19 pandemic, some memory services have adapted to the new environment by shifting to remote assessments of patients to meet service user demand. However, the use of remote cognitive assessments has been inconsistent, and there has been little evaluation of the outcome of such a change in clinical practice.

Emerging research has highlighted computerised cognitive tests, such as the Integrated Cognitive Assessment (ICA), as the leading candidates for adoption in clinical practice. This is true both during the pandemic and in the post-COVID-19 era as part of healthcare innovation.

Objectives

The Accelerating Dementias Pathways Technologies (ADePT) Study was initiated in order to address this challenge and develop a real-world evidence basis to support the adoption of ICA as an inexpensive screening tool for the detection of cognitive impairment and improving the efficiency of the dementia care pathway.

Methods

Ninety-nine patients aged 55-90 who have been referred to a memory clinic by a general practitioner (GP) were recruited. Participants completed the ICA either at home or in the clinic along with medical history and usability questionnaires. The GP referral and ICA outcome were compared with the specialist diagnosis obtained at the memory clinic.

Participants were given the option to carry out a retest visit where they were again given the chance to take the ICA test either remotely or face-to-face.

Results

The primary outcome of the study compared GP referral with specialist diagnosis of MCI/dementia. Of those the GP referred to memory clinics, 78% were necessary referrals, with ∼22% unnecessary referrals, or patients who should have been referred to other services as they had disorders other than MCI/dementia. In the same population the ICA was able to correctly identify cognitive impairment in ∼90% of patients, with approximately 9% of patients being false negatives. From the subset of unnecessary GP referrals, the ICA classified ∼72% of those as not having cognitive impairment, suggesting that these unnecessary referrals may not have been made if the ICA was in use.

Conclusions

The results from this study demonstrate the potential of the ICA as a screening tool, which can be used to support accurate referrals from primary care settings, along with the work conducted in memory clinics and in secondary care.
Retinal Vascular Parameters and Risk of Heart Failure
Authors: Wu Yuting , Wang Yueye , Chen Qi , Wang Ruobing , He Mingguang , Shi Danli
Published: June 2023

Aim

To investigate the association of retinal vascular parameters (calibre, tortuosity, fractal dimension and the number of segments) with incident heart failure (HF) in the UK Biobank.

Methods

Participants with fundus images in UK Biobank were included. Retinal vascular parameters were assessed by an artificial intelligence system (RMHAS). Incident HF events were determined by hospital inpatient data, death register records and self-reported medical condition. Cox proportional hazards regression models (CPH) were used to investigate the links between retinal vascular variables and the risk of HF.

Results

We included 56470 individuals. After a median of 10.95-year follow-up, 1062 incident HF events were reported. After adjusting for conventional HF risk factors in CPH, we found larger retinal venular calibre (hazard ratio [HR], 1.54; 95% confidence interval [CI], 1.12-2.14), smaller arteriolar fractal dimension (HR, 1.98; 95% CI, 1.38-2.85), smaller venular fractal dimension (HR, 1.52; 95% CI, 1.09-2.13), the smaller number of arteriolar segments (HR, 2.18; 95% CI, 1.47-3.24) and the smaller number of venular segments (HR, 1.85; 95% CI, 1.29-2.64) were linked to an increased risk of HF. The addition of retinal vessel measurements to traditional HF risk factors increased the discrimination capability for predicting future HF, with C statistics changing from 0.799 to 0.813.

Conclusions

Wider retinal venular calibre, lower vascular fractal dimension and a smaller number of vessel segments were associated with a higher risk of incident HF events. These results point to the potential application of using early retinal vasculature changes to identify people at higher risk of HF.
Human subcutaneous adipose tissue variability is driven by VEGFA, ACTA2, adipocyte density, and ancestral history of the patient
Authors: DeBari Megan K , Johnston Elizabeth K , Scott Jacqueline V , Ilzuka Erica , Sun Wenhuan , Webster-Wood Victoria A , Abbott Rosalyn D
Published: June 2023

Adipose tissue is a dynamic regulatory organ that has profound effects on the overall health of patients. Unfortunately, inconsistencies in human adipose tissues are extensive and multifactorial including large variability in cellular sizes, lipid content, inflammation, extracellular matrix components, mechanics, and cytokines secreted. Given the high human variability, and since much of what is known about adipose tissue is from animal models, we sought to establish correlations and patterns between biological, mechanical, and epidemiological properties of human adipose tissues. To do this, twenty-six independent variables were cataloged for twenty patients that included patient demographics and factors that drive health, obesity, and fibrosis. A factorial analysis for mixed data (FAMD) was used to analyze patterns in the dataset (with BMI > 25) and a correlation matrix was used to identify interactions between quantitative variables. Vascular endothelial growth factor A (VEGFA) and actin alpha 2, smooth muscle (ACTA2) gene expression were the highest loading in the first two dimensions of the FAMD. The number of adipocytes was also a key driver of patient-related differences, where a decrease in the density of adipocytes was associated with aging. Aging was also correlated with a decrease in overall lipid percentage of subcutaneous tissue (with lipid deposition being favored extracellularly), an increase in transforming growth factor-β1 (TGFβ1), and an increase in M1 macrophage polarization. An important finding was that self-identified race contributed to variance between patients in this study, where Black patients had significantly lower gene expression levels of TGFβ1 and ACTA2. This finding supports the urgent need to account for patient ancestry in biomedical research to develop better therapeutic strategies for all patients. Another important finding was that TGFβ induced factor homeobox 1 (TGIF1), an understudied signaling molecule, is highly correlated with leptin signaling and was correlated with metabolic inflammation. Finally, this study revealed an interesting gene expression pattern where M1 and M2 macrophage markers were correlated with each other, and leptin, in patients with a BMI > 25. This finding supports growing evidence that macrophage polarization in obesity involves a complex, interconnecting network system rather than a full switch in activation patterns from M2 to M1 with increasing body mass. Overall, this study reinforces key findings in animal studies and identifies important areas for future research, where human and animal studies are divergent. Understanding key drivers of human patient variability is required to unravel the complex metabolic health of unique patients.
Single-chain fluorescent integrators for mapping G-protein-coupled receptor agonists
Authors: Kroning Kayla , Gannot Noam , Li Xingyu , Zhou Guanwei , Sescil Jennifer , Putansu Aubrey , Shen Jiaqi , Wilson Avery , Fiel Hailey , Li Peng , Wang Wenjing
Published: June 2023

GPCRs transduce the effects of many neuromodulators including dopamine, serotonin, epinephrine, acetylcholine, and opioids. The localization of synthetic or endogenous GPCR agonists impacts their action on specific neuronal pathways. In this paper, we show a series of single-protein chain integrator sensors to determine GPCR agonist localization in the whole brain. We previously engineered integrator sensors for the mu and kappa opioid receptor agonists called M- and K-SPOTIT, respectively. Here, we show a new integrator sensor design platform called SPOTall that we used to engineer sensors for the beta-2-adrenergic receptor (B2AR), the dopamine receptor D1, and the cholinergic receptor muscarinic 2 agonists. For multiplexed imaging of SPOTIT and SPOTall, we engineered a red version of the SPOTIT sensors. Finally, we used M-SPOTIT and B2AR-SPOTall to detect morphine, isoproterenol, and epinephrine in the mouse brain. The SPOTIT and SPOTall sensor design platform can be used to design a variety of GPCR integrator sensors for unbiased agonist detection of many synthetic and endogenous neuromodulators across the whole brain.
Temperature-dependent twist of double-stranded RNA probed by magnetic tweezers experiments and molecular dynamics simulations
Authors: Dohnalová Hana , Seifert Mona , Matoušková Eva , Papini Flávia S. , Lipfert Jan , Dulin David , Lankaš Filip
Published: June 2023

RNA plays critical roles in the transmission and regulation of genetic information and is increasingly used in biomedical and biotechnological applications. Functional RNAs contain extended double-stranded regions and the structure of double-stranded RNA (dsRNA) has been revealed at high-resolution. However, the dependence of the properties of the RNA double helix on environmental effects, notably temperature, is still poorly understood. Here, we use single-molecule magnetic tweezers measurements to determine the dependence of the dsRNA twist on temperature. We find that dsRNA unwinds with increasing temperature, even more than DNA, with ΔTwRNA= −14.4 ± 0.7 º/(°C·kbp), compared to ΔTwDNA= −11.0 ± 1.2 º/(°C·kbp). All-atom molecular dynamics (MD) simulations using a range of nucleic acid force fields, ion parameters, and water models correctly predict that dsRNA unwinds with rising temperature, but significantly underestimate the magnitude of the effect. These MD data, together with additional MD simulations involving DNA and DNA-RNA hybrid duplexes, reveal a linear correlation between twist temperature decrease and the helical rise, in line with DNA but at variance with RNA experimental data. We speculate that this discrepancy might be caused by some unknown bias in the RNA force fields tested, or by as yet undiscovered transient alternative structures in the RNA duplex. Our results provide a baseline to model more complex RNA assemblies and to test and develop new parameterizations for RNA simulations. They may also inspire physical models of temperature-dependent dsRNA structure.
An abundant future for quagga mussels in deep European lakes
Authors: Kraemer Benjamin M. , Boudet Salomé , Burlakova Lyubov E. , Haltiner Linda , Ibelings Bas W. , Karatayev Alexander Y. , Karatayev Vadim , Rossbacher Silvan , Stöckli Raphael , Straile Dietmar , Piet Spaak
Published: June 2023

Quagga mussels have expanded their range across the northern hemisphere in recent decades owing to their dispersal abilities, prolific reproduction rates, and broad ecological tolerances. Their remarkable capacity to filter particulates from the water column has had profound effects on inland aquatic ecosystems. In the North American Great Lakes, quagga mussel populations have increased inexorably since the late 1980’s, but it remains unclear whether quagga mussels will follow a similar trajectory in Europe where they have appeared more recently. Here we apply knowledge from a 33-year quagga population monitoring effort in the North American lakes to predict future quagga populations in deep European lakes, where quaggas are quickly becoming a conspicuous part of the underwater landscape. We predict that quagga mussel biomass in Lakes Biel, Constance, and Geneva may increase by a factor of 9 – 20 by 2045. Like in North America, this increase may be characterized by a shift to larger individuals and deeper depths as the population matures. If realized, this rapid expansion of quagga mussels would likely drive the largest aquatic ecosystem change in deep European lakes since the eutrophication period of the mid-20thcentury.
Single-cell sequencing of individual retinal organoids reveals determinants of cell fate heterogeneity
Authors: Tresenrider Amy , Sridhar Akshayalakshmi , Eldred Kiara C. , Cuschieri Sophia , Hoffer Dawn , Trapnell Cole , Reh Thomas A.
Published: June 2023

With a critical need for more completein vitromodels of human development and disease, organoids hold immense potential. Their complex cellular composition makes single-cell sequencing of great utility; however, the limitation of current technologies to a handful of treatment conditions restricts their use in screens or studies of organoid heterogeneity. Here, we apply sci-Plex, a single-cell combinatorial indexing (sci)-based RNA-seq multiplexing method to retinal organoids. We demonstrate that sci-Plex and 10x methods produce highly concordant cell class compositions and then expand sci-Plex to analyze the cell class composition of 410 organoids upon modulation of critical developmental pathways. Leveraging individual organoid data, we develop a method to measure organoid heterogeneity, and we identify that activation of Wnt signaling early in retinal organoid cultures increases retinal cell classes up to six weeks later. Our data show sci-Plex’s potential to dramatically scale-up the analysis of treatment conditions on relevant human models.
A new pipeline SPICE identifies novel JUN-IKZF1 composite elements
Authors: Li Peng , Pulugulla Sree H. , Das Sonali , Oh Jangsuk , Spolski Rosanne , Lin Jian-Xin , Leonard Warren J.
Published: June 2023

Transcription factor partners can cooperatively bind to DNA composite elements to augment gene transcription. Here, we report a novel protein-DNA binding screening pipeline, termed Spacing Preference Identification of Composite Elements (SPICE), that can systematically predict protein binding partners and DNA motif spacing preferences. Using SPICE, we successfully identified known composite elements, such as AP1-IRF composite elements (AICEs) and STAT5 tetramers, and also uncovered several novel binding partners, including JUN-IKZF1 composite elements. One such novel interaction was identified at CNS9, an upstream conserved noncoding region in the humanIL10gene, which harbors a non-canonical IKZF1 binding site. We confirmed cooperative binding of JUN and IKZF1 and showed that the activity of anIL10-luciferase reporter construct in primary B and T cells depended on both this site and the AP1 binding site within this composite element. Overall, our findings reveal an unappreciated global association of IKZF1 and AP1 and establish SPICE as a valuable new pipeline for predicting novel transcription binding complexes.
Heat stress disrupts acid-base homeostasis independent of symbiosis in the model cnidarianExaiptasia diaphana
Authors: Allen-Waller Luella , Jones Katelyn G. , Martynek Marcelina P. , Brown Kristen T. , Barott Katie L.
Published: June 2023

Heat stress threatens the survival of symbiotic cnidarians by causing their photosymbiosis to break down in a process known as bleaching. The direct effects of temperature on cnidarian host physiology remain difficult to describe because heat stress depresses symbiont performance, leading to host stress and starvation. The symbiotic sea anemoneExaiptasia diaphanaprovides an opportune system in which to disentangle direct vs. indirect effects of heat stress on the host, since it can survive indefinitely without symbionts. Here, we tested the hypothesis that heat stress directly influences cnidarian physiology by comparing symbiotic and aposymbiotic individuals of a clonal strain ofE. diaphana. We exposed anemones to a range of temperatures (ambient, +2°C, +4°C, +6°C) for 15-18 days, then measured their symbiont population densities, autotrophic carbon assimilation and translocation, photosynthesis, respiration, and host intracellular pH (pHi). Anemones with initially high symbiont densities experienced dose-dependent symbiont loss with increasing temperature, resulting in a corresponding decline in host photosynthate accumulation. In contrast, anemones with low initial symbiont densities did not lose symbionts or assimilate less photosynthate as temperature increased, similar to the response of aposymbiotic anemones. Interestingly, pHidecreased in anemones at higher temperatures regardless of symbiont presence, cell density, or photosynthate translocation, indicating that heat stress disrupts cnidarian acid-base homeostasis independent of symbiosis dysfunction, and that acid-base regulation may be a critical point of vulnerability for hosts of this vital mutualism.

Summary Statement

Warming oceans threaten marine invertebrates. We found that heat disrupts acid-base homeostasis in a model symbiotic sea anemone regardless of symbiont presence or function, highlighting bleaching-independent effects of climate change.
Scalable projected Light Sheet Microscopy for high-resolution imaging of living and cleared samples
Authors: Chen Yannan , Chauhan Shradha , Gong Cheng , Dayton Hannah , Xu Cong , Cruz Estanislao Daniel De La , Datta Malika S. , Leong Kam W. , Dietrich Lars E.P. , Tomer Raju
Published: June 2023

Light sheet fluorescence microscopy (LSFM) is a widely used imaging technique for living and large cleared samples. However, high-performance LSFM systems are often prohibitively expensive and not easily scalable for high-throughput applications. Here, we introduce a cost-effective, scalable, and versatile high-resolution imaging framework, called projected Light Sheet Microscopy (pLSM), which repurposes readily available off-the-shelf consumer-grade components and an over-the-network control architecture to achieve high-resolution imaging of living and cleared samples. We extensively characterize the pLSM framework and showcase its capabilities through high-resolution, multi-color imaging and quantitative analysis of mouse and post-mortem human brain samples cleared using various techniques. Moreover, we show the applicability of pLSM for high-throughput molecular phenotyping of human induced pluripotent cells (iPSC)-derived brain and vessel organoids. Additionally, we utilized pLSM for comprehensive live imaging of bacterial pellicle biofilms at the air-liquid interface, uncovering their intricate layered architecture and diverse cellular dynamics across different depths. Overall, the pLSM framework has the potential to further democratize LSFM by making high-resolution light sheet microscopy more accessible and scalable.
Systematic disease-agnostic identification of therapeutically actionable targets using the genetics of human plasma proteins
Authors: Karim Mohd Anisul , Ariano Bruno , Schwartzentruber Jeremy , Roldan-Romero Juan Maria , Mountjoy Edward , Hayhurst James , Buniello Annalisa , Mohammed Elmutaz Shaikho Elhaj , Carmona Miguel , Holmes Michael V , Robins Chloe , Surendran Praveen , Haddad Stephen , Scott Robert A , Leach Andrew R. , Ochoa David , Maranville Joseph , McDonagh Ellen M. , Dunham Ian , Ghoussaini Maya
Published: June 2023

Proteome-wide Mendelian randomization (MR) has emerged as a promising approach in uncovering novel therapeutic targets. However, genetic colocalization analysis has revealed that a third of MR associations lacked a shared causal signal between the protein and disease outcome, raising questions about the effectiveness of this approach. The impact of proteome-wide MR, stratified by cis-trans status, in the presence or absence of genetic colocalization, on therapeutic target identification remains largely unknown.

In this study, we conducted genome-wide MR and cis/trans-genetic colocalization analyses using proteomic and complex trait genome-wide association studies. Using two different gold-standard datasets, we found that the enrichment of target-disease pairs supported by MR increased with more p-value stringent thresholds MR p-value, with the evidence of enrichment limited to colocalizing cis-MR associations.

Using a phenome-wide proteogenetic colocalization approach, we identified 235 unique targets associated with 168 binary traits at high confidence (at colocalization posterior probability of shared signal > 0.8 and 5% FDR-corrected MR p-value). The majority of the target-trait pairs did not overlap with existing drug targets, highlighting opportunities to investigate novel therapeutic hypotheses. 42% of these non-overlapping target-trait pairs were supported by GWAS, interacting protein partners, animal models, and Mendelian disease evidence. These high confidence target-trait pairs assisted with causal gene identification and helped uncover translationally informative novel biology, especially from trans-colocalizing signals, such as the association of lower intestinal alkaline phosphatase with a higher risk of inflammatory bowel disease inFUT2non-secretors.

Beyond target identification, we used MR of colocalizing signals to infer therapeutic directions and flag potential safety concerns. For example, we found that most genetically predicted therapeutic targets for inflammatory bowel disease could potentially worsen allergic disease phenotypes, except forTNFRSF6Bwhere we observed directionally consistent associations for both phenotypes.

Our results are publicly available to download or browse in a web application enabling others to use proteogenomic evidence to appraise therapeutic targets.
The periaqueductal grey in chronic low back pain: dysregulated metabolites and function
Authors: Sirucek Laura , De Schoenmacker Iara , Gorrell Lindsay , Lütolf Robin , Langenfeld Anke , Baechler Mirjam , Wirth Brigitte , Hubli Michèle , Zölch Niklaus , Schweinhardt Petra
Published: June 2023

Mechanisms underlying chronic pain are insufficiently understood. Preclinical evidence suggests a potential contribution of excitatory glutamatergic and inhibitory GABAergic imbalances in pain-relevant brain areas, such as a lower excitatory/inhibitory tone in the brainstem periaqueductal grey (PAG). This cross-sectional magnetic resonance spectroscopy (MRS) study investigated whether a lower excitatory/inhibitory tone is also observed in the PAG of patients with non-specific chronic low back pain (CLBP) and whether this would relate to altered psychophysical measures of descending pain modulation and experimental pressure pain sensitivity. Specifically, the ratio between pooled glutamate and glutamine and GABA levels (Glx/GABA), Glx and GABA in the PAG were compared between CLBP patients and pain-free controls. Further, associations of Glx/GABA with conditioned pain modulation (CPM) effects and pressure pain thresholds (PPTs) were assessed.

MRS was acquired on a 3T Philipps MR system using a point-resolved spectroscopy sequence optimized with very selective saturation pulses (OVERPRESS) and voxel-based flip angle calibration in a 1.1 mL volume of interest. Data from 41 CLBP patients (median [interquartile range]: 54 years [41 - 65], 22 females) and 29 age- and sex-matched controls (47 years [34 - 67], 17 females) fulfilled MRS quality criteria. CPM and PPTs were assessed at the lower back as most painful area and the non-dominant hand as pain-free control area. The CPM paradigm consisted of PPTs applied before, during (parallel CPM effect) and after a cold water bath and an ambient temperature water bath as control paradigm to identify ‘true’ CPM effects.

In the PAG of CLBP patients, a lower Glx/GABA ratio, i.e. a lower excitatory/inhibitory tone, was observed (P= 0.002,partial η2= 0.14) driven by decreased Glx (P= 0.012,partial η2= 0.11) and increased GABA (P= 0.038,d= 0.46). CLBP patients showed disrupted associations between Glx/GABA and PPTs compared to controls in both areas (lower back:P= 0.004,partial η2= 0.12; hand:P= 0.002,partial η2= 0.16). In controls, lower Glx/GABA was associated with lower PPTs (lower back:r= 0.48,P= 0.009, hand:r= 0.53,P= 0.003), but this link was missing in CLBP patients (r’s> -0.23,P’s> 0.150). Additionally, CLBP patients with more severe clinical pain showed smaller CPM effects at the hand (rho= 0.54,P= 0.003).

These findings suggest a dysfunction of the PAG in patients with CLBP and might indicate altered descending inhibition of deep tissue afferents.
Use of Point-of-care Haemoglobin Tests to Diagnose Childhood Anaemia in Low-and Middle-Income Countries: A Systematic Review
Authors: Brehm Rebecca , South Annabelle , George Elizabeth C
Published: June 2023

Objectives

Anaemia is a major cause of mortality and transfusion in children in Low- and Middle-Income Countries (LMICs), however current diagnostics are slow, costly, and frequently unavailable. Point-of-care haemoglobin tests (POC(Hb)Ts) could improve patient outcomes and use of resources by providing rapid and affordable results. We systematically reviewed the literature to investigate what, where and how POC(Hb)Ts are being used by health facilities in LMICs to diagnose childhood anaemia, and to explore challenges to their use.

Methods

We searched a total of nine databases and trial registries up to 10thJune 2022 using the concepts: anaemia, POC(Hb)T, LMIC and clinical setting. Adults ≥21 years and literature published >15 years ago were excluded. A single reviewer conducted screening, data extraction and quality assessment (of diagnostic studies) using QUADAS-2. Outcomes including POC(Hb)T used, location, setting, challenges and diagnostic accuracy were synthesised.

Results

Of 626 records screened, 41 studies were included. Evidence is available on the use of 15 POC(Hb)Ts in hospitals (n=28, 68%), health centres (n=9, 22%) and clinics/units (n=10, 24%) across 16 LMICs. HemoCue (HemoCue AB, Ängelholm, Sweden) was the most used test (n=31, 76%). Key challenges reported were overestimation of haemoglobin concentration, clinically unacceptable limits of agreement, errors/difficulty in sampling, environmental factors, cost, inter-observer variability, and supply of consumables. Five POC(Hb)Ts (33%) could not detect haemoglobin levels below 4g/dl. Diagnostic accuracy varied, with sensitivity and specificity to detect anaemia ranging from 24.2-92.2% and 70-96.7%, respectively.

Conclusions

POC(Hb)Ts have been successfully utilised in health facilities in LMICs to diagnose childhood anaemia. However, limited evidence is available, and challenges exist that must be addressed before wider implementation. Further research is required to confirm accuracy, clinical benefits, and cost-effectiveness.
Cavernous Angioma Symptomatic Hemorrhage (CASH) Trial Readiness II: Imaging Biomarkers and Trial Modeling
Authors: Hage Stephanie , Kinkade Serena , Girard Romuald , Flemming Kelly D. , Kim Helen , Torbey Michel T. , Huang Judy , Huston John , Shu Yunhong , Selwyn Reed G. , Hart Blaine L. , Mabray Marc C. , Feghali James , Sair Haris I. , Narvid Jared , Lupo Janine M. , Lee Justine , Stadnik Agnieszka , Alcazar Roberto , Shenkar Robert , Hobson Nicholas , DeBiasse Dorothy , Lane Karen , McBee Nichole , Treine Kevin , Ostapkovich Noeleen , Wang Ying , Thompson Richard E. , Mendoza-Puccini Carolina , Koenig James , Carroll Timothy , Hanley Daniel F. , Awad Issam A.
Published: June 2023

Background

Quantitative susceptibility mapping (QSM) and dynamic contrast enhanced quantitative perfusion (DCEQP) MRI sequences assessing iron deposition and vascular permeability were previously correlated with new hemorrhage in cavernous angiomas. We assessed their prospective changes in cavernous angiomas with symptomatic hemorrhage (CASH) in a multisite trial readiness project (clinicaltrials.govNCT03652181).

Methods

Patients with CASH in the prior year, without prior or planned lesion resection or irradiation were enrolled. Mean QSM and DCEQP of CASH lesion were acquired at baseline, and at 1- and 2-year follow-ups. Sensitivity and specificity of biomarker changes were analyzed in relation to predefined lesional symptomatic hemorrhage (SH) or asymptomatic change (AC). Sample size calculations for hypothesized therapeutic effects were conducted.

Results

We logged 143 QSM and 130 DCEQP paired annual assessments. Annual QSM change was greater in cases with SH than in cases without SH (p= 0.019). Annual QSM increase by ≥ 6% occurred in 7 of 7 cases (100%) with recurrent SH and in 7 of 10 cases (70%) with AC during the same epoch, and 3.82 times more frequently than clinical events. DCEQP change had lower sensitivity for SH and AC than QSM change, and greater variance. A trial with smallest sample size would detect a 30% difference in QSM annual change in 34 or 42 subjects (one and two-tailed, respectively), power 0.8, alpha 0.05.

Conclusions

Assessment of QSM change is feasible and sensitive to recurrent bleeding in CASH. Evaluation of an intervention on QSM percent change may be used as a time-averaged difference between 2 arms using a repeated measures analysis. DCEQP change is associated with lesser sensitivity and higher variability than QSM. These results are the basis of an application for certification by the U.S. F.D.A. of QSM as a biomarker of drug effect in CASH.
Inhibition of BCR::ABL1 tyrosine kinase activity Aids in the Generation of Stable Chronic Myeloid Leukemia Induced Pluripotent Stem Cells
Authors: Bama Benjamin Esther Sathya , Babu Dinesh , Joshi Gaurav , Rajamani Bharathi M , Nandy Krittika , Rani Sonam , Anandan Senthamizhselvi , Premkumar Chitra , Maddali Madhavi , Abraham Aby , Velayudhan Shaji R , Balasubramanian Poonkuzhali
Published: June 2023

Induced pluripotent stem cells (iPSCs) generated from patients with chronic myeloid leukemia (CML) have the potential for disease modeling to study disease pathogenesis and screening therapeutic interventions. In this study, we aimed to generate iPSCs from CD34+hematopoietic progenitors of CML patients with varying responses to tyrosine kinase inhibitor (TKI) therapy. The generated CML-CD34-iPSC colonies displayed atypical “dome-shaped” morphology and underwent spontaneous differentiation in a few days. However, supplementation with imatinib (IM), the most widely used TKI to treat CML patients, in the culture medium improved the stability and maintenance of all isolated CML-CD34-iPSC colonies, allowing them to be maintained for more than 20 passages without significant differentiation. In contrast to previous studies, our results indicate that suppressing the BCR::ABL1 oncogenic pathway is essential for efficiently generating stable CML-iPSC colonies. Furthermore, we successfully differentiated these iPSCs to CD34+hematopoietic progenitors both in the presence and absence of IM. This robust protocol for generating CML-iPSCs provides a valuable resource for disease modelling. The generated iPSCs will be a valuable tool for investigating CML pathophysiology, drug resistance mechanisms, and drug screening to identify novel and effective therapies for this disease.
Asymmetric distribution of color-opponent response types across mouse visual cortex supports superior color vision in the sky
Authors: Franke Katrin , Cai Chenchen , Ponder Kayla , Fu Jiakun , Sokoloski Sacha , Berens Philipp , Tolias Andreas S.
Published: June 2023

Color is an important visual feature that informs behavior, and the retinal basis for color vision has been studied across various vertebrate species. While many studies have investigated how color information is processed in visual brain areas of primate species, we have limited understanding of how it is organized beyond the retina in other species, including most dichromatic mammals. In this study, we systematically characterized how color is represented in the primary visual cortex (V1) of mice. Using large-scale neuronal recordings and a luminance and color noise stimulus, we found that more than a third of neurons in mouse V1 are color-opponent in their receptive field center, while the receptive field surround predominantly captures luminance contrast. Furthermore, we found that color-opponency is especially pronounced in posterior V1 that encodes the sky, matching the statistics of natural scenes experienced by mice. Using unsupervised clustering, we demonstrate that the asymmetry in color representations across cortex can be explained by an uneven distribution of green-On/UV-Off color-opponent response types that are represented in the upper visual field. Finally, a simple model with natural scene-inspired parametric stimuli shows that green-On/UV-Off color-opponent response types may enhance the detection of “predatory”-like dark UV-objects in noisy daylight scenes. The results from this study highlight the relevance of color processing in the mouse visual system and contribute to our understanding of how color information is organized in the visual hierarchy across species.
Meaning-making behavior in a small-brained hominin,Homo naledi, from the late Pleistocene: contexts and evolutionary implications
Authors: Fuentes Agustin , Kissel Marc , Spikins Penny , Molopyane Keneiloe , Hawks John , Berger Lee R.
Published: June 2023

Explorations in the Dinaledi Subsystem of the Rising Star cave system have yielded some of the earliest evidence of a mortuary practice in hominins. Because the evidence is attributable to the small-brainedHomo naledi, these analyses call into question several assumptions about behavioral and cognitive evolution in Pleistocene hominins. The evidence from the Dinaledi Subsystem, and at other locations across the Rising Star cave system may widen the phylogenetic breadth of mortuary, and possibly funerary, behaviors. These discoveries may also associate the creation of meaning making and increased behavioral complexity with a small-brained hominin species, challenging certain assertions about the role of encephalization and cognition in hominin and human evolution. We suggest that the hominin socio-cognitive niche is more diverse than previously thought. If true, technological, meaning-making activities, and cognitive advances in human evolution are not associated solely with the evolution of larger brained members of the genusHomo.

One-Sentence Summary

Evidence for complex behaviors associated with a small-brained hominin suggest that large brains are not solely responsible for the manifestation of human-like behavioral complexity.
Isolation by environment is more important than isolation by distance along a tropical gradient in direct developing frogs
Authors: Percino-Daniel Ruth , Jones Kara S. , Maigret Thomas A. , Weisrock David W. , Piñero Daniel
Published: June 2023

Abiotic factors are important for defining population structure and limiting gene flow, especially in ectotherm species, the challenge is to identify which ones are the most important and can produce a pattern of isolation by environment. Our study aim is to quantify the extent to which divergence is driven by abiotic factors such as temperature, precipitation and elevation. To do so, we used a direct-developing frog species,Craugastor lokithat occurs along a steep elevation gradient. Using restriction-site associated DNA sequencing (RADseq) from individuals collected from 100 m to 2250 m of elevation at 13 localities at Sierra Madre de Chiapas in southern Mexico we described population structure using a variety of model-based clustering and landscape genomics approaches. We found that populations sampled at higher elevation correspond probably to an undescribed new species ofCraugastor, and that populations fromCraugastor lokibetween 120 m and 1500 m are clustered in two different genetic groups: a Pacific slope group and a Central Depression slope group. We found signatures of isolation by environment more important that isolation by distance in contributing to genetic divergence in this group of frogs at a fine scale. The environmental variables such as: mean temperature of wettest and warmest quarter, annual mean temperature, and seasonality in temperature and precipitation play an important role on population differentiation. Our results underscore the importance of abiotic factors as drivers and highlight the use of different approaches to illuminate fine scale population divergence given the complexity of disentangling the contribution of both patterns of isolation.
DGRPool: A web tool leveraging harmonizedDrosophilaGenetic Reference Panel phenotyping data for the study of complex traits
Authors: Gardeux Vincent , Bevers Roel P.J. , David Fabrice P.A. , Rosschaert Emily , Rochepeau Romain , Deplancke Bart
Published: June 2023

Genome-wide association studies have advanced our understanding of complex traits, but studying how a GWAS variant can affect a specific trait in the human population remains challenging due to environmental variability.Drosophila melanogasteris in this regard an excellent model organism for studying the relationship between genetic and phenotypic variation due to its simple handling, standardized growth conditions, low cost, and short lifespan. TheDrosophilaGenetic Reference Panel (DGRP) in particular has been a valuable tool for studying complex traits, but proper harmonization and indexing of DGRP phenotyping data is necessary to fully capitalize on this resource. To address this, we created a web tool calledDGRPool(dgrpool.epfl.ch), which aggregates phenotyping data of 1034 phenotypes across 135 DGRP studies in a common environment. DGRPool enables users to download data and run various tools such as genome-wide (GWAS) and phenome-wide (PheWAS) association studies. As a proof-of-concept, DGRPool was used to study the longevity phenotype and uncovered both established and unexpected correlations with other phenotypes such as locomotor activity, starvation resistance, desiccation survival, and oxidative stress resistance. DGRPool has the potential to facilitate new genetic and molecular insights of complex traits inDrosophilaand serve as a valuable, interactive tool for the scientific community.
Attention Modulates Human Visual Responses to Objects by Tuning Sharpening
Authors: Doostani Narges , Hossein-Zadeh Gholam-Ali , Cichy Radoslaw Martin , Vaziri-Pashkam Maryam
Published: June 2023

Visual stimuli compete with each other for cortical processing and attention biases this competition in favor of the attended stimulus. How does the relationship between the stimuli affect the strength of this attentional bias? Here, we used functional MRI to explore the effect of target-distractor similarity in neural representation on attentional modulation in the human visual cortex using univariate and multivariate pattern analyses. Using stimuli from four object categories (human bodies, cats, cars and houses), we investigated attentional effects in the primary visual area V1, the object-selective regions LO and pFs, the body-selective region EBA, and the scene-selective region PPA. We demonstrated that the strength of the attentional bias towards the target is not fixed but decreases with increasing target-distractor similarity. Simulations provided evidence that this result pattern is explained by tuning sharpening rather than an increase in gain. Our findings provide a mechanistic explanation for behavioral effects of target-distractor similarity on attentional biases and suggest tuning sharpening as the underlying mechanism in object-based attention.
But, what are the cells doing? Image Analysis pipeline to follow single cells in the zebrafish embryo
Authors: Bercowsky-Rama Arianne , Venzin Olivier F. , Rohde Laurel A. , Chiaruttini Nicolas , Oates Andrew C.
Published: June 2023

Microscopy has rapidly evolved at pace with live markers, enabling ever higher spatiotemporal resolution of multicellular dynamics within larger fields of view. Consequently, we are now in the era of widespread production of terabyte (TB)-sized time-lapse movies of experimental model systems, including developing embryos and organoids. Working with these large datasets has presented a new set of hurdles, particularly due to the lack of standardized open-source pipelines for acquiring, handling and analyzing the data. Moreover, although long-term tracking of a cell throughout an entire process, for example vertebrate organogenesis, is key to revealing the underlying cellular dynamics, this has proven largely elusive. To specifically address the question “But, what are the cells doing?”, we created an image analysis pipeline optimized to track single cells in light-sheet acquired datasets (1 TB sized time-lapse, 8h of imaging, 30 min gene expression cycle, cell movement speed (1µm /1 minute), 200-400 µm tissue depth). Our modular pipeline optimizes and connects the following: image acquisition parameters to improve tracking feasibility; hardware specifications; data handling and compression tools; pre-processing steps; state-of-the-art cell tracking tools (Mastodon, MaMuT) and a novel open-source/ python-based tool (Paleontologist) to analyze and visualize spatiotemporal dynamics of the tracked cells. Importantly, our pipeline is adaptable to a variety of experimental systems and accessible to researchers regardless of expertise in coding and image analysis.

One-sentence Summary

User-friendly cell-tracking pipeline that connects image acquisition in multicellular systems through to data analysis of cellular dynamics.
QTL Mapping of Seed Fe Concentration in an Interspecific RIL Population Derived fromLens culinaris×Lens ervoides
Authors: Podder Rajib , Gela Tadesse S. , Bett Kirstin E. , Vandenberg Albert
Published: June 2023

Biofortification of lentil (Lens culinarisMedik.) was investigated to potentially increase bioavailable iron (Fe) in the human diet. This study assessed the genetic variation for seed Fe concentration (SFeC) and identified the genomic regions associated with SFeC in an interspecific mapping population derived from crossing betweenL. culinariscv. ‘Eston’ andL. ervoidesaccession IG 72815. A total of 134 RILs were evaluated in three environments. The SFeC data for individual environments and best linear unbiased prediction (BLUP) of the SFeC across environments were used for QTL analysis. The seeds of the RILs exhibited variation for SFeC from 47.0 to 102.9 mg kg-1and several RILs showed transgressive segregation for SFeC. QTL analysis identified two QTLs on chromosomes 2 and 6 that accounted for 11.9-14.0% and 12.5-20.5%, respectively, of the total phenotypic variation for SFeC. The SNP markers linked to the identified QTLs may prove useful for increasing SFeC via marker-assisted selection. RILs with high SFeC can be incorporated into the lentil breeding program to broaden the genetic base of the breeding pool and/or used for the development of genetic resources for future genomic studies.
Initiation of B-type starch granules in wheat endosperm requires the plastidial α-glucan phosphorylase PHS1
Authors: Kamble Nitin Uttam , Makhamadnojov Farrukh , Fahy Brendan , Martins Carlo , Saalbach Gerhard , Seung David
Published: June 2023

PHS1 is a plastidial α-glucan phosphorylase that can elongate and degrade maltooligosaccharides (MOS), but its exact physiological role in plants is poorly understood. Here, we discover a specialised role of PHS1 in establishing the unique bimodal characteristic of starch granules in the wheat endosperm. Wheat endosperm contains large A-type granules that initiate at early grain development, and small B-type granules that initiate in later grain development. We demonstrate that PHS1 interacts with BGC1 – a carbohydrate-binding protein essential for normal B-type granule initiation. Mutants of tetraploid durum wheat deficient in all homeologs of PHS1 had normal A-type granules, but fewer and larger B-type granules. Grain size and starch content were not affected by the mutations. Further, by assessing granule numbers during grain development in thephs1mutant, and using a double mutant defective in both PHS1 and BGC1, we demonstrate that PHS1 is exclusively involved in B-type granule initiation. The total starch content and number of starch granules per chloroplast in leaves were not affected by loss of PHS1, suggesting that its role in granule initiation in wheat is limited to the endosperm. We therefore propose that the initiation of A- and B-type granules occur via distinct biochemical mechanisms, where PHS1 plays an exclusive role in B-type granule initiation.