bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic effects of sequence-conserved enhancer-like elements on human complex traits
Authors: Zhu Xiang , Ma Shining , Wong Wing Hung
Published: August 2022

Non-coding sequences that are evolutionarily conserved and bio-chemically active offer clues to mechanistic interpretations of human genome-wide association studies (GWAS). However, their genetic effects have not been systematically examined across a wide range of human tissues and traits. Here we develop a simple method to identify functional elements exhibiting high levels of human-mouse sequence conservation and enhancer-like biochemical activity, which scales well to 313 epigenomic datasets across 106 tissues and cell types. Combining these elements with 468 GWAS of European (EUR) and East Asian (EAS) ancestries, we identify tissue-specific enrichments of heritability and causal variants for many traits, as well as candidate genes that are functionally relevant to body mass index (BMI) and schizophrenia but were not reported in previous GWAS. Our findings provide a comprehensive assessment of how sequence-conserved enhancer-like elements affect complex traits, and reinforce the importance of integrating evolutionary and biochemical data to elucidate human disease genetics.
Microneurography as a Minimally Invasive Method to Assess Target Engagement During Neuromodulation
Authors: Verma Nishant , Knudsen Bruce , Gholston Aaron , Skubal Aaron , Blanz Stephan , Settell Megan , Frank Jennifer , Trevathan James , Ludwig Kip
Published: August 2022

Objective

Peripheral neural signals recorded during neuromodulation therapies provide insights into local neural target engagement and serve as a sensitive biomarker of physiological effect. Although these applications make peripheral recordings important for furthering neuromodulation therapies, the invasive nature of conventional nerve cuffs and longitudinal intrafascicular electrodes (LIFEs) limit their clinical utility. Furthermore, cuff electrodes typically record clear asynchronous neural activity in small animal models but not in large animal models. Microneurography, a minimally invasive technique, is already used routinely in humans to record asynchronous neural activity in the periphery. However, the relative performance of microneurography microelectrodes compared to cuff and LIFE electrodes in measuring neural signals relevant to neuromodulation therapies is not well understood.

Approach

To address this gap, we recorded cervical vagus nerve (cVN) electrically evoked compound action potentials (ECAPs) and spontaneous activity in a human-scaled large animal model – the pig. Additionally, we recorded sensory evoked activity and both invasively and non-invasively evoked CAPs from the great auricular nerve (GAN). In aggregate, this study assesses the potential of microneurography electrodes to measure neural activity during neuromodulation therapies with statistically powered and pre-registered outcomes (https://osf.io/y9k6j).

Main results

The cuff recorded the largest ECAP signal (p<0.01) and had the lowest noise floor amongst the evaluated electrodes. Despite the lower signal to noise ratio, microneurography electrodes were able to detect the threshold for neural activation with similar sensitivity to cuff and LIFE electrodes once a dose-response curve was constructed. Furthermore, the microneurography electrode was the only electrode to record distinct sensory evoked neural activity (p<0.01).

Significance

The results show that microneurography electrodes can measure neural signals relevant to neuromodulation therapies. Microneurography could further neuromodulation therapies by providing a real-time biomarker to guide electrode placement and stimulation parameter selection to optimize local neural fiber engagement and study mechanisms of action.
Leveraging Scaffold Information to Predict Protein-ligand Binding Affinity with an Empirical Graph Neural Network
Authors: Xia Chunqiu , Feng Shi-Hao , Xia Ying , Pan Xiaoyong , Shen Hong-Bin
Published: August 2022

Motivation

Protein-ligand binding affinity prediction is an important task in structural bioinformatics for drug discovery and design. Although various scoring functions have been proposed, it remains challenging to accurately evaluate the binding affinity of a protein-ligand complex with known bound structure due to the potential preference of scoring system. In recent years, deep learning techniques have been applied to scoring functions without sophisticated feature engineering. Nevertheless, existing methods cannot model the differential contribution of atoms in various regions of proteins, and the relationship between atom properties and intermolecular distance is also not fully explored.

Results

We propose a novel empirical graph neural network for accurate protein-ligand binding affinity prediction (EGNA). Graphs of protein, ligand and their interactions are constructed based on different regions of each bound complex. Proteins and ligands are effectively represented by graph convolutional layers, enabling the EGNA to capture interaction patterns precisely by simulating empirical scoring functions. The contributions of different factors on binding affinity can thus be transparently investigated. EGNA is compared with the state-of-the-art machine learning-based scoring functions on two widely used benchmark datasets. The results demonstrate the superiority of EGNA and its good generalization capability.

Availability and implementation

The web server and source code of EGNA is available at www.csbio.sjtu.edu.cn/bioinf/EGNA and https://github.com/chunqiux/EGNA.

Contact

hbshen@sjtu.edu.cn or 2008xypan@sjtu.edu.cn

Supplementary information

Supplementary data are available at Bioinformatics online.
LARGE VOLUME SURFACTANT ADMINISTRATION IN PREMATURE INFANTS LESS THAN 35 WEEKS USING MINIMALLY INVASIVE SURFACTANT THERAPY
Authors: Ethawi Yahya , Hussain Abrar , Minski John , Miller Joe , Alvaro Ruben
Published: August 2022

Abstract

Large volume surfactant administration in premature infants less than 35 weeks using minimally invasive surfactant therapy (MIST).

Background

Surfactant in small volume preparations can be successfully administered to premature infants using a narrow-bore vascular catheter inserted into the trachea under direct vision. It was not known if surfactant in large volume preparations could be administered effectively to spontaneously breathing premature infants while maintaining them on nasal continuous positive airway pressure (nCPAP).

Objective

To evaluate the feasibility of administering a large volume of surfactant (5 ml/kg) in spontaneously breathing premature infants on nCPAP using a vascular catheter.

Methods

Single-arm interventional trial in two level III nurseries in Canada. Spontaneously breathing premature infants between 24 and 34 weeks’ gestation, born between July 4th, 2012 and September 5th, 2012 were eligible for the trial in the first 24 hours of life. A 16-gauge vascular catheter was inserted under direct vision through the vocal cords to administer 5 ml/kg of surfactant while maintaining the infants on nCPAP.

Results

Twenty-one premature infants were enrolled. The mean gestational age was 29 ± 3 (range 24 to 34 weeks) with mean birth weight of 1474 ± 575 g. Surfactant was successfully administered in 20 infants (95 %). There was a clear effect after surfactant administration with a decrease in oxygen requirement from 0.34 ± 0.111 before the procedure, to 0.26 ± 0.08 after the procedure (p = .001), and a decrease in nCPAP pressure from 7.2 ± 0.5 cm H2O before the procedure to 5.9 ± 0.5 after the procedure (p < .0001). The mean duration for surfactant administration was 8.3 ± 3.4 minutes. The procedure was temporarily stopped in three cases due to bradycardia and/or apnea with desaturations that spontaneously recovered without intervention. Coughing and reflux of the surfactant were transiently observed in four cases (19 %).

Conclusion

It is feasible to administer large volumes of surfactant without interrupting nCPAP via a vascular catheter, to premature infants less than 35 weeks’ gestation. Further trials are needed to confirm the safety and efficacy of this method compared to other methods of surfactant administration.
Movement guidelines for young children: Engaging stakeholders to design dissemination strategies in the Hong Kong early childhood education context
Authors: Capio Catherine M. , Jones Rachel A. , Ng Catalina S. M. , Sit Cindy H. P. , Chung Kevin K. H.
Published: August 2022

Background

Early childhood is a critical period during which patterns of movement behaviors are formed. The World Health Organization had endorsed guidelines for physical activity, sedentary behavior and sleep over a 24-hour time period, which had been adopted by the Centre for Health Protection of Hong Kong. This paper reports on stakeholder engagements that were conducted to inform the design of strategies to disseminate the guidelines in early childhood education settings.

Methods

Using a mixed-methods study design, we sought to (a) assess the stakeholders’ levels of awareness and knowledge of the Hong Kong movement guidelines for young children, and (b) identify the factors that influence the uptake of the said guidelines. We conducted an online survey of early childhood education teachers (N =314), twelve focus groups involving teachers (N = 18) and parents (N = 18), and individual interviews of key informants (N = 7) and domestic workers who provide care for preschool-aged children (N = 7). Descriptive statistics was used for the quantitative data and thematic analysis was performed on the qualitative data using an inductive and semantic approach following a realist framework.

Findings

Our findings show that teachers were aware of the movement guidelines for young children, but their knowledge of the specific guidelines was deficient; parents and domestic workers had limited awareness and knowledge of the guidelines. Uptake of the movement guidelines is enabled by parent engagement, activities in the ECE centers, home-school cooperation, and community activities. The challenges include time poverty of parents, local curriculum requirements, limited physical spaces, social values, and pandemic-related restrictions.

Conclusion

We recommend that dissemination strategies in the context of early childhood education settings should deliver knowledge content and support the stakeholders in mitigating the challenges associated with time, space, and social conditions.
Brain microstructural changes and fatigue after COVID-19
Authors: de Carvalho Bispo Diógenes Diego , de Paula Brandão Pedro Renato , Pereira Danilo Assis , Maluf Fernando Bisinoto , Dias Bruna Arrais , Paranhos Hugo Rafael , Glehn Felipe von , de Oliveira Augusto César Penalva , Regattieri Neysa Aparecida Tinoco , Silva Lucas Scardua , Yasuda Clarissa Lin , de Sousa Munhoz Soares Alexandre Anderson , Descoteaux Maxime
Published: August 2022

Background

Fatigue and cognitive complaints are the most frequent persistent symptoms in patients after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This study aimed to assess fatigue and neuropsychological performance and investigate changes in the thickness and volume of gray matter (GM) and microstructural abnormalities in the white matter (WM) in a group of patients with mild-to-moderate coronavirus disease 2019 (COVID-19).

Methods

We studied 56 COVID-19 patients and 37 matched controls using magnetic resonance imaging (MRI). Cognition was assessed using Montreal Cognitive Assessment and Cambridge Neuropsychological Test Automated Battery, and fatigue was assessed using Chalder Fatigue Scale (CFQ-11). T1-weighted MRI was used to assess GM thickness and volume. Fiber-specific apparent fiber density (FD), free water index, and diffusion tensor imaging data were extracted using diffusion-weighted MRI (d-MRI). d-MRI data were correlated with clinical and cognitive measures using partial correlations and general linear modeling.

Results

COVID-19 patients had mild-to-moderate acute illness (95% non-hospitalized). The average period between real-time quantitative reverse transcription polymerase chain reaction-based diagnosis and clinical/MRI assessments was 93.3 (±26.4) days. The COVID-19 group had higher CFQ-11 scores than the control group (p < 0.001). There were no differences in neuropsychological performance between groups. The COVID-19 group had lower FD in the association, projection, and commissural tracts, but no change in GM. The corona radiata, corticospinal tract, corpus callosum, arcuate fasciculus, cingulate, fornix, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, superior longitudinal fasciculus, and uncinate fasciculus were involved. CFQ-11 scores correlated with microstructural changes in patients with COVID-19.

Conclusions

Quantitative d-MRI detected changes in the WM microstructure of patients recovering from COVID-19. This study suggests a possible brain substrate underlying the symptoms caused by SARS-CoV-2 during medium- to long-term recovery.

Key points

Patients with COVID-19 had microstructural changes in the WM at a mean follow-up of 3 months.

There is a possible brain substrate underlying the symptoms caused by SARS-CoV-2 during medium- to long-term recovery.

A serial d-MRI study following up on a non-hospitalized sample of patients with milder COVID-19 forms is warranted.
Resistance of Musa balbisiana accessions of the Philippines to banana bunchy top virus
Authors: Dela Cueva Fe M. , Perez Nicole Angelee M. , Benjamin Ann Fatima A. , Yanos Lyka A. , Gueco Lavernee S. , Thomas John E.
Published: August 2022

Mitigation of banana bunchy top disease (BBTD) is still a challenge worldwide. BBTD is caused by banana bunchy top virus (BBTV), the most important virus affecting banana. Currently, no cultivar or accession of banana has complete resistance to BBTD. A total of 36 wild Musa spp. accessions, including 34 Musabalbisiana and two M. acuminata subsp. errans (‘Agutay’), were screened for resistance against BBTV. In greenhouse tests using viruliferous banana aphids (Pentalonia nigronervosa), all M. balbisiana accessions remained symptomless and BBTV was not detected in any of these plants by PCR at three- and six-months post inoculation. In contrast, 100% disease incidence was recorded in M. acuminata subsp. errans and in cv. Lakatan susceptible control plants. The PCR-negative M.balbisiana plants were then transferred to a field with high BBTV inoculum pressure where they remained symptomless and PCR-negative for up to five years, while all cv. Lakatan developed BBTD. This study confirmed the resistance of wild M.balbisiana accessions to BBTV. It is therefore expected to provide a resource for conventional and marker assisted breeding.
Universal gut microbial relationships in the gut microbiome of wild baboons
Authors: Roche Kimberly E. , Björk Johannes R. , Dasari Mauna R. , Grieneisen Laura , Jansen David , Gould Trevor J. , Gesquiere Laurence R. , Barreiro Luis B. , Alberts Susan C. , Blekhman Ran , Gilbert Jack A. , Tung Jenny , Mukherjee Sayan , Archie Elizabeth A.
Published: August 2022

Ecological relationships between bacteria mediate the services that gut microbiomes provide to their hosts. Knowing the overall direction and strength of these relationships within hosts, and their generalizability across hosts, is essential to learn how microbial ecology scales up to affect microbiome assembly, dynamics, and host health. Here we gain insight into these patterns by inferring thousands of correlations in bacterial abundance between pairs of gut microbiome taxa from extensive time series data (5,534 microbiome profiles from 56 wild baboon hosts over a 13-year period). We model these time series using a statistically robust, multinomial logistic-normal modeling framework and test the degree to which bacterial abundance correlations are consistent across hosts (i.e., “universal”) or individualized to each host. We also compare these patterns to two publicly available human data sets. We find that baboon gut microbial relationships are largely universal: correlation patterns within each baboon host reflect a mixture of idiosyncratic and shared patterns, but the shared pattern dominates by almost 2-fold. Surprisingly, the strongest and most consistently correlated bacterial pairs across hosts were overwhelmingly positively correlated and typically belonged to the same family—a 3-fold enrichment compared to pairs drawn from the data set as a whole. The bias towards universal, positive bacterial correlations was also apparent in monthly samples from human infants, and bacterial families that had universal relationships in baboons also tended to be universal in human infants. Together, our results advance our understanding of the relationships that shape gut microbial ecosystems, with implications for microbiome personalization, community assembly and stability, and the feasibility of microbiome interventions to improve host health.
Physiological and behavioural resistance of malaria vectors in rural West-Africa : a data mining study to address their fine-scale spatiotemporal heterogeneity, drivers, and predictability
Authors: Taconet Paul , Soma Dieudonne Diloma , Zogo Barnabas , Mouline Karine , Simard Frederic , Koffi Alphonsine Amanan , Dabire Roch Kounbobr , Pennetier Cedric , Moiroux Nicolas
Published: August 2022

Abstract

Insecticide resistance and behavioural adaptation of malaria mosquitoes affect the efficacy of long-lasting insecticide nets - currently the main tool for malaria vector control. To develop and deploy complementary, efficient and cost-effective control interventions, a good understanding of the drivers of these physiological and behavioural traits is needed. In this data-mining exercise, we modelled a set of indicators of physiological resistance to insecticide (prevalence of three target-site mutations) and behavioural resistance phenotypes (early- and late-biting, exophagy) of anopheles mosquitoes in two rural areas of West-Africa, located in Burkina Faso and Cote d’Ivoire. To this aim, we used mosquito field collections along with heterogeneous, multi-source and multi-scale environmental data. The objectives were i) to assess the small-scale spatial and temporal heterogeneity of physiological resistance to insecticide and behavioural resistance phenotypes, ii) to better understand their drivers, and iii) to assess their spatio-temporal predictability, at scales that are consistent with operational action. The explanatory variables covered a wide range of potential environmental determinants of vector resistance to insecticide or behavioural resistance phenotypes : vector control, human availability and nocturnal behaviour, macro and micro-climatic conditions, landscape, etc. The resulting models revealed many statistically significant associations, although their predictive powers were overall weak. We interpreted and discussed these associations in light of several topics of interest, such as : respective contribution of public health and agriculture in the selection of physiological resistances, biological costs associated with physiological resistances, biological mechanisms underlying biting behaviour, and impact of micro-climatic conditions on the time or place of biting. To our knowledge, our work is the first modeling insecticide resistance and feeding behaviour of malaria vectors at such fine spatial scale with such a large dataset of both mosquito and environmental data.
Biophysical Characterization of an Essential Mammalian Protein; Transcription Termination Factor I (TTF1)
Authors: Tiwari Kumud , Singh Gajender , Singh Samarendra Kumar
Published: August 2022

Mammalian Transcription Terminator Factor 1 (TTF1) is an essential protein which plays diverse cellular physiological functions like transcription regulation (both initiation and termination), replication fork blockage, chromatin remodelling, DNA damage repair etc. Hence, understanding the structure and mechanism conferred by its variable confirmations becomes significantly important. But so far, almost nothing is known about the structure of either the full-length protein or any of its domain in isolation. Moving towards achieving the above goals, our lab has codon optimised, expressed and purified N-terminal 190 amino acid deleted TTF1 (ΔN190TTF1) protein, since full length protein even after multiple trials could not be purified in soluble form. In this article, we have characterized this essential protein by studying its homogeneity, molecular size and secondary structure using tools like dynamic light scattering (DLS), circular dichroism (CD) spectroscopy, Raman spectroscopy and atomic force microscopy (AFM). By CD and DLS we have shown that the purified protein is homogenous and soluble. CD spectroscopy also revealed that ΔN190TTF1 is a helical protein which was further confirmed by analysis of Raman spectra and Amide I region deconvolution studies. AFM imaging data discovered the size of single protein molecule to be 94 nm which is in agreement with the size determined by the DLS study as well. Our structural and biophysical characterization of this essential protein will open avenues towards solving the structure to atomic resolution and also will encourage the research to investigate the mechanism behind its diverse functions attributed to its various domains.
Analysis of Kinetic of eyelids of little owl Athene noctua
Authors: Mahmoud Fatma Abdel-Regal , Shawki Nahed Ahmed , Abdel-Mageed Amany Mohamed , Al-Nefeiy Fatma A.
Published: August 2022

The present study used the video’s recording technique to record the kinetic activity of lids, beside the anatomical, and the histological studies of the eyelids structure. The present authors found that the fundemental eyelids movements can be uniquely and reliably characterized by their anatomical relationships that confirmed also via video record of kinetic performance of these eyelids. The results show that levator palpebrae muscle split into many directions as a main generate motor to increasing the movement of the upper lid. In other side, the contraction of Depressor palpebral inferioris muscle together with the active upward forces of levator palpebrae muscle resultin g in opening the eye. While, the closure of lids arise from the passive downward forces and relaxation of the levator palpebrae and Depressor palpebral inferioris muscle as well as, the cooperation action of retractor anguli oculi lateralis and medialis muscle. The results also recorded that NM movement is reversely proportion to the level of kinetic of other eyelids.. The mobility of Nm in little owl occurs under effect artificially external stress. These anatomical data and sequence video records have confirmed that the upper eyelid move more compare to other lids. The present authors also suggest that the mobility of lids may stimulate through external pressure force of some surrounding structure like periorbital sheet. Also, the histological study exhibited that the structure of two eyelids is very similar in the little owl and the variability are showing in the number of cell layers that forms their epithelium of skin and palpebral surfaces, the distribution of pigment granules within them, as well as, the degree of keratinization on their surface.

This study gives a comprehensive description of eyelids movement in little owl and discusses the impact of some surrounding conditions in kinetic performance of these eyelids
The PIP4K2 inhibitor THZ-P1-2 exhibits antileukemia activity by disruption of mitochondrial homeostasis and autophagy
Authors: Lima Keli , Pereira-Martins Diego Antonio , de Miranda Lívia Bassani Lins , Coelho-Silva Juan Luiz , Silva Leandro Giovana da , Weinhäuser Isabel , de Cássia Cavaglieri Rita , de Leal Aline Medeiros , da Silva Wellington Fernandes , de Lima Lange Ana Paula Alencar , Pereira Velloso Elvira Deolinda Rodrigues , Griessinger Emmanuel , Hilberink Jacobien R , Huls Gerwin , Schuringa Jan Jacob , Rego Eduardo Magalhães , Machado-Neto João Agostinho
Published: August 2022

Treatment of acute leukemia is challenging due to genetic heterogeneity between and even within patients. Leukemic stem cells (LSCs) are relatively drug-resistant and frequently lead to relapse. Their plasticity and capacity to adapt to extracellular stress, in which mitochondrial metabolism and autophagy play important roles, further complicates treatment. Genetic models of phosphatidylinositol-5-phosphate 4-kinase type 2 proteins (PIP4K2s) inhibition demonstrated the relevance of these enzymes in mitochondrial homeostasis and autophagic flux. Here, we uncover the cellular and molecular effects of THZ-P1-2, a pan-inhibitor of PIP4K2s, in acute leukemia cells. THZ-P1-2 reduced cell viability and induced DNA damage, apoptosis, loss of mitochondrial membrane potential, and accumulation of acidic vesicular organelles. Protein expression analysis revealed that THZ-P1-2 impaired autophagy flux. In addition, THZ-P1-2 induced cell differentiation and showed synergistic effects with venetoclax in resistant leukemic models. In primary leukemia cells, LC-MS/MS-based proteome analysis revealed that sensitivity to THZ-P1-2 was associated with mitochondrial metabolism, cell cycle, cell-of-origin, and the TP53 pathway. Minimal effects of THZ-P1-2 observed in healthy CD34+ cells suggested a favorable therapeutic window. Our study provides insight into pharmacological inhibition of PIP4Ks targeting mitochondrial homeostasis and autophagy shedding light on a new class of drugs for acute leukemias.
Engineering Pseudomonas putida KT2440 for chain length tailored free fatty acid and oleochemical production
Authors: Valencia Luis E. , Incha Matthew R. , Schmidt Matthias , Pearson Allison N. , Thompson Mitchell G. , Roberts Jacob , Mehling Marina , Yin Kevin , Sun Ning , Oka Asun , Shih Patrick M. , Blank Lars M. , Gladden John , Keasling Jay D.
Published: August 2022

Despite advances in understanding the metabolism of Pseudomonas putida KT2440, a promising bacterial host for producing valuable chemicals from plant-derived feedstocks, a strain capable of producing free fatty acid-derived chemicals has not been developed. Guided by functional genomics, we engineered P. putida to produce medium- and long-chain free fatty acids (FFAs) to titers of up to 670 mg/L, paving the road for the production of high-value oleochemicals and biofuels from cheap feedstocks, such as plant biomass, using this host. Additionally, by taking advantage of the varying substrate preferences of paralogous native fatty acyl-CoA ligases, we employed a strategy to control FFA chain length that resulted in a P. putida strain specialized in producing medium-chain FFAs. Finally, we demonstrate the production of oleochemicals in these strains by synthesizing medium-chain fatty acid methyl esters, compounds useful as biodiesel blending agents, in various media including sorghum hydrolysate at titers greater than 300 mg/L.
Classifications of Logically Coherent Concurrent Diagnoses According to ICHD3: A Pilot Application of Automated Diagnosis Through Prime Representation
Authors: Zhang Pengfei
Published: August 2022

Introduction

In clinical practice, headache presentations may fit more than one ICHD3 diagnoses. This project seeks to exhaustively list all these logically consistent “codiagnoses” according to ICHD3 criteria. We limit our project to cases where only two diagnoses are involved.

Methods

We included the ICHD3 criterias for “Migraine” (1.1, 1.2, 1.3), “Tension-type headache” (2.1, 2.2, 2.3, 2.4), “Trigeminal autonomic cephalalgias” (3.1, 3.2, 3.3, 3.4, 3.5), as well as all “Other primary headache disorders”. We excluded “Complications of migraine”(1.5) and “Episodic syndrome that may be associated with migraine” (1.6) since these diagnoses require codiagnoses of migraine as first assumption. We also excluded “probable” diagnosis criteria.

Each phenotype in the above criteria is assigned an unique prime number. We then encoded each ICHD3 criteria into integers, call “criteria representations”, through multiplication in a list format. “Codiagnoses representations” are generated by multiplying all possible pairings of criteria representations.

To eliminate logical inconsistent codiagnses, we manually encode a list of logically inconsistent phenotypes through multiplication: For example, headache lasting “seconds” would be logically inconsistent with “headache lasting hours”; the prime representation for both are multiplied together. We called this list the “inconsistency representations”.

All codiagnoses representation divisible by any inconsistency representations are filtered out, generating a list of codiagnoses represenation that are logically consistent. This list is then translated back into ICHD3 diagnoses.

Results

A total of 103 prime numbers were used to encode phenotypes from the included ICHD3 criteria diagnosis with 578 encodings generated. We generated 99 pairs of illogical phenotypes. Once illogical phenotypes were excluded, a total of 253,842 composite numbers representing unique dual-diagnosis clinical profiles were obtained. The number of profiles, although unique, yields duplicate dual diagnoses; once these duplicates are removed, we obtained 145 possible logical dual diagnoses.

Of the dual diagnoses, 2 contains with intersecting phenotypes due to subset relationships, 14 dual diagnoses with intersecting phenotype without subset relationships, 129 contains dual diagnoses as a result of non-intersecting phenotypes.

Conclusion

Prime number representations of primary headache disorders not only offer clinicians with an automated way of diagnosing headaches but also provides a powerful method of investigating co-diagnosis in headache classifications. Applications of this method to the investigations of dual diagnosis and headaches may offer insight into “loopholes” in the ICHD3 as well as potential explanation for sources of a number of controversies in headache disorders. Futures applications of the method includes extending the methodology to all of ICHD3.
Single-step purification of functionalized protein nanostructures using multimodal chromatography
Authors: Winter Daniel L. , Lebhar Hélène , McCluskey Joshua B. , Glover Dominic J.
Published: August 2022

Protein nanostructures produced through the self-assembly of individual subunits are attractive scaffolds to attach and position functional molecules for applications in biomaterials, metabolic engineering, tissue engineering, and a plethora of nanomaterials. However, the assembly of multicomponent protein nanomaterials is generally a laborious process that requires each protein component to be separately expressed and purified prior to assembly. Moreover, excess components not incorporated into the final assembly must be removed from the solution and thereby necessitate additional processing steps. Here, we developed an efficient approach to purify functionalized protein filament assemblies directly from bacterial lysates in a single step through a type of multimodal chromatography that combines size-exclusion, hydrophilic interaction, and ion exchange to separate recombinant protein assemblies from excess free subunits and bacterial proteins. In this approach, the ultrastable filamentous protein gamma-prefoldin was employed as a material scaffold that can be functionalized with a variety of protein domains through SpyTag/SpyCatcher conjugation chemistry. The purification of recombinant gamma-prefoldin filaments from bacterial lysates using multimodal chromatography was optimized across a wide range of salt concentrations and pH. Subsequently, functionalized protein assemblies were purified from bacterial lysates using multimodal chromatography in a single step and shown to befree of unincorporated subunits. The assembly and purification of protein nanostructures with varying amounts of functionalization was confirmed using polyacrylamide gel electrophoresis, Förster resonance energy transfer, and transmission electron microscopy. We envision that the use of multimodal chromatography will increase the throughput of protein nanostructure prototyping as well as enable the upscaling of the bioproduction of protein nanodevices.
Contrasting effects of Ksr2, an obesity gene, on trabecular bone volume and bone marrow adiposity
Authors: Gomez Gustavo A. , Rundle Charles H. , Xing Weirong , Kesavan Chandrasekhar , Pourteymoor Sheila , Lewis Robert E. , Powell David R. , Mohan Subburaman
Published: August 2022

Pathological obesity and its complications are associated with an increased propensity for bone fractures. Humans with certain genetic polymorphisms at the kinase suppressor of ras2 (Ksr2) locus develop severe early-onset obesity and type 2 diabetes (T2D). Both conditions are phenocopied in mice with Ksr2 deleted, but whether this affects bone health remains unknown. Here we studied the bones of global Ksr2 null mice and found that Ksr2 negatively regulates femoral, but not vertebral, bone mass in two genetic backgrounds, while the paralogous gene, Ksr1, was dispensable for bone homeostasis. Mechanistically, KSR2 regulates bone formation by influencing adipocyte differentiation at the expense of osteoblasts in the bone marrow. Compared with Ksr2’s known role as a regulator of feeding by its function in the hypothalamus, pair feeding and osteoblast-specific conditional deletion of Ksr2 reveals that Ksr2 can regulate bone formation autonomously. Despite the gains in appendicular bone mass observed in absence of Ksr2, bone strength, as well as fracture healing response remains compromised in these mice. This study highlights the interrelationship between adiposity and bone health and provides mechanistic insights into how Ksr2, an adiposity and diabetic gene, regulates bone metabolism.
The Day-1 Mobility Loss Model: Development, Validation, and Clinical Applicability of a Model to Predict Hospital Acquired Mobility Loss in Older Adults
Authors: Shah Sachin J. , Hoffman Ari , Pierce Logan , Covinsky Kenneth E.
Published: August 2022

Background

Mobility loss is common in hospitalized older adults, and resources to prevent mobility loss are finite. Our goal was to develop a rapid, universal screening tool that identifies individuals at risk of losing the ability to walk during hospitalization on the first hospital day. Second, we determined if the model could inform the use of mobility-preserving interventions.

Methods

We included patients admitted to a general medical service, aged ≥65 years, who could walk on admission (Braden Scale Activity subset >=3). Patients were considered to have a new mobility impairment if the activity score was <3 on discharge. We used predictors available on the first hospital day to develop (2017-18) and validate (2019) a prediction model. We determined the association between predicted risk and therapy use in the validation cohort to highlight the model’s clinical utility.

Results

5542 patients were included (median age 76yrs, 48% women); 7.6% were discharged unable to walk. The model included six predictors: age, marital status, medication administrations, Glasgow Coma Scale verbal score, serum albumin, and urinary catheter presence. In the validation cohort, the model discriminated well (c-statistic 0.75) and was strongly associated with hospital-acquired mobility loss (lowest decile 1%, highest decile 24%). In the validation cohort, therapy consultation ordering increased linearly with predicted risk; however, observed mobility loss increased exponentially.

Conclusion

The Day-1 Mobility Loss model predicts the risk of mobility loss in hospitalized older adults on the first hospital day. Further, it identifies at-risk older adults who may benefit from mobility interventions.
Genome-wide association study of ischemic stroke risk in Sickle Cell confirms ADAMTS2, CDK18, uncovers 12 novel loci
Authors: Earley Eric Jay , Kelly Shannon , Fang Fang , Alencar Cecília Salete , de Oliveira Werneck Rodrigues Daniela , Soares Cruz Dahra Teles , Sabino Ester , Custer Brian , Dinardo Carla , Page Grier P.
Published: August 2022

Background

Ischemic stroke is a common complication of sickle cell disease (SCD) and without screening or intervention can affect 11% of children with SCD before the age of 20. This study sought to find genetic biomarkers for risk of stroke occurring at younger ages.

Methods

Within the Trans-Omics for Precision Medicine (TOPMed), a genome-wide association study (GWAS) of ischemic stroke was performed on 1,333 individuals with SCD from Brazil (178 cases, 1155 controls). Via a novel proportional hazards analysis approach, we searched for variants associated with strokes occurring at younger ages.

Results

Fourteen genomic regions were associated with early ischemic stroke at genome wide significance (P<5×10−8). This included variants near two genes which have been previously linked to non-SCD early onset stroke (<65 years): ADAMTS2 (rs147625068, P= 3.70 × 10−9) and CDK18 (rs12144136, P= 2.38 × 10−9), respectively. Individuals harboring multiple risk alleles exhibited increasing rates of stroke at earlier timepoints (P < 0.001, Gehan-Wilcoxon) than those carrying only one. Enrichment tests suggest systemic dysregulation of gene expression in the hypothalamus (P = 0.03, FDR), substantia nigra (P = 0.03), spleen (P = 0.005) and coronary (P = 0.0005), tibial (P = 0.03) and aorta arteries (P = 0.03.

Conclusions

This findings from this study support a model of shared genetic architecture underlying ischemic stroke risk between SCD individuals and non-SCD individuals <65 years. In addition, results suggest an additive liability due to carrying multiple risk alleles.
Perspectives on the enhancement of commercially available antibiotics by natural products
Authors: Nitsch-Velasquez Lucia , Barrios Sara B. , Montoya Ricardo A. , Canales Rosy
Published: August 2022

Background

Opportunistic resistant bacteria are health and economically relevant in the health care systems and in industries worldwide, especially in the so-called resistant bacteria era (RBE). Enhancing the activity of commercially available antibiotics (CAAs) with different types of natural products (NPs) is a successful antimicrobial strategy, for instance the amoxicillin and clavulanate mixture.

Objective

To find research trends in this field during 2015-2020 and to detect potential drug hits with potential to diversify formulations and materials design that can be useful to manage the RBE.

Systematic review results

It yielded 190 reports of synergistic effects of CAAs and NPs. The analyzed variables were: a) natural products origin: plant family, genera, secondary metabolite type; b) strains: +/- Gram, genera, most frequent species, application field; and c) CAAs: family, most frequent CAAs. The families with potential to have more bioactive species were Apocynaceae, Rubiaceae, Euphorbiaceae (Isbio factor). Lonicera had the highest reports amount.

Polyphenols and flavonoids were the majority of pure NPs tested. Several potential drug hits for antibiotic activity enhancement at synergistic level were identified together with potential mechanisms of action: berberine (drug efflux inhibitor–DEI, biofilm inhibitor–BI), curcumin (BI), essential oils (BI), 3-o-metyl-butylgallato (inhibition of fatty acid saturation), among others. About the half of the tested strains were gram positive, being Methicillin Resistant Staphylococcus aureus (MRSA) the most frequently tested. Escherichia coli was the gram negative strain most frequently reported, including enterotoxigenic and extended spectrum beta-lactamases producers. The growth of other foodborne genera strains, such as Listeria and Salmonella, were also inhibited. Aminoglycosides were the family most reported, with gentamicin as the most commonly studied.

Conclusions

NPs as either as plant extracts from a variety of families, or as purified compounds specially flavonoids and polyphenols, have shown effective results to enhance the antibiotic activity of CAAs against gram positive and negative strains relevant to HC and FI. Their mechanisms of action are starting to be determined, as the case EPIs and BIs. Further research is needed to achieve co-formulations and materials design useful for those fields, that can certainly be positively impacted by pursuing this strategy.
A randomized stepped wedge trial of an intensive combination approach to roll back the HIV epidemic in Nigerian Adolescents: iCARE Nigeria treatment support protocol
Authors: Taiwo Babafemi O. , Kuhns Lisa M. , Omigbodun Olayinka , Awolude Olutosin , Kuti Kehinde M. , Adetunji Adedotun , Berzins Baiba , Janulis Patrick , Akanmu Sulaimon , Agbaji Oche , David Agatha N. , Akinbami Akinsegun , Adekambi Abiodun Folashade , Johnson Amy K. , Okonkwor Ogochukwu , Oladeji Bibilola D. , Cervantes Marbella , Adewumi Olubusuyi M. , Kapogiannis Bill , Garofalo Robert
Published: August 2022

Background

Nigeria is one of six countries with half the global burden of youth living with HIV. Interventions to date have been inadequate as AIDS-related deaths in Nigeria’s youth have remained unchanged in recent years. The iCARE Nigeria HIV treatment support intervention, a combination of peer navigation and SMS text message medication reminders to promote viral suppression, demonstrated initial efficacy and feasibility in a pilot trial among youth living with HIV in Nigeria. This paper describes the study protocol for the large-scale trial of the intervention.

Methods

The iCARE Nigeria-Treatment study is a randomized stepped wedge trial of a combination (peer navigation and text message reminder) intervention, delivered to youth over a period of 48 weeks to promote viral suppression. Youth receiving HIV treatment at six clinical sites in the North Central and South Western regions of Nigeria were recruited for participation. Eligibility criteria included registration as a patient at participating clinics, aged 15-24 years, on antiretroviral therapy for at least three months, ability to understand and read English, Hausa, Pidgin English, or Yoruba, and intent to remain a patient at the study site during the study period. The six clinic sites were divided into three clusters and randomized to a sequence of control and intervention periods for comparison. The primary outcome is plasma HIV-1 viral load suppression, defined as viral load ≤ 200 copies/mL, in the intervention period versus the control period at 48 weeks of intervention.

Discussion

Evidence-based interventions to promote viral load suppression among youth in Nigeria are needed. This study will determine efficacy of a combination intervention (peer navigation and text message reminder) and collect data on potential implementation barriers and facilitators to inform scale-up if efficacy is confirmed.

Trial registration

ClinicalTrials.gov number, NCT 04950153, retrospectively registered July 6, 2021, https://clinicaltrials.gov/.
Beyond mean fitness: demographic stochasticity and resilience matter at tree species climatic edges
Authors: Guyennon Arnaud , Reineking Björn , Salguero-Gomez Roberto , Dahlgren Jonas , Lehtonen Aleksi , Ratcliffe Sophia , Ruiz-Benito Paloma , Zavala Miguel A. , Kunstler Georges
Published: August 2022

Aim

Linking local population dynamics and species distributions is critical to predicting the impacts of climate change. While many studies focus on the mean fitness of populations, theory shows that species distributions can be shaped by demographic stochasticity or population resilience. Here we examine how mean fitness (measured by invasion rate), demographic stochasticity, and resilience (measured by the ability to recover from disturbance) constrain populations at the edges compared to the climatic center.

Location

Europe: Spain, France, Germany, Finland, and Sweden.

Period

Forest inventory data used for fitting the models cover the period from 1985 to 2013.

Major taxa

Dominant European tree species; Angiosperms and Gymnosperms.

Methods

We developed dynamic population models covering the entire life cycle of 25 European tree species with climatically dependent recruitment models fitted to forest inventory data. We then ran simulations using integral projection and individual-based models to test how invasion rates, risk of stochastic extinction, and ability to recover from stochastic disturbances differ between the center and edges of species’ climatic niches.

Results

Results varied among species, but in general, demographic constraints were stronger at warm edges and for species in harsher climates. Conversely, recovery was more limiting at cold edges. In addition, we found that for several species, constraints at the edges were due to demographic stochasticity and recovery capacity rather than mean fitness.

Main conclusion

Our results highlight that mean fitness is not the only mechanism at play at the edges; demographic stochasticity and population capacity to recover also matter for European tree species. To understand how climate change will drive species range shifts, future studies will need to analyse the interplay between population mean growth rate and stochastic demographic processes as well as disturbances.
DNA language models are powerful predictors of genome-wide variant effects
Authors: Benegas Gonzalo , Batra Sanjit Singh , Song Yun S.
Published: August 2022

The expanding catalog of genome-wide association studies (GWAS) provides biological insights across a variety of species, but identifying the causal variants behind these associations remains a significant challenge. Experimental validation is both labor-intensive and costly, highlighting the need for accurate, scalable computational methods to predict the effects of genetic variants across the entire genome. Inspired by recent progress in natural language processing, unsupervised pre-training on large protein sequence databases has proven successful in extracting complex information related to proteins. These models showcase their ability to learn variant effects in coding regions using an unsupervised approach. Expanding on this idea, we here introduce theGenomicPre-trainedNetwork (GPN), a model designed to learn genome-wide variant effects through unsupervised pre-training on genomic DNA sequences. Our model also successfully learns gene structure and DNA motifs without any supervision. To demonstrate its utility, we train GPN onunalignedreference genomes ofArabidopsis thalianaand seven related species within the Brassicales order, and evaluate its ability to predict the functional impact of genetic variants inArabidopsis thalianaby utilizing allele frequencies from the 1001 Genomes Project and a comprehensive database of GWAS. Notably, GPN outperforms predictors based on popular conservation scores such as phyloP and phastCons. Our predictions forArabidopsis thalianacan be visualized as sequence logos in the UCSC Genome Browser (https://genome.ucsc.edu/s/gbenegas/gpn-arabidopsis). We provide code (https://github.com/songlab-cal/gpn) to train GPN for any given species using its DNA sequence alone, enabling unsupervised prediction of variant effects across the entire genome.