bluuebunny/crossref_metadata_2025 huggingface dataset:
Brain-targeted drug delivery - nanovesicles directed to specific brain cells by brain-targeting ligands
Authors: Moreira Ricardo , Nóbrega Clévio , de Almeida Luís Pereira , Mendonça Liliana
Published: May 2024

Neurodegenerative diseases are characterized by extensive loss of function or death of brain cells, hampering the life quality of patients. Brain-targeted drug delivery is challenging, with a low success rate this far. Therefore, the application of targeting ligands in drug vehicles, such as lipid-based and polymeric nanoparticles, holds the promise to overcome the blood-brain barrier (BBB) and direct therapies to the brain, in addition to protect their cargo from degradation and metabolization. In this review, we discuss the barriers to brain delivery and the different types of brain-targeting ligands currently in use in brain-targeted nanoparticles, such as peptides, proteins, aptamers, small molecules, and antibodies. Moreover, we present a detailed review of the different targeting ligands used to direct nanoparticles to specific brain cells, like neurons (C4-3 aptamer, neurotensin, Tet-1, RVG, and IKRG peptides), astrocytes (Aquaporin-4, D4, and Bradykinin B2 antibodies), oligodendrocytes (NG-2 antibody and the biotinylated DNA aptamer conjugated to a streptavidin core Myaptavin-3064), microglia (CD11b antibody), neural stem cells (QTRFLLH, VPTQSSG, and NFL-TBS.40–63 peptides), and to endothelial cells of the BBB (transferrin and insulin proteins, and choline). Reports demonstrated enhanced brain-targeted delivery with improved transport to the specific cell type targeted with the conjugation of these ligands to nanoparticles. Hence, this strategy allows the implementation of high-precision medicine, with reduced side effects or unwanted therapy clearance from the body. Nevertheless, the accumulation of some of these nanoparticles in peripheral organs has been reported indicating that there are still factors to be improved to achieve higher levels of brain targeting. This review is a collection of studies exploring targeting ligands for the delivery of nanoparticles to the brain and we highlight the advantages and limitations of this type of approach in precision therapies.
High-density lipoprotein mimetic nano-therapeutics targeting monocytes and macrophages for improved cardiovascular care: a comprehensive review
Authors: Zhen Juan , Li Xiangjun , Yu Haitao , Du Bing
Published: May 2024

The prevalence of cardiovascular diseases continues to be a challenge for global health, necessitating innovative solutions. The potential of high-density lipoprotein (HDL) mimetic nanotherapeutics in the context of cardiovascular disease and the intricate mechanisms underlying the interactions between monocyte-derived cells and HDL mimetic showing their impact on inflammation, cellular lipid metabolism, and the progression of atherosclerotic plaque. Preclinical studies have demonstrated that HDL mimetic nanotherapeutics can regulate monocyte recruitment and macrophage polarization towards an anti-inflammatory phenotype, suggesting their potential to impede the progression of atherosclerosis. The challenges and opportunities associated with the clinical application of HDL mimetic nanotherapeutics, emphasize the need for additional research to gain a better understanding of the precise molecular pathways and long-term effects of these nanotherapeutics on monocytes and macrophages to maximize their therapeutic efficacy. Furthermore, the use of nanotechnology in the treatment of cardiovascular diseases highlights the potential of nanoparticles for targeted treatments. Moreover, the concept of theranostics combines therapy and diagnosis to create a selective platform for the conversion of traditional therapeutic medications into specialized and customized treatments. The multifaceted contributions of HDL to cardiovascular and metabolic health via highlight its potential to improve plaque stability and avert atherosclerosis-related problems. There is a need for further research to maximize the therapeutic efficacy of HDL mimetic nanotherapeutics and to develop targeted treatment approaches to prevent atherosclerosis. This review provides a comprehensive overview of the potential of nanotherapeutics in the treatment of cardiovascular diseases, emphasizing the need for innovative solutions to address the challenges posed by cardiovascular diseases.
Toxicological inhalation studies in rats to substantiate grouping of zinc oxide nanoforms
Authors: Thoma Tizia , Ma-Hock Lan , Schneider Steffen , Honarvar Naveed , Treumann Silke , Groeters Sibylle , Strauss Volker , Marxfeld Heike , Funk-Weyer Dorothee , Seiffert Svenja , Wohlleben Wendel , Dammann Martina , Wiench Karin , Lombaert Noömi , Spirlet Christine , Vasquez Marie , Dewhurst Nicole , Landsiedel Robert
Published: May 2024

Background

Significant variations exist in the forms of ZnO, making it impossible to test all forms in in vivo inhalation studies. Hence, grouping and read-across is a common approach under REACH to evaluate the toxicological profile of familiar substances. The objective of this paper is to investigate the potential role of dissolution, size, or coating in grouping ZnO (nano)forms for the purpose of hazard assessment. We performed a 90-day inhalation study (OECD test guideline no. (TG) 413) in rats combined with a reproduction/developmental (neuro)toxicity screening test (TG 421/424/426) with coated and uncoated ZnO nanoforms in comparison with microscale ZnO particles and soluble zinc sulfate. In addition, genotoxicity in the nasal cavity, lungs, liver, and bone marrow was examined via comet assay (TG 489) after 14-day inhalation exposure.

Results

ZnO nanoparticles caused local toxicity in the respiratory tract. Systemic effects that were not related to the local irritation were not observed. There was no indication of impaired fertility, developmental toxicity, or developmental neurotoxicity. No indication for genotoxicity of any of the test substances was observed. Local effects were similar across the different ZnO test substances and were reversible after the end of the exposure.

Conclusion

With exception of local toxicity, this study could not confirm the occasional findings in some of the previous studies regarding the above-mentioned toxicological endpoints. The two representative ZnO nanoforms and the microscale particles showed similar local effects. The ZnO nanoforms most likely exhibit their effects by zinc ions as no particles could be detected after the end of the exposure, and exposure to rapidly soluble zinc sulfate had similar effects. Obviously, material differences between the ZnO particles do not substantially alter their toxicokinetics and toxicodynamics. The grouping of ZnO nanoforms into a set of similar nanoforms is justified by these observations.
The isolation strategy and chemical analysis of oil cells from Asari Radix et Rhizoma
Authors: Hu Haibo , Liu Guangxue , Li Yaoli
Published: May 2024

Background

Single-cell analysis, a rapidly evolving field, encounters significant challenges in detecting individual cells within complex plant tissues, particularly oil cells (OCs). The intricate process of single-cell isolation, coupled with the inherent chemical volatility of oil cells, necessitates a comprehensive methodology.

Results

This study presents a method for obtaining intact OC from Asari Radix et Rhizoma (ARR), a traditional herbal medicine. The developed approach facilitates both qualitative and quantitative analysis of diverse OCs. To determine the most reliable approach, four practical methods—laser capture microdissection, micromanipulation capturing, micromanipulation piping, and cell picking—were systematically compared and evaluated, unequivocally establishing cell picking as the most effective method for OC isolation and chemical analysis. Microscopic observations showed that OCs predominantly distribute in the cortex of adventitious and fibrous roots, as well as the pith and cortex of the rhizome, with distinct morphologies—oblong in roots and circular in rhizomes. Sixty-three volatile constituents were identified in OCs, with eighteen compounds exhibiting significant differences. Safrole, methyleugenol, and asaricin emerged as the most abundant constituents in OCs. Notably, cis-4-thujanol and tetramethylpyrazine were exclusive to rhizome OCs, while isoeugenol methyl ether was specific to fibrous root OCs based on the detections. ARR roots and rhizomes displayed marked disparities in OC distribution, morphology, and constituents.

Conclusion

The study highlights the efficacy of cell picking coupled with HS–SPME–GC–MS as a flexible, reliable, and sensitive method for OC isolation and chemical analysis, providing a robust methodology for future endeavors in single-cell analyses.
A newborn Screening Programme for Inborn errors of metabolism in Galicia: 22 years of evaluation and follow-up
Authors: Couce María L. , Bóveda María-Dolores , Castiñeiras Daisy E. , Vázquez-Mosquera María-Eugenia , Barbosa-Gouveia Sofía , De Castro María-José , Iglesias-Rodríguez Agustin J. , Colón Cristóbal , Cocho José A. , Sánchez Paula
Published: May 2024

Background

There is a notable lack of harmonisation in newborn screening (NBS) programmes worldwide. The Galician programme for early detection of inborn errors of metabolism (IEM) was one of the first NBS programmes in Europe to incorporate mass spectrometry (July 2000). This programme currently screens for 26 IEMs in dried blood and urine samples collected 24–72 h after birth.

Results

In its 22-year history, this programme has analysed samples from 440,723 neonates and identified 326 cases of IEM with a prevalence of 1:1351. The most prevalent IEMs were hyperphenylalaninaemia (n = 118), followed by medium chain acyl-CoA dehydrogenase deficiency (MCADD, n = 26), galactosaemia (n = 20), and cystinurias (n = 43). Sixty-one false positives and 18 conditions related to maternal pathologies were detected. Urine samples have been identified as a useful secondary sample to reduce the rate of false positives and identify new defects. There were 5 false negatives. The overall positive value was 84.23%. The fatality rate over a median of 12.1 years of follow-up was 2.76%. The intelligence quotient of patients was normal in 95.7% of cases, and school performance was largely optimal, with pedagogic special needs assistance required in < 10% of cases. Clinical onset of disease preceded diagnosis in 4% of cases. The age at which first NBS report is performed was reduced by 4 days since 2021.

Conclusions

This study highlights the benefits of collecting urine samples, reduce NBS reporting time and expanding the number of IEMs included in NBS programmes.
Comparison of the ScreenFire and Xpert HPV assays for the detection of human papillomavirus and cervical precancer among women living with HIV in Malawi
Authors: Mungo Chemtai , Guliam Anagha , Chinula Lameck , Inturrisi Federica , Msowoya Lizzie , Mkochi Tawonga , Jawadu Siniya , de Sanjosé Silvia , Schiffman Mark , Tang Jennifer H. , Smith Jennifer S.
Published: May 2024

Background

The World Health Organization recommends human papillomavirus (HPV) testing for primary cervical cancer screening, including among women living with HIV (WLWH). Low-and-middle-income countries account for 85% of the cervical cancer burden globally, yet have limited access to HPV-based screening, largely due to cost. This study aims to compare the performance of a rapid, isothermal amplification HPV assay (ScreenFire) to that of the Xpert HPV assay for the detection of HPV and cervical precancer among WLWH in Malawi.

Methods

We utilized stored self- and provider-collected specimens from a prospective cohort study of WLWH in Malawi from July 2020 to February 2022. Specimens were tested with both Xpert and ScreenFire HPV assays. The overall and within-channel non-hierarchical agreement between ScreenFire and Xpert was determined for both self- and provider-collected specimens. Hierarchical ScreenFire HPV positivity by channel was compared to Xpert for each histological diagnosis—cervical intraepithelial neoplasia grade 2 or worse (CIN2+) compared to <CIN2.

Results

315 matched self- and provider-collected specimens had valid results from both Xpert and ScreenFire testing and were included in analyses, of which 279 and 36 were HPV positive and HPV negative, respectively, on Xpert self-collection. Of the 315, 245 (78%) had normal pathology, 21 CIN1 (7%), 14 CIN2 (4%), and 35 CIN3 (11%). Of the 245 with normal pathology, 213 (87%) and 188 (77%) were HPV-positive on Xpert and ScreenFire self-collected specimens, respectively. Among provider-collected specimens, the assays had 80% agreement on overall HPV positivity (unweighted kappa 0.59, 95% 0.50–0.69). ScreenFire was HPV-positive in 90% of self-collected specimens that were HPV-positive on Xpert. Channel agreement between the assays was high for both self- and provider-collected specimens, but slightly lower for HPV18/45. In hierarchical analysis, ScreenFire demonstrated high concordance with Xpert testing for detecting CIN2+ cases in all channels, missing no HPV 16 or HPV 18/45 positive CIN2+ case that was positive on Xpert, in both self- and provider-collected specimens.

Conclusion

In this study of stored specimens, the ScreenFire HPV assay performed well in the detection of HPV and CIN2+ among WLWH compared to the Xpert HPV assay. If supported by larger validation studies, ScreenFire could be an affordable alternative point-of-care HPV assay for use in LMICs.
Comparative 3D genome analysis between neural retina and retinal pigment epithelium reveals differential cis-regulatory interactions at retinal disease loci
Authors: D’haene Eva , López-Soriano Víctor , Martínez-García Pedro Manuel , Kalayanamontri Soraya , Rey Alfredo Dueñas , Sousa-Ortega Ana , Naranjo Silvia , Van de Sompele Stijn , Vantomme Lies , Mahieu Quinten , Vergult Sarah , Neto Ana , Gómez-Skarmeta José Luis , Martínez-Morales Juan Ramón , Bauwens Miriam , Tena Juan Jesús , De Baere Elfride
Published: May 2024

Background

Vision depends on the interplay between photoreceptor cells of the neural retina and the underlying retinal pigment epithelium (RPE). Most genes involved in inherited retinal diseases display specific spatiotemporal expression within these interconnected retinal components through the local recruitment of cis-regulatory elements (CREs) in 3D nuclear space.

Results

To understand the role of differential chromatin architecture in establishing tissue-specific expression at inherited retinal disease loci, we mapped genome-wide chromatin interactions using in situ Hi-C and H3K4me3 HiChIP on neural retina and RPE/choroid from human adult donor eyes. We observed chromatin looping between active promoters and 32,425 and 8060 candidate CREs in the neural retina and RPE/choroid, respectively. A comparative 3D genome analysis between these two retinal tissues revealed that 56% of 290 known inherited retinal disease genes were marked by differential chromatin interactions. One of these was ABCA4, which is implicated in the most common autosomal recessive inherited retinal disease. We zoomed in on retina- and RPE-specific cis-regulatory interactions at the ABCA4 locus using high-resolution UMI-4C. Integration with bulk and single-cell epigenomic datasets and in vivo enhancer assays in zebrafish revealed tissue-specific CREs interacting with ABCA4.

Conclusions

Through comparative 3D genome mapping, based on genome-wide, promoter-centric, and locus-specific assays of human neural retina and RPE, we have shown that gene regulation at key inherited retinal disease loci is likely mediated by tissue-specific chromatin interactions. These findings do not only provide insight into tissue-specific regulatory landscapes at retinal disease loci, but also delineate the search space for non-coding genomic variation underlying unsolved inherited retinal diseases.

Graphical Abstract
Robust differential expression testing for single-cell CRISPR screens at low multiplicity of infection
Authors: Barry Timothy , Mason Kaishu , Roeder Kathryn , Katsevich Eugene
Published: May 2024

Single-cell CRISPR screens (perturb-seq) link genetic perturbations to phenotypic changes in individual cells. The most fundamental task in perturb-seq analysis is to test for association between a perturbation and a count outcome, such as gene expression. We conduct the first-ever comprehensive benchmarking study of association testing methods for low multiplicity-of-infection (MOI) perturb-seq data, finding that existing methods produce excess false positives. We conduct an extensive empirical investigation of the data, identifying three core analysis challenges: sparsity, confounding, and model misspecification. Finally, we develop an association testing method — SCEPTRE low-MOI — that resolves these analysis challenges and demonstrates improved calibration and power.
RECOVER-NEURO: study protocol for a multi-center, multi-arm, phase 2, randomized, active comparator trial evaluating three interventions for cognitive dysfunction in post-acute sequelae of SARS-CoV-2 infection (PASC)
Authors: Knopman David S. , Laskowitz Daniel T. , Koltai Deborah C. , Charvet Leigh E. , Becker Jacqueline H. , Federman Alex D. , Wisnivesky Juan , Mahncke Henry , Van Vleet Thomas M. , Bateman Lucinda , Kim Dong-Yun , O’Steen Ashley , James Melissa , Silverstein Adam , Lokhnygina Yuliya , Rich Jennifer , Feger Bryan J. , Zimmerman Kanecia O.
Published: May 2024

Background

Post-acute sequelae of SARS-CoV-2 infection (PASC) symptoms have broad impact, and may affect individuals regardless of COVID-19 severity, socioeconomic status, race, ethnicity, or age. A prominent PASC symptom is cognitive dysfunction, colloquially referred to as “brain fog” and characterized by declines in short-term memory, attention, and concentration. Cognitive dysfunction can severely impair quality of life by impairing daily functional skills and preventing timely return to work.

Methods

RECOVER-NEURO is a prospective, multi-center, multi-arm, phase 2, randomized, active-comparator design investigating 3 interventions: (1) BrainHQ is an interactive, online cognitive training program; (2) PASC-Cognitive Recovery is a cognitive rehabilitation program specifically designed to target frequently reported challenges among individuals with brain fog; (3) transcranial direct current stimulation (tDCS) is a noninvasive form of mild electrical brain stimulation.

The interventions will be combined to establish 5 arms: (1) BrainHQ; (2) BrainHQ + PASC-Cognitive Recovery; (3) BrainHQ + tDCS-active; (4) BrainHQ + tDCS-sham; and (5) Active Comparator. The interventions will occur for 10 weeks. Assessments will be completed at baseline and at the end of intervention and will include cognitive testing and patient-reported surveys. All study activities can be delivered in Spanish and English.

Discussion

This study is designed to test whether cognitive dysfunction symptoms can be alleviated by the use of pragmatic and established interventions with different mechanisms of action and with prior evidence of improving cognitive function in patients with neurocognitive disorder. If successful, results will provide beneficial treatments for PASC-related cognitive dysfunction.

Trial registration

ClinicalTrials.gov NCT05965739. Registered on July 25, 2023.
Superiority trial for the development of an ideal method for the closure of midline abdominal wall incisions to reduce the incidence of wound complications after elective gastroenterological surgery: study protocol for a randomized controlled trial
Authors: Fukai Shota , Mizusawa Yuki , Noda Hiroshi , Tsujinaka Shingo , Maeda Yukihisa , Hasebe Ryuji , Eguchi Yusuke , Kanemitsu Rina , Matsuzawa Natsumi , Abe Iku , Endo Yuhei , Fukui Taro , Takayama Yuji , Ichida Kosuke , Inoue Koetsu , Muto Yuta , Watanabe Fumiaki , Futsuhara Kazushige , Miyakura Yasuyuki , Rikiyama Toshiki
Published: May 2024

Background

The recent guidelines from the European and American Hernia Societies recommend a continuous small-bite suturing technique with slowly absorbable sutures for fascial closure of midline abdominal wall incisions to reduce the incidence of wound complications, especially for incisional hernia. However, this is based on low-certainty evidence. We could not find any recommendations for skin closure. The wound closure technique is an important determinant of the risk of wound complications, and a comprehensive approach to prevent wound complications should be developed.

Methods

We propose a single-institute, prospective, randomized, blinded-endpoint trial to assess the superiority of the combination of continuous suturing of the fascia without peritoneal closure and continuous suturing of the subcuticular tissue (study group) over that of interrupted suturing of the fascia together with the peritoneum and interrupted suturing of the subcuticular tissue (control group) for reducing the incidence of midline abdominal wall incision wound complications after elective gastroenterological surgery with a clean-contaminated wound. Permuted-block randomization with an allocation ratio of 1:1 and blocking will be used. We hypothesize that the study group will show a 50% reduction in the incidence of wound complications. The target number of cases is set at 284. The primary outcome is the incidence of wound complications, including incisional surgical site infection, hemorrhage, seroma, wound dehiscence within 30 days after surgery, and incisional hernia at approximately 1 year after surgery.

Discussion

This trial will provide initial evidence on the ideal combination of fascial and skin closure for midline abdominal wall incision to reduce the incidence of overall postoperative wound complications after gastroenterological surgery with a clean-contaminated wound. This trial is expected to generate high-quality evidence that supports the current guidelines for the closure of abdominal wall incisions from the European and American Hernia Societies and to contribute to their next updates.

Trial registration

UMIN-CTR UMIN000048442. Registered on 1 August 2022. https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000055205
Establishment and partial characterisation of a new cell line derived from adult tissues of the tsetse fly Glossina morsitans morsitans
Authors: Bell-Sakyi Lesley , Haines Lee R. , Petrucci Giovanni , Beliavskaia Alexandra , Hartley Catherine , Khoo Jing Jing , Makepeace Benjamin L. , Abd-Alla Adly M. M. , Darby Alistair C.
Published: May 2024

Background

Insect cell lines play a vital role in many aspects of research on disease vectors and agricultural pests. The tsetse fly Glossina morsitans morsitans is an important vector of salivarian trypanosomes in sub-Saharan Africa and, as such, is a major constraint on human health and agricultural development in the region.

Methods

Here, we report establishment and partial characterisation of a cell line, GMA/LULS61, derived from tissues of adult female G. m. morsitans. GMA/LULS61 cells, grown at 28 °C in L-15 (Leibovitz) medium supplemented with foetal bovine serum and tryptose phosphate broth, have been taken through 23 passages to date and can be split 1:1 at 2-week intervals. Karyotyping at passage 17 revealed a predominantly haploid chromosome complement. Species origin and absence of contaminating bacteria were confirmed by PCR amplification and sequencing of fragments of the COI gene and pan-bacterial 16S rRNA gene respectively. However, PCR screening of RNA extracted from GMA/LULS61 cells confirmed presence of the recently described Glossina morsitans morsitans iflavirus and Glossina morsitans morsitans negevirus, but absence of Glossina pallipides salivary gland hypertrophy virus. GMA/LULS61 cells supported infection and growth of 6/7 different insect-derived strains of the intracellular bacterial symbiont Wolbachia.

Conclusions

The GMA/LULS61 cell line has potential for application in a variety of studies investigating the biology of G. m. morsitans and its associated pathogenic and symbiotic microorganisms.

Graphical Abstract
Response to semaglutide of non-drinker subjects with type 2 diabetes
Authors: Petralli Giovanni , Raggi Francesco , Zoppo Alice Del , Rovera Chiara , Salvati Antonio , Brunetto Maurizia Rossana , Solini Anna
Published: May 2024

Background

Metabolic dysfunction-associated Steatotic Liver Disease (MASLD) displays a worse prognosis in subjects with type 2 diabetes (T2D); effective treatments are, so far, scanty. Semaglutide showed efficacy in improving steatohepatitis. We longitudinally observed a MASLD cohort of T2D subjects starting semaglutide, to detect an improvement of non-invasive surrogates of steatosis and fibro-inflammatory liver involvement, evaluating the role of mild alcohol consumption.

Patients and methods

In 62 overweight/obese T2D subjects with MASLD (36 non-drinker and 26 mild alcohol consumers), anthropometric, bio-humoral and transient elastography (TE) data were collected before (T0) and after an average time of 6.4 month (T1) from injective semaglutide prescription. Circulating levels of hormones (GIP, GLP-1, glucagon, insulin) and inflammatory markers (TNFα, MCP-1, IL-18, IL-10) were measured. Steatotic and necro-inflammatory liver involvement was evaluated with FibroScan controlled attenuation parameter (CAP) and liver stiffness (LS), respectively.

Results

Significant (p < 0.006) T0-T1 reductions of BMI, waist circumference, fasting glucose, and HbA1c were observed. AST (-10 ± 3 IU/L), ALT (-18 ± 5 IU/L), GGT (-33 ± 15 IU/L), CAP (-25 ± 8 dB/m) and LS (-0.8 ± 0.4 kPa) were reduced, too. GLP-1 increased (+ 95.9 pM, p < 0.0001) and IL-18 was reduced (-46.6 pg/ml, p = 0.0002). After adjustment for confounders, CAP improving was only related to GLP-1 increase (ß=-0.437, p = 0.0122). Mild alcohol intake did not influence these relations.

Conclusion

Use of semaglutide in subjects with T2D and MASLD is associated with a significant decline of liver steatosis and necroinflammation proxies; mild alcohol assumption did not exert any influence. An independent effect of GLP-1 raise was observed on reduction of steatosis, irrespective of alcohol consumption.
Prospective association of the infant gut microbiome with social behaviors in the ECHO consortium
Authors: Laue Hannah E. , Bonham Kevin S. , Coker Modupe O. , Moroishi Yuka , Pathmasiri Wimal , McRitchie Susan , Sumner Susan , Hoen Anne G. , Karagas Margaret R. , Klepac-Ceraj Vanja , Madan Juliette C. ,   program collaborators for Environmental influences on Child Health Outcomes, Smith P. B. , Newby K. L. , Jacobson L. P. , Catellier D. J. , Gershon R. , Cella D. , Koinis Mitchell D. , Deoni S. , D’Sa V.
Published: May 2024

Background

Identifying modifiable risk factors of autism spectrum disorders (ASDs) may inform interventions to reduce financial burden. The infant/toddler gut microbiome is one such feature that has been associated with social behaviors, but results vary between cohorts. We aimed to identify consistent overall and sex-specific associations between the early-life gut microbiome and autism-related behaviors.

Methods

Utilizing the Environmental influences on Children Health Outcomes (ECHO) consortium of United States (U.S.) pediatric cohorts, we gathered data on 304 participants with fecal metagenomic sequencing between 6-weeks to 2-years postpartum (481 samples). ASD-related social development was assessed with the Social Responsiveness Scale (SRS-2). Linear regression, PERMANOVA, and Microbiome Multivariable Association with Linear Models (MaAsLin2) were adjusted for sociodemographic factors. Stratified models estimated sex-specific effects.

Results

Genes encoding pathways for synthesis of short-chain fatty acids were associated with higher SRS-2 scores, indicative of ASDs. Fecal concentrations of butyrate were also positively associated with ASD-related SRS-2 scores, some of which may be explained by formula use.

Limitations

The distribution of age at outcome assessment differed in the cohorts included, potentially limiting comparability between cohorts. Stool sample collection methods also differed between cohorts. Our study population reflects the general U.S. population, and thus includes few participants who met the criteria for being at high risk of developing ASD.

Conclusions

Our study is among the first multicenter studies in the U.S. to describe prospective microbiome development from infancy in relation to neurodevelopment associated with ASDs. Our work contributes to clarifying which microbial features associate with subsequent diagnosis of neuropsychiatric outcomes. This will allow for future interventional research targeting the microbiome to change neurodevelopmental trajectories.
Factors associated with timely initiation of antenatal care among reproductive age women in The Gambia: a multilevel fixed effects analysis
Authors: Daniels-Donkor Silas Selorm , Afaya Agani , Daliri Dennis Bomansang , Laari Timothy Tienbia , Salia Solomon Mohammed , Avane Mabel Apaanye , Afaya Richard Adongo , Yakong Vida Nyagre , Ayanore Martin Amogre , Alhassan Robert Kaba
Published: May 2024

Background

A significant factor impacting the incidence of maternal and neonatal fatalities is the timely initiation of antenatal care (ANC) services in healthcare facilities. Despite the recommendations by the World Health Organization and the numerous benefits of timely initiation of ANC, studies have revealed that the overall prevalence of timely ANC initiation in 36 sub-Saharan African countries remains low and women in The Gambia also initiate ANC late. However, no known study in The Gambia has focused on assessing the factors associated with timely initiation of ANC at the time of writing this paper. Thus, this study aimed to assess the prevalence and factors associated with the timely initiation of ANC among reproductive-age women in The Gambia.

Methods

A cross-sectional survey design was used in this study and conducted among 5,734 reproductive-age women using data from the 2019–2020 Gambia Demographic and Health Survey (GDHS). Using STATA version 14.0, we conducted the analysis using descriptive and inferential statistics. Multilevel logistic regression models were fitted to determine the factors associated with timely ANC utilization and adjusted odds ratios were used to present the results with statistical significance set at p < 0.05.

Results

The overall prevalence of timely initiation of ANC services among reproductive-age women in The Gambia was 43.0%. We found that women aged 30–34 [aOR = 1.79, 95% CI = 1.30–2.47], those who were married [aOR = 2.69, 95% CI = 1.85–3.90] as well as women from the richest households [aOR = 1.63, 95% CI = 1.20, 2.20] had higher odds of seeking timely ANC services as compared to their counterparts. Also, those who had given birth to two children [aOR = 0.74, 95% CI = 0.6 -0.91] had lower odds of initiating timely ANC as compared to those who had given birth only once. Women who reside in rural areas [aOR = 1.72, 95%CI = 1.34, 2.20] also had higher odds of seeking timely ANC services than those residing in urban areas.

Conclusion

Individual-level factors such as maternal age, marital status, parity, wealth status, place of residence, and religion were associated with the timely initiation of ANC services among reproductive-age women. These factors ought to be considered in efforts to increase the timely initiation of ANC among reproductive-age women in The Gambia.
Remote family education and support program for parents of patients with adolescent and early adulthood eating disorders based on interpersonal psychotherapy: study protocol for a pilot randomized controlled trial
Authors: Katsuki Fujika , Watanabe Norio , Kondo Masaki , Sawada Hanayo , Yamada Atsurou
Published: May 2024

Background

In cases of adolescent and early adulthood eating disorders, despite the importance of the patients’ relationship with their parents, conflict and confusion frequently occur among them. Interpersonal psychotherapy (IPT) is a present-focused psychotherapy that emphasizes the interpersonal context of symptoms. We developed a remote family education and support program exclusively for parents of patients with eating disorders, based on the principle of IPT. The use of IPT is expected to reduce conflicts in the patient-parent relationship. Consequently, parents will be better able to listen to patients, and patients will be better able to express their thoughts and desires. In this study, we describe the protocol for a randomized controlled trial designed to examine the effectiveness of this program in promoting effective communication in their home based on active listening skills of parents of patients with adolescent and early adulthood eating disorders.

Methods

Participants will be parents of patients aged 12–29 years with adolescent and early adulthood eating disorders. Individually randomized, parallel-group trial design will be employed. Seventy participants will be allocated to one of two treatment conditions: (1) remote family education and support program (four, 150 min weekly group sessions) for parents plus treatment-as-usual for patients (consultation by physicians or no treatment), or (2) waiting for the control condition (parents will wait to start the program for 8 weeks) plus treatment-as-usual for patients. The primary outcome measure will be parents’ active listening ability as measured by the Active Listening Attitude Scale at 8 weeks after randomization. Additionally, perception of social support (Social Provision Scale-10 item), loneliness (UCLA Loneliness Scale), mental health status (K6), family function (Family Assessment Device), and parent-evaluated eating disorder symptoms (Anorectic Behavior Observation Scale) will be assessed. Data from the intention-to-treat sample will be analyzed 8 weeks after randomization.

Discussion

This is the first study to evaluate the effectiveness of a family education and support program for parents of patients with adolescent and early adulthood eating disorders based on IPT. If this type of intervention is effective, although indirect, it could be a new support method for this patient population.

Trial registration: Clinical Trials. gov ID NCT05840614.
Dismantling the myth of “all foods fit” in eating disorder treatment
Authors: Brewerton Timothy D. , Dennis Kim , Wiss David A.
Published: May 2024

We call for a reevaluation of the long-standing dogmatic nutritional principle that “all foods fit” for all cases of eating disorders (EDs) and its corollary, “there are no bad foods” (for anyone ever) during ED treatment. Based on accumulated scientific research, we challenge these ideologies as outdated, confusing, and potentially harmful to many patients. We review the evidence that indicates the folly of these assumptions and show there are a variety of exceptions to these rules, including (1) food allergies, sensitivities, and intolerances, (2) religious and spiritual preferences or doctrines, and (3) the ubiquitous emergence and widespread availability of ultra-processed foods leading to the potential development of addiction-like eating and a higher prevalence of various medical and psychiatric comorbidities, as well as higher mortality. This evidence supports a nutritional psychiatry approach that should be integrated into (rather than dissociated from) ED treatment research and practice.
Rapid detection of virulence-related genes by multiplex PCR in five pathogenic bacteria of mulberry bacterial wilt
Authors: Yuan Ting , Qazi Izhar Hyder , Huang Xinpeng , Liu Jiping
Published: May 2024

Mulberry bacterial wilt is a devastating disease that is difficult to control and causes serious economic losses to the sericulture industry. This disease is mostly caused by a diverse group of pathogenic and opportunistic bacteria including,Ralstonia pseudosolanacearum,Pantoea ananatis,Enterobacter cloacaecomplex (ECC),Klebsiella pneumoniaespecies complex (KpSC), andK. oxytocacomplex (KoC). Due to the lack of a rapid and reliable test to simultaneously detect these complex pathogens of mulberry wilt, we developed a multiplex PCR (mPCR) assay to detect five virulence-related genes carried by the pathogenic bacteria of mulberry bacterial wilt disease. The primers were designed for the virulence-related genes:pleD(GGDF structural domain-containing protein),yjfP(esterase),pelY(peripheral pectate lyase),ampD(N-acetyl-anhydromuranmyl-L-alanine amidase), andripW(type III effector). Overall, the developed mPCR assay showed highly specific, sensitive and reproducible detection of target pathogens. Briefly, the results showed that the mPCR was highly specific in individual reactions, and the lowest detection concentration of the five pathogenic bacteria was 1.87 × 103 CFU/mL (DNA = 2.45 pg/μL). From 46 natural mulberry wilt samples, the mPCR detection rates ofP. ananatis,ECC,KpSC,KoCandR. pseudosolanacearumwere 8.69, 91.3, 34.7, 23.9 and 65.21%, respectively. The traditional culture media isolation methods showed comparable results. The pathogenicity test of 84 suspected pathogenic bacteria revealed that the morbidity (average morbidity level) caused by the pathogenic bacteria detected by mPCR was ≥ 65.5%, while the morbidity of the undetected pathogenic bacteria was ≤ 35.5%. Based on these results, we believe that the mPCR developed in the present study will be useful in rapid, reproducible, and sensitive detection of the pathogenic bacteria causing mulberry bacterial wilt including,R. pseudosolanacearum,P. ananatis,ECC,KpSC, andKoC.

Graphical abstract
Therapeutic potential of oleic acid supplementation in myotonic dystrophy muscle cell models
Authors: Moreno Nerea , Sabater-Arcis Maria , Sevilla Teresa , Alonso Manuel Perez , Ohana Jessica , Bargiela Ariadna , Artero Ruben
Published: May 2024

Background

We recently reported that upregulation of Musashi 2 (MSI2) protein in the rare neuromuscular disease myotonic dystrophy type 1 contributes to the hyperactivation of the muscle catabolic processes autophagy and UPS through a reduction in miR-7 levels. Because oleic acid (OA) is a known allosteric regulator of MSI2 activity in the biogenesis of miR-7, here we sought to evaluate endogenous levels of this fatty acid and its therapeutic potential in rescuing cell differentiation phenotypes in vitro. In this work, four muscle cell lines derived from DM1 patients were treated with OA for 24 h, and autophagy and muscle differentiation parameters were analyzed.

Results

We demonstrate a reduction of OA levels in different cell models of the disease. OA supplementation rescued disease-related phenotypes such as fusion index, myotube diameter, and repressed autophagy. This involved inhibiting MSI2 regulation of direct molecular target miR-7 since OA isoschizomer, elaidic acid (EA) could not cause the same rescues. Reduction of OA levels seems to stem from impaired biogenesis since levels of the enzyme stearoyl-CoA desaturase 1 (SCD1), responsible for converting stearic acid to oleic acid, are decreased in DM1 and correlate with OA amounts.

Conclusions

For the first time in DM1, we describe a fatty acid metabolism impairment that originated, at least in part, from a decrease in SCD1. Because OA allosterically inhibits MSI2 binding to molecular targets, reduced OA levels synergize with the overexpression of MSI2 and contribute to the MSI2 > miR-7 > autophagy axis that we proposed to explain the muscle atrophy phenotype.
Effects of Metreleptin in Patients With Generalized Lipodystrophy Before vs After the Onset of Severe Metabolic Disease
Authors: Brush Maiah , Auh Sungyoung , Cochran Elaine , Tuska Rebecca , Koh Christopher , Kleiner David E , Lightbourne Marissa , Brown Rebecca J
Published: May 2024

Context

Leptin replacement therapy with metreleptin improves metabolic abnormalities in patients with generalized lipodystrophy (GLD).

Objective

Determine how timing of metreleptin initiation in the clinical course of GLD affects long-term metabolic health.

Methods

Retrospective analysis of patients ≥6 months old with congenital (n = 47) or acquired (n = 16) GLD treated with metreleptin at the National Institutes of Health since 2001. Least squares means for glycated hemoglobin (HbA1c), insulin area under the curve from oral glucose tolerance tests, triglycerides, urine protein excretion, platelets, transaminases, and aspartate aminotransferase (AST) to Platelet Ratio Index for early and late treatment groups, defined by baseline metabolic health, were analyzed during median 72 (24-108) months’ follow-up.

Results

Compared to late groups, early groups based on metabolic status had higher mean ± SEM insulin area under the curve (20 831 ± 1 vs 11 948 ± 1), lower HbA1c (5.3 ± 0.3 vs 6.8 ± 0.3%), triglycerides (101 ± 1 vs 193 ± 1 mg/dL), urine protein excretion (85 ± 1.5 vs 404 ± 1.4 mg/24 h), alanine aminotransferase (30 ± 1 vs 53 ± 1 U/L), AST (23 ± 1 vs 40 ± 1 U/L), and AST to Platelet Ratio Index (0.22 ± 1.3 vs 0.78 ± 1.3), and higher platelets (257 ± 24 vs 152 ± 28 K/µL) during follow-up (P < .05). Compared to patients ≥6 years old at baseline, patients <6 years had lower HbA1c (4.5 ± 0.5 vs 6.4 ± 0.2%) and higher AST (40 ± 1vs 23 ± 1 U/L) during follow (P < .05).

Conclusion

Patients with GLD who initiated metreleptin before the onset of severe metabolic complications had better long-term control of diabetes, proteinuria, and hypertriglyceridemia. Early treatment may also result is less severe progression of liver fibrosis, but further histological studies are needed to determine the effects of metreleptin therapy on liver disease.
Royal Authority, Ritual, and the Bureaucratic Career of the Descendants of Li Rusong and Rumei in Eighteenth- and Nineteenth-Century Chosŏn
Authors: Han Seunghyun
Published: May 2024

This essay examines Chosŏn monarchs’ patronage of the Nongsŏ Yi clan, a representative Ming descent group in Chosŏn, during the eighteenth and nineteenth centuries. The clan claimed its descent from Li Rusong and Rumei, the commanders of the Ming expeditionary forces during the Imjin War. This essay investigates the bureaucratic advancement of Li Rusong and Rumei's descendants, closely analyzing the monarchs’ roles in making the clan a military yangban family and the obstacles that constrained such royal endeavors. It will also illuminate the close relationship between the intensification of Ming loyalism and the surging bureaucratic fortunes of the Nongsŏ Yi clan, placing special emphasis on how the rulers made use of Ming loyalist rituals to nurture the careers of the Nongsŏ Yi. This study also examines the bureaucratic vicissitudes of the Nongsŏ Yi during the nineteenth century, when the rulers exhibited a diminished interest in boosting Ming loyalism. This essay will also shed light on the status of Ming loyalism and the changing nature of rulership in nineteenth-century Chosŏn.
The Drosophila Nesprin-1 homolog MSP300 is required for muscle autophagy and proteostasis
Authors: van der Graaf Kevin , Srivastav Saurabh , Nishad Rajkishor , Stern Michael , McNew James A.
Published: May 2024

Nesprin proteins, which are components of the linker of nucleoskeleton and cytoskeleton (LINC) complex, are located within the nuclear envelope and play prominent roles in nuclear architecture. For example, LINC complex proteins interact with both chromatin and the cytoskeleton. Here, we report that the Drosophila Nesprin MSP300 has an additional function in autophagy within larval body wall muscles. RNAi-mediated MSP300 knockdown in larval body wall muscles resulted in defects in the contractile apparatus, muscle degeneration and defective autophagy. In particular, MSP300 knockdown caused accumulation of cytoplasmic aggregates that contained poly-ubiquitylated cargo, as well as the autophagy receptor ref(2)P (the fly homolog of p62 or SQSTM) and Atg8a. Furthermore, MSP300 knockdown larvae expressing an mCherry–GFP-tagged Atg8a transgene exhibited aberrant persistence of the GFP signal within these aggregates, indicating failure of autophagosome maturation. These autophagy deficits were similar to those exhibited by loss of the endoplasmic reticulum (ER) fusion protein Atlastin (Atl), raising the possibility that Atl and MSP300 might function in the same pathway. In support of this possibility, we found that a GFP-tagged MSP300 protein trap exhibited extensive localization to the ER. Alteration of ER-directed MSP300 might abrogate important cytoskeletal contacts necessary for autophagosome completion.
Biphasic burrowing in Atlantic hagfish (Myxine limosa)
Authors: Fudge Douglas S. , Lee Joshua , Guillen Kennedy , Donatelli Cassandra M. , Lowe Andrew , Arnold Luke , Kahale-Lua Keolani , Quinteros Christian , Ly Peter , Atkins Larissa , Bressman Noah , McCord Charlene L.
Published: May 2024

Myxine limosa is a burrowing species of hagfish that occurs in the western North Atlantic in areas with muddy substrate and at depths generally greater than 100 meters. Burrowing of M. limosa has been observed from submersibles, but little is known about the behavior of these animals within the substrate or the biomechanical mechanisms involved. Here, we investigated burrowing in M. limosa by observing individuals as they burrowed through transparent gelatin. A photoelastic setup using crossed polarizers allowed us to visualize stress development in the gelatin as the hagfish moved through it. We found that M. limosa created U-shaped burrows in gelatin using a stereotyped, two-phase burrowing behavior. In the first (‘thrash’) phase, hagfish drove their head and their anterior body into the substrate using vigorous sinusoidal swimming movements, with their head moving side-to-side. In the second (‘wriggle’) phase, swimming movements ceased, with propulsion coming exclusively from the anterior, submerged portion of body. The wriggle phase involved side-to-side head movements and movements of the submerged part of the body that resembled the internal concertina strategy used by caecilians and uropeltid snakes. The entire burrowing process took on average 7.6 min to complete and ended with the hagfish's head protruding from the substrate and the rest of its body generally concealed. Understanding the burrowing activities of hagfishes could lead to improved understanding of sediment turnover in marine benthic habitats, new insights into the reproductive behavior of hagfishes, or even inspiration for the design of burrowing robots.
Transcription factors ERα and Sox2 have differing multiphasic DNA- and RNA-binding mechanisms
Authors: Hemphill Wayne O. , Steiner Halley R. , Kominsky Jackson R. , Wuttke Deborah S. , Cech Thomas R.
Published: May 2024

Many transcription factors (TFs) have been shown to bind RNA, leading to open questions regarding the mechanism(s) of this RNA binding and its role in regulating TF activities. Here, we use biophysical assays to interrogate thekon,koff, andKdfor DNA and RNA binding of two model human TFs, ERα and Sox2. Unexpectedly, we found that both proteins exhibit multiphasic nucleic acid–binding kinetics. We propose that Sox2 RNA and DNA multiphasic binding kinetics can be explained by a conventional model for sequential Sox2 monomer association and dissociation. In contrast, ERα nucleic acid binding exhibited biphasic dissociation paired with novel triphasic association behavior, in which two apparent binding transitions are separated by a 10–20 min “lag” phase depending on protein concentration. We considered several conventional models for the observed kinetic behavior, none of which adequately explained all the ERα nucleic acid–binding data. Instead, simulations with a model incorporating sequential ERα monomer association, ERα nucleic acid complex isomerization, and product “feedback” on isomerization rate recapitulated the general kinetic trends for both ERα DNA and RNA binding. Collectively, our findings reveal that Sox2 and ERα bind RNA and DNA with previously unappreciated multiphasic binding kinetics, and that their reaction mechanisms differ with ERα binding nucleic acids via a novel reaction mechanism.