bluuebunny/crossref_metadata_2025 huggingface dataset:
Non-invasive cortical stimulation for drug-resistant pain
Authors: Garcia-Larrea Luis
Published: June 2023

Purpose of review

Neuromodulation techniques are being increasingly used to alleviate pain and enhance quality of life. Non-invasive cortical stimulation was originally intended to predict the efficacy of invasive (neurosurgical) techniques, but has now gained a place as an analgesic procedure in its own right.

Recent findings

Repetitive transcranial magnetic stimulation (rTMS): Evidence from 14 randomised, placebo-controlled trials (~750 patients) supports a significant analgesic effect of high-frequency motor cortex rTMS in neuropathic pain. Dorsolateral frontal stimulation has not proven efficacious so far. The posterior operculo-insular cortex is an attractive target but evidence remains insufficient. Short-term efficacy can be achieved with NNT (numbers needed to treat) ~2–3, but long-lasting efficacy remains a challenge.

Like rTMS, transcranial direct-current stimulation (tDCS) induces activity changes in distributed brain networks and can influence various aspects of pain. Lower cost relative to rTMS, few safety issues and availability of home-based protocols are practical advantages. The limited quality of many published reports lowers the level of evidence, which will remain uncertain until more prospective controlled studies are available.

Both rTMS and tDCS act preferentially upon abnormal hyperexcitable states of pain, rather than acute or experimental pain. For both techniques, M1 appears to be the best target for chronic pain relief, and repeated sessions over relatively long periods of time may be required to obtain clinically significant benefits. Patients responsive to tDCS may differ from those improved by rTMS.
John Herbert Beynon. 29 December 1923—24 August 2015
Authors: Boyd Robert
Published: June 2023

John Herbert Beynon was born in a Welsh mining village in 1923, graduated BSc (Hons, physics) at 19, then worked on weapons research for the war effort in World War Two. In 1947 he started a 22-year career at Imperial Chemical Industries (ICI) in Manchester, where, with his technician Albert Williams, he revolutionized mass spectrometry from a physics method to an essential technique for organic chemistry. In 1960 he completed his landmark book
Mass spectrometry and its applications to organic chemistry
, which was reprinted by the American Society for Mass Spectrometry as a ‘Classic Book’. He continued his creative work in 1969–1974 at Purdue University. In 1974 he started his Royal Society Research Professorship at Swansea University, his alma mater. Collaborations here with a long string of students, postdoc, visiting professors and scientists from many countries resulted in about 65% of his list of 395 peer-reviewed publications. His unexpected retirement led to a compendium of 32 articles in his honour. He then initiated and edited a new journal,
Rapid Communications in Mass Spectrometry
.
Doomed drones? Using passage experiments and mathematical modelling to determine Deformed wing virus population dynamics in male honeybees
Authors: Woodford Luke , Steketee Pieter C. , Evans David J.
Published: June 2023

Varroa destructor
is an ectoparasitic mite of honeybees which vectors a range of pathogenic viruses, the most notable being Deformed wing virus (DWV). Mites parasitise bees during pupal development and male honeybees, drones, have a longer development cycle than female workers (24 versus 21 days), allow for more progeny mites to develop per foundress (1.6–2.5 compared to 0.7–1.45). How this longer exposure time influences evolution of the transmitted virus population is unknown. Using uniquely tagged viruses recovered from cDNA we investigated the replication, competition and morbidity of DWV genotypes in drones. Assays examining virus replication and morbidity revealed drones are highly susceptible to both predominant genotypes of DWV. In virus passage studies using an equimolar inocula of major DNA genotypes and their recombinants, the recombinant form dominated but did not reach 100% of the virus population within 10 passages. Using an
in-silico
model of the virus–mite–bee system we examined bottlenecks during virus acquisition by the mite and subsequent injection of viruses into the host, which may play a significant role in shaping virus diversity. This study furthers our understanding of the variables influencing DWV diversity changes and provides insight into areas of future research in the mite–virus–bee system.
Larsenimonas rhizosphaerae sp. nov., isolated from a tidal mudflat
Authors: Lee Soon Dong , Kim In Seop
Published: June 2023

A Gram-reaction-negative, aerobic, motile, rod-shaped bacterium, designated GH3-8T, was isolated from rhizosphere mudflats of halophytes on the seashore of Gangwha Island, Republic of Korea. Growth was observed at pH 4–10 (optimum, pH 7–8), at 4–40 °C (optimum, 37 °C) and in the presence of 0.5–20 % (w/v) NaCl (optimum, 4 %). The predominant respiratory quinone was Q-9. The major fatty acids were C18 : 1 ω7c, C16 : 0, summed feature 3 (C16 : 1 ω7c and/or C16 : 1 ω6c) and C12 : 0 3OH. The polar lipids contained phosphatidylethanolamine, phosphatidylglycerol, an unidentified phosphoglycolipid, an unidentified phosphoglycoaminolipid, an unidentified glycoaminolipid, two unidentified phospholipids and two unidentified lipids. Phylogenetic analysis based on 16S rRNA gene sequences exhibited that the isolate belonged to the family

Halomonadaceae

, with the most closely related species,

Larsenimonas suaedae

(98.1 % sequence similarity) and

Larsenimonas salina

(97.9 %). Sequence similarity values between the isolate and other representatives of the family

Halomonadaceae

were all below 95.3 %. The values of average nucleotide identity between strain GH3-8T and members of the genus

Larsenimonas

were 73.42 % with

L. salina

CCM 8464T and 72.38 % with

L. suaedae

DSM 22428T. Strain GH3-8T showed digital DNA–DNA hybridization values of 18.5–18.6 % with members of the genus

Larsenimonas

. Based on phenotypic and chemotaxonomic distinctiveness together with low overall genomic relatedness indices and phylogenetic data, the isolate is considered to represent a new species of the genus

Larsenimonas

, for which the name Larsenimonas rhizosphaerae sp. nov. is proposed, with the type strain GH3-8T (=KCTC 62127T=NBRC 113214T).
Correlation analysis for alterations of intestinal flora in hepatocellular carcinoma patients: combinatorial detection of Coriobacterium, Atopobium, Coprococcus and Veillonella dispar may be a new method for HCC diagnosis
Authors: Xu Wenqian , Jiang Yan , Tao Jinglong , Liu Yunhong , Xia Yongwu , Chen Cheng , Jiang Xiaoxin
Published: June 2023

Introduction. Hepatocellular carcinoma (HCC) is one of the most common malignant tumours in the world. Due to the characteristics of low early diagnosis rate, high malignancy and rapid progression, the majority of diagnosed patients are in the middle or late stage. Accumulating evidence reveals that intestinal flora imbalance will aggravate HCC by disturbing immune regulation, especially interleukin expression. Therefore, intestinal flora-based methods have the potential to be new diagnostic or therapeutic methods for HCC.

Hypothesis. Compositions of intestinal florae were different between HCC patients and healthy people. Further, intestinal florae may alleviate or aggravate HCCs.

Methods. To determine which intestinal florae and interleukin aggravate HCCs, we studied the differences in intestinal florae composition and interleukin (IL) indices between HCC patients and healthy people. A total of 64 HCC patients and 24 healthy people were recruited, and their fresh stool samples and serum samples were collected for 16S rRNA sequencing and metabolite index measurement.

Results. Data showed that 484 operational taxonomic units (OTUs) and 476 OTUs were detected in the HCC and control groups, respectively. From the phylum level to the species level, 5, 6, 10, 15, 23 and 19 colonies showed differential abundance between the HCC group and healthy people. Moreover, interleukin-6 expression and interleukin-10 expression were significantly different between two groups. Of note, differences of

Coriobacterium

,

Atopobium

and

Coprococcus

at genus level and

Veillonella dispar

at species level in two groups were significantly related to IL-6 and IL-10.

Conclusion. The abundance of intestinal florae in the HCC group was different from the control group. Additionally, combinatorial detection of

Coriobacterium

,

Atopobium

and

Coprococcus

at genus level and

V. dispar

at species level may be a new method for HCC diagnosis.
The utility of wearable headband electroencephalography and pulse photoplethysmography to assess cortical hyperarousal in individuals with stress-related mental disorders
Authors: Blaskovich Borbala , Bullón-Tarrasó Esteban , Pöhlchen Dorothee , Manafis Alexandros , Neumayer Hannah , Besedovsky Luciana , Brückl Tanja ,   BeCOME Working Group, Simor Peter , Binder Florian P. , Spoormaker Victor I.
Published: June 2023

Study Objectives

Several stress-related mental disorders are characterized by disturbed sleep, but objective sleep biomarkers are not routinely examined in psychiatric patients. We examined the use of wearable-based sleep biomarkers in a psychiatric sample with headband electroencephalography (EEG) including pulse photoplethysmography (PPG), with an additional focus on microstructural elements as especially the shift from low to high frequencies appears relevant for several stress-related mental disorders (cortical hyperarousal).

Methods

We acquired 483 nights and could analyze 372 nights of sufficient quality from 83 healthy participants and those with a confirmed stress-related mental disorder (anxiety-affective spectrum). We analyzed the data with respect to macrostructural and microstructural characteristics according to the newly described spectral slope fitting over the whole frequency spectrum.

Results

The headbands were accepted well by patients and the data quality was sufficient for most nights. The macrostructural analyses revealed trends for significance regarding sleep continuity but not sleep depth variables. The spectral analyses yielded no between-group differences except for a group × age interaction, with the normal age-related decline in the low versus high frequency power ratio flattening in the patient group. PPG analyses showed that the mean heart rate was higher in the patient group in pre-sleep epochs, a difference that reduced during sleep and dissipated at wakefulness.

Conclusions

Wearable devices that record EEG and/or PPG could be used over multiple nights to assess relevant markers such as sleep fragmentation, cortical hyperarousal, and sympathetic drive throughout the sleep–wake cycle in patients with stress-related mental disorders.
Atypical intrinsic neural timescale in the left angular gyrus in Alzheimer’s disease
Authors: Murai Shota A. , Mano Tatsuo , Sanes Jerome N. , Watanabe Takamitsu
Published: June 2023

Alzheimer’s disease (AD) is characterised by cognitive impairment and progressive brain atrophy. Recent human neuroimaging studies showed that such AD symptoms are linked with anatomical and functional changes seen in the default mode network (DMN), but the key brain region whose atrophy disturbs the neural activity of the DMN and consequently contributes to the symptoms of AD remains unclear. Here, we examined the intrinsic neural timescales (INT) of the regions in the DMN aiming to identify such a crucial brain area. We investigated INT since prior work demonstrated its utility in quantifying local neural dynamics and bridging knowledge gaps between atypical local neuroanatomical features and symptoms in neuropsychiatric disorders. We used resting-state functional MRI data and compared INT between individuals diagnosed with AD and age-/sex-/handedness-matched cognitively normal individuals. To exclude the possibility that a region outside of the DMN has such a critical role, we first performed an exploratory whole-brain analysis and found that only the left angular gyrus, a region within the DMN, exhibited a shorter INT in the AD group compared to those with normal cognition. We also identified an AD-specific decrease in the grey matter volume in the left angular gyrus and revealed that such regional atrophy shortened the INT of the angular gyrus and consequently reduced the overall INT of the DMN. Moreover, we found that the overall shorter DMN INT led to the symptoms of AD, particularly, its impairments of attention control. Taken together, our findings indicate that the left angular gyrus serves as a key brain region whose structural atrophy and resultantly shorter INT destabilise DMN neural dynamics and contribute substantially to AD cognitive decline. Clinically, the outcome of this study indicates that INT of the left angular gyrus could serve as a convenient biomarker for the cognitive symptoms of AD.
Dietary nutrient balances and serum cholesterol: a new approach to an old question
Authors: Corrêa Leite Maria Léa
Published: June 2023

The continuing controversy concerning the relationships between diet and serum cholesterol levels highlights the need for innovative analytical approaches to the question. It is now acknowledged that dietary data are compositional in nature, but it is less widely recognised that the same is also true of any variable expressed in concentration units (mg/mL), such as serum cholesterol. Compositional data are parts of a whole and convey essentially relative information, which means they need to be interpreted in terms of the ratios between the individual components of the composition. The various formulations of log-ratio transformations proposed for compositional data analysis provide new variables that can be included in standard regression models as dependent and explanatory variables. Using data from an Italian population-based study, we describe the use of such methods to evaluate the relationships between a two-part composition (non-HDL and HDL cholesterol and their total) and three dietary nutrient compositions, and define multivariate linear regression equations that have one cholesterol log-ratio and the composition total as dependent variables and some macro- and micronutrient log-ratios as explanatory terms. Two alternative models are fitted: one containing the nutrient log-ratios in the form of their simplified expression as orthogonal balances; the other estimating the impact of nutrient pivot balances, which express the relative dominance of each of the parts of the dietary compositions. This approach to investigating the relationship between diet and serum cholesterol allows the simultaneous examination of the effects of non-redundant dietary components on both the quantitative and qualitative aspects of serum cholesterol profiles, and provides insights into some matters concerning public health.
A single blinded, phase IV, adaptive randomised control trial to evaluate the safety of coadministration of seasonal influenza and COVID-19 vaccines (The FluVID study)
Authors: Ramsay JA , Jones M , Vande More AM , Hunt SL , Williams PCM , Messer M , Wood N , Macartney K , Lee FJ , Britton WJ , Snelling TL , Caterson ID
Published: June 2023

Objectives

We evaluated the frequency of moderate and severe adverse events following coadministration of seasonal influenza vaccine (SIV) versus placebo with COVID-19 vaccines among adults to support practice guidelines.

Methods

FluVID is a participant-blinded, phase IV, randomised control trial. On the same day as the participant’s scheduled COVID-19 vaccine, participants were randomised to receive SIV or saline placebo; those assigned placebo at visit one then received SIV a week later, and vice versa. Self-reported adverse events were collected for daily seven days following each visit.

The primary endpoint was any solicited adverse event of at least moderate severity occurring up to seven days following receipt of SIV or placebo. This was modelled using a Bayesian logistic regression model. Analyses were performed by COVID-19 vaccine type and dose number.

Results

Overall, 248 participants were enrolled; of these, 195 had received BNT162b2 and 53 had received mRNA1273 COVID-19 vaccines according to national guidelines. After randomisation, 119 were assigned to receive SIV and 129 were assigned to receive placebo at visit one.

Adverse events were most frequently reported as mild (grade 1) in nature. Among 142 BNT162b2 booster dose one and 43 BNT162b2 booster dose two recipients, the posterior median risk difference for moderate/severe adverse events following SIV versus placebo was 13% (95% credible interval [CrI] -0.03 to 0.27) and 13% (95%CrI -0.37 to 0.12), respectively. Among 18 mRNA1273 booster dose one and 35 mRNA1273 booster dose two recipients, the posterior median risk difference of moderate/severe adverse events following influenza vaccine versus placebo was 6% (95%CrI -0.29 to 0.41) and -4% (95%CrI -0.30 to 0.23), respectively.

Conclusion

Adverse events following SIV and COVID-19 co-administration were generally mild and occurred with similar frequency to events following COVID-19 vaccine alone. We found no evidence to justify routine separation of SIV and COVID-19 vaccine doses.

Clinical trial registration

ACTRN12621001063808

Highlights

The coadministration of mRNA COVID-19 and influenza vaccines typically resulted in mild events that were limited to 4 days.

Frequency and nature of adverse events were similar to those in other randomised trials.

This trial demonstrates a suitable design for evaluating vaccine schedules and coadministration.
Chronotype changes after sex hormone use: a prospective cohort study in transgender users of gender-affirming hormones
Authors: Morssinkhof Margot W. L. , Zwager Annefleur , Tuuk Karin van der , Heijer Martin den , van der Werf Ysbrand D. , Stenvers Dirk Jan , Broekman Birit F. P.
Published: June 2023

Background

Chronotype, an individual’s preferred sleep-wake timing, is influenced by sex and age. Men report a later chronotype than women and age is associated with earlier chronotype. The sex-related changes in chronotype coincide with puberty and menopause. However, the effects of sex hormones on human chronotype remain unclear.

Aim

To examine the impact of 3 months of gender-affirming hormone therapy (GAHT) on chronotype in transgender persons.

Methods

This study used data from 93 participants from the prospective RESTED cohort, including 49 transmasculine (TM) participants starting testosterone and 44 transfeminine (TF) participants starting estrogens and antiandrogens. Midpoint of sleep and sleep duration were measured using the ultra-short Munich ChronoType Questionnaire (µMCTQ).

Results

After 3 months of GAHT, TM participants’ midpoint of sleep increased by 24 minutes (95%CI: 3 to 45), whereas TF participants’ midpoint of sleep decreased by 21 minutes (95%CI: −38 to −4). Total sleep duration did not change significantly in either group.

Conclusion

This study provides the first prospective assessment of sex hormone use and chronotype in transgender persons, showing that GAHT can change chronotype in line with cisgender sex differences. These findings provide a basis for future studies on biological mechanisms and clinical consequences of chronotype changes.
Anti-SARS-CoV-2 Antibody Kinetics up to 6 months of follow-up: Result from a Nation-wide Population-based, Age Stratified Sero-Epidemiological Prospective Cohort Study in India
Authors: Misra Puneet , Singh Arvind Kumar , Mishra Baijayantimala , Behera Bijayini , Patro Binod Kumar , Medigeshi Guruprasad R , Joshi Hari Shanker , Ahmad Mohammad , Chaturvedi P K , Chinnakali Palanivel , Haldar Partha , Bairwa Mohan , Kharya Pradeep , Dhodapkar Rahul , Rath Ramashankar , Guleria Randeep , Rai Sanjay K , Kar Sitanshu Sekhar , Kant Shashi , Sarkar Sonali , Baidya Subrata , Meena Suneeta , Mandal Suprakash , Kishore Surekha , Majumder Tapan , Hada Vivek
Published: June 2023

Repeated serological testing tells about the change in the overall infection in a community. This study aimed to evaluate changes in antibody prevalence and kinetics in a closed cohort over six months in different sub-populations in India. The study included 10,000 participants from rural and urban areas in five states and measured SARS-CoV-2 antibodies in serum in three follow-up rounds. The overall seroprevalence increased from 73.9% in round one to 90.7% in round two and 92.9% in round three. Among seropositive rural participants in round one, 98.2% remained positive in round two, and this percentage remained stable in urban and tribal areas in round three. The results showed high antibody prevalence that increased over time and was not different based on area, age group, or sex. Vaccinated individuals had higher antibody prevalence, and nearly all participants had antibody positivity for up to six months.
Genomic Sequencing Surveillance and Antigenic Site Mutations of Respiratory Syncytial Virus in Arizona, USA
Authors: Holland LaRinda A. , Holland Steven C. , Smith Matthew F. , Leonard Victoria R. , Murugan Vel , Nordstrom Lora , Mulrow Mary , Salgado Raquel , White Michael , Lim Efrem S.
Published: June 2023

We conducted Respiratory Syncytial Virus (RSV) genomic sequencing surveillance of 100 RSV-A and 27 RSV-B specimens collected between November 2022 and April 2023 in Arizona, USA. We identified mutations in the pre-fusion F protein antigenic sites in both RSV-A and RSV-B. Continued genomic surveillance will be important to ensure RSV vaccine effectiveness.
Multiple imputation strategies for missing event times in a multi-state model analysis
Authors: Curnow E. , Hughes R. A. , Birnie K. , Tilling K. , Crowther M. J.
Published: June 2023

In clinical studies, multi-state model (MSM) analysis is often used to describe the sequence of events that patients experience, enabling better understanding of disease progression. A complicating factor in many MSM studies is that the exact event times may not be known. Motivated by a real dataset of patients who received stem cell transplants, we considered the setting in which some event times were exactly observed and some were missing. In our setting, there was little information about the time intervals in which the missing event times occurred and missingness depended on the event type, given the analysis model covariates. These additional challenges limited the usefulness of some missing data methods (maximum likelihood, complete case analysis, and inverse probability weighting). We show, for the first time in the MSM context, that multiple imputation (MI) of event times can perform well in this setting. MI is a flexible method that can be used with any complete data analysis model. Through an extensive simulation study, we show that MI by predictive mean matching (PMM), in which sampling is from a set of observed times without reliance on a specific parametric distribution, has little bias when event times are missing at random, conditional on the observed data. Applying PMM separately for each sub-group of patients with a different pathway through the MSM tends to further reduce bias and improve precision. We recommend MI using PMM methods when performing MSM analysis with Markov models and partially observed event times.
Health Care Workers Knowledge, Attitudes, and Practice Towards Childhood Tuberculosis in Primary Health Facilities in Lusaka, Zambia
Authors: Kaumba Paul Chabala , Kagujje Mary , Chungu Chalilwe , Nyangu Sarah , Sanjase Nsala , Maimbolwa Minyoi Mubita , Shuma Brian , Chilukutu Lophina , Muyoyeta Monde
Published: June 2023

BACKGROUND

Zambia is among the countries with high tuberculosis (TB) and Tuberculosis/Human Immunodeficiency Virus (TB/HIV) burdens, with a significant number of cases affecting children. However, a considerable portion of TB cases, especially in children, remains undiagnosed. This study aimed to assess and understand the factors influencing the knowledge, attitudes, and practices of health care workers (HCWs) regarding childhood TB in Zambia.

METHOD

Using a cross-sectional survey design, a self-administered anonymous questionnaire was employed to evaluate HCWs’ knowledge, attitudes, and practices related to TB. The study was conducted at two primary health facilities in Lusaka, Zambia, between July and August 2020. The questionnaire data collected was later transcribed to an electronic system called DHIS 2.

RESULTS

Out of 238 participants, the majority (72.3%) were female HCWs. Most staff members across various departments demonstrated awareness of the primary TB symptom, which is coughing. However, approximately half of the participants had limited knowledge regarding the transmission of TB through oral activities such as singing and laughing. Furthermore, the study found that 21.4% of HCWs reported regular interaction with children in their daily work, while 17.2% did not.

Among the HCWs, 73.1% referred children to the TB clinic to submit a sputum sample, 55.5% requested a sample from the patient, 55.9% expedited the process for children, 58.4% provided education on cough etiquette, and 42.4% recorded the child in the presumptive TB register. Only a negligible 0.8% of HCWs did not take any action for children exhibiting TB symptoms.

CONCLUSION

The study highlighted variations in knowledge levels based on gender, department, and training history among the HCWs. Those working in the TB department generally exhibited better knowledge and attitudes regarding TB, with a 50/50% variation. Therefore, it is crucial to enhance the TB knowledge, attitudes, and practices of female HCWs, who constitute most staff involved in TB diagnosis and treatment.

This study emphasizes the importance of improving the understanding of childhood TB among HCWs, particularly among female staff. Enhancing their knowledge and attitudes towards TB will contribute to early diagnosis and improved management of TB cases, ultimately reducing the burden of childhood TB in Zambia.
Maternal, placental and fetal response to a non-viral, polymeric nanoparticle gene therapy in nonhuman primates
Authors: Wilson Rebecca L. , Kropp Schmidt Jenna , Davenport Baylea N. , Ren Emily , Keding Logan T. , Shaw Sarah A. , Schotzko Michele L. , Antony Kathleen M. , Simmons Heather A. , Golos Thaddeus G. , Jones Helen N.
Published: June 2023

Background

Currently, there are no placenta-targeted treatments to alter thein uteroenvironment. Water-soluble polymers have a distinguished record of clinical relevance outside of pregnancy. We have demonstrated the effective delivery of polymer-based nanoparticles containing a non-viral humaninsulin-like 1 growth factor(IGF1) transgene to correct placental insufficiency in small animal models of fetal growth restriction (FGR). Our goal was to extend these studies to the pregnant nonhuman primate (NHP) and assess maternal, placental and fetal responses to nanoparticle-mediatedIGF1treatment.

Methods

Pregnant macaques underwent ultrasound-guided intraplacental injections of nanoparticles (GFP-orIGF1-expressing plasmid under the control of the trophoblast-specificPLAC1promoter complexed with a HPMA-DMEAMA co-polymer) at approximately gestational day 100 (term = 165 days). Fetectomy was performed 24 h (GFP; n =1), 48 h (IGF1; n = 3) or 10 days (IGF1; n = 3) after nanoparticle delivery. Routine pathological assessment was performed on biopsied maternal tissues, and placental and fetal tissues. Maternal blood was analyzed for complete blood count (CBC), immunomodulatory proteins and growth factors, progesterone (P4) and estradiol (E2). Placental ERK/AKT/mTOR signaling was assessed using western blot and qPCR.

Findings

Fluorescent microscopy and in situ hybridization confirmed placental uptake and transgene expression in villous syncytiotrophoblast. No off-target expression was observed in maternal and fetal tissues. Histopathological assessment of the placenta recorded observations not necessarily related to theIGF1nanoparticle treatment. In maternal blood, CBCs, P4 and E2 remained within the normal range for pregnant macaques across the treatment period. Changes to placental ERK and AKT signaling at 48 h and 10 d afterIGF1nanoparticle treatment indicated an upregulation in placental homeostatic mechanisms to prevent over activity in the normal pregnancy environment.

Interpretation

Maternal toxicity profile analysis and lack of adverse reaction to nanoparticle-mediatedIGF1treatment, combined with changes in placental signaling to maintain homeostasis indicates no deleterious impact of treatment.

Funding

National Institutes of Health, and Wisconsin National Primate Research Center.
Listeria monocytogenesinfection in pregnant macaques alters the maternal gut microbiome
Authors: Hugon Anna Marie , Deblois Courtney L. , Simmons Heather A. , Mejia Andres , Schotzo Michele L. , Czuprynski Charles J. , Suen Garret , Golos Thaddeus G.
Published: June 2023

Objectives

The bacteriumListeria monocytogenes(Lm) is associated with adverse pregnancy outcomes. Infection occurs through consumption of contaminated food that is disseminated to the maternal-fetal interface. The influence on the gastrointestinal microbiome during Lm infection remains unexplored in pregnancy. The objective of this study was to determine the impact of listeriosis on the gut microbiota of pregnant macaques.

Methods

A nonhuman primate model of listeriosis in pregnancy has been previously described [1, 2]. Both pregnant and nonpregnant cynomolgus macaques were inoculated with L. monocytogenes and bacteremia and fecal shedding were monitored for 14 days. Nonpregnant animal tissues were collected at necropsy to determine bacterial burden, and fecal samples from both pregnant and nonpregnant animals were evaluated by 16S rRNA next-generation sequencing.

Results

Unlike pregnant macaques, nonpregnant macaques did not exhibit bacteremia, fecal shedding, or tissue colonization by Lm. Dispersion of Lm during pregnancy was associated with a significant decrease in alpha-diversity of the host gut microbiome, compared to nonpregnant counterparts. The combined effects of pregnancy and listeriosis were associated with a significant loss in microbial richness, although there were increases in some genera and decreases in others.

Conclusions

Although pregnancy alone is not associated with gut microbiome disruption, we observed dysbiosis with listeriosis during pregnancy. The macaque model may provide an understanding of the roles that pregnancy and the gut microbiota play in the ability of Lm to establish intestinal infection and disseminate throughout the host, thereby contributing to adverse pregnancy outcomes and risk to the developing fetus.

Summary sentence

Intestinal microbial composition in macaques is influenced by significant interaction between the pregnant state and exposure toListeria monocytogenes, associated in particular with significant changes toAkkermansia, Eubacteria ruminantum, Methanobrevibacter, Prevotella,andTreponema.
APOGEE 2: multi-layer machine-learning model for the interpretable prediction of mitochondrial missense variants
Authors: Bianco Salvatore Daniele , Parca Luca , Petrizzelli Francesco , Biagini Tommaso , Giovannetti Agnese , Liorni Niccolò , Napoli Alessandro , Carella Massimo , Procaccio Vincent , Lott Marie , Zhang Shiping , Vescovi Angelo Luigi , Wallace Douglas C. , Caputo Viviana , Mazza Tommaso
Published: June 2023

APOGEE 2 is a mitochondrially-centered ensemble method designed to improve the accuracy of pathogenicity predictions for interpreting missense mitochondrial variants. Built on the joint consensus recommendations by the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP), APOGEE 2 features an improved machine learning method and a curated training set for enhanced performance metrics. It offers region-wise assessments of genome fragility and mechanistic analyses of specific amino acids that cause perceptible long-range effects on protein structure. With clinical and research use in mind, APOGEE 2 scores and pathogenicity probabilities are precompiled and available in MitImpact. APOGEE 2’s ability to address challenges in interpreting mitochondrial missense variants makes it an essential tool in the field of mitochondrial genetics.
dingo: a Python package for metabolic flux sampling
Authors: Chalkis Apostolos , Fisikopoulos Vissarion , Tsigaridas Elias , Zafeiropoulos Haris
Published: June 2023

We presentdingo, a Python package that supports a variety of methods to sample from the flux space of metabolic models, based on state-of-the-art random walks and rounding methods. For uniform samplingdingo’s implementation of the Multiphase Monte Carlo Sampling algorithm, provides a significant speed-up and outperforms existing software. Indicatively,dingocan sample from the flux space of the largest metabolic model up to now (Recon3D) in less than 30 hours using a personal computer, under several statistical guarantees; this computation is out of reach for other similar software. In addition, supports common analysis methods, such as Flux Balance Analysis (FBA) and Flux Variability Analysis (FVA), and visualization components.dingocontributes to the arsenal of tools in metabolic modeling by enabling flux sampling in high dimensions (in the order of thousands).

Availability and implementation

https://github.com/GeomScale/dingo

Contact

tolis.chal@gmail.gr,haris.zafeiropoulos@kuleuven.be
High-accuracy meets high-throughput for microbiome profiling with near full-length 16S rRNA amplicon sequencing on the Nanopore platform
Authors: Lin Xuan , Waring Katherine , Tyson John , Ziels Ryan M.
Published: June 2023

Amplicon sequencing of small subunit (SSU) rRNA genes is a foundational method for studying microbial communities within various environmental, human, and engineered ecosystems. Currently, short-read platforms are commonly employed for high-throughput applications of SSU rRNA amplicon sequencing, but at the cost of poor taxonomic classification. The low-cost Oxford Nanopore Technologies (ONT) platform is capable of sequencing full-length SSU rRNA genes, but the lower raw-read accuracies of previous ONT sequencing chemistries have limited accurate taxonomic classification and de novo generation of operational taxonomic units (OTUs) and amplicon sequence variants (ASVs). Here, we examine the potential for Nanopore sequencing with newer (R10.4+) chemistry to provide high-throughput and high-accuracy full-length 16S rRNA gene amplicon sequencing. We present a sequencing workflow utilizing unique molecular identifiers (UMIs) for error-correction of SSU rRNA (e.g. 16S rRNA) gene amplicons, termed ssUMI. Using two synthetic microbial community standards, the ssUMI workflow generated consensus sequences with 99.99% mean accuracy using a minimum UMI subread coverage threshold of 3x, and was capable of generating error-free ASVs and 97% OTUs with no false-positives. Non-corrected Nanopore reads generated error-free 97% OTUs but with reduced detection sensitivity, and also generated false-positive ASVs. We showcase the cost-competitive and high-throughput scalability of the ssUMI workflow by sequencing 90 time-series samples from seven different wastewater matrices, generating ASVs that were tightly clustered based on sample matrix type. This work demonstrates that highly accurate full-length 16S rRNA gene amplicon sequencing on Nanopore is possible, paving the way to more accessible microbiome science.
Controlling target brain regions by optimal selection of input nodes
Authors: Manjunatha Karan Kabbur Hanumanthappa , Baron Giorgia , Benozzo Danilo , Silvestri Erica , Corbetta Maurizio , Chiuso Alessandro , Bertoldo Alessandra , Suweis Samir , Allegra Michele
Published: June 2023

The network control theory framework holds great potential to inform neurostimulation experiments aimed at inducing desired activity states in the brain. However, the current applicability of the framework is limited by inaccurate modeling of brain dynamics, and an overly ambitious focus on whole-brain activity control. In this work, we leverage recent progress in linear modeling of brain dynamics (effective connectivity) and we exploit the concept of target controllability to focus on the control of a single region or a small subnetwork of nodes. We discuss when control may be possible with a reasonably low energy cost and few stimulation loci, and give general predictions on where to stimulate depending on the subset of regions one wishes to control. Importantly, using the robustly asymmetric effective connectome instead of the symmetric structural connectome (as in previous research), we highlight the fundamentally different roles in- and out-hubs have in the control problem, and the relevance of inhibitory connections. The large degree of inter-individual variation in the effective connectome implies that the control problem is best formulated at the individual level, but we discuss to what extent group results may still prove useful.
DnaK duplicates and regionally evolves for the increase of proteomic complexity in bacteria
Authors: Pan Zhuo , Zhuo Li , Wan Tian-yu , Chen Rui-yun , Li Yue-zhong
Published: June 2023

Hsp70 is important for organismic cells to maintain proteostasis and the chaperone protein is duplicated in all eukaryotes and many prokaryotes. Although the functioning mechanism of Hsp70 has been clearly illuminated, the chaperone duplication and functional evolution has been less investigated. DnaK is a highly conserved bacterial Hsp70 family. Here we showed that thednaKgene is present in 98.9% bacteria and 6.4% bacteria possess duplicateddnaKs; the occurrence and duplication is positively corelated to the increase of proteomic complexity. We identified the interactomes of the two DnaK paralogs inMyxococcus xanthusDK1622, which are mostly nonoverlapped, but both preferring the α&β domain proteins. Consistent with the proteomes, the MxDnaK substrates are both significantly size-larger and pI-higher than that of the singleE. coliDnaK. MxDnaK1 is heat-shock inducible, prefers to bind cytosolic proteins, while MxDnaK2 is decreased by heat shock, and is more associated with membrane proteins. The nucleotide binding domain and the substrate binding beta domain are responsible for the significant changes of DnaK substrates, and the former also determines the dimerization of MxDnaK2, but not MxDnaK1. Our work highlights that DnaK is duplicated and regionally evolved for the increase of proteomic complexity in bacteria.
Timing of dense granule biogenesis in asexual malaria parasites
Authors: Vallintine Tansy , van Ooij Christiaan
Published: June 2023

Malaria is an important infectious disease that continues to claim hundreds of thousands of lives annually. The disease is caused by infection of host erythrocytes by apicomplexan parasites of the genusPlasmodium. The parasite contains three different apical organelles – micronemes, rhoptries and dense granules – whose contents are secreted to mediate binding to and invasion of the host cell and the extensive remodelling of the host cell that occurs following invasion. Whereas the roles of micronemes and rhoptries in binding and invasion of the host erythrocyte have been studied in detail, the role of dense granules (DGs) inPlasmodiumparasites are poorly understood. They have been proposed to control host cell remodelling through regulated protein secretion after invasion, but many basic aspects of the biology of DGs remain unknown. Here we describe DG biogenesis timing for the first time, using RESA localisation as a proxy for DG formation timing. We show that DG formation commences approximately 37 minutes prior to schizont egress, as measured by the recruitment of the DG marker RESA. Furthermore, using a bioinformatics approach, we aimed to predict additional cargo of the DGs and identified the J-dot protein HSP40 as a DG protein, further supporting the very early role of these organelles in the interaction of the parasite with the host cell.
Rational engineering of an elevator-type metal transporter ZIP8 reveals a conditional selectivity filter critically involved in determining substrate specificity
Authors: Jiang Yuhan , Li Zhen , Sui Dexin , Sharma Gaurav , Wang Tianqi , MacRenaris Keith , Takahashi Hideki , Merz Kenneth , Hu Jian
Published: June 2023

Engineering of transporters to alter substrate specificity as desired holds great potential for applications, including metabolic engineering. However, the lack of knowledge on molecular mechanisms of substrate specificity hinders designing effective strategies for transporter engineering. Here, we applied an integrated approach to rationally alter the substrate preference of ZIP8, a Zrt-/Irt-like protein (ZIP) metal transporter with multiple natural substrates, and uncovered the determinants of substrate specificity. By systematically replacing the differentially conserved residues with the counterparts in the zinc transporter ZIP4, we created a zinc-preferring quadruple variant (Q180H/E343H/C310A/N357H), which exhibited largely reduced transport activities towards Cd2+, Fe2+, and Mn2+whereas increased activity toward Zn2+. Combined mutagenesis, modeling, covariance analysis, and computational studies revealed a conditional selectivity filter which functions only when the transporter adopts the outward-facing conformation. The demonstrated approach for transporter engineering and the gained knowledge about substrate specificity will facilitate engineering and mechanistic studies of other transporters.
Deep learning image analysis for filamentous fungi taxonomic classification: Dealing with small data sets with class imbalance and hierarchical grouping
Authors: Stiller Stefan , Dueñas Juan F. , Hempel Stefan , Rillig Matthias C. , Ryo Masahiro
Published: June 2023

Deep learning applications in taxonomic classification for animals and plants from images have become popular, while those for microorganisms are still lagging behind. Our study investigated the potential of deep learning for the taxonomic classification of hundreds of filamentous fungi from colony images, which is typically a task that requires specialized knowledge. We isolated soil fungi, annotated their taxonomy using standard molecular barcode techniques, and took images of the fungal colonies grown in petri dishes (n = 606). We applied a convolutional neural network with multiple training approaches and model architectures to deal with some common issues in ecological datasets: small amounts of data, class imbalance, and hierarchically structured grouping. Model performance was overall low due mainly to the relatively small data set, class imbalance, and the high morphological plasticity exhibited by fungal colonies. However, our approach indicates that morphological features such as color, patchiness, and colony extension rate, could be used for the recognition of fungal colonies at higher taxonomic ranks (i.e., phylum, class, and order). Model explanation implies that image recognition characters appear at different positions within the colony (e.g., outer or inner hyphae), depending on the taxonomic resolution. Our study suggests the potential of deep learning applications for better understanding the taxonomy and ecology of filamentous fungi amenable to axenic culturing. Meanwhile, our study also highlights some technical challenges in deep learning image analysis in ecology, highlighting that the domain of applicability of these methods needs to be carefully considered.
Clinical features of PPP2 syndrome type R5D (Jordan's syndrome) to support standardization of care
Authors: Levine Alexis D. , Chung Wendy K.
Published: June 2023

PPP2 syndrome type R5D, or Jordan's syndrome, is a neurodevelopmental disorder caused by pathogenic missense variants inPPP2R5D, a β-subunit of the Protein Phosphatase 2A (PP2A). The condition is characterized by global developmental delays, seizures, macrocephaly, ophthalmological abnormalities, hypotonia, attention disorder, social and sensory challenges often associated with autism, disordered sleep, and feeding difficulties. Among affected individuals, there is a broad spectrum of severity, and each person only has a subset of all associated symptoms. Some, but not all, of the clinical variability is due to differences in thePPP2R5Dgenotype. These suggested clinical care guidelines for the evaluation and treatment of individuals with PPP2 syndrome type R5D are based on data from 100 individuals reported in the literature and from an ongoing natural history study. As more data are available, particularly for adults and regarding treatment response, we anticipate that revisions to these guidelines will be made.
Tetracycline-modifying enzymeSmTetX fromStenotrophomonas maltophilia
Authors: Malý Martin , Kolenko Petr , Stránský Jan , Švecová Leona , Dušková Jarmila , Koval' Tomáš , Skálová Tereza , Trundová Mária , Adámková Kristýna , Černý Jiří , Božíková Paulína , Dohnálek Jan
Published: June 2023

The resistance of the emerging human pathogenStenotrophomonas maltophiliato tetracycline antibiotics mainly depends on multidrug efflux pumps and ribosomal protection enzymes. However, the genomes of several strains of this Gram-negative bacterium code for a FAD-dependent monooxygenase (SmTetX) homologous to tetracycline destructases. This protein was recombinantly produced and its structure and function were investigated. Activity assays usingSmTetX showed its ability to modify oxytetracycline with a catalytic rate comparable to those of other destructases.SmTetX shares its fold with the tetracycline destructase TetX fromBacteroides thetaiotaomicron; however, its active site possesses an aromatic region that is unique in this enzyme family. A docking study confirmed tetracycline and its analogues to be the preferred binders amongst various classes of antibiotics.
Legitimacy-building role of incubators: a multiple case study of activities and impacts of business incubators in a developing Chinese city
Authors: Cheng Ying , Liu Yanyan , Cross Adam R.
Published: June 2023

Purpose

Business incubators are advantageous to new venture legitimacy because they provide rich access to entrepreneurial resources, and their incubation networks can offer endorsement to incubatees. However, empirical evidence on this topic is limited, and the existing literature relies predominantly on the Western context. Given that not all developing country incubators have resourceful and reputable external entrepreneurial networks as in the industrialized countries, and that new ventures need to build legitimacy along cognitive and socio-political dimensions that require different actions to influence different stakeholders, this study investigates empirically how business incubators facilitate their incubatees to build legitimacy in a context where resource and reputation conditions are weak. The purpose of this paper is to clarify how business incubators perform legitimacy-building roles effectively.

Design/methodology/approach

A multiple case study of business incubators in Chongqing, a second-tier Chinese city, is presented. Using grounded theory, this paper draws its findings from a synthesis of interviews and secondary data of seven incubators and their ten incubatees.

Findings

The legitimacy-building role of business incubators is performed well in this research context. Evidence is presented that incubators play different roles in building different dimensions of incubatees’ legitimacy. Government-associated incubators play a salient role in building incubatees’ socio-political legitimacy whilst non-government related incubators shape their incubatees’ cognitive legitimacy.

Originality/value

This study contributes to the business incubators literature by revealing how incubators perform the legitimacy-building role when their resource endorsement is weak. The results suggest that incubators need to strengthen their ties with external stakeholders and that new ventures need to take key stakeholders into consideration when they select incubators to enter.