bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimization of biomass production of Acetobacter
pasteurianus SRCM101388
Authors: Kim Jun-Tae , Cho Sung-Ho , Jeong Do-Youn , Kim Young-Soo
Published: March 2023

In this study, culture conditions were optimized to confirm the feasibility of
Acetobacter pasteurianus as a starter for fermentation vinegar. Acetobacter
pasteurianus strain can be used as a food ingredient. The optimal temperature
and pH conditions of the selected Acetobacter pasteurianus
SRCM101388 were 28°C and pH 6.00, respectively. The response surface
methodology (RSM) was used to optimize the composition of the medium, and
Plackett-Burman design (PBD) was used to obtain the effective selection of
culture medium, resulting in that glucose, sucrose, and yeast extract had the
highest effect on increasing biomass. The optimal concentration, which was
performed by central composite design (CCD), were determined to be 10.73 g/L of
glucose, 3.98 g/L of sucrose, and 18.73 g/L of yeast extract, respectively. The
optimal concentrations of trace elements for the production of biomass were
found to be 1 g/L of ammonium sulfate, 0.5 g/L of magnesium sulfate, 2 g/L of
sodium phosphate monobasic, 2 g/L of sodium phosphate dibasic, and the final
optimized medium was pH 6.10. When incubated in a 5 L jar fermenter, the
SRCM101388 strain showed a faster-dissolved oxygen (DO) reduction at a lower
agitation rate (rpm), and it was able to grow even at reduced DO level when
aeration was maintained. The amount of final biomass produced was
2.53±0.12×109CFU/mL (9.40±0.02 log CFU/mL)
when incubated for 18 hours at 150 rpm, 0.5 vvm, pH 6.0, and 28°C.
Effect of one-size-fits-all amplification in Bluetooth hearing devices for hearing impaired listeners’ speech recognition
Authors: Bell Neila , Gibbs Leah , Ham Jusung , Howerton Kayla , Choi Inyong , Lee Jaeseong , Bang Kyoung Ho , Moon Han-gil
Published: March 2023

Hearing loss is a highly prevalent chronic condition that degrades the quality of life. Although hearing aids provide immediate and efficient benefits to listeners with mild-to-moderate hearing loss, the prevalence of hearing aid use has been low. Consumer wireless earbuds are increasingly being equipped with the ability to amplify external sounds, which can be an affordable alternative to hearing aids. This study compared the amplification performance of non-customized Bluetooth consumer hearables to high-end hearing aids when used by people with mild-to-moderate hearing loss. We found that such a non-customized consumer device significantly enhances the speech recognition of listeners with mild-to-moderate hearing loss, although its performance did not reach the hearing aids. These results determine the extent to which inexpensive and accessible non-customized Bluetooth hearables can help people with mild-to-moderate hearing loss.
Stochastic population models to identify optimal and cost-effective harvest strategies for feral pig eradication
Authors: Hamnett Peter W. , Saltré Frédérik , Page Brad , Tarran Myall , Korcz Matt , Fielder Kate , Andrews Lindell , Bradshaw Corey J. A.
Published: March 2023

Eradicating feral pigs from island ecosystems can assist in restoring damaged biodiversity values and protect commercial industries such as agriculture. Although many feral pig eradications have been attempted, management decisions are often led by practitioner experience rather than empirical evidence. Few interventions have been guided by population models to identify harvest rates necessary to achieve eradication within a specified time frame, nor have they applied data on control effort and cost to evaluate the relative cost-effectiveness of proposed control strategies. We used effort and cost data from a feral pig-control program on Kangaroo Island, South Australia over 17 months to derive functional-response relationships between control effort (hours pig-1) and pig abundance for four control methods: (i) ground-based shooting, (ii) trapping with remote triggers, (iii) poison baiting, and (iv) thermal-assisted aerial culling. We developed a stochastic Leslie matrix with compensatory density feedback on survival and fertility to project population trajectories from an initial population (N0) of 250 female pigs with an estimated island-wide carrying capacity (K) of 2500 over 3 and 10 years for populations subjected to an annual harvest of 35% to 95%. We built functional-response models to calculate annual effort and cost for six cull scenarios across all harvest rates. We derived total cost and effort over 3- and 10-year projections from the sum of annual cost and effort within the projection intervals. Pig populations were reduced to < 10%N0based on harvest rates > 70% and 50% for culls of 3- and 10-year duration, respectively. In all scenarios except ‘trapping only’, the total cost to reduce population to ≤ 10% ofN0decreased with increasing harvest proportion, with lower total costs incurred over 3 years compared to 10 years. The simulations suggest that the most cost-effective approach for most scenarios is to maximise annual harvest and complete eradication effort over the shortest periods.
MAHOMES II: A webserver for predicting if a metal binding site is enzymatic
Authors: Feehan Ryan , Copeland Matthew , Franklin Meghan W. , Slusky Joanna S. G.
Published: March 2023

Recent advances have enabled high-quality computationally generated structures for proteins with no solved crystal structures. However, protein function data remains largely limited to experimental methods and homology mapping. Since structure determines function, it is natural that methods capable of using computationally generated structures for functional annotations need to be advanced. Our laboratory recently developed a method to distinguish between metalloenzyme and non-enzyme sites. Here we report improvements to this method by upgrading our physicochemical features to alleviate the need for structures with sub-angstrom precision and using machine learning to reduce training data labeling error. Our improved classifier identifies protein bound metal sites as enzymatic or non-enzymatic with 94% precision and 92% recall. We demonstrate that both adjustments increased predictive performance and reliability on sites with sub-angstrom variations. We constructed a set of predicted metalloprotein structures with no solved crystal structures and no detectable homology to our training data. Our model had an accuracy of 90 - 97.5% depending on the quality of the predicted structures included in our test. Finally, we found the physicochemical trends that drove this model’s successful performance were local protein density, second shell ionizable residue burial, and the pocket’s accessibility to the site. We anticipate that our model’s ability to correctly identify catalytic metal sites could enable identification of new enzymatic mechanisms and improvede novometalloenzyme design success rates.

Significance statement

Identification of enzyme active sites on proteins with unsolved crystallographic structures can accelerate discovery of novel biochemical reactions, which can impact healthcare, industrial processes, and environmental remediation. Our lab has developed an ML tool for predicting sites on computationally generated protein structures as enzymatic and non-enzymatic. We have made our tool available on a webserver, allowing the scientific community to rapidly search previously unknown protein function space.
Improving radio transmitter attachment methods for small mammals through captive trials and field studies
Authors: Robinson Freya , Van de Weyer Nikki , Henry Steve , Hinds Lyn A. , Brown Peter R. , Ruscoe Wendy A.
Published: March 2023

Radio tracking can be used to collect information about animal movement, home range, behaviour and habitat use. Many field studies have fitted radio transmitters to small rodents using permanent nylon cable tie collars and successfully collected movement and fate data. The approach to animal welfare within the context of scientific research prioritises minimising adverse effects on the research animals. While a range of electronically activated release mechanisms exist in radio tracking collars for larger mammals, weight and size restrictions make these unsuitable for smaller animals (< 30 g). Our aim was to identify a radio transmitter model and attachment method of an appropriate size and weight, which would remain attached to a house mouse (Mus musculus) for >20 days to collect movement data and then detach or show signs of detaching after 30 days. Laboratory and field trials established that cable ties with a cotton thread weak-link, using heat shrink to attach a customised radio transmitter worked for wild house mice in agricultural fields. Glue-on methods did not stay attached for long enough to obtain more than a few days tracking data.

Short summary

Collecting meaningful radio tracking data for small mammals weighing <30 grams relies on selecting radio transmitter attachment methods suitable for the target species while prioritising animal welfare. Developing a non-permanent radio transmitter attachment for house mice is challenging due to size and weight constraints however, by trialling methods in the laboratory and field we developed a suitable radio collar with an in-built weak-link. Our non-permanent weak-link radio collar is an important improvement on existing permanent radio collars for small mammals.
TCR Repertoire Analysis of CD4-Positive T Cells from Blood and an Affected Organ in an Autoimmune Mouse Model
Authors: Ishikawa Tatsuya , Horie Kenta , Takakura Yuki , Ohki Houko , Maruyama Yuya , Hayama Mio , Miyauchi Maki , Miyao Takahisa , Hagiwara Naho , Kobayashi Tetsuya J. , Akiyama Nobuko , Akiyama Taishin
Published: March 2023

One hallmark of some autoimmune diseases is the variability of symptoms among individuals. Organs affected by the disease differ between patients, posing a challenge in diagnosing the affected organs. Although numerous studies have investigated the correlation between T cell antigen receptor (TCR) repertoires and the development of infectious and immune diseases, the correlation between TCR repertoires and variations in disease symptoms among individuals remains unclear. This study aimed to investigate the correlation of TCRα and β repertoires in blood T cells with the extent of autoimmune signs that varies among individuals. We sequenced TCRα and β of CD4+CD44highCD62LlowT cells in the blood and stomachs of mice deficient in autoimmune regulator (Aire) (AIRE KO), a mouse model of human autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). Data analysis revealed that the degree of similarity in TCR sequences between the blood and stomach varied among individual AIRE KO mice and reflected the extent of T cell infiltration in the stomach. We identified a set of TCR sequences whose frequencies in blood might correlate with extent of the stomach manifestations. Our results propose a potential of using TCR repertoires not only for diagnosing disease development but also for diagnosing affected organs in autoimmune diseases.
Regulation of B cell function and expression of CD11c, T-bet, and FcRL5 in response to different activation signals
Authors: Kleberg Linn , Courey-Ghaouzi Alan-Dine , Lautenbach Maximilian Julius , Färnert Anna , Sundling Christopher
Published: March 2023

CD11c, FcRL5, or T-bet are commonly expressed by B cells expanding during inflammation, where they can make up >30% of mature B cells. However, the association between the proteins and differentiation and function in the host response remain largely unclear. We have assessed the co-expression of CD11c, T-bet and FcRL5 in an in vitro B cell culture system to determine how stimulation via the B cell receptor (BCR), toll-like receptor 9 (TLR9), and different cytokines influence CD11c, T-bet, and FcRL5 expression. We observed different expression dynamics for all markers, but a largely overlapping regulation of CD11c and FcRL5 in response to BCR and TLR9 activation, while T-bet was strongly dependent on IFN-γ signalling. Investigating plasma cell differentiation and antigen-presenting cell (APC) functions, there was no association between marker expression and antibody secretion or T cell help. Rather the functions were associated with TLR9-signalling and B cell-derived IL-6 production, respectively. These results suggest that the expression of CD11c, FcRL5, and T-bet and plasma cell differentiation and improved APC functions occur in parallel and are regulated by similar activation signals, but that they are not interdependent.
A deep population reference panel of tandem repeat variation
Authors: Jam Helyaneh Ziaei , Li Yang , DeVito Ross , Mousavi Nima , Ma Nichole , Lujumba Ibra , Adam Yagoub , Maksimov Mikhail , Huang Bonnie , Dolzhenko Egor , Qiu Yunjiang , Kakembo Fredrick Elishama , Joseph Habi , Onyido Blessing , Adeyemi Jumoke , Bakhtiari Mehrdad , Park Jonghun , Javadzadeh Sara , Jjingo Daudi , Adebiyi Ezekiel , Bafna Vineet , Gymrek Melissa
Published: March 2023

Tandem repeats (TRs) represent one of the largest sources of genetic variation in humans and are implicated in a range of phenotypes. Here we present a deep characterization of TR variation based on high coverage whole genome sequencing from 3,550 diverse individuals from the 1000 Genomes Project and H3Africa cohorts. We develop a method, EnsembleTR, to integrate genotypes from four separate methods resulting in high-quality genotypes at more than 1.7 million TR loci. Our catalog reveals novel sequence features influencing TR heterozygosity, identifies population-specific trinucleotide expansions, and finds hundreds of novel eQTL signals. Finally, we generate a phased haplotype panel which can be used to impute most TRs from nearby single nucleotide polymorphisms (SNPs) with high accuracy. Overall, the TR genotypes and reference haplotype panel generated here will serve as valuable resources for future genome-wide and population-wide studies of TRs and their role in human phenotypes.
E2EGraph: An End-to-end Graph Learning Model for Interpretable Prediction of Pathlogical Stages in Prostate Cancer
Authors: Zhan Wenkang , Song Chen , Das Supratim , Rebbeck Timothy R. , Shi Xinghua
Published: March 2023

Prostate cancer is one of the deadliest cancers worldwide. An accurate prediction of pathological stages using the expressions and interactions of genes is effective for clinical assessment and treatment. However, identification of interactions using biological procedure is time consuming and prohibitively expensive. A graph is a powerful representation for the complex interactome of genes, their transcripts, and proteins. Recently, Graph Neural Networks (GNNs) have gained great attention in machine learning due to their capability to capture the graphical interactions among data entities. To leverage GNNs for predicting pathological stage stages, we developed an end-to-end graph representation and learning model, namely E2EGraph, which can automatically generate a graph representation using gene expression data and a multi-head graph attention network to learn the strength of interactions among genes and make the prediction. To ensure the reliability of model prediction, we identify critical components of graph representation and GNN model to interpret prediction results from multiple perspectives at gene and patient levels. We evaluated E2EGraph to predict pathological stages of prostate cancer using The Cancer Genome Atlas (TCGA) data. Our experimental results demonstrate that E2EGraph reaches the state-of-art prediction performance while being effective in identifying marker genes indicated by interpretability. Our results point to a direction where adaptive graph construction and attention based GNNs can be leveraged for various prediction tasks and interpretation of model prediction in a variety of data domains including disease prediction.
Optical coherence tomography of human fetal membrane sub-layers during dynamic loading
Authors: Samimi Kayvan , Contreras Guzman Emmanuel , Wu May , Carlson Lindsey , Feltovich Helen , Hall Timothy J. , Myers Kristin M. , Oyen Michelle L. , Skala Melissa C.
Published: March 2023

Fetal membranes have important mechanical and antimicrobial roles in maintaining pregnancy. However, the small thickness (<800 μm) of fetal membranes places them outside the resolution limits of most ultrasound and magnetic resonance systems. Optical imaging methods like optical coherence tomography (OCT) have the potential to fill this resolution gap. Here, OCT and machine learning methods were developed to characterize theex vivoproperties of human fetal membranes under dynamic loading. A saline inflation test was incorporated into an OCT system, and tests were performed on n=33 and n=32 human samples obtained from labored and C-section donors, respectively. Fetal membranes were collected in near-cervical and near-placental locations. Histology, endogenous two photon fluorescence microscopy, and second harmonic generation microscopy were used to identify sources of contrast in OCT images of fetal membranes. A convolutional neural network was trained to automatically segment fetal membrane sub-layers with high accuracy (Dice coefficients >0.8). Intact amniochorion bilayer and separated amnion and chorion were individually loaded, and the amnion layer was identified as the load-bearing layer within intact fetal membranes for both labored and C-section samples, consistent with prior work. Additionally, the rupture pressure and thickness of the amniochorion bilayer from the near-placental region were greater than those of the near-cervical region for labored samples. This location-dependent change in fetal membrane thickness was not attributable to the load-bearing amnion layer. Finally, the initial phase of the loading curve indicates that amniochorion bilayer from the near-cervical region is strain-hardened compared to the near-placental region in labored samples. Overall, these studies fill a gap in our understanding of the structural and mechanical properties of human fetal membranes at high resolution under dynamic loading events.
Novel hydroxamic acid derivative induces apoptosis and constrains autophagy in leukemic cells
Authors: Fischer Marten A. , Mustafa Al-Hassan M. , Hausmann Kristin , Ashry Ramy , Kansy Anita G. , Liebl Magdalena C. , Brachetti Christina , Piée-Staffa Andrea , Zessin Matthes , Ibrahim Hany S. , Hofmann Thomas G. , Schutkowski Mike , Sippl Wolfgang , Krämer Oliver H.
Published: March 2023

Introduction

Posttranslational modification of proteins by reversible acetylation regulates key biological processes. Histone deacetylases (HDACs) catalyze protein deacetylation and are frequently dysregulated in tumors. This has spurred the development of HDAC inhibitors (HDACi). Such epigenetic drugs modulate protein acetylation, eliminate tumor cells, and are approved for the treatment of blood cancers.

Objectives

We aimed to identify novel, nanomolar HDACi with increased potency over existing agents and selectivity for the cancer-relevant class I HDACs (HDAC1/-2/-3/-8). Moreover, we wanted to define how such drugs control the apoptosis-autophagy interplay. As test systems, we used human leukemic cells and embryonic kidney-derived cells.

Methods

We synthesized novel pyrimidine-hydroxamic acid HDACi (KH9/KH16/KH29) and performed in vitro activity assays and molecular modeling of their direct binding to HDACs. We analyzed how these HDACi affect leukemic cell fate, acetylation, and protein expression with flow cytometry and immunoblot. The publicly available DepMap database of CRISPR-Cas9 screenings was used to determine sensitivity factors across human leukemic cells.

Results

Novel HDACi show nanomolar activity against class I HDACs. These agents are superior to the clinically used hydroxamic acid HDACi vorinostat. Within the KH-series of compounds, KH16 (yanostat) is the most effective inhibitor of HDAC3 (IC50= 6 nM) and the most potent inducer of apoptosis (IC50= 110 nM; p<0.0001) in leukemic cells. KH16 though spares embryonic kidney-derived cells. Global data analyses of knockout screenings verify that HDAC3 is a dependency factor in human blood cancer cells of different lineages, independent of mutations in the tumor suppressor p53. KH16 alters pro- and anti-apoptotic protein expression, stalls cell cycle progression, and induces a caspase-dependent processing of the autophagy proteins ULK1 and p62.

Conclusion

These data reveal that HDACs are required to stabilize autophagy proteins through a suppression of apoptosis in leukemic cells. HDAC3 appears as a valid anti-cancer target for pharmacological intervention.

Highlights

Novel HDACi with nanomolar activity against leukemic cells were synthesized.

HDACi of the KH-series are superior to a clinical grade HDACi.

HDACi of the KH-series modulate acetylation and phosphorylation of proteins.

The new HDACi KH16 regulates cell cycle arrest, apoptosis, and autophagy.

Apoptosis acts upstream of autophagy in KH16-treated cells.
Characterization of a mouse model of ICF syndrome reveals enhanced CD19 activation in inducing hypogammaglobulinemia
Authors: Ying Zhengzhou , Hardikar Swanand , Plummer Joshua B. , Hamidi Tewfik , Liu Bin , Chen Yueping , Shen Jianjun , Mu Yunxiang , McBride Kevin M. , Chen Taiping
Published: March 2023

Immunodeficiency, centromeric instability and facial anomalies (ICF) syndrome is a rare autosomal recessive disorder characterized by DNA hypomethylation and antibody deficiency. It is caused by mutations inDNMT3B, ZBTB24, CDCA7orHELLS. While progress has been made in elucidating the roles of these genes in regulating DNA methylation, little is known about the pathogenesis of the life-threatening hypogammaglobulinemia phenotype. Here we show that mice deficient forZbtb24in the hematopoietic lineage recapitulate major clinical features of patients with ICF syndrome. Specifically, Vav-Cre-mediated ablation ofZbtb24does not affect lymphocyte development but results in reduced plasma cells and low levels of IgM, IgG1 and IgA.Zbtb24-deficient mice are hyper- and hypo-responsive to T-dependent and Tindependent type 2 antigens, respectively, and marginal zone B cell activation is impaired. B cells fromZbtb24-deficient mice display elevated CD19 phosphorylation. Heterozygous disruption ofCd19can revert the hypogammaglobulinemia phenotype in these mice. Mechanistically,Il5ra(interleukin-5 receptor subunit alpha) is derepressed inZbtb24-deficient B cells, and elevated IL-5 signaling enhances CD19 phosphorylation. Our results reveal a novel link between IL-5 signaling and CD19 activation and suggest that abnormal CD19 activity contributes to immunodeficiency in ICF syndrome.

SIGNIFICANCE STATEMENT

ICF syndrome is a rare immunodeficiency disorder first reported in the 1970s. The lack of appropriate animal models has hindered the investigation of the pathogenesis of antibody deficiency, the major cause of death in ICF syndrome. Here we show that, in mice, disruption ofZbtb24, one of the ICF-related genes, in the hematopoietic lineage results in low levels of immunoglobulins. Characterization of these mice reveals abnormal B cell activation due to elevated CD19 phosphorylation. Mechanistically,Il5ra(interleukin-5 receptor subunit alpha) is derepressed inZbtb24-deficient B cells, and increased IL-5 signaling enhances CD19 phosphorylation.
What can we learn when fitting a simple telegraph model to a complex gene expression model?
Authors: Jiao Feng , Li Jing , Liu Ting , Zhu Yifeng , Che Wenhao , Bleris Leonidas , Jia Chen
Published: March 2023

In experiments, the distributions of mRNA or protein numbers in single cells are often fitted to the random telegraph model which includes synthesis and decay of mRNA or protein, and switching of the gene between active and inactive states. While commonly used, this model does not describe how fluctuations are influenced by crucial biological mechanisms such as feedback regulation, non-exponential gene inactivation durations, and multiple gene activation pathways. Here we investigate the dynamical properties of four relatively complex gene expression models by fitting their steady-state mRNA or protein number distributions to the simple telegraph model. We show that despite the underlying complex biological mechanisms, the telegraph model with three effective parameters can accurately capture the steady-state gene product distributions, as well as the conditional distributions in the active gene state, of the complex models. Some effective parameters are reliable and can reflect realistic dynamic behaviors of the complex models, while others may deviate significantly from their real values in the complex models. The effective parameters can also be applied to characterize the capability for a complex model to exhibit multimodality. Using additional information such as single-cell data at multiple time points, we provide an effective method of distinguishing the complex models from the telegraph model. Furthermore, using measurements under varying experimental conditions, we show that fitting the mRNA or protein number distributions to the telegraph model may even reveal the underlying gene regulation mechanisms of the complex models. The effectiveness of these methods is confirmed by analysis of single-cell data forE. coliand mammalian cells. All these results are robust with respect to cooperative transcriptional regulation and extrinsic noise. In particular, we find that faster relaxation speed to the steady state results in more precise parameter inference under large extrinsic noise.
Iohexol-measured glomerular filtration rate and urinary biomarker changes between vancomycin and vancomycin plus piperacillin-tazobactam in a translational rat model
Authors: Chang Jack , Pais Gwendolyn M. , Marianski Sylwia , Valdez Kimberly , Lesnicki Emily , Barreto Erin F. , Rhodes Nathaniel J. , Yarnold Paul R. , Scheetz Marc H.
Published: March 2023

Recent clinical studies have reported additive nephrotoxicity with the combination of vancomycin and piperacillin-tazobactam. However, preclinical models have failed to replicate this finding. This study assessed differences in iohexol-measured glomerular filtration rate (GFR) and urinary injury biomarkers among rats receiving this antibiotic combination.

Male Sprague-Dawley rats received either intravenous vancomycin, intraperitoneal piperacillin-tazobactam, or both for 96 hours. Iohexol-measured GFR was used to quantify real-time kidney function changes. Kidney injury was evaluated via the urinary biomarkers: kidney injury molecule-1 (KIM-1), clusterin, and osteopontin.

Compared to the control, rats that received vancomycin had numerically lower GFR after drug dosing on day 3. Rats in this group also had elevations in urinary KIM-1 on experimental days 2 and 4. Increasing urinary KIM-1 was found to correlate with decreasing GFR on experimental days 1 and 3. Rats that received vancomycin+piperacillin-tazobactam did not exhibit worse kidney function or injury biomarkers compared to vancomycin alone.

The combination of vancomycin+piperacillin-tazobactam does not cause additive nephrotoxicity in a translational rat model. Future clinical studies investigating this antibiotic combination should employ more sensitive biomarkers of kidney function and injury, similar to those utilized in this study.
Diversity ofCFTRvariants across ancestries characterized using 454,727 UK biobank whole exome sequences
Authors: Ideozu Justin E. , Liu Mengzhen , Riley-Gillis Bridget M. , Paladugu Sri R. , Rahimov Fedik , Krishnan Preethi , Tripathi Rakesh , Dorr Patrick , Levy Hara , Singh Ashvani , Waring Jeffery F. , Vasanthakumar Aparna
Published: March 2023

Limited understanding of the diversity ofCFTRvariants across ancestries hampers efforts to advance molecular diagnosis of cystic fibrosis (CF). The consequences pose a risk of delayed diagnoses and subsequently worsened health outcomes for patients. Characterizing the distribution ofCFTRvariants across ancestries is, therefore, critical for revolutionizing molecular diagnoses of CF. By interrogating 454,727 UK biobank whole exome Sequences, we detected over 4,000CFTRvariants, including novel ancestry-specific variants, across six ancestries. F508del was the most prevalent CF-causing variant found across the ancestries, except in East Asia, where V520F was the most prevalent. Sixteen participants had two CF-causing variants, with two diagnosed as CF. We found 154 participants with a CF-causing and varying clinical consequences (VCC) variant. Overall, participants with multiple clinically relevant variants reported indications significantly associated with CF and its pulmonary phenotypes [Bonferroni adjusted p<0.05]. Potentially, participants with classical CF phenotypes may benefit from current CF therapies.
Analyzing the amplification of touch sense in visually impaired individuals and comparison with normal individuals
Authors: Desai Dev Himanshubhai
Published: March 2023

Background

It has been said for ages that if a person loses one of the basic senses like sight or hearing, other senses are amplified to make up for it. This has been substantially proved without a doubt that amplification helps the specially-abled individual in their day-to-day life to an extent. These increases are present but have not been quantified and measured on how much the increases are present.

Aim

1)To estimate and compare sensitivity of touch between visually impaired and normal people and analyze the amplification if present.

Methodology

A Cross-Sectional Case-control Study was carried out. Individuals with 6/6 vision and normal in other senses were first examined with the Static Two-point discrimination test to have a baseline value and then different categories of visually impaired individuals were subjected to this test. The test was carried out on the forehead and fingertips of all subjects. Their results were compared using different statistical tools.

Results

Total 45 visually impaired individuals with various severity of blindness with 20 Normal individuals taken for the study. Two-point discrimination values for normal individuals (Fingertip=3.43±1.519,Forehead=13.531±2.364), whereas for all and any type of visually impaired individual (fingertip=2.83±0.27,Forehead=13.08±0.26)is statistically(Fingertip, p=0.0101)(Forehead, p=0.4461).R-value for time spent since the disability and degree of amplification is -0.356.

Conclusion

A significant difference is present between the values of test between visually impaired and normal individuals. Appreciable that with various degrees of blindness, the average values of two-point-discrimination value are different. Totally blind shows the highest sensitivity.
Social Networks and Cardiovascular Disease Events in the Jackson Heart Study
Authors: Glover LáShauntá , Sutton Janiyah , O’Brien Emily , Sims Mario
Published: March 2023

Background

Cardiovascular disease (CVD) disproportionately affects African American adults. Greater social networks (SN), or social connectedness, may lower the risk of CVD events.

Objective

Determine the association of SN and incident CVD and test mediation by depressive symptoms, hypertension control and diabetes control.

Methods

We used the Social Network Index (SNI) at exam 1 (2000-2004) to develop a continuous standardized SN score and binary categories (high vs. low) among participants in the Jackson Heart Study (n=5252, mean age=54.8 years). Surveillance of coronary heart disease (CHD), stroke, and heart failure (HF) events occurred after exam 1 (2005 for HF) until 2016. Using Cox proportional hazards regression, we estimated the association of SN and CVD events by sex and tested the mediation of depressive symptoms, hypertension control and diabetes control. Models adjusted for age, education, health behaviors, and CVD co-morbidities.

Results

Among women, the SN score was associated with a lower risk of CHD and HF after full adjustment (HR 0.78, 95% CI 0.68, 0.89 and HR 0.78, 95% CI 0.63, 0.95, respectively), but the association with stroke attenuated after adjustment for co-morbidities (HR 95% CI 0.88 95% CI 0.67, 1.14). SN scores were also associated with CHD in men (HR 0.84, 95% CI 0.70, 0.99) after full adjustment. High vs. low SN was associated with CHD in men and women, but not after adjustment for co-morbidities. There was no evidence of mediation by depressive symptoms, diabetes control, and hypertension control.

Conclusion

Higher SN may lower the risk of CVD events, especially in women.
Genetic tracing of the white-bellied pangolin’s trade in western central Africa
Authors: Dipita Alain Din , Missoup Alain Didier , Aguillon Samantha , Lecompte Emilie , Momboua Brice Roxan , Chaber Anne-Lise , Abernethy Katharine , Njiokou Flobert , Tindo Maurice , Ntie Stephan , Gaubert Philippe
Published: March 2023

African pangolins are intensively harvested to feed illegal trade networks. We focused on the conservation genetics of the most trafficked African species, the white-bellied pangolin (WBP;Phataginus tricuspis), through the genotyping of 562 individuals from reference populations and urban bushmeat markets in a vibrant trade hub from western Central Africa. Across Cameroon, Equatorial Guinea and northern Gabon, we observed a lack of genetic differentiation and a signature of isolation-by-distance possibly due to unsuspected dispersal capacities involving a Wahlund effect. Despite a higher level of genetic diversity compared to western Africa, we detected a 74-83% decline in the effective population size of WBP during the Middle Holocene. Private allele frequency tracing approach indicated up to 600 km sourcing distance by large urban markets from Cameroon, involving transnational trade activities. The 20 microsatellites markers used in this study provided the necessary power to distinguish among all WBP individuals and should be considered a valuable resource for future forensic applications. Because lineage admixture was detected in the study area, we recommend a multi- locus approach for tracing the WBP trade. The Yaoundé market was a major recruiter of genetic diversity in the region, and should receive urgent conservation action to mitigate the pangolin trade.
Impact of Phosphorylation on the Physiological Form of Human alpha-Synuclein in Aqueous Solution
Authors: de Bruyn Emile , Dorn Anton Emil , Rossetti Giulia , Fernandez Claudio , Outeiro Tiago F. , Schulz Jörg B. , Carloni Paolo
Published: March 2023

Serine 129 can be phosphorylated in pathological inclusions formed by the intrinsically disordered protein humanα-synuclein (AS), a key player in Parkinson’s disease and other synucleinopathies. Here, molecular simulations provide insight into the structural ensemble of phosphorylated AS. The simulations suggest that phosphorylation does not impact the structural content of the physiological AS conformational ensemble in aqueous solution, as the phosphate group is mostly solvated. The hydrophobic region of AS containsβ-hairpin structures, which may increase the propensity of the protein to undergo amyloid formation, as seen in the non-physiological (non-acetylated) form of the protein in a recent molecular simulation study. Our findings are consistent with existing experimental data, with the caveat of the observed limitations of the force field for the phosphorylated moiety.

Abstract Figure
Optimization of extraction, Structural characterization of immunomodulatory acidic polysaccharide fromEuphorbia caducifolia
Authors: Venumadhav Kusuma , Seshagirirao Kottapalli
Published: March 2023

Heating confluence method in combination with response surface methodology (RSM) was performed to optimize polysaccharides extraction fromEuphorbia caducifoliaHaines. The Box-Behnken Design was used to optimize the extraction conditions with three parameters such as temperature (A), Solid to liquid ratio (B), and time (C). The percentage yields obtained were fitted to a 2ndorder polynomial equation using multiple regression analysis. From the regression equation, the optimal polysaccharides extraction parameters for 2.3% of yield are Temperature-120°C, Solid to liquid ratio-75 g/L, and Time-2 h. Further, crude polysaccharide was purified and disclosed GlaUA, Rha, Glc, Gal, Xyl and Ara (1:2.5:4:3.6:3.7:3.3) ratio of poysaccharide. Thermogram of the EC polysaccharide showed typical natural polysaccharide behavior, and hydrophilic nature of polysaccharide attributed to endothermic water loss. Furthermore, purified polysaccharides exhibited strongin vitrofree radical scavenging activities, reducing ability, and immunomodulatory activity by the effective production of pro-inflammatory cytokines with RAW 264.7 cells.
Unusual starch grains from theEuphorbia caducifoliaHaines
Authors: Venumadhav Kusuma , Seshagirirao Kottapalli
Published: March 2023

Nature has chosen the starch as a universal form for storing carbohydrate. In granule form, it is semi-crystalline, water-insoluble, dense and a ubiquitous constituent. Structure of the starch granules depends on their biological source and varies from part to part of the sources. In sequence to that, starch granules from the latex ofEuphorbia caducifoliawas isolated and characterized under different conditions to reveal its uniqueness in the structure. A flat dumbbell-shaped starch was notified with distinctive “maltese cross” under various microscopes. These starches are found to be high amylose contents, which resist water solubility, swelling index, and turbidity of the starches. X-Ray Diffraction studies states the presence C type pattern of crystallinity whereas typical polysaccharide spectrum was observed with ATR studies. Gelatinization of the starches remarked them as highly thermal stable and retrogradation studies failed to detect realignment of the heat disrupted amylose and amylopectin. Lintnerization of starch granules reveals the high complexity of the structure. Thus, latex starch granules from theE caducifoliaare considered to be unusual because of their highly complex structure, shape and properties.
Mitochondrial electron transport chain, ceramide and Coenzyme Q are linked in a pathway that drives insulin resistance in skeletal muscle
Authors: Diaz-Vegas Alexis , Madsen Soren , Cooke Kristen C. , Carroll Luke , Khor Jasmine X. Y. , Turner Nigel , Lim Xin Ying , Astore Miro A. , Morris Jonathan , Don Anthony , Garfield Amanda , Zarini Simona , Zemski Berry Karin A. , Ryan Andrew , Bergman Bryan C. , Brozinick Joseph T. , James David E. , Burchfield James G.
Published: March 2023

Insulin resistance (IR) is a complex metabolic disorder that underlies several human diseases, including type 2 diabetes and cardiovascular disease. Despite extensive research, the precise mechanisms underlying IR development remain poorly understood. Here, we provide new insights into the mechanistic connections between cellular alterations associated with IR, including increased ceramides, deficiency of coenzyme Q (CoQ), mitochondrial dysfunction, and oxidative stress. We demonstrate that elevated levels of ceramide in the mitochondria of skeletal muscle cells results in CoQ depletion and loss of mitochondrial respiratory chain components, leading to mitochondrial dysfunction and IR. Further, decreasing mitochondrial ceramide levels in vitro and in animal models (under chow and high fat diet) increased CoQ levels and was protective against IR. CoQ supplementation also rescued ceramide-associated IR. Examination of the mitochondrial proteome from human muscle biopsies revealed a strong correlation between the respirasome system and mitochondrial ceramide as key determinants of insulin sensitivity. Our findings highlight the mitochondrial Ceramide-CoQ-respiratory chain nexus as a potential foundation of an IR pathway that may also play a critical role in other conditions associated with ceramide accumulation and mitochondrial dysfunction, such as heart failure, cancer, and aging. These insights may have important clinical implications for the development of novel therapeutic strategies for the treatment of IR and related metabolic disorders.
Predominant myosin super-relaxed state in canine myocardium with naturally occurring dilated cardiomyopathy
Authors: Ochala Julien , Lewis Christopher T. A. , Beck Thomas , Iwamoto Hiroyuki , Hessel Anthony L. , Campbell Kenneth S. , Pyle W. Glen
Published: March 2023

Dilated cardiomyopathy (DCM) is a naturally occurring heart failure condition in humans and dogs, notably characterized by a reduced contractility and ejection fraction. As the identification of its underlying cellular and molecular mechanisms remain incomplete, the aim of the present study was to assess whether the molecular motor myosin and its known relaxed conformational states are altered in DCM. For that, we dissected and skinned thin cardiac strips from left ventricle obtained from six DCM Doberman Pinschers and six non-failing controls (NF). We then used a combination of Mant-ATP chase experiments and X-ray diffraction to assess both energetic and structural changes of myosin. Using the Mant-ATP chase protocol, we observed that in DCM dogs, the amount of myosin molecules in the ATP-conserving conformational state also known as super-relaxed (SRX), is significantly increased when compared with NF dogs. This alteration can be rescued by applying EMD-57033, a small molecule activating myosin. Conversely, with X-ray diffraction, we found that in DCM dogs, there is a higher proportion of myosin heads in the vicinity of actin when compared with NF dogs (1,0 to 1,1 intensity ratio). Hence, we observed an uncoupling between energetic (Mant-ATP chase) and structural (X-ray diffraction) data. Taken together, these results may indicate that in the heart of Doberman Pinschers with DCM, myosin molecules are potentially stuck in a non-sequestered but ATP-conserving SRX state, that can be counterbalanced by EMD-57033 demonstrating the potential for a myosin-centered pharmacological treatment of DCM.

New & noteworthy

The key finding of the present study is that, in left ventricles of dogs with a naturally occurring dilated cardiomyopathy, relaxed myosin molecules favor a non-sequestered super-relaxed state potentially impairing sarcomeric contractility. This alteration is rescuable by applying a small molecule activating myosin known as EMD-57033.
Repeated unilateral injections of botulinum toxin in masticatory muscles in adult rats do not amplify condylar and alveolar bone loss nor modify the volume of the hypertrophic bone proliferation at enthesis
Authors: Dechaufour Pierre , Libouban Hélène , Chappard Daniel , Kün-Darbois Jean-Daniel
Published: March 2023

Objectives

Botulinum toxin (BTX) induces muscle paralysis. It is used in human in masticatory muscles injections performed often repeatedly. A single BTX injection in masticatory muscles in animal induces mandibular bone loss (alveolar and condylar) with a muscle enthesis hypertrophic metaplasia. Our aim was to evaluate mandibular bone changes after unilateral repeated injections of BTX in temporal and masseter muscles in adult rats.

Materials and Methods

Mature male rats were randomized into 3 groups: one, two or three injections. Each injection was performed 4 weeks after the prior injection. Each rat received injections in right masseter and temporalis muscles. The left side was the control side. Microcomputed tomography was used to perform 2D and 3D analyses.

Results

Bone loss was evidenced on the right sides of alveolar and condylar bone. Alveolar bone volume increased in both control left side and injected right side whereas condylar bone volume remained constant in all groups, for both left and right sides. Enthesis bone hypertrophic metaplasias were evidenced on the BTX injected sides without any modification with the number of injections.

Conclusions

BTX repeated injections in masticatory muscles lead to major mandibular condylar and alveolar bone loss that does not worsen. They lead to the occurrence of an enthesis bone proliferation that is not dependent on the number of injections.

Clinical relevance

These results are an argument for the safety of BTX injections in masticatory muscles in human.
Estimating the Lambda measure in multiple-merger coalescents
Authors: Miró Pina Verónica , Joly Émilien , Siri-Jégousse Arno
Published: March 2023

Multiple-merger coalescents, also known as Λ-coalescents, have been used to describe the genealogy of populations that have a skewed offspring distribution or that undergo strong selection. Inferring the characteristic measure Λ, which describes the rates of the multiple-merger events, is key to understand these processes. So far, most inference methods only work for some particular families of Λ-coalescents that are described by only one parameter, but not for more general models. This article is devoted to the construction of a non-parametric estimator of the density of Λ that is based on the observation at a single time of the so-called Site Frequency Spectrum (SFS), which describes the allelic frequencies in a present population sample. First, we produce estimates of the multiple-merger rates by solving a linear system, whose coefficients are obtained by appropriately subsampling the SFS. Then, we use a technique that aggregates the information extracted from the previous step through a kernel type of re-construction to give a non-parametric estimation of the measure Λ. We give a consistency result of this estimator under mild conditions on the behavior of Λ around 0. We also show some numerical examples of how our method performs.
A spatial approach to jointly estimate Wright’s neighborhood size and long-term effective population size
Authors: Hancock Zachary B. , Toczydlowski Rachel H. , Bradburd Gideon S.
Published: March 2023

Spatially continuous patterns of genetic differentiation, which are common in nature, are often poorly described by existing population genetic theory or methods that assume panmixia or discrete, clearly definable populations. There is therefore a need for statistical approaches in population genetics that can accommodate continuous geographic structure, and that ideally use georeferenced individuals as the unit of analysis, rather than populations or subpopulations. In addition, researchers are often interested describing the diversity of a population distributed continuously in space, and this diversity is intimately linked to the dispersal potential of the organism. A statistical model that leverages information from patterns of isolation-by-distance to jointly infer parameters that control local demography (such as Wright’s neighborhood size), and the long-term effective size (Ne) of a population would be useful. Here, we introduce such a model that uses individual-level pairwise genetic and geographic distances to infer Wright’s neighborhood size and long-termNe. We demonstrate the utility of our model by applying it to complex, forward-time demographic simulations as well as an empirical dataset of the Red Sea clownfish (Amphiprion bicinctus). The model performed well on simulated data relative to alternative approaches and produced reasonable empirical results given the natural history of clownfish. The resulting inferences provide important insights into the population genetic dynamics of spatially structure populations.