bluuebunny/crossref_metadata_2025 huggingface dataset:
The bounded coalescent model: conditioning a genealogy on a minimum root date
Authors: Carson Jake , Ledda Alice , Ferretti Luca , Keeling Matt , Didelot Xavier
Published: January 2022

The coalescent model represents how individuals sampled from a population may have originated from a last common ancestor. The bounded coalescent model is obtained by conditioning the coalescent model such that the last common ancestor must have existed after a certain date. This conditioned model arises in a variety of applications, such as speciation, horizontal gene transfer or transmission analysis, and yet the bounded coalescent model has not been previously analysed in detail. Here we describe a new algorithm to simulate from this model directly, without resorting to rejection sampling. We show that this direct simulation algorithm is more computationally efficient than the rejection sampling approach. We also show how to calculate the probability of the last common ancestor occurring after a given date, which is required to compute the probability of realisations under the bounded coalescent model. Our results are applicable in both the isochronous (when all samples have the same date) and heterochronous (where samples can have different dates) settings. We explore the effect of setting a bound on the date of the last common ancestor, and show that it affects a number of properties of the resulting phylogenies. All our methods are implemented in a new R package called BoundedCoalescent which is freely available online.
ABRIDGE: An ultra-compression software for SAM alignment files
Authors: Banerjee Sagnik , Andorf Carson
Published: January 2022

Advancement in technology has enabled sequencing machines to produce vast amounts of genetic data, causing an increase in storage demands. Most genomic software utilizes read alignments for several purposes including transcriptome assembly and gene count estimation. Herein we present, ABRIDGE, a state-of-the-art compressor for SAM alignment files offering users both lossless and lossy compression options. This reference-based file compressor achieves the best compression ratio among all compression software ensuring lower space demand and faster file transmission. Central to the software is a novel algorithm that retains non-redundant information. This new approach has allowed ABRIDGE to achieve a compression 16% higher than the second-best compressor for RNA-Seq reads and over 35% for DNA-Seq reads. ABRIDGE also offers users the option to randomly access location without having to decompress the entire file. ABRIDGE is distributed under MIT license and can be obtained from GitHub (https://github.com/sagnikbanerjee15/Abridge) and docker hub. We anticipate that the user community will adopt ABRIDGE within their existing pipeline encouraging further research in this domain.
A Wake-Up Call: Determination of Antibiotics Residue Level in Raw Meat in Abattoir and Selected Slaughterhouses in Five Local Government in Kano State, Nigeria
Authors: Lateefat Habeeb Modupe , Olaniyi Opasola Afolabi , Misbahu Garba , Raimi Olalekan Morufu
Published: January 2022

The frequent use of antibiotics may result in drug residues that can be discovered at varying quantities in animal products such as milk or meat. The presence of pharmaceutical residues in food above the MRLs has been perceived globally by various persons. Antibiotics residues are present in food, which can endanger human health by causing antibiotic sensitivity, allergic reactions, microflora imbalance, bacterial resistance to antibiotics in microorganisms, and financial loss to the food industry. Farmers around the world utilize them on a sporadic basis for both preventative and curative purposes. This study assessed the antibiotics residues in raw meat sold in 6 slaughter houses in Kano States. The study is a descriptive cross-sectional study involving six (6) major slaughter house in Kano state. Muscle, Kidney and liver samples were collected from each slaughterhouse. The antibiotic residues in the meat samples were analysed using high performance liquid chromatography (HPLC) for tetracycline, ciprofloxacin and oxytetracycline residue results were presented in charts and tables. Out of a total of 18 beef samples analyzed during this study, 15 (83%) of the total samples had detectable levels of tetracycline residues from which 6(33.3%) had tetracycline residues at violative levels above the WHO/FAO maximum residue limits (MRLs), out of those 18 beef samples analyzed during this study, 6(33%) of the total samples had detectable levels of oxytetracycline residues from which 3(17%) had oxytetracycline residues at violative levels above the WHO/FAO maximum residue limits (MRLs) and out of those 18 beef samples analyzed during this study, 12(67%) of the total samples had detectable levels of ciprofloxacin, all levels are below the WHO/FAO maximum residue limits (MRLs). This high level of tetracycline and oxytetracycline residues in greater proportion of meat destined for human consumption at violative levels could be as a result of the indiscriminate use and misuse of veterinary drugs as commonly practiced among livestock producers and marketers without observing withdrawal period prior to slaughter. These results indicate that consumers may be predisposed to health hazards and hinder international meat trade from Nigeria. Regulatory authorities should therefore ensure compliance with good agricultural practices including withdrawal period of drugs used for treatment of food animals.
Elixirs of Life, threats to Human and Environmental Well-being: Assessment of Antibiotic Residues in Raw Meat Sold Within Central Market Kaduna Metropolis, Kaduna State, Nigeria
Authors: Lateefat Habeeb Modupe , Olaniyi Opasola Afolabi , Yusuf Adiama Babatunde , Azaman Ibrahim , Raimi Morufu Olalekan
Published: January 2022

Antibiotics, which are commonly used to treat human illnesses, are also used in animals for therapy, prophylaxis, and growth promotion. Sub-therapeutic antibiotic doses have typically been utilized for the last-mentioned purpose, which has contributed to resistance development. According to scientific data, certain antibiotic applications in food-producing animals can result in antibiotic resistance in intestinal bacteria, which can then be passed to the general population, causing treatment-resistant sickness. These antibiotic applications can also result in antibiotic resistance in non-pathogenic bacteria, whose resistance genes can be passed to disease-causing bacteria, resulting in antibiotic-resistant illnesses in people. Thus, this study assessed the antibiotics residues in raw meat sold in 6 slaughter houses in Kaduna State. The study is a descriptive cross-sectional study involving 6 slaughter houses in Central market Kaduna. Muscle, Kidney and liver samples were collected from each slaughterhouse. The antibiotic residues in the meat samples were analyzed using high performance liquid chromatography (HPLC) for tetracycline, ciprofloxacin and oxytetracycline residue results were presented in charts and tables. 18 different samples of beef (6 Muscles, 6 Liver and 6 Kidney) collected from abattoirs and meat vendors, the results shown that all beefs use three or more antimicrobial drugs. This research result revealed that 4(67%) tetracycline (oxytetracycline)were detected in meat samples at higher concentration), Oxytetraxycline (352.88 ± 221.58) of muscles is higher than (332.2± 217.05 of Liver and (263.33 ± 153.98) of Kidney is lower to muscles and liver. The Concentration of oxytetracycline were highest in muscles in samples 2. 3 and 6 which is above the WHO maximum residual limit. The concentration of streptomycin in the muscle, liver and kidney were detected (182.78 ± 56.23), (169.2 ± 58.39), (155.1 ± 50.20) but were within WHO Maximum residual limit. These high level of oxytetracycline residues in greater proportion of muscle samples destined for human consumption beyond MRLs could be as a result of the abuse of veterinary drugs as commonly practiced among livestock producers and vendors without observing withdrawal period prior to slaughter. The high-contamination rate of beef meat in the study areas is likely that consumers experience a high risk of exposure to drug residues.
Combination therapy of metformin with sodium selenite reverses effects of monotherapy on nitric oxide production, IL-1β and TNF-α release, and upregulates relative expression of Bcl-2 by LPS-activated human primary monocytes in T-cell acute lymphoblastic leukemia
Authors: Rostane Fella , Sari Nidel , Bali Ilyes , Messali Rabia , Hadjidj Zeyneb , Miliani Maroua , Belhassena Imène , El Mezouar Charazed , Aribi Mourad
Published: January 2022

Objectives

We examined the influence of the ex vivo combination therapy of metformin (Met, 1,1-dimethylbiguanide hydrochloride) with sodium selenite (Ss, Na2SeO3) on the changes in the production of nitric oxide (NO) and selected cytokines by circulating monocytes (MOs) during T-cell acute lymphoblastic leukemia (T-ALL).

Methods

Assays were performed on MO cell samples isolated from children with T-ALL.

Results

Met+Ss combination therapy reversed the Ss effect on the upregulation of NO production. Both Met+Ss and Ss treatment alone induced a significant downregulation of extracellular calcium ions consumption (ecCa2+) levels. Additionally, Met treatment induced a significant upregulation of IL-1β and TNF-α production; such effects were significantly reversed after combination with Ss treatment. Moreover, Met+Ss induced no significant effect on the production of IL-10, IL-6 and TNF-α, but a slight increase in IFN-γ levels. Furthermore, treatment with Ss alone induced a slight increase of IFN-γ. Finally, Met+Ss induced a marked upregulation of relative Bcl-2 expression in MOs.

Conclusions

Met+Ss combination therapy results in downregulation of NO production, IL-1β and TNF-α release as well as in upregulation of the relative expression levels of Bcl-2-associated survival of primary MOs in human T-ALL.
Interferon lambda signals in maternal tissues to exert protective and pathologic effects in a gestational-stage dependent manner
Authors: Casazza Rebecca L. , Philip Drake T. , Lazear Helen M.
Published: January 2022

Interferon lambda (IFN-λ, type III IFN) is constitutively secreted from human placental cells in culture and reduces Zika virus (ZIKV) transplacental transmission in mice. However, the roles of IFN-λ during healthy pregnancy and in restricting congenital infection remain unclear. Here we used mice lacking the IFN-λ receptor (Ifnlr1-/-) to generate pregnancies lacking either maternal or fetal IFN-λ responsiveness and found that the antiviral effect of IFN-λ resulted from signaling exclusively in maternal tissues. This protective effect depended on gestational stage, as infection earlier in pregnancy (E7 rather than E9) resulted in enhanced transplacental transmission of ZIKV. In Ifnar1-/- dams, which sustain robust ZIKV infection, maternal IFN-λ signaling caused fetal resorption and intrauterine growth restriction. Pregnancy pathology elicited by poly(I:C) treatment also was mediated by maternal IFN-λ signaling, specifically in maternal leukocytes, and also occurred in a gestational stage-dependent manner. These findings identify an unexpected effect of IFN-λ signaling specifically in maternal (rather than placental or fetal) tissues, which is distinct from the pathogenic effects of IFN-αβ (type I IFN) during pregnancy. These results highlight the complexity of immune signaling at the maternal-fetal interface, where disparate outcomes can result from signaling at different gestational stages.

IMPORTANCE

Pregnancy is an immunologically complex situation, which must balance protecting the fetus from maternal pathogens with preventing maternal immune rejection of non-self fetal and placental tissue. Cytokines, such as interferon lambda (IFN-λ), contribute to antiviral immunity at the maternal-fetal interface. We found in a mouse model of congenital Zika virus infection that IFN-λ can have either a protective antiviral effect or cause immune-mediated pathology, depending on the stage of gestation when IFN-λ signaling occurs. Remarkably, both the protective and pathologic effects of IFN-λ occurred through signaling exclusively in maternal immune cells, rather than in fetal or placental tissues, or in other maternal cell types, identifying a new role for IFN-λ at the maternal-fetal interface.
Narrowing gap in regional and age-specific excess mortality in the first year and a half of COVID-19 in Hungary
Authors: Tóth Csaba G.
Published: January 2022

In the first year and a half of the pandemic, the excess mortality in Hungary was 28,400, which was 1,700 lower than the official statistics on COVID-19 deaths. This discrepancy can be partly explained by protective measures instated during the COVID-19 pandemic that decreased the intensity of the seasonal flu outbreak, which caused on average 3,000 deaths per year. Compared to the second wave of the COVID-19 pandemic, the third wave showed a reduction in the differences in excess mortality between age groups and regions. The excess mortality rate for people aged 75+ fell significantly in the third wave, partly due to the vaccination schedule and the absence of a normal flu season. For people aged 40–77, the excess mortality rate rose slightly in the third wave. Between regions, excess mortality was highest in Northern Hungary and Western Transdanubia, and much lower in Central Hungary, where the capital is located. The excess mortality rate for men was almost twice as high as that for women in almost all age groups.
High Sensitivity and NPV for BinaxNOW Rapid Antigen Test in Children at a Mass Testing Site During Prevalent Delta Variant Period
Authors: Sun Kristie J. , Vaeth Mary Jane E. , Robinson Matthew , Elhabashy Maryam , Gupta Ishaan , Purekal Sophia , Hammershaimb E. Adrianne , Peralta Ria , Mitchell Asia , Foyez Maisha , Johnson J. Kristie , Ficke James R , Manabe Yukari C. , Campbell James D. , Callahan Charles W. , Locke Charles F. , Kantsiper Melinda ,   CONQUER COVID Consortium, Siddiqui Zishan K.
Published: January 2022

SARS-CoV-2 continues to develop new, increasingly infectious variants including delta and omicron. We evaluated the efficacy of the Abbott BinaxNOW Rapid Antigen Test against Reverse Transcription Polymerase Chain Reaction (“RT-PCR”) in 1054 pediatric participants presenting to a high-volume Coronavirus Disease 2019 (COVID-19) testing site while the delta variant was predominant. Participants were grouped by COVID-19 exposure and symptom status. RT-PCR demonstrated an overall prevalence of 5.2%. For all participants, sensitivity of the BinaxNOW was 92.7% (95% CI 82.4%-98.0%) and specificity was 98.0% (95% CI 97.0%-98.8%). For symptomatic participants, positive predictive value (PPV) was 72.7% (95% CI 54.5%-86.7%) and negative predictive value (NPV) was 99.2% (95% CI 98.2%-100%). Among asymptomatic participants, PPV was 71.4% (95% CI 53.7%-85.4%) and NPV was 99.7% (95% CI 99.0%-100%). Our reported sensitivity and NPV are higher than other pediatric studies, potentially because of higher viral load from the delta variant, but specificity and PPV are lower.

Importance

The BinaxNOW rapid antigen COVID-19 test had a sensitivity of nearly 92% in both symptomatic and asymptomatic children when performed at a high-throughput setting during the more transmissible delta variant dominant period. The test may play an invaluable role in asymptomatic screening and keeping children safe in school.
The chronic wound virome: phage diversity and associations with wounds and healing outcomes
Authors: Verbanic Samuel , Deacon John M. , Chen Irene A.
Published: January 2022

Two leading impediments to chronic wound healing are polymicrobial infection and biofilm formation. Recent studies have characterized the bacterial fraction of these microbiomes and have begun to elucidate compositional correlations to healing outcomes. However, the factors that drive compositional shifts are still being uncovered. The virome may play an important role in shaping bacterial community structure and function. Previous work on the skin virome determined that it was dominated by bacteriophages, viruses that infect bacteria. To characterize the virome, we enrolled 20 chronic wound patients presenting at an outpatient wound care clinic in a microbiome survey, collecting swab samples from healthy skin and chronic wounds before and after a single, sharp debridement procedure. We investigated the virome using a virus-like particle enrichment procedure, shotgun metagenomic sequencing, and a k-mer-based, reference-dependent taxonomic classification method. Taxonomic composition, diversity, and associations to covariates are presented. We find that the wound virome is highly diverse, with many phages targeting known pathogens, and may influence bacterial community composition and functionality in ways that impact healing outcomes.

Importance

Chronic wounds are an increasing medical burden. These wounds are known to be rich in microbial content, including both bacteria and bacterial viruses (phages). The viruses may play an important role in shaping bacterial community structure and function. We analyzed the virome and bacterial composition of 20 patients with chronic wounds. The viruses found in wounds are highly diverse compared to normal skin, unlike the bacterial composition, where diversity is decreased. These data represent an initial look at this relatively understudied component of the chronic wound microbiome.
Adherence of SARS-CoV-2 delta variant to surgical mask and N95 respirators
Authors: Lorenzo-Leal Ana C. , Vimalanathan Selvarani , Bach Horacio
Published: January 2022

The use of facial protection, including masks and respirators, has been adopted globally due to the COVID-19 pandemic. These products have been demonstrated to be effective in reducing the transmission of the virus. To determine whether or not the virus adheres to masks and respirators, we dissected four respirators and one surgical mask into layers. These individual layers were contaminated with the SARS-CoV-2 delta variant, and its release by vortexing was performed. Samples were used to infect Vero cells, and a plaque assay was used to determine to evaluate the adherence of the virus. Results showed that a cumulative log reduction of the layers reduced the load of the virus six-folds. Our study confirms the effectiveness of facial protection in reducing the transmission and or infection of the virus.
Neurofeedback-guided kinesthetic motor imagery training in Parkinson’s disease: Randomized trial
Authors: Tinaz Sule , Kamel Serageldin , Aravala Sai S. , Elfil Mohamed , Bayoumi Ahmed , Patel Amar , Scheinost Dustin , Sinha Rajita , Hampson Michelle
Published: January 2022

Background

Parkinson’s disease (PD) causes difficulty with maintaining the speed, size, and vigor of movements, especially when they are internally generated. We previously proposed that the insula is important in motivating intentional movement via its connections with the dorsomedial frontal cortex (dmFC). We demonstrated that subjects with PD can increase the right insula-dmFC functional connectivity using fMRI-based neurofeedback (NF) combined with kinesthetic motor imagery (MI). The current study is a randomized clinical trial testing whether NF-guided kinesthetic MI training can improve motor performance and increase task-based and resting-state right insula-dmFC functional connectivity in subjects with PD.

Methods

We assigned nondemented subjects with mild PD (Hoehn & Yahr stage ≤ 3) to the experimental kinesthetic MI with NF (MI-NF, n=22) and active control visual imagery (VI, n=22) groups. Only the MI-NF group received NF-guided MI training (10-12 runs). The NF signal was based on the right insula-dmFC functional connectivity strength. All subjects also practiced their respective imagery tasks at home daily for 4 weeks. Post-training changes in 1) task-based and resting-state right insula-dmFC functional connectivity were the imaging outcomes, and 2) MDS-UPDRS motor exam and motor function scores were the clinical outcomes.

Results

The MI-NF group did not show significant NF regulation and was not significantly different from the VI group in any of the imaging or clinical outcome measures. The MI-NF group reported subjective improvement in kinesthetic body awareness. There was significant and comparable improvement only in motor function scores in both groups. This improvement correlated with NF regulation of the right insula-dmFC functional connectivity only in the MI-NF group. Both groups showed specific training effects in whole-brain functional connectivity with distinct neural circuits supporting kinesthetic motor and visual imagery (exploratory outcome).

Conclusions

The functional connectivity-based NF regulation was unsuccessful in our cohort with mild PD. However, kinesthetic MI practice by itself or in combination with other imagery techniques is a promising tool in motor rehabilitation in PD.

Highlights

Parkinson’s disease (PD) causes difficulty with sustained motor performance

Insula and dorsomedial frontal cortex (dmFC) are implicated in motivating movement

Regulation of insula-dmFC functional connectivity with neurofeedback (NF) failed

Motor imagery practice regardless of NF improved motor function and body awareness

Motor imagery is a promising strategy for motor rehabilitation in PD
Stability of plasma metabolomics over 10 years among women
Authors: Zeleznik Oana A. , Wittenbecher Clemens , Deik Amy , Jeanfavre Sarah , Avila-Pacheco Julian , Rosner Bernard , Rexrode Kathryn M. , Clish Clary B. , Hu Frank B. , Eliassen A. Heather
Published: January 2022

Background

In epidemiological studies, samples are often collected long before disease onset or outcome assessment. Understanding the long-term stability of biomarkers measured in these samples is crucial. We estimated within-person stability over 10 years of metabolites and metabolite features (N=5938) in the Nurses’ Health Study (NHS): The primary dataset included 1880 women with 1184 repeated samples donated 10 years apart while the secondary dataset included 1456 women with 488 repeated samples donated 10 years apart.

Methods

We quantified plasma metabolomics using two liquid chromatography mass spectrometry platforms (lipids and polar metabolites) at the Broad Institute (Cambridge, MA). Intra-class correlations were used to estimate long-term stability (10 years) of metabolites and were calculated as the proportion of the total variability (within-person + between-person) attributable to between-person variability. Within-person variability was estimated among participants who donated two blood samples approximately 10 years apart while between-person variability was estimated among all participants.

Results

In the primary dataset, the median ICC was 0.43 (1st quartile [Q1]: 0.36; 3rd quartile [Q3]: 0.50) among known metabolites and 0.41 (Q1: 0.34; Q3: 0.48) among unknown metabolite features. The most stable (median ICCs: 0.54-0.57) metabolite classes were nucleosides, nucleotides and analogues, phosphatidylcholine plasmalogens, diglycerides, and cholesteryl esters. The least stable (median ICCs: 0.26-0.36) metabolite classes were lysophosphatidylethanolamines, lysophosphatidylcholines and steroid and steroid derivatives. Results in the secondary dataset were similar (Spearman correlation=0.87) to corresponding results in the primary dataset.

Conclusion

Within-person stability over 10 years is reasonable for lipid, lipid-related, and polar metabolites, and varies by metabolite class. Additional studies are required to estimate within-person stability over 10 years of other metabolites groups.
Gata2, Nkx2-2 and Skor2 form a transcription factor network regulating development of a midbrain GABAergic neuron subtype with characteristics of REM sleep regulatory neurons
Authors: Kirjavainen Anna , Singh Parul , Lahti Laura , Seja Patricia , Lelkes Zoltan , Makkonen Aki , Kilpinen Sami , Ono Yuichi , Salminen Marjo , Aitta-Aho Teemu , Stenberg Tarja , Molchanova Svetlana , Achim Kaia , Partanen Juha
Published: January 2022

The midbrain reticular formation is a mosaic of diverse GABAergic and glutamatergic neurons that have been associated with a variety of functions, including the regulation of sleep. However the molecular characteristics and development of the midbrain reticular formation neurons are poorly understood. As the transcription factor Gata2 is required for the development of all GABAergic neurons derived from the embryonic mouse midbrain, we hypothesized that the genes expressed downstream of Gata2 could contribute to the diversification of GABAergic neuron subtypes in this brain region. Here, we show that Gata2 is indeed required for the expression of several lineage-specific transcription factors in post-mitotic midbrain GABAergic neuron precursors. These include a homeodomain transcription factor Nkx2-2 and a SKI family transcriptional repressor Skor2, which are co-expressed in a restricted group of GABAergic precursors in the midbrain reticular formation. Both Gata2, and Nkx2-2 function is required for the expression of Skor2 in GABAergic precursors. In the adult mouse as well as rat midbrain, the Nkx2-2 and Skor2 expressing GABAergic neurons locate at the boundary of the ventrolateral periaqueductal gray and the midbrain reticular formation, an area shown to contain REM-off neurons regulating REM sleep. In addition to the characteristic localization, the Skor2 positive cells increase their activity upon REM sleep inhibition, send projections to a pontine region associated with sleep control and are responsive to orexins, consistent with the known properties of the midbrain REM-off neurons.
Head-to-tail peptide cyclization: new directions and application to urotensin II and Nrf2
Authors: Karami Yasaman , Murail Samuel , Giribaldi Julien , Lefranc Benjamin , Defontaine Florian , Lesouhaitier Olivier , Leprince Jérôme , de Vries Sjoerd J. , Tufféry Pierre
Published: January 2022

Backbone head-to-tail cyclization is one effective strategy to stabilize the conformation of bioactive peptides, preventing enzymatic degradation and improving their bioavailibility. However, very little is known about the requirements to rationally design linkers for the cyclization of linear peptides. Recently, we have shown that large scale data-mining of protein structures can lead to the precise identification of protein loop conformations. Here, we transpose this approach to head-to-tail peptide cyclization. We first show that given a linker sequence and the conformation of the linear peptide, it is possible to accurately predict the cyclized peptide conformation improving by over 1 Å over pre-existing protocols. Secondly, and more importantly, we show that it is possible to elaborate on the information inferred from protein structures to propose effective candidate linker sequences constrained by length and amino acid composition. As experimental validation, we first apply our approach to design linkers for the head-to-tail cyclizations of a peptide derived from Nrf2. The designed cyclized peptide shows a 26-fold increase in binding affinity. We then consider urotensin II, a cyclic peptide already stabilized by a disulfide bond, that exerts a broad array of biological activities. The designed head-to-tail cyclized peptide, the first synthesized bicyclic 14-residue long urotensin II analogue shows an excellent retention of in vitro activity. Overall, we propose the first framework for the rational peptide head-to-tail cyclization and reveal its potential for cyclic peptide-based drug design.
HLJ1 amplifies endotoxin–induced sepsis severity by promoting IL-12 heterodimerization in macrophages
Authors: Luo Wei-Jia , Yu Sung-Liang , Chang Chia-Ching , Chien Min-Hui , Liao Keng-Mao , Chang Ya-Ling , Chuang Ya-Hui , Chen Jeremy J.W. , Yang Pan-Chyr , Su Kang-Yi
Published: January 2022

Heat shock protein (HSP) 40 has emerged as a key actor in both innate and adaptive immunity, whereas the role of HLJ1, a molecular chaperone in HSP40 family, in modulating endotoxin–induced sepsis severity is still unclear. Here, we use single-cell RNA sequencing to characterize mouse liver nonparenchymal cell populations under LPS (lipopolysaccharide) stimulation, and show that HLJ1 deletion affected IFN-γ-related gene signatures in distinct immune cell clusters. HLJ1 deficiency also leads to reduced serum levels of IL-12 in LPS-treated mice, contributing to dampened production of IFN-γ in natural killer cells but not CD4+ or CD8+ T cells, and subsequently to improved survival rate. Adoptive transfer of HLJ1-deleted macrophages into LPS-treated mice results in reduced IL-12 and IFN-γ levels and protects the mice from IFN-γ–dependent mortality. In the context of molecular mechanisms, HLJ1 is an LPS-inducible protein in macrophages and converts misfolded IL-12p35 homodimers to monomers, which maintains bioactive IL-12p70 heterodimerization and secretion. This study suggests HLJ1 causes IFN-γ–dependent septic lethality by promoting IL-12 heterodimerization, and targeting HLJ1 has therapeutic potential in inflammatory diseases involving activating IL-12/IFN-γ axis.
Plant peptidoglycan precursor biosynthesis: Conservation between moss chloroplasts and Gram negative bacteria
Authors: Dowson Amanda J. , Lloyd Adrian J. , Cuming Andrew C. , Roper David I. , Frigerio Lorenzo , Dowson Christopher G.
Published: January 2022

An accumulation of evidence suggests that peptidoglycan, consistent with a bacterial cell wall, is synthesised around the chloroplasts of many photosynthetic eukaryotes, from glaucophyte algae to land plants at least as evolved as pteridophyte ferns, but the biosynthetic pathway has not been demonstrated. We employed mass spectrometry and enzymology in a twofold approach to characterize the synthesis of peptidoglycan in chloroplasts of the moss Physcomitrium (Physcomitrella) patens. To drive the accumulation of peptidoglycan pathway intermediates, P.patens was cultured with the antibiotics phosphomycin, D-cycloserine and carbenicillin, which inhibit key peptidoglycan pathway proteins in bacteria. Mass spectrometry of the TCA-extracted moss metabolome revealed elevated levels of five of the predicted intermediates from UDP-GlcNAc through to the UDP-MurNAc-D,L-diaminopimelate (DAP)-pentapeptide.

Most Gram negative bacteria, including cyanobacteria, incorporate meso-diaminopimelate (D,L-DAP) into the third residue of the stem peptide of peptidoglycan, as opposed to L-lysine, typical of most Gram positive bacteria. To establish the specificity of D,L-DAP incorporation into the P.patens precursors, we analysed the recombinant protein, UDP-MurNAc-tripeptide ligase (MurE), from both P.patens and the cyanobacterium Anabaena sp. strain PCC 7120. Both ligases incorporated D,L-DAP in almost complete preference to L-Lys, consistent with the mass spectrophotometric data, with catalytic efficiencies similar to previously documented Gram negative bacterial MurE ligases. We discuss how these data accord with the conservation of active site residues common to DL-DAP-incorporating bacterial MurE ligases and of the probability of a horizontal gene transfer event within the plant peptidoglycan pathway.
Autophagy and evasion of immune system by SARS-CoV-2. Structural features of the Non-structural protein 6 from Wild Type and Omicron viral strains interacting with a model lipid bilayer. †
Authors: Bignon Emmanuelle , Marazzi Marco , Grandemange Stéphanie , Monari Antonio
Published: January 2022

The viral cycle of SARS-CoV-2 is based on a complex interplay with the cellular machinery, which is mediated by specific proteins eluding or hijacking the cellular defense mechanisms. Among the complex pathways called by the viral infection autophagy is particularly crucial and is strongly influenced by the action of the non-structural protein 6 (Nsp6) interacting with the endoplasmic reticulum membrane. Importantly, differently from other non-structural proteins Nsp6 is mutated in the recently emerged Omicron variant, suggesting a possible different role of autophagy. In this contribution we explore, for the first time, the structural property of Nsp6 thanks to long-time scale molecular dynamic simulations and machine learning analysis, identifying the interaction patterns with the lipid membrane. We also show how the mutation brought by the Omicron variant may indeed modify some of the specific interactions, and more particularly help anchoring the viral protein to the lipid bilayer interface.

Electronic Supplementary Information (ESI) available

Analysis protein of the secondary structure and of the specific lipid/amino acid interactions. RMSF per amino acid. Distribution of the distance between the center of mass of the 89 to 99 α-helix and the center of the lipid bilayer. Analysis of the behavior of the 195 to 207 α-helix. See DOI: 10.1039/x0xx00000x
Nanometer-Resolution Long-term Tracking of Single Cargos Reveals Dynein Motor Mechanisms
Authors: Peng Chunte Sam , Zhang Yunxiang , Liu Qian , Marti G. Edward , Huang Yu-Wen Alvin , Südhof Thomas C. , Cui Bianxiao , Chu Steven
Published: January 2022

Cytoplasmic dynein is essential for intracellular transport, but because of its complexity, we still do not fully understand how this 1.5 megadalton protein works. Here, we used novel optical probes that enable single-particle tracking (SPT) of individual cargos transported by dynein motors in live neurons over 900μm. Analyses using the Fluctuation Theorem (FT) showed that the number of dynein molecules switches between 1-5 motors during the transport. Clearly resolved single-molecular steps revealed that the dwell times between individual steps were accurately described by an enzymatic cycle dominated by two equal and thermally-activated rate constants. Based on these data, we propose a new molecular model whereby each step requires the hydrolysis of 2 ATPs. The model is consistent with extensive structural, single-molecule and biochemical measurements.
Signaling modality within gp130 receptor enhances tissue regeneration
Authors: Shkhyan Ruzanna , Flynn Candace , Lamoure Emma , Handel Ben Van , Sarkar Arijita , Li Jinxiu , York Jesse , Banks Nicholas , Van der Horst Robert , Liu Nancy Q. , Lee Siyoung , Bajaj Paul , Vadivel Kanagasabai , Harn Hans I-Chen , Lozito Thomas , Lieberman Jay R. , Chuong Cheng-Ming , Hurtig Mark S. , Evseenko Denis
Published: January 2022

Adult mammals are incapable of multi-tissue regeneration and augmentation of this potential may drastically shift current therapeutic paradigms. Here, we found that a common co-receptor of IL-6 cytokines, glycoprotein 130 (gp130), serves as a major nexus integrating various context-specific signaling inputs to either promote regenerative outcomes or aggravate disease progression. Via genetic and pharmacological experiments in vitro and in vivo, we demonstrated that a signaling tyrosine 814 (Y814) within gp130 serves as a major cellular stress sensor. Mice with constitutively inactivated Y814 (F814) exhibit regenerative, not reparative, responses after wounding in skin and anti-degenerative responses in the synovial joint. In addition, pharmacological inhibition of gp130 Y814 results in regeneration of multiple tissues in several species as well as disease modification in animal models of osteoarthritis. Our study characterizes a novel molecular mechanism that, if selectively manipulated, enhances the intrinsic regenerative capacity while preventing pathological outcomes in injury and disease.

Gp130 Y814 signaling module serves as a cellular stress sensor responsible for hindering tissue regeneration while triggering pathological outcomes after injury.
Intestinal Bacteroides Modulates Systemic Inflammation and the Microbial Ecology in a Mouse Model of CF: Evidence for Propionate and other Short Chain Fatty Acids Reducing Systemic Inflammatory Cytokines
Authors: Price Courtney E. , Valls Rebecca A. , Ramsey Alexis R. , Loeven Nicole A. , Jones Jane T. , Barrack Kaitlyn E. , Schwartzman Joseph D , Royce Darlene B. , Cramer Robert A. , Madan Juliette C. , Ross Benjamin D. , Bliska James , O’Toole George A.
Published: January 2022

Persons with cystic fibrosis, starting in early life, have intestinal microbiome dysbiosis characterized in part by a decreased relative abundance of the genus Bacteroides. Bacteroides is a major producer of the intestinal short chain fatty acid (SCFA) propionate. We demonstrate here that CFTR-/- Caco-2 intestinal epithelial cells are responsive to the anti-inflammatory effects of propionate. Furthermore, Bacteroides isolates inhibit the IL-1β-induced inflammatory response of CFTR-/- Caco-2 intestinal epithelial cells and do so in a propionate-dependent manner. Bacteroides isolates also produce low levels of butyrate; this SCFA is positively correlated with inhibition of the inflammatory response. Finally, the introduction of Bacteroides-supplemented stool from infants with CF into the gut of CftrF508del mice results in an increase in propionate in the stool as well as the reduction in several systemic pro-inflammatory cytokines. Bacteroides supplementation also reduced the fecal relative abundance of E. coli, indicating a potential interaction between these two microbes, consistent with previous clinical studies. Together, our data indicate the important role of Bacteroides and Bacteroides-derived propionate in the context of the developing microbiome in infants and children with CF, which could help explain the observed gut-lung axis in CF.
Neuronal apoptosis drives remodeling states of microglia and shifts in survival pathway dependence
Authors: Anderson Sarah R , Roberts Jacqueline M , Ghena Nate , Irvin Emmalyn , Schwakopf Joon , Cooperstein Isabelle , Bosco Alejandra , Vetter Monica L
Published: January 2022

Microglia serve critical remodeling roles that shape the developing nervous system, responding to the changing neural environment with phagocytosis or soluble factor secretion. Recent single-cell sequencing (scRNAseq) studies have revealed the context-dependent diversity in microglial properties and gene expression, but the cues promoting this diversity are not well defined. Here, we ask how interactions with apoptotic neurons shape microglial state, including lysosomal and lipid metabolism gene expression and independence from Colony-stimulating factor 1 receptor (CSF1R) for survival. Using early postnatal mouse retina, a CNS region undergoing significant developmental remodeling, we performed scRNAseq on microglia from mice that are wild-type, lack neuronal apoptosis (Bax KO), or are treated with CSF1R inhibitor (PLX3397). We find that interactions with apoptotic neurons drives multiple microglial remodeling states, subsets of which are resistant to CSF1R inhibition. We find that TAM receptor Mer and complement receptor 3 are required for clearance of apoptotic neurons, but that Mer does not drive expression of remodeling genes. We show TAM receptor Axl is negligible for phagocytosis or remodeling gene expression but is consequential for microglial survival in the absence of CSF1R signaling. Thus, interactions with apoptotic neurons shift microglia towards distinct remodeling states and through Axl, alters microglial dependence on survival pathway, CSF1R.
Tiling mechanisms of the compound eye through geometrical tessellation
Authors: Hayashi Takashi , Tomomizu Takeshi , Sushida Takamichi , Akiyama Masakazu , Ei Shin-Ichiro , Sato Makoto
Published: January 2022

Tilling patterns are observed in many biological structures. Hexagonal tilling, commonly observed in the compound eyes of wild-type Drosophila, is dominant in nature; this dominance can probably be attributed to physical restrictions such as structural robustness, minimal boundary length, and space filling efficiency. Surprisingly, tetragonal tiling patterns are also observed in some Drosophila small eye mutants and aquatic crustaceans. Herein, geometrical tessellation is shown to determine the ommatidial tiling patterns. In small eye mutants, the hexagonal pattern is transformed into a tetragonal pattern as the relative positions of neighboring ommatidia are stretched along the dorsal-ventral axis. Hence, the regular distribution of ommatidia and their uniform growth collectively play an essential role in the establishment of tetragonal and hexagonal tiling patterns in compound eyes.
Rapid macropinocytic transfer of α-synuclein to lysosomes
Authors: Bayati Armin , Banks Emily , Han Chanshuai , Luo Wen , Reintsch Wolfgang E. , Zorca Cornelia E. , Shlaifer Irina , Del Cid Pellitero Esther , Vanderperre Benoit , McBride Heidi M. , Fon Edward A. , Durcan Thomas M. , McPherson Peter S.
Published: January 2022

The nervous system spread of alpha-synuclein fibrils is thought to cause Parkinson’s disease (PD) and other synucleinopathies, yet the mechanisms underlying internalization and cellular spread are enigmatic. Here we use confocal and super-resolution microscopy, subcellular fractionation and electron microscopy (EM) of immunogold labelled alpha-synuclein preformed fibrils (PFF) to demonstrate that this fibril form of alpha-synuclein undergoes rapid internalization and is targeted directly to lysosomes in as little as 2 minutes. Uptake of PFF is disrupted by macropinocytic inhibitors and circumvents classical endosomal pathways. Immunogold-labelled PFF are seen at the highly curved inward edge of membrane ruffles, in newly formed macropinosomes, in multivesicular bodies and in lysosomes. While most fibrils remain in lysosomes, a portion is transferred to neighboring naïve cells along with markers of exosomes. These data indicate that PFF use a unique internalization mechanism as a component of cell-to-cell propagation.
Income satisfaction among Millennials during COVID-19: the interplay among cognitive, noncognitive and financial factors
Authors: Chhatwani Malvika
Published: January 2022

Purpose

The purpose of this study is to examine income satisfaction among Millennials during COVID-19. The authors explore the roles of cognitive factors: financial literacy and noncognitive factors: personality traits. Further, the authors also determine if financial status moderates the linkage between consumers' financial literacy and income satisfaction.

Design/methodology/approach

The sample size of the study is 1754, and the data were collected from April to December 2020. The authors employ ordered logistic regression analysis in the study.

Findings

The authors find that financially literate Millennials report high-income satisfaction during the pandemic. However, the impact of the cognitive factor gets nullified after considering the role of noncognitive factors. Further, income moderates the linkage between financial literacy and income satisfaction such that financially literate consumers in the high-income category derived more income satisfaction.

Practical implications

Consumer financial education should become more pervasive, and the focus should be placed on high-income consumers as, without financial literacy, they may not report high-income satisfaction. Further, the marketers should also keep in mind that personality traits play an important role in consumers' overall satisfaction, so financial services and products should be designed considering consumer personality traits.

Originality/value

The primary contribution of the paper is to show the positive impact of cognitive and noncognitive factors on income satisfaction. Moreover, personality traits are stronger predictors of income satisfaction such that extroverted individuals have high satisfaction, whereas openness to experience and neuroticism is negatively related to income satisfaction among Millennials.
Left to their own devices? Antecedents and contingent effects of workplace anxiety in the WFH selling environment
Authors: Rangarajan Deva , Badrinarayanan Vishag , Sharma Aditi , Singh Rakesh Kumar , Guda Sridhar
Published: January 2022

Purpose

The main purpose of this research is to understand how the sudden shift to work from home (WFH) after the onset of the COVID-19 pandemic has caught several sales organizations underprepared and ill-equipped to combat emergent challenges. In this research, the authors provide initial evidence into how the WFH arrangement impacts salespeople and sales organizations. Specifically, this research is guided by two objectives: to understand how the shift to WFH environment is affecting salespeople, and to explore how organizations can mitigate dysfunctional effects of the shift to WFH practices and enhance salespeople’s commitment toward this new reality.

Design/methodology/approach

The authors did preliminary in-depth interviews with 13 executives operating in the business-to-business (B2B) space to identify themes that reflected the reality faced by B2B sales organizations when transitioning to WFH. The authors then conducted a quantitative study involving a survey with 130 B2B salespeople.

Findings

The findings from the qualitative research suggested that the WFH situation is quite different from the more traditional remote selling situations that B2B salespeople are used to. More specifically, salespeople experienced more anxiety because of the WFH situations. This finding was supported in the empirical study done by the authors where stress associated with WFH and job insecurity had a significant impact on salesperson anxiety.

Research limitations/implications

The study primarily used subjective responses of salespeople with no objective measures. Furthermore, this study is cross-sectional in nature. Future research should build on the present work to understand the long-term consequences of WFH and factor in customer responses to the same. The impact of increased use of technology in the sales process will need further attention, including the sales management implication for the same.

Originality/value

Given the unforeseen nature of the COVID pandemic and how unprepared salespeople and sales organizations were to deal with it, this study is one of the first studies that documents the impact of WFH situations on salespeople.
Corporate memory dynamics in project-based organizations (PBOs): multiple case study in Brazilian engineering design firms and a framework proposal
Authors: Barbosa Leandro César Mol , Carvalho Rodrigo Baroni , Choo Chun Wei , Versiani Ângela França , Pedron Cristiane Drebes
Published: January 2022

Purpose

This study aims to investigate how the processes of memory acquisition, retention, retrieval and application occur in project-based organizations (PBOs). In this kind of organization, the nature of corporate memory is influenced by the transience, uniqueness and independence of the project portfolio. Such understanding may help practitioners to mitigate the effects of project transience and promote knowledge sharing among project teams.

Design/methodology/approach

An empirical and qualitative study was carried out through a multiple case study approach conducted in three Brazilian Engineering Design Firms, which are organized by projects. Document analysis, direct observation and semi-structured interviews with engineers, project managers and executives were conducted.

Findings

The memory acquisition process takes place in five forms which have different sources and destinations when comparing PBOs with traditional organizational settings. Memory retention in PBOs crosses organizational boundaries and establishes a knowledge network of former employees and third parties. The PBOs project memory can be divided into volatile and perennial memory, where the former can be lost throughout project execution and the latter is internalized, becoming an inseparable part of the corporate memory. Memory retrieval in PBOs is also distinct since it has particular mechanisms depending on whether the knowledge is technical or administrative.

Originality/value

The research investigates the corporate memory processes within the volatile context of PBOs in a Latin-American developing country whose culture favors tacit knowledge exchange. The paper proposes a framework that unveils different patterns of knowledge acquisition, temporary and perennial retention structures, intensive usage of external knowledge in memory retrieval and particular memory applications in PBOs. The framework may guide scholars, project managers, engineers and practitioners in navigating through the uniqueness of organizational learning flows and structures in PBOs.