bluuebunny/crossref_metadata_2025 huggingface dataset:
HIV Viral Load Patterns and Risk Factors Among Women in Prevention of Mother-To-Child Transmission Programs to Inform Differentiated Service Delivery
Authors: Jiang Wenwen , Ronen Keshet , Osborn Lusi , Drake Alison L. , Unger Jennifer A. , Matemo Daniel , Richardson Barbra A. , Kinuthia John , John-Stewart Grace
Published: November 2023

Background:

Differentiated service delivery (DSD) approaches decrease frequency of clinic visits for individuals who are stable on antiretroviral therapy. It is unclear how to optimize DSD models for postpartum women living with HIV (PWLH). We evaluated longitudinal HIV viral load (VL) and cofactors, and modelled DSD eligibility with virologic failure (VF) among PWLH in prevention of mother-to-child transmission programs.

Methods:

This analysis used programmatic data from participants in the Mobile WAChX trial (NCT02400671). Women were assessed for DSD eligibility using the World Health Organization criteria among general people living with HIV (receiving antiretroviral therapy for ≥6 months and having at least 1 suppressed VL [<1000 copies/mL] within the past 6 months). Longitudinal VL patterns were summarized using group-based trajectory modelling. VF was defined as having a subsequent VL ≥1000 copies/mL after being assessed as DSD-eligible. Predictors of VF were determined using log-binomial models among DSD-eligible PWLH.

Results:

Among 761 women with 3359 VL results (median 5 VL per woman), a 3-trajectory model optimally summarized longitudinal VL, with most (80.8%) women having sustained low probability of unsuppressed VL. Among women who met DSD criteria at 6 months postpartum, most (83.8%) maintained viral suppression until 24 months. Residence in Western Kenya, depression, reported interpersonal abuse, unintended pregnancy, nevirapine-based antiretroviral therapy, low-level viremia (VL 200–1000 copies/mL), and drug resistance were associated with VF among DSD-eligible PWLH.

Conclusions:

Most postpartum women maintained viral suppression from early postpartum to 24 months and may be suitable for DSD referral. Women with depression, drug resistance, and detectable VL need enhanced services.
Factors Associated With Mortality in Patients With Immune-Mediated Rheumatic Diseases and COVID-19 From Latin America
Authors: Isnardi Carolina Ayelen , Alpizar-Rodriguez Deshire , Calderaro Débora Cerqueira , Marques Claudia Diniz Lopes , Pons-Estel Guillermo Javier , Xavier Ricardo Machado , Saurit Verónica , Pisoni Cecilia Nora , Tissera Yohana Soledad , D'Angelo Exeni Maria Eugenia , Alba Paula , Pereira Dora , Gobbi Carla Andrea , Gamba Maria Julieta , Alfaro María Agustina , Virasoro Belén María , Colunga-Pedraza Iris Jazmín , Irazoque-Palazuelos Fedra , Reyes-Cordero Greta , Rodriguez-Reyna Tatiana S. , Veloz-Aranda Jose Antonio , Skinner-Taylor Cassandra Michele , Juárez-Mora Ingrid Maribel , Silveira Luis H. , Pacheco Tena Cesar Francisco , Xibille-Friedmann Daniel Xavier , Ferreira Gilda Aparecida , Kakehasi Adriana Maria , Pinheiro Marcelo Medeiros , Gomides Ana Paula Monteiro , Pileggi Gecilmara Cristina Salviato , da Mota Licia Maria Henrique , dos Reis-Neto Edgard Torres , Ribeiro Sandra Lúcia Euzébio , de Azevedo Valadares Lilian David , Martínez-Martínez Marco Ulises
Published: November 2023

Objective

To describe characteristics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients with rheumatic immune-mediated inflammatory diseases (IMIDs) from Argentina, Mexico and Brazil, and to assess factors associated with mortality in this population.

Methods

Data from 3 national registries, SAR-COVID (Argentina), CMR-COVID (Mexico), and ReumaCoV-Brasil (Brazil), were combined. Adult patients with IMIDs and SARS-CoV-2 infection were recruited. Sociodemographic data, comorbidities, IMID clinical characteristics and treatment, and SARS-CoV-2 infection presentation and outcomes were recorded.

Results

A total of 4827 individuals were included: 2542 (52.7%) from SAR-COVID, 1167 (24.2%) from CMR-COVID, and 1118 (23.1%) from ReumaCoV-Brasil. Overall, 82.1% were female with a mean age of 49.7 (SD, 14.3) years; 22.7% of the patients were hospitalized, and 5.3% died because of COVID-19 (coronavirus disease 2019). Argentina and Brazil had both 4% of mortality and Mexico 9.4%. In the multivariable analysis, older age (≥60 years; odds ratio [OR], 7.4; 95% confidence interval [CI], 4.6–12.4), male sex (OR, 1.5; 95% CI, 1.1–2.1), living in Mexico (OR, 3.0; 95% CI, 2.0–4.4), comorbidity count (1 comorbidity: OR, 1.5; 95% CI, 1.0–2.1), diagnosis of connective tissue disease or vasculitis (OR, 1.8; 95% CI, 1.3–2.4), and other diseases (OR, 2.6; 95% CI, 1.6–4.1) compared with inflammatory joint disease, high disease activity (OR, 4.2; 95% CI, 2.5–7.0), and treatment with glucocorticoids (OR, 1.9; 95% CI, 1.4–2.5) or rituximab (OR, 4.2; 95% CI, 2.7–6.6) were associated with mortality.

Conclusions

Mortality in patients with IMIDs was particularly high in Mexicans. Ethnic, environmental, societal factors, and different COVID-19 mitigation measures adopted have probably influenced these results.
The Endothelium Modulates the Prothrombotic Phenotype of Factor V Leiden: Evidence from an Ex Vivo Model
Authors: Schwarz Nadine , Müller Jens , McRae Hannah L. , Reda Sara , Pezeshkpoor Behnaz , Oldenburg Johannes , Pötzsch Bernd , Rühl Heiko
Published: November 2023

Background

Clinical expressivity of the thrombophilic factor V Leiden (FVL) mutation is highly variable. Increased activated protein C (APC) formation in response to thrombin formation has been observed in asymptomatic FVL carriers in vivo. Here we further explored this association using a recently developed endothelial colony forming cell (ECFC)-based ex-vivo model.

Methods

ECFCs and citrated plasma were obtained from FVL carriers with/without previous venous thromboembolism (VTE+/-, n=7 each) and seven healthy controls. Coagulation was activated by tissue factor in defibrinated recalcified plasma added to confluent cell cultures. Thrombin and APC concentration were measured over time and the respective areas under the curve (AUC) calculated. Additionally, inhibition kinetics of exogenously added APC and APC sensitivity of the prothrombinase complex were measured in plasma. Expression of thrombomodulin and endothelial protein C receptor (EPCR) on ECFCs was assessed using cell-based enzyme-linked immunosorbent assays.

Results

In autologous plasma on ECFCs, the APC response to thrombin formation (AUC APC/AUC thrombin), was higher in FVL VTE-than FVL VTE+ patients (0.138 versus 0.028,P=0.026). APC inactivation kinetics, APC sensitivity, and thrombomodulin/EPCR expression on ECFCs did not differ between these cohorts and compared to healthy controls. Cross-over experiments with plasma from FVL VTE- and FVL VTE+ patients on non-FVL ECFCs yielded indistinguishable results. In contrast, in normal plasma on FVL VTE-ECFCs the APC response remained significantly higher than on FVL VTE+ ECFCs (0.052 versus 0.022,P=0.011).

Conclusions

Consistent with results from previous in vivo experiments, APC response rates to thrombin formation were higher in asymptomatic FVL carriers compared to those with previous VTE. Our observations suggest that this increased APC response is driven by the endothelium. Further studies are warranted to elucidate yet unknown endothelial mechanisms that might modulate the clinical expressivity of FVL.
Engineered odorant receptors illuminate structural principles of odor discrimination
Authors: de March Claire A. , Ma Ning , Billesbølle Christian B. , Tewari Jeevan , del Torrent Claudia Llinas , van der Velden Wijnand J. C. , Ojiro Ichie , Takayama Ikumi , Faust Bryan , Li Linus , Vaidehi Nagarajan , Manglik Aashish , Matsunami Hiroaki
Published: November 2023

A central challenge in olfaction is understanding how the olfactory system detects and distinguishes odorants with diverse physicochemical properties and molecular configurations. Vertebrate animals perceive odors via G protein-coupled odorant receptors (ORs). In humans, ∼400 ORs enable the sense of smell. The OR family is composed of two major classes: Class I ORs are tuned to carboxylic acids while Class II ORs, representing the vast majority of the human repertoire, respond to a wide variety of odorants. How ORs recognize chemically diverse odorants remains poorly understood. A fundamental bottleneck is the inability to visualize odorant binding to ORs. Here, we uncover fundamental molecular properties of odorant-OR interactions by employing engineered ORs crafted using a consensus protein design strategy. Because such consensus ORs (consORs) are derived from the 17 major subfamilies of human ORs, they provide a template for modeling individual native ORs with high sequence and structural homology. The biochemical tractability of consORs enabled four cryoEM structures of distinct consORs with unique ligand recognition properties. The structure of a Class I consOR, consOR51, showed high structural similarity to the native human receptor OR51E2 and yielded a homology model of a related member of the human OR51 family with high predictive power. Structures of three Class II consORs revealed distinct modes of odorant-binding and activation mechanisms between Class I and Class II ORs. Thus, the structures of consORs lay the groundwork for understanding molecular recognition of odorants by the OR superfamily.
A liquid-to-solid phase transition of biomolecular condensates drivesin vivoformation of yeast amyloids and prions
Authors: Alieva Maya K. , Nikishina Sophia B. , Kireev Igor I. , Golyshev Sergei A. , Tyurin-Kuzmin Pyotr A. , Ivanova Liudmila V. , Alexandrov Alexander I. , Kushnirov Vitaly V. , Dergalev Alexander A.
Published: November 2023

Liquid-liquid phase separation (LLPS) and liquid-solid phase transition (LSPT) of amyloidogenic proteins are now being intensively studied as a potentially widespread mechanism of pathological amyloids formation. However, the possibility and importance of such a mechanism in living systems is still questionable. Here, we investigated the possibility of such LSPT for a series of yeast prion proteins-based constructs overproduced in yeast cells lacking any pre-existing amyloid template. By combining fluorescence and electron microscopy with biochemical and genetic approaches, we have shown that three such constructs (containing the prion domains (PDs) of either Sup35, Rnq1 or Mot3 proteins) form amyloid fibrils via the intermediate stage of liquid-like condensates, that age over time into the more solid-like hydrogels and amyloid bodies. In turn, LSPT of these constructs triggers prion conversion of the corresponding wild-type protein. Two other constructs studied (Ure2- and Sap30-based) are unable to phase separate in vivo and their amyloidogenesis is therefore strongly suppressed. Using PrK-resistant amyloid core mapping, we showed that Sup35PD amyloids formed via LSPT have a different molecular architecture compared to those formed via amyloid cross-seeding. Finally, we showed that physiological LLPS of wild-type Sup35 protein can increase its prion conversion in yeast.
DFNA5-mediated pyroptosis is a driver for venetoclax and azacytidine synergy in myeloid leukemia
Authors: Mahesh Aarthi Nivasini , Xin-Yi Joanne Lai , Jia Lin Mandy Tng , Lin Weilin , Wan Jia Cheng , Yoon Junho , Chen Kaiwen , Bhatt Shruti
Published: November 2023

Acute myeloid leukemia (AML) remains the deadliest adult leukemia with dismal clinical outcomes. Since 2020, a combination of BCL-2 inhibitor (venetoclax, VEN) with hypomethylating agent (azacytidine/decitabine, AZA/DAC) has become a new standard of care in elderly or unfit AML patients. However, the underlying mechanism of synergy between venetoclax and azacytidine combination is not well understood. While apoptosis is regarded as the primary mode of cell death mechanism caused by the venetoclax and azacytidine combination, we provide novel evidence for pyroptosis as additional cell death mechanisms in response to venetoclax and azacytidine combination therapy. We found that long-term treatment with azacytidine caused hypomethylation and significant upregulation in DFNA5/GSDME, pore forming Gasdermin family gene that is otherwise silent in myeloid leukemia. We found that azacytidine mediates N-terminal pore-forming DFNA5 cleavage, membrane rupture, and subsequent pyroptosis ofDFNA5overexpressing cells in response to venetoclax and azacytidine. Deletion ofDFNA5reduced total cell viability, whereDFNA5KO cells exclusively underwent apoptosis while DFNA5 OE cells showed increased propidium iodide uptake, a marker for membrane rupture. Overall, our study establishesDFNA5as an important mediator of venetoclax and azacytidine-induced cell death via non-apoptotic mechanisms.
Cell-selective proteomics reveal novel effectors secreted by an obligate intracellular bacterial pathogen
Authors: Sanderlin Allen G. , Margolis Hannah K. , Meyer Abigail F. , Lamason Rebecca L.
Published: November 2023

Pathogenic bacteria secrete protein effectors to hijack host machinery and remodel their infectious niche.Rickettsiaspp. are obligate intracellular bacteria that can cause life- threatening disease, but their absolute dependence on the host cell environment has impeded discovery of rickettsial effectors and their host targets. We implemented bioorthogonal non-canonical amino acid tagging (BONCAT) duringR. parkeriinfection to selectively label, isolate, and identify secreted effectors. As the first use of BONCAT in an obligate intracellular bacterium, our screen more than doubles the number of experimentally validated effectors forR. parkeri. The novel secreted rickettsial factors (Srfs) we identified includeRickettsia-specific proteins of unknown function that localize to the host cytoplasm, mitochondria, and ER. We further show that one such effector, SrfD, interacts with the host Sec61 translocon. Altogether, our work uncovers a diverse set of previously uncharacterized rickettsial effectors and lays the foundation for a deeper exploration of the host-pathogen interface.
A meta-analysis of rice phosphoproteomics data to understand variation in cell signalling across the rice pan-genome
Authors: Ramsbottom Kerry A , Prakash Ananth , Riverol Yasset Perez , Camacho Oscar Martin , Sun Zhi , Kundu Deepti J. , Bowler-Barnett Emily , Martin Maria , Fan Jun , Chebotarov Dmytro , McNally Kenneth L , Deutsch Eric W , Vizcaíno Juan Antonio , Jones Andrew R
Published: November 2023

Phosphorylation is the most studied post-translational modification, and has multiple biological functions. In this study, we have re-analysed publicly available mass spectrometry proteomics datasets enriched for phosphopeptides from Asian rice (Oryza sativa). In total we identified 15,522 phosphosites on serine, threonine and tyrosine residues on rice proteins.

We identified sequence motifs for phosphosites, and link motifs to enrichment of different biological processes, indicating different downstream regulation likely caused by different kinase groups. We cross-referenced phosphosites against the rice 3,000 genomes, to identify single amino acid variations (SAAVs) within or proximal to phosphosites that could cause loss of a site in a given rice variety. The data was clustered to identify groups of sites with similar patterns across rice family groups, for example those highly conserved in Japonica, but mostly absent in Aus type rice varieties - known to have different responses to drought. These resources can assist rice researchers to discover alleles with significantly different functional effects across rice varieties.

The data has been loaded into UniProt Knowledge-Base - enabling researchers to visualise sites alongside other data on rice proteins e.g. structural models from AlphaFold2, PeptideAtlas and the PRIDE database - enabling visualisation of source evidence, including scores and supporting mass spectra.
Predicting protein folding pathway using a novel folding force field model derived from known protein universe
Authors: Zhao Kailong , Zhao Pengxin , Wang Suhui , Xia Yuhao , Zhang Guijun
Published: November 2023

The protein folding problem has emerged as a new challenge with the significant advances in deep learning driven protein structure prediction methods. While the structures of almost all known proteins have been successfully predicted, the process by which they fold remains an enigma. Understanding the intricate folding mechanism is of paramount importance, as it directly impacts the stable expression and biological function of proteins. Here, we propose FoldPAthreader, a protein folding pathway prediction method that designs a novel folding force field model by exploring the intrinsic relationship between protein evolutionary history and folding mechanisms from the known protein universe. Further, the folding force field is used to guide Monte Carlo conformational sampling, driving the protein chain fold into its native state by exploring a series of transition states and potential intermediates. On the 30 targets we collected, FoldPAthreader can successfully predict 70% of the proteins whose folding pathway is consistent with wet-lab experimental data. The results show that the folding force field can capture key dynamic features of hydrogen bonding and hydrophobic interactions. Importantly, for the widely studied BPTI and TIM proteins, the folding pathway predicted by FoldPAthreader have the same microscopic dynamic properties as those simulated by molecular dynamics.

Significance Statement

Protein folding is the process by which a protein acquires its functional conformations by gradually transforming from random coils into a specific three-dimensional structure. In the post-Alphafold2 era, functional analysis of protein macromolecules should not only rely on the final state structure, but should pay more attention to the structural folding process, that is, the various intermediate states formed during the folding process. At present, there is no folding force field specifically used for protein folding pathway prediction in computational biology. Here we extracted folding information from 100-million-level structure database and designed a new folding force field for folding pathway prediction, proving a hypothesis that the protein evolutionary history implicitly contains folding information of individual protein. This study may provide new insights into the understanding of protein folding mechanisms, which is expected to advance drug discovery.
The thiol methyltransferase activity of TMT1A (METTL7A) is conserved across species
Authors: González Dalmasy José M. , Fitzsimmons Christina M. , Frye William J.E. , Perciaccante Andrew J. , Jewell Connor P. , Jenkins Lisa M. , Batista Pedro J. , Robey Robert W. , Gottesman Michael M.
Published: November 2023

Although few resistance mechanisms for histone deacetylase inhibitors (HDACis) have been described, we recently demonstrated that TMT1A (formerly METTL7A) and TMT1B (formerly METTL7B) can mediate resistance to HDACis with a thiol as the zinc-binding group by methylating and inactivating the drug. TMT1A and TMT1B are poorly characterized, and their normal physiological role has yet to be determined. As animal model systems are often used to determine the physiological function of proteins, we investigated whether the ability of these methyltransferases to methylate thiol-based HDACis is conserved across different species. We found that TMT1A was conserved across rats, mice, chickens, and zebrafish, displaying 85.7%, 84.8%, 60.7% and 51.0% amino acid sequence identity, respectively, with human TMT1A. Because TMT1B was not found in the chicken or zebrafish, we focused our studies on the TMT1A homologs. HEK-293 cells were transfected to express mouse, rat, chicken, or zebrafish homologs of TMT1A and all conferred resistance to the thiol-based HDACIs NCH-51, KD-5170 and romidepsin compared to empty vector-transfected cells. Additionally, all homologs blunted the downstream effects of HDACi treatment such as increased p21 expression, increased acetylated histone H3, and cell cycle arrest. Increased levels of dimethylated romidepsin were also found in the culture medium of cells transfected to express any of the TMT1A homologs after a 24 h incubation with romidepsin compared to empty-vector transfected cells. Our results indicate that the ability of TMT1A to methylate molecules is conserved across species. Animal models may therefore be useful in elucidating the role of these enzymes in humans.
Investigating the Effect of Visual Threat in Virtual Reality on Perceiving Postural Instability Onset
Authors: McIlroy Robert E , Barnett-Cowan Michael
Published: November 2023

Background

Sensory information processing plays a crucial role in monitoring the timing of external and internal events, including the control of balance. While previous research has investigated the role of vision in the perceived timing of postural instability onset with eyes closed and open, it is important to further explore the influence of visual context. Virtual reality offers a unique opportunity to manipulate visual information and assess its impact on balance control and the perceived timing of sensory events.

Research Question

Does visual information, particularly visual threat presented in virtual reality, alter the perceived timing of postural instability onset?

Methods

Two temporal order judgment tasks were conducted using virtual reality to manipulate visual information. Participants were placed on a virtual skyscraper to induce visual threat. The experiments investigated the impact of visual information on the perceived onset of postural instability while manipulating the presence/absence of visual threat.

Results

With vision available but without visual threat, the onset of a postural perturbation needed to occur 10.71-12.33 ms before a reference sound stimulus to be perceived as simultaneous. With visual threat, the onset needed to occur 4.45 ms before auditory cue onset to be perceived as simultaneous. While these delays were not significantly different from true simultaneity of perturbation and sound onset, participants were significantly more precise in their judgments when threatening visual information was present.

Significance

Our results show that visual context, particularly visual threat presented in virtual reality, may alter the perception of perturbation onset and the precision of judgments made. This has implications for understanding the role of vision in balance control and developing interventions to improve balance and prevent falls.
Targeted brain-specific tauopathy compromises peripheral skeletal muscle integrity and function
Authors: Alava Bryan , Hery Gabriela , Sidhom Silvana , Prokop Stefan , Esser Karyn , Abisambra Jose
Published: November 2023

Tauopathies are neurodegenerative disorders in which the pathological intracellular aggregation of the protein tau causes cognitive deficits. Additionally, clinical studies report muscle weakness in populations with tauopathy. However, whether neuronal pathological tau species confer muscle weakness, and whether skeletal muscle maintains contractile capacity in primary tauopathy remains unknown. Here, we identified skeletal muscle abnormalities in a mouse model of primary tauopathy, expressing human mutant P301L-tau using adeno-associated virus serotype 8 (AAV8). AAV8-P301L mice showed grip strength deficits, hyperactivity, and abnormal histological features of skeletal muscle. Additionally, spatially resolved gene expression of muscle cross sections were altered in AAV8-P301L myofibers. Transcriptional changes showed alterations of genes encoding sarcomeric proteins, proposing a weakness phenotype. Strikingly, specific force of the soleus muscle was blunted in AAV8-P301L tau male mice. Our findings suggest tauopathy has peripheral consequences in skeletal muscle that contribute to weakness in tauopathy.
A human immune/muscle xenograft model of FSHD muscle pathology
Authors: Daman Katelyn , Yan Jing , Burzenski Lisa M. , Kady Jamie , Shultz Leonard D. , Brehm Michael A. , Emerson Charles P.
Published: November 2023

Background

Facioscapulohumeral muscular dystrophy (FSHD) disease progression is associated with muscle inflammation, although its role in FSHD muscle pathology is unknown.

Methods

We have developed a novel humanized mouse strain, NSG-SGM3-W41, that supports the co- engraftment of human hematopoietic stem cells (HSCs) and muscle myoblasts as an experimental model to investigate the role of innate immunity in FSHD muscle pathology.

Results

The NSG-SGM3-W41 mouse supports the selective expansion of human innate immune cell lineages following engraftment of human HSCs and the co-engraftment and differentiation of patient-derived FSHD or control muscle myoblasts. Immunohistological and NanoString RNA expression assays establish that muscle xenografts from three FSHD subjects were immunogenic compared to those from unaffected first-degree relatives. FSHD muscle xenografts preferentially accumulated human macrophages and B cells and expressed early complement genes of the classical and alternative pathways including complement factor C3 protein, which is a mediator of early complement function through opsonization to mark damaged cells for macrophage engulfment. FSHD muscle xenografts also underwent immune donor dependent muscle turnover as assayed by human spectrin β1 immunostaining of muscle fibers and by NanoString RNA expression assays of muscle differentiation genes.

Conclusions

The NSG-SGM3-W41 mouse provides an experimental model to investigate the role of innate immunity and complement in FSHD muscle pathology and to develop FSHD therapeutics targeting DUX4 and the innate immunity inflammatory responses.
The biophysical basis of bacterial colony growth
Authors: Pokhrel Aawaz R. , Steinbach Gabi , Krueger Adam , Day Thomas C. , Tijani Julianne , Ng Siu Lung , Hammer Brian K. , Yunker Peter J.
Published: November 2023

Bacteria often attach to surfaces and grow densely-packed communities called biofilms. As biofilms grow, they expand across the surface, increasing their surface area and access to nutrients. Thus, the overall growth rate of a biofilm is directly dependent on its “range expansion” rate. One factor that limits the range expansion rate is vertical growth; at the biofilm edge there is a direct trade-off between horizontal and vertical growth—the more a biofilm grows up, the less it can grow out. Thus, the balance of horizontal and vertical growth impacts the range expansion rate and, crucially, the overall biofilm growth rate. However, the biophysical connection between horizontal and vertical growth remains poorly understood, due in large part to difficulty in resolving biofilm shape with sufficient spatial and temporal resolution from small length scales to macroscopic sizes. Here, we experimentally show that the horizontal expansion rate of bacterial colonies is controlled by the contact angle at the biofilm edge. Using white light interferometry, we measure the three-dimensional surface morphology of growing colonies, and find that small colonies are surprisingly well-described as spherical caps. At later times, nutrient diffusion and uptake prevent the tall colony center from growing exponentially. However, the colony edge always has a region short enough to grow exponentially; the size and shape of this region, characterized by its contact angle, along with cellular doubling time, determines the range expansion rate. We found that the geometry of the exponentially growing biofilm edge is well-described as a spherical-cap-napkin-ring, i.e., a spherical cap with a cylindrical hole in its center (where the biofilm is too tall to grow exponentially). We derive an exact expression for the spherical-cap-napkin-ring-based range expansion rate; further, to first order, the expansion rate only depends on the colony contact angle, the thickness of the exponentially growing region, and the cellular doubling time. We experimentally validate both of these expressions. In line with our theoretical predictions, we find that biofilms with long cellular doubling times and small contact angles do in fact grow faster than biofilms with short cellular doubling times and large contact angles. Accordingly, sensitivity analysis shows that biofilm growth rates are more sensitive to their contact angles than to their cellular growth rates. Thus, to understand the fitness of a growing biofilm, one must account for its shape, not just its cellular doubling time.
Poc1 is a basal body inner junction protein that promotes triplet microtubule integrity and interconnections
Authors: Ruehle Marisa D. , Li Sam , Agard David A. , Pearson Chad G.
Published: November 2023

Basal bodies (BBs) are conserved eukaryotic structures that organize motile and primary cilia. The BB is comprised of nine, cylindrically arranged, triplet microtubules (TMTs) that are connected to each other by inter-TMT linkages which maintain BB structure. During ciliary beating, forces transmitted to the BB must be resisted to prevent BB disassembly. Poc1 is a conserved BB protein important for BBs to resist ciliary forces. To understand how Poc1 confers BB stability, we identified the precise position of Poc1 binding in theTetrahymenaBB and the effect of Poc1 loss on BB structure. Poc1 binds at the TMT inner junctions, stabilizing TMTs directly. From this location, Poc1 also stabilizes inter-TMT linkages throughout the BB, including the cartwheel pinhead and the inner scaffold. Moreover, we identify a molecular response to ciliary forces via a molecular remodeling of the inner scaffold, as determined by differences in Fam161A localization. Thus, while not essential for BB assembly, Poc1 promotes BB interconnections that establish an architecture competent to resist ciliary forces.
Gut microbiota-dependent increase in phenylacetic acid induces endothelial cell senescence during aging
Authors: Saeedi Saravi Seyed Soheil , Pugin Benoit , Constancias Florentin , Thomas Aurélien , Gludic Sylvain Le , Allemann Meret Sarah , Karsai Gergely , Lee Pratintip , Menni Cristina , Attaye Ilias , Beer Jürg H.
Published: November 2023

Endothelial cell (EC) senescence plays a crucial role in the development of cardiovascular diseases in aging population. Gut microbiota alterations are emerging as significant factors present in cellular senescence associated with aging. However, little is known about how aging-related changes in gut microbiota are causally implicated in EC senescence. Here we show that gut microbiota-dependent phenylacetic acid (PAA) and its derivative, phenylacetylglutamine (PAGln), are elevated in a human aging cohort (TwinsUK, n=7,303) and in aged mice. Metagenomic analyses revealed a marked increase in the abundance of PAA-producing microbial pathways (PPFOR and VOR), which were positively associated with the abundance ofClostridiumsp. ASF356, higher circulating PAA concentrations, and endothelial dysfunction in old mice. We found that PAA potently induces EC senescence and attenuates angiogenesis. Mechanistically, PAA increases mitochondrial H2O2generation, which aggravates IL6-mediated HDAC4 translocation and thereby upregulates VCAM1. In contrast, exogenous acetate, which was reduced in old mice, rescues the PAA-induced EC senescence and restores angiogenic capacity through markedly alleviating the SASP and epigenetic alteration. Our studies provide direct evidence of PAA-mediated crosstalk between aging gut microbiota and EC senescence and suggest a microbiota-based therapy for promoting healthy aging.

Highlights

Aging-related gut microbiota alterations contribute to a marked elevation of plasma PAA and PAGln in humans and mice

Clostridiumsp. ASF356 contributes to PPFOR-mediated PAA formation in aged mice

Gut-derived PAA promotes endothelial senescence and impairs angiogenesis

PAA induces mitochondrial H2O2generation, by which drives epigenetic alterations and SASP in ECs

Acetate rescues PAA-induced EC senescence and mitochondrial dysfunction

Acetate improves angiogenesis by reducing HDAC4 phosphorylation and SASP
Differential responses of primary neuron-secreted MCP-1 and IL-9 to type 2 diabetes and Alzheimer’s disease-associated metabolites
Authors: Ball Brendan K. , Kuhn Madison K. , Fleeman Rebecca M. , Proctor Elizabeth A. , Brubaker Douglas K.
Published: November 2023

Type 2 diabetes (T2D) is implicated as a risk factor for Alzheimer’s disease (AD), the most common form of dementia. In this work, we investigated neuroinflammatory responses of primary neurons to potentially circulating, blood-brain barrier (BBB) permeable metabolites associated with AD, T2D, or both. We identified nine metabolites associated with protective or detrimental properties of AD and T2D in literature (lauric acid, asparagine, fructose, arachidonic acid, aminoadipic acid, sorbitol, retinol, tryptophan, niacinamide) and stimulated primary mouse neuron cultures with each metabolite before quantifying cytokine secretion via Luminex. We employed unsupervised clustering, inferential statistics, and partial least squares discriminant analysis to identify relationships between cytokine concentration and disease-associations of metabolites. We identified MCP-1, a cytokine associated with monocyte recruitment, as differentially abundant between neurons stimulated by metabolites associated with protective and detrimental properties of AD and T2D. We also identified IL-9, a cytokine that promotes mast cell growth, to be differentially associated with T2D. Indeed, cytokines, such as MCP-1 and IL-9, released from neurons in response to BBB-permeable metabolites associated with T2D may contribute to AD development by downstream effects of neuroinflammation.
JUNmRNA Translation Regulation is Mediated by Multiple 5’ UTR and Start Codon Features
Authors: González-Sánchez Angélica M. , Castellanos-Silva Eimy A. , Díaz-Figueroa Gabriela , Cate Jamie H. D.
Published: November 2023

Regulation of mRNA translation by eukaryotic initiation factors (eIFs) is crucial for cell survival. In humans, eIF3 stimulates translation of theJUNmRNA which encodes the transcription factor JUN, an oncogenic transcription factor involved in cell cycle progression, apoptosis, and cell proliferation. Previous studies revealed that eIF3 activates translation of theJUNmRNA by interacting with a stem loop in the 5′ untranslated region (5′ UTR) and with the 5′ -7-methylguanosine cap structure. In addition to its interaction site with eIF3, theJUN5′ UTR is nearly one kilobase in length, and has a high degree of secondary structure, high GC content, and an upstream start codon (uAUG). This motivated us to explore the complexity ofJUNmRNA translation regulation in human cells. Here we find that JUN translation is regulated in a sequence and structure-dependent manner in regions adjacent to the eIF3-interacting site in theJUN5′ UTR. Furthermore, we identify contributions of an additional initiation factor, eIF4A, inJUNregulation. We show that enhancing the interaction of eIF4A withJUNby using the compound Rocaglamide A (RocA) repressesJUNtranslation. We also find that both the upstream AUG (uAUG) and the main AUG (mAUG) contribute toJUNtranslation and that they are conserved throughout vertebrates. Our results reveal additional layers of regulation forJUNtranslation and show the potential ofJUNas a model transcript for understanding multiple interacting modes of translation regulation.
Genome-wide assessment of runs of homozygosity in Sahiwal cattle of Pakistan
Authors: Sesay Abdul Rahman , Saif-ur-Rehman Mohammad , Ramzan Faisal , Awan Faisal Saeed
Published: November 2023

Runs of homozygosity (ROH) are extensive stretches of homozygous genotypes present in an individual genome inherited from each of its parents. Selection pressures have been one of the core causes of a reduction in genetic diversity in some genomic regions, leading to an accumulation of ROH in these regions. An individual’s ROH can provide information about the past of his population, including the extent of inbreeding, recent bottlenecks, and positive selection. The study aimed to evaluate the degree of autozygosity throughout the genome in Sahiwal cattle to discern and describe ROH patterns. In addition, we also estimated the rate of inbreeding based on ROH in Sahiwal cattle. A sample of 98 Sahiwal bulls from various public institutional herds and private livestock farms in the Punjab province of Pakistan was used for this study. All animals were genotyped using the 140k BovineHD SNP chip. The study identified ROH in all animals. The mean ROH per animal was 29.71, with values extending from 2.35 to 85.31. The mean length of the ROH was 5.84 Mb, and the longest segment was 51.43 Mb (1,727 SNPs) found on BTA3. Results revealed that genome-wide ROH for Sahiwal was typically composed of many short and medium segments (2–4 Mb and 4–8 Mb), accounting for approximately 54.18% of all detected ROH. The inbreeding coefficient based on ROH (FROH) ranged from 0.016 to 0.057. The study revealed several genes, including STAT1, ATP1A1, OLR1, and CD4, which are known genes related to milk production. Thus, understanding ROH patterns, an inbreeding coefficient derived from ROH, and candidate genes associated with significant economic traits can help explain the mechanisms governing these traits in Sahiwal cattle.
Mass spectrometry imaging links interxylary cork formation with phytochemical distribution inScutellaria baicalensis
Authors: Huang Lieyan , Nie Lixing , Dong Jing , Yao Lingwen , Kang Shuai , Jin Hongyu , Wei Feng , Ma Shuangcheng
Published: November 2023

Interxylary cork, an anomalous cork structure of plant, is occasionally seen in older roots ofScutellaria baicalensisGeorgi (Lamiaceae). Xylem tissues encircled by interxylary corks gradually decay. Efforts have been made to elucidate the development of interxylary cork inS. baicalensis, but the variation of phytochemical accumulation in different root tissues segmented by interxylary cork has not been studied. In this investigation, mass spectrometry imaging was employed to visualize thein situphytochemicals in the decayed root ofS. baicalensis(Kuqin). A special flavonoid was observed to show especially high mass intensity in the cork region, and its spatial distribution was regarded as a reflection of cork development. Interxylary corks were found to be successively formed in the root ofS. baicalensis. After the continuous formation of interxylary corks, root tissues were divided into different parts by interxylary corks, including the non-decayed part, slightly decayed part and severely decayed part. Interestingly, pharmaceutically important flavonoids presented different accumulation tendencies in tissues of different decaying degrees. Owing to the non-targeted analytical function of mass spectrometry imaging, the holistic difference of chemical composition of decayed and non-decayed tissues of Kuqin was deciphered. To our knowledge, this is the first experiment that maps out the successive formation of interxylary corks inS. baicalensisusing mass spectrometry imaging. Also, our research successfully correlates plant anatomy with the spatial distribution of phytochemicals, which sets a good example for the exploration of plant science from the dimension of spatial information.
Microbial ecology of coastal northern Gulf of Mexico waters
Authors: Henson Michael W. , Thrash J. Cameron
Published: November 2023

Estuarine and coastal ecosystems are of high economic and ecological importance, owing to their diverse communities and the disproportionate role they play in carbon cycling, particularly in carbon sequestration. Organisms inhabiting these environments must overcome strong natural fluctuations in salinity, nutrients, and turbidity as well as numerous climate change-induced disturbances such as land loss, sea level rise, and, in some locations, increasingly severe tropical cyclones that threaten to disrupt future ecosystem health. The northern Gulf of Mexico (nGoM) along the Louisiana coast contains dozens of estuaries, including the Mississippi-Atchafalaya River outflow, which dramatically influence the region due to their vast upstream watershed. Nevertheless, the microbiology of these estuaries and surrounding coastal environments have received little attention. To improve our understanding of microbial ecology in the understudied coastal nGoM, we conducted a 16S rRNA gene amplicon survey at eight sites and multiple timepoints along the Louisiana coast and one inland swamp spanning freshwater to high brackish salinities, totaling 47 duplicated Sterivex (0.2-2.7 µm) and prefilter (> 2.7 µm) samples. We cataloged over 13,000 ASVs from common freshwater and marine clades such as SAR11 (Alphaproteobacteria),Synechococcus(Cyanobacteria), and acI andCandidatusActinomarina (Actinobacteria). We observed preferences for freshwater or marine habitats in many organisms and also characterized a group of taxa with specialized distributions across brackish water sites, supporting the hypothesis of an endogenous brackish-water community. Additionally, we observed brackish-water preferences for several aquatic clades typically considered marine or freshwater taxa, such as SAR11 subclade II, SAR324, and the acI Actinobacteria. The data presented here expand the geographic coverage of microbial ecology in estuarine communities, help delineate the autochthonous and allochthonous members of these environments, and provide critical aquatic microbiological baseline data for coastal and estuarine sites in the nGoM.
Cardiac Molecular Analysis Reveals Aging-Associated Metabolic Alterations Promoting Glycosaminoglycans Accumulation Via Hexosamine Biosynthetic Pathway
Authors: Grilo Luís F. , Zimmerman Kip D. , Puppala Sobha , Chan Jeannie , Huber Hillary F. , Li Ge , Jadhav Avinash Y. L. , Wang Benlian , Li Cun , Clarke Geoffrey D. , Register Thomas C. , Oliveira Paulo J. , Nathanielsz Peter W. , Olivier Michael , Pereira Susana P. , Cox Laura A.
Published: November 2023

Age is a prominent risk factor for cardiometabolic disease, and often leads to heart structural and functional changes. However, precise molecular mechanisms underlying cardiac remodeling and dysfunction resulting from physiological aging per se remain elusive. Understanding these mechanisms requires biological models with optimal translation to humans. Previous research demonstrated that baboons undergo age-related reduction in ejection fraction and increased heart sphericity, mirroring changes observed in humans.

The goal of this study was to identify early cardiac molecular alterations that precede functional adaptations, shedding light on the regulation of age-associated changes.

We performed unbiased transcriptomics of left ventricle (LV) samples from female baboons aged 7.5-22.1 years (human equivalent ∼30-88 years). Weighted-gene correlation network and pathway enrichment analyses were performed to identify potential age-associated mechanisms in LV, with histological validation. Myocardial modules of transcripts negatively associated with age were primarily enriched for cardiac metabolism, including oxidative phosphorylation, tricarboxylic acid cycle, glycolysis, and fatty-acid β-oxidation. Transcripts positively correlated with age suggest upregulation of glucose uptake, pentose phosphate pathway, and hexosamine biosynthetic pathway (HBP), indicating a metabolic shift towards glucose-dependent anabolic pathways. Upregulation of HBP commonly results in increased glycosaminoglycan precursor synthesis. Transcripts involved in glycosaminoglycan synthesis, modification, and intermediate metabolism were also upregulated in older animals, while glycosaminoglycan degradation transcripts were downregulated with age. These alterations would promote glycosaminoglycan accumulation, which was verified histologically. Upregulation of extracellular matrix (ECM)-induced signaling pathways temporally coincided with glycosaminoglycan accumulation. We found a subsequent upregulation of cardiac hypertrophy-related pathways and an increase in cardiomyocyte width.

Overall, our findings revealed a transcriptional shift in metabolism from catabolic to anabolic pathways that leads to ECM glycosaminoglycan accumulation through HBP prior to upregulation of transcripts of cardiac hypertrophy-related pathways. This study illuminates cellular mechanisms that precede development of cardiac hypertrophy, providing novel potential targets to remediate age-related cardiac diseases.
Conservation of heat stress acclimation by the inositol polyphosphate multikinase, IPMK responsible for 4/6-InsP7production in land plants
Authors: Yadav Ranjana , Liu Guizhen , Rana Priyanshi , Pullagurla Naga Jyothi , Qiu Danye , Jessen Henning J. , Laha Debabrata
Published: November 2023

Inositol pyrophosphates (PP-InsPs) are soluble cellular messengers that integrate environmental cues to induce adaptive responses in eukaryotes. In plants, the biological functions of various PP-InsP species are poorly understood, largely due to the absence of canonical enzymes present in other eukaryotes. The recent identification of a new PP-InsP isomer with yet unknown enantiomeric identity, 4/6-InsP7in the eudicotArabidopsis thaliana, further highlights the intricate PP-InsP signalling network employed by plants. The abundance of 4/6-InsP7in land plants, the enzyme(s) responsible for its synthesis, and the physiological functions of this species are all currently unknown. In this study, we show that 4/6-InsP7is the major PP-InsP species present across land plants. Our findings demonstrate that theArabidopsisinositol polyphosphate multikinase (IPMK) homolog, AtIPK2α generates 4/6-InsP7in vitro. Furthermore, the cellular level of 4/6-InsP7is controlled by the twoArabidopsisIPMK isoforms, AtIPK2α and AtIPK2β. Notably, the activity of these IPMK proteins is critical for heat stress acclimation inArabidopsis. During heat stress, the expression of genes encoding various heat shock proteins controlled by the heat shock factors (HSFs) is affected in the AtIPK2-deficient plants. Furthermore, we show that the transcription activity of HSF is regulated by the AtIPK2 proteins. Our parallel investigations using the liverwortMarchantia polymorphasuggest that the InsP6kinase activity of IPMK and the role of IPMK in regulating the heat stress response are evolutionarily conserved. Collectively, our study indicates that IPMK has played a critical role in transducing environmental cues for biological processes during land plant evolution.
Linkage among halal quality standard certification and SME’s performance: Palestinian food halal certified SME’s context
Authors: Amer Mahmoud
Published: November 2023

Purpose

The aim of this study is to study the relationship between halal certification and small and medium entreprise (SME) performance in a turbulent environment such as the Palestinian environment.

Design/methodology/approach

In this study quantitative cross-sectional research design using questionnaires distributed over 51 certified SME’s used, and analysis was performed using partial least squares-structural equational modeling.

Findings

The current study revealed that there is a positive relationship between certification and business performance of SME’s in terms of financial and operational performance, and operational performance can mediate the effect between certification and financial performance. It is recommended to conduct further research with larger sample sizes and conduct research using different research designs, such as the longitudinal research design.

Practical implications

Certification of Halal also has a positive relationship with performance, even in a turbulent environment like Palestine. Accordingly, Palestinian food manufacturing firms are called to implement food safety standards like the Halal certificate to gain beside the good gained image the good financial performance.

Originality/value

This study was conducted in one of the most turbulent environments, as well as in developing countries, enriching the literature with results from emerging/turbulence and developing countries.