bluuebunny/crossref_metadata_2025 huggingface dataset:
Auditory Brainstem Response as an Objective Measure of Temporal Resolution
Authors: Athreya Varsha M , Barman Animesh
Published: October 2022

Background and Aims

Temporal resolution is assessed using behavioral tests, which are highly affected by extraneous variables. We explored the relationship between behavioral Across-Channel Gap Detection Threshold (AC GDT) and different temporal parameters of an objective measure, Auditory Brainstem Response (ABR), to account for the extraneous variables.

Settings and Design

We conducted an experimental study on thirty native Kannada-speaking adults with normal hearing sensitivity in the age range of 18-25 years.

Materials and Methods

We estimated the Gap detection threshold (GDT) using an across-channel (AC) paradigm, and Auditory Brainstem Response (ABR) was recorded at 80 dBnHL for three repetition rates of 11.1, 30.1, and 90.1/sec.

Statistical Analyses used

Normality testing, the Friedman test, post-hoc analysis by Wilcoxon Signed-Rank test, along with descriptive statistics was performed using SPSS v20 (IBM Statistical Package for Social Sciences, New York, USA).

Results

The results showed a significant positive correlation between AC GDT scores and latency of wave I for the repetition rates of 11.1 and 30.1/sec and latency of wave V at 30.1 and 90.1/sec. There was a negative correlation (but not significant) between AC GDT scores and the slope of wave V across the repetition rates.

Conclusions

The results suggest a relationship between the behavioral and electrophysiological measures of temporal processing. Measuring the latency of wave I and wave V of ABR would give an estimate of their AC GDT scores, especially in difficult-to-test populations.

Key messages

To test temporal resolution abilities in individuals with normal hearing sensitivity, we can use an objective measure of latency of wave I and wave V of ABR. ABR can be highly useful in reducing testing time and obtaining reliable estimates in children and individuals with associated disorders like autism, below-average intelligence, and so on.
Enhancing HIV-1 neutralization by increasing the local concentration of MPER-directed bnAbs
Authors: Kim Soohyun , Interrante Maria V. Filsinger , Kim Peter S.
Published: October 2022

Broadly neutralizing antibodies (bnAbs) against the membrane-proximal external region (MPER) of the gp41 component of the HIV-1 envelope (Env) are characterized by long hydrophobic heavy-chain complementarity-determining regions (HCDR3s) that interact with MPER and some viral membrane lipids, to achieve increased local concentrations. Here, we show that increasing the local concentration of MPER-directed bnAbs at the cell surface via binding to the high affinity Fc receptor (FcγRI) potentiates their ability to prevent viral entry in a manner analogous to the previously reported observation whereby the lipid binding activity of MPER bnAbs increases their concentration at the viral surface membrane. However, binding of MPER-directed bnAb 10E8 to FcγRI abolishes the neutralization synergy that is seen with the N-heptad repeat (NHR)-targeting antibody D5_AR and NHR-targeting small molecule enfuvirtide (T20), possibly due to decreased accessibility of the NHR in the FcγRI-10E8-MPER complex. Taken together, our results suggest that lipid-binding activity and FcγRI-mediated potentiation function in concert to improve the potency of MPER-directed bnAbs by increasing their local concentration near the site of viral fusion. Therefore, lipid-binding may not be a strict requirement for potent neutralization by MPER-targeting bnAbs, as alternative methods can achieve similar increase in local concentration while avoiding potential liabilities associated with immunologic host tolerance.

Author summary

The trimeric glycoprotein Env is the only viral protein expressed on the surface of HIV-1, is the target of broadly neutralizing antibodies, and is the focus of most vaccine development efforts. Broadly neutralizing antibodies targeting the membrane proximal external region (MPER) of Env show lipid-binding characteristics and modulating this interaction affects neutralization. In this study, we tested the neutralization potencies of variants of the MPER-targeting antibody 10E8 with different viral membrane-binding and host FcγRI-binding capabilities. Our results suggest that binding to both lipid and FcγRI improves the neutralization potency of MPER-directed antibodies by concentrating the antibody at sites of viral fusion. As such, lipid-binding may not be uniquely required for MPER-targeting broadly neutralizing antibodies, as alternative methods to increase local concentration can achieve similar improvements in potency.
Cytoplasmic folding, mis-folding, and early stages of aggregation
Authors: Samuel Russell Premila P. , Rickard Meredith M. , Boob Mayank , Gruebele Martin , Pogorelov Taras V.
Published: October 2022

We examine how cellular interactions in an all-atom model of theHomo sapienscytoplasm influence the early folding events of Protein B (PB), a three-helix bundle protein. While PB is known to fold duringin vitrosimulations in three microseconds, all three initially unfolded PB copies in our cytoplasm model never completely reached their native topology across our 31 microsecond simulation. We were able to capture initial formation of all three helices and a compact topology similar to the native state. Sticking interactions between PB and surrounding macromolecules, as well as other unfolded PBs, became competitive with PB folding. Interaction between PB copies seeded beta-strand formation, modeling initial events of protein aggregation. Finally, the fold-switching potential of PB related GA domains has been explored in previous studies, and the sticking and crowding in our model thus initiates sampling of helix/sheet structural plasticity of PB.
Integrated SARS-CoV-2 serological and virological screening across an acute fever surveillance platform to monitor temporal changes in anti-spike antibody levels and risk of infection during sequential waves of variant transmission — Dominican Republic, March 2021 to August 2022
Authors: Nilles Eric J. , de St. Aubin Michael , Dumas Devan , Duke William , Etienne Marie Caroline , Abdalla Gabriela , Jarolim Petr , Oasan Timothy , Garnier Salome , Iihoshi Naomi , Lopez Beatriz , de la Cruz Lucia , Puello Yosanly Cornelio , Baldwin Margaret , Roberts Kathryn W. , Peña Farah , Durski Kara , Sanchez Isaac Miguel , Gunter Sarah M. , Kneubehl Alexander R. , Murray Kristy O. , Lino Allison , Strobel Sarah , Baez Amado Alejandro , Lau Colleen L. , Kucharski Adam , Gutiérrez Emily Zielinski , Skewes-Ramm Ronald , Vasquez Marietta , Paulino Cecilia Then
Published: October 2022

The global SARS-CoV-2 immune landscape and population protection against emerging variants is largely unknown. We assessed SARS-CoV-2 antibody changes in the Dominican Republic and implications for immunological protection against variants of concern. Between March 2021 and August 2022, 2,300 patients with undifferentiated febrile illnesses were prospectively enrolled. Sera was tested for total anti-spike antibodies and simultaneously collected nasopharyngeal samples for acute SARS-CoV-2 infection with RT-PCR. Geometric mean anti-spike titers increased from 6.6 BAU/ml (95% CI 5.1–8.7) to 1,332 BAU/ml (1055–1,682). Multivariable binomial odds ratios for acute SARS-CoV-2 infection were 0.55 (0.40–0.74), 0.38 (0.27–0.55), and 0.27 (0.18–0.40) for the second, third, and fourth versus the first anti-S quartile, with similar findings by viral strain. Integrated serological and virological screening can leverage existing acute fever surveillance platforms to monitor population-level immunological markers and concurrently characterize implications for emergent variant transmission in near real-time.
Association between endotypes of prematurity and pharmacological closure of patent ductus arteriosus: A systematic review and meta-analysis
Authors: Gonzalez-Luis Gema , Borges-Lujan Moreyba , Villamor Eduardo
Published: October 2022

Endotypes leading to very and extremely preterm birth are clustered into two groups: infection/inflammation and dysfunctional placentation. We conducted a systematic review of observational studies exploring the association between these two endotypes and the pharmacological closure of patent ductus arteriosus (PDA) induced by cyclooxygenase (COX) inhibitors. Chorioamnionitis represented the infectious-inflammatory endotype, while dysfunctional placentation proxies were hypertensive disorders of pregnancy (HDP) and small for gestational age (SGA) or intrauterine growth restriction. PubMed/Medline and Embase databases were searched. The random-effects odds ratio (OR) and 95% confidence interval (CI) were calculated for each association. We included 30 studies (12639 infants). Meta-analysis showed a significant association between exposure to HDP and increased rate of pharmacological closure of PDA (17 studies, OR 1.41, 95% CI 1.10-1.81, p=0.006). In contrast, neither chorioamnionitis (13 studies, OR 0.75, 95% CI 0.47-1.18, p=0.211) nor SGA (17 studies, OR 1.20, 95% CI 0.96-1.50, p=0.115) were significantly associated with the response to therapy. Subgroup analyses showed that the higher response to COX inhibitors in the HDP group was significant for indomethacin (OR 1.568, 95% CI 1.147-2.141, p=0.005) but not for ibuprofen (OR 1.107, 95% CI 0.248-4.392, p=0.894) or for the studies using both drugs (OR 1.280, 95% CI 0.935-1.751, p=0.124). However, meta-regression showed that this difference between the drugs was not statistically significant (p=404). In conclusion, our data suggest that the pathologic condition that triggers prematurity may alter the response to pharmacological treatment of PDA. The DA of infants exposed to HDP appears to be more responsive to COX inhibitors.
The nematode effector Mj-NEROSs interacts with ISP influencing plastid ROS production to suppress plant immunity
Authors: Stojilković Boris , Xiang Hui , Chen Yujin , Bauters Lander , Van de Put Hans , Steppe Kathy , Liao Jinling , de Almeida Engler Janice , Gheysen Godelieve
Published: October 2022

Root-knot nematodes are an important group of plant pathogens that mainly infect plant roots. They establish a feeding site in the host upon infection while secreting hundreds of effectors. These effector proteins are crucial for successful pathogen propagation. Although many effectors have been described, their targets and molecular mode of action are still unknown. Here we report the analysis of the RKN effector, Mj-NEROSs (MeloidogynejavanicanematodeeffectorROS suppressor), which emerges to have an essential role in suppressing host immunity by inhibiting INF1-induced cell death and reducing callose deposition. Secreted from the subventral esophageal glands to giant cells, Mj-NEROSs localizes in plastids where it interacts withISP, interfering with the electron transport rate and ROS production. Moreover, our transcriptome analysis shows the downregulation of ROS-related genes upon Mj-NEROSs expression. We propose that Mj-NEROSs manipulates root plastids leading to transcriptional changes, lowering ROS production, and suppressing host immunity.
Vaccine- and BTI-elicited pre-Omicron immunity more effectively neutralizes Omicron sublineages BA.1, BA.2, BA.4 and BA.5 than pre-Omicron infection alone
Authors: da Silva Eveline Santos , Servais Jean-Yves , Kohnen Michel , Arendt Victor , Gilson Georges , Staub Therese , Seguin-Devaux Carole , Perez-Bercoff Danielle
Published: October 2022

Since the emergence of SARS-CoV-2 Omicron BA.1 and BA.2, several Omicron sublineages have emerged, supplanting their predecessors. BA.5 is the current dominant sublineage. Here we compared the neutralization of Omicron sublineages BA.1, BA.2, BA.4 and BA.5 by human sera collected from individuals who were infected with the ancestral B.1 (D614G) strain, vaccinated (3 doses), or with hybrid immunity from vaccination (2 doses) followed by pre-Omicron breakthrough infection (BTI) with Gamma or Delta. All Omicron sublineages exhibited extensive escape from all sera compared to the ancestral B.1 strain and to Delta, albeit to different levels depending on the origin of the sera. Convalescent sera were unable to neutralize BA.1, and partly neutralized BA.2, BA.4 and BA.5. Vaccinee sera partly neutralized BA.2, but BA.1, BA.4 and BA.5 evaded neutralizing antibodies. BTI sera were either non-neutralizing or partially neutralizing. In this case, they had similar neutralizing ability against all Omicron sublineages. Despite similar levels of anti-Spike and anti-Receptor Binding Domain (RBD) antibody in all groups, BTI sera had the highest cross-neutralizing ability against all Omicron sublineages and convalescent sera were the least neutralizing. The NT50:antibody titer ratio, which reflects antibody avidity, was significantly higher in sera from BTI patients compared to convalescent sera, underscoring qualitative differences in antibodies elicited by infection alone and by vaccination. Together these findings highlight the importance of vaccination to trigger highly cross-reactive antibodies that neutralize phylogenetically and antigenically distant strains, and suggest that immune imprinting by first generation vaccines may restrict, but not abolish cross-neutralization.
Amyloid-β1–42oligomers enhance mGlu5R-dependent synaptic weakening via NMDAR activation and complement C3aR/C5aR signaling
Authors: Ng Ai Na , Salter Eric W. , Georgiou John , Bortolotto Zuner A. , Collingridge Graham L.
Published: October 2022

Synaptic dysfunction, weakening, and loss of synapses are well-correlated with the pathology of Alzheimer’s disease (AD). Oligomeric amyloid beta (oAβ) is considered a major synaptotoxic trigger for AD. Recent studies have implicated hyperactivation of the complement cascade as the driving force for loss of synapses caused by oAβ. However, the initial synaptic cues that trigger pathological complement activity remain elusive. Here, we examined a form of synaptic long-term depression (LTD) mediated by metabotropic glutamate receptors (mGluR) which is disrupted in rodent models of AD. Exogenous application of oAβ (1-42) to mouse hippocampal slices enhanced the magnitude of mGlu subtype 5 receptor (mGlu5R)-dependent LTD. We found that the enhanced synaptic weakening occurred via both NMDARs and complement C3aR/C5aR signaling. Our findings reveal a mechanistic interaction between mGlu5R, NMDARs, and the complement cascade in synaptic weakening induced by oAβ, which could represent an early trigger of synaptic loss and degeneration in AD.
Identifying brain areas for tactile perception through natural touch with MR-compatible tactile stimulus delivery system
Authors: Hwang Seong-Hwan , Park Doyoung , Paeng Somang , Lee Sue-Hyun , Kim Hyoung F.
Published: October 2022

Primates actively touch objects with their hands to collect information. In investigations of the tactile information processes, participants should experience tactile stimuli through active touch while brain activities are monitored. Here, we developed a pneumatic tactile stimulus delivery system (pTDS) that delivers various tactile stimuli on a programmed schedule and allows tactile perception through voluntary finger touches during MRI scanning. A pneumatic actuator moved tactile blocks and placed one in a finger hole. The time when an index finger touched a tactile stimulus was detected with a photosensor, allowing analysis of the touch-elicited brain responses. The brain responses were examined while the participants actively touched braille objects presented by the pTDS. BOLD responses during tactile perception were significantly stronger in a finger touch area of the contralateral somatosensory cortex compared with that of visual perception. This pTDS enables MR study of brain mechanisms for tactile processes through natural finger touch.
Complete functional analysis of type IV pilus components of a reemergent plant pathogen reveals neofunctionalization of paralog genes
Authors: Merfa Marcus V , Zhu Xinyu , Shantharaj Deepak , Gomez Laura M. , Naranjo Eber , Potnis Neha , Cobine Paul A. , De La Fuente Leonardo
Published: October 2022

Type IV pilus (TFP) is a multifunctional bacterial structure involved in twitching motility, adhesion, biofilm formation, as well as natural competence. Here, by mutagenesis and functional analysis, we dissected the roles of all genes required for TFP biosynthesis and regulation in the reemergent plant pathogenic fastidious prokaryoteXylella fastidiosa. This xylem-limited, insect-transmitted pathogen lives constantly under flow conditions and therefore is highly dependent on TFP for host colonization. In addition, TFP-mediated natural transformation is a process that impacts genomic diversity and environmental fitness. Ten out of the thirty-eight genes analyzed were essential for movement and natural competence. Interestingly, seven sets of paralogs exist, and mutations showed opposing phenotypes, indicating evolutionary neofunctionalization of subunits within TFP. The minor pilin FimT3 was the only protein exclusively required for natural competence. We determined that FimT3 (but not the other two FimT paralogs) is a DNA receptor that is conserved amongX. fastidiosastrains and binds DNA non-specifically via an electropositive surface. Among plant pathogens, this gene was also found in the genome of strains of the plant associated Xanthomonadaceae family. Overall, we highlight here the complex regulation of TFP inX. fastidiosa, providing a blueprint to understand TFP in other bacteria living under flow conditions.
Spt5 C-terminal repeat domain phosphorylation and length negatively regulate heterochromatin through distinct mechanisms
Authors: MacKinnon Sarah , Pagé Viviane , Martin Ryan D. , Hébert Terence E. , Tanny Jason C.
Published: October 2022

Heterochromatin is a condensed chromatin structure that represses transcription of repetitive DNA elements and developmental genes, and is required for genome stability. Paradoxically, transcription of heterochromatic sequences is required for establishment of heterochromatin in diverse eukaryotic species. As such, components of the transcriptional machinery can play important roles in establishing heterochromatin. How these factors coordinate with heterochromatin proteins at nascent heterochromatic transcripts remains poorly understood. In the model eukaryoteSchizosaccharomcyes pombe (S. pombe), heterochromatin nucleation can be coupled to processing of nascent transcripts by the RNA interference (RNAi) pathway, or to other post-transcriptional mechanisms that are RNAi-independent. Here we show that the RNA polymerase II processivity factor Spt5 negatively regulates heterochromatin inS. pombethrough its C-terminal domain (CTD). The Spt5 CTD is analogous to the CTD of the RNA polymerase II large subunit, and is comprised of multiple repeats of an amino acid motif that is phosphorylated by Cdk9. We provide evidence that genetic ablation of Spt5 CTD phosphorylation results in aberrant RNAi-dependent nucleation of heterochromatin at an ectopic location, as well as inappropriate spread of heterochromatin proximal to centromeres. In contrast, truncation of Spt5 CTD repeat number enhanced RNAi-independent heterochromatin formation and bypassed the requirement for RNAi. We relate these phenotypes to the known Spt5 CTD-binding factor Rtf1. This separation of function argues that Spt5 CTD phosphorylation and CTD length restrict heterochromatin through unique mechanisms. More broadly, our findings argue that Spt5 CTD repeat length and phosphorylation have distinct regulatory effects on transcription.
E2 ubiquitin conjugase Bendless is essential for PINK1-Park activity to regulate Mitofusin under mitochondrial stress
Authors: Cheramangalam Rajit Narayanan , Anand Tarana , Pandey Priyanka , Balasubramanian Deepa , Varghese Reshmi , Singhal Neha , Jaiswal Sonal Nagarkar , Jaiswal Manish
Published: October 2022

Cells under mitochondrial stress often co-opt mechanisms to maintain energy homeostasis, mitochondrial quality control and cell survival. A mechanistic understanding of such responses is crucial for further insight into mitochondrial biology and diseases. Through an unbiased genetic screen inDrosophila, we identify that mutations inlrpprc2, a homolog of the humanLRPPRCgene that is linked to the French-Canadian Leigh syndrome, results in PINK1-Park activation. While the PINK1-Park pathway is well known to induce mitophagy, we show that in the case oflrpprc2mutants, PINK1-Park regulates mitochondrial dynamics by inducing degradation of the mitochondrial fusion protein Mitofusin/Marf. We also discover that Bendless, a K63-linked E2 conjugase, is a regulator of Marf, as loss ofbendlessresults in increased Marf levels. We show that Bendless is required for PINK1 stability, and subsequently for PINK1-Park mediated Marf degradation under physiological conditions, and in response to mitochondrial stress as seen inlrpprc2. Additionally, we show that loss of Bendless inlrpprc2mutant eye results in photoreceptor degeneration, indicating a neuroprotective role for Bendless-PINK1-Park mediated Marf degradation. Based on our observations, we propose that certain forms of mitochondrial stress activate Bendless-PINK1-Park to limit mitochondrial fusion, which is a cell-protective response.
Molecular basis of SARS-CoV-2 Omicron variant evasion from shared neutralizing antibody response
Authors: Patel Anamika , Kumar Sanjeev , Lai Lilin , Chakravarthy Chennareddy , Valanparambil Rajesh , Reddy Elluri Seetharami , Gottimukkala Kamalvishnu , Bajpai Prashant , Raju Dinesh Ravindra , Edara Venkata Viswanadh , Davis-Gardner Meredith E. , Linderman Susanne , Dixit Kritika , Sharma Pragati , Mantus Grace , Cheedarla Narayanaiah , Verkerke Hans P. , Frank Filipp , Neish Andrew S. , Roback John D. , Davis Carl W. , Wrammert Jens , Ahmed Rafi , Suthar Mehul S. , Sharma Amit , Murali-Krishna Kaja , Chandele Anmol , Ortlund Eric A.
Published: October 2022

A detailed understanding of the molecular features of the neutralizing epitopes developed by viral escape mutants is important for predicting and developing vaccines or therapeutic antibodies against continuously emerging SARS-CoV-2 variants. Here, we report three human monoclonal antibodies (mAbs) generated from COVID-19 recovered individuals during first wave of pandemic in India. These mAbs had publicly shared near germline gene usage and potently neutralized Alpha and Delta, but poorly neutralized Beta and completely failed to neutralize Omicron BA.1 SARS-CoV-2 variants. Structural analysis of these three mAbs in complex with trimeric spike protein showed that all three mAbs are involved in bivalent spike binding with two mAbs targeting class-1 and one targeting class-4 Receptor Binding Domain (RBD) epitope. Comparison of immunogenetic makeup, structure, and function of these three mAbs with our recently reported class-3 RBD binding mAb that potently neutralized all SARS-CoV-2 variants revealed precise antibody footprint, specific molecular interactions associated with the most potent multi-variant binding / neutralization efficacy. This knowledge has timely significance for understanding how a combination of certain mutations affect the binding or neutralization of an antibody and thus have implications for predicting structural features of emerging SARS-CoV-2 escape variants and to develop vaccines or therapeutic antibodies against these.
SORORIN is an evolutionary conserved antagonist of WAPL
Authors: Mota Ignacio Prusén , Galova Marta , Schleiffer Alexander , Nguyen Tan-Trung , Kovacikova Ines , Nishiyama Tomoko , Gregan Juraj , Peters Jan-Michael , Schlögelhofer Peter
Published: October 2022

Cohesin mediates sister chromatid cohesion to enable chromosome segregation and DNA damage repair. To perform these functions, cohesin needs to be protected from WAPL, which otherwise releases cohesin from DNA. It has been proposed that cohesin is protected from WAPL by SORORIN. However,in vivoevidence for this antagonism is missing and SORORIN is only known to exist in vertebrates and insects. It is therefore unknown how important and widespread SORORIN’s functions are. Here we report the identification of SORORIN orthologs inSchizosaccharomyces pombe(Sor1) andArabidopsis thaliana(AtSORORIN).sor1Δmutants display cohesion defects, which are partially alleviated bywpl1Δ. Atsororinmutant plants display dwarfism, tissue specific cohesion defects and chromosome mis-segregation. Furthermore,Atsororinmutant plants are sterile and separate sister chromatids prematurely at anaphase I. The somatic, but not the meiotic deficiencies can be alleviated by loss of WAPL. These results providein vivoevidence for SORORIN antagonizing WAPL, reveal that SORORIN is present in organisms beyond the animal kingdom and indicate that it has acquired tissue specific functions in plants.
A palmitate-rich metastatic niche enables metastasis growth via p65 acetylation
Authors: Altea-Manzano Patricia , Doglioni Ginevra , Cuadros Alejandro M. , Nolan Emma , Fernandez-Garcia Juan , Wu Qi , Cidre-Aranaz Florencia , Montagne Aurelie , Planque Mélanie , Marin-Bejar Oskar , Van Elsen Joke , Vermeire Ines , Broekaert Dorien , Riera-Domingo Carla , Richard François , Geukens Tatjana , De Schepper Maxim , Leduc Sophia , Hatse Sigrid , Lambrechts Yentl , Kay Emily Jane , Lilla Sergio , Demeyer Sofie , Geldhof Vincent , Boeckx Bram , Alekseenko Alisa , de la Calle Arregui Celia , Floris Giuseppe , Marine Jean-Christophe , Lambrechts Diether , Pelechano Vicent , Mazzone Massimiliano , Zanivan Sara , Cools Jan , Wildiers Hans , Baud Véronique , Grünewald Thomas G.P. , Desmedt Christine , Malanchi Ilaria , Fendt Sarah-Maria
Published: October 2022

Cancer cells outgrowing in distant organs of metastasis rewire their metabolism to fuel on the available nutrients. While this is often considered an adaptive pressure limiting metastasis formation, some nutrients available at the metastatic site naturally or through changes in organ physiology may inherently promote metastatic growth. We find that the lung, a frequent site of metastasis, is a lipid-rich environment. Moreover, we observe that pathological conditions such as pre-metastatic niche formation and obesity further increase the availability of the fatty acid palmitate in the lung. We find that targeting palmitate processing inhibits spheroid growthin vitroand metastasis formation in lean and obese mice. Mechanistically, we discover that breast cancer cells use palmitate to synthesize acetyl-CoA in a carnitine palmitoyltransferase 1a (CPT1a)-dependent manner. Lysine acetyltransferase 2a (KAT2a), whose expression is promoted by palmitate availability, relies on the available acetyl-CoA to acetylate the NF-κB subunit p65. This favors nuclear location of p65 and activates a pro-metastatic transcriptional program. Accordingly, deletion of KAT2a phenocopies CPT1a silencingin vitroas well asin vivoand patients with breast cancer show co-expression of both proteins in metastases across palmitate-rich metastatic sites. In conclusion, we find that palmitate-rich environments foster metastasis growth by increasing p65 acetylation resulting in elevated NF-κB signaling.
UBAP2L-dependent coupling of PLK1 localization and stability during mitosis
Authors: Guerber Lucile , Vuidel Aurore , Liao Yongrong , Kleiss Charlotte , Grandgirard Erwan , Sumara Izabela , Pangou Evanthia
Published: October 2022

PLK1 is an important regulator of mitosis whose protein levels and activity fluctuate during the cell cycle. PLK1 dynamically localizes to various mitotic structures to regulate chromosome segregation. However, the signaling pathways linking localized PLK1 activity to its protein stability remain elusive. Here, we identify the Ubiquitin-Binding Protein 2-Like (UBAP2L) that controls both, the localization and the protein stability of PLK1.We demonstrate that UBAP2L is a spindle-associated protein whose depletion leads to severe mitotic defects. UBAP2L depleted cells are characterized by increased PLK1 protein levels and abnormal PLK1 accumulation in several mitotic structures such as kinetochores, centrosomes and mitotic spindle. UBAP2L deficient cells exit mitosis and enter the next interphase in the presence of aberrant PLK1 kinase activity. The C-terminal domain of UBAP2L mediates its function on PLK1 independently of its role in stress response signaling. Importantly, the mitotic defects of UBAP2L depleted cells are largely rescued upon chemical inhibition of PLK1. Overall, our data suggest that UBAP2L is required to finetune the ubiquitin-mediated PLK1 turnover during mitosis as a means to maintain genome fidelity.
Loss of function in the autism and schizophrenia-associated geneCYFIP1in human microglia supports a role in synaptic pruning
Authors: Sheridan Steven D. , Horng Joy E. , Yeh Hana , McCrea Liam , Fu Ting , Perlis Roy H.
Published: October 2022

Background

TheCYFIP1gene, located in the neurodevelopmental risk locus 15q11.2, is highly expressed in microglia, but its role in human microglial function as it relates to neurodevelopment is not well understood.

Methods

We generated multiple CRISPR knockoutsof CYFIP1in patient-derived models of microglia to characterize function and phenotype. Using microglia-like cells reprogrammed from peripheral blood mononuclear cells, we quantified phagocytosis of synaptosomes (isolated and purified synaptic vesicles) from human iPSC-derived neuronal cultures as anin vitromodel of synaptic pruning. We repeated these analyses in human iPSC-derived microglia, and characterized microglial development and function through morphology and motility.

Results

CYFIP1knockout using orthogonal CRISPR constructs in multiple patient-derived cell lines was associated with statistically significant decrease in synaptic vesicle phagocytosis in microglia models derived from both PBMCs and iPSCs (p<0.0001). Morphology was also shifted toward a more ramified profile (p<0.0001), and motility was significantly reduced (p<0.0001). However, iPSC-CYFIP1knockout lines retained the ability to differentiate to functional microglia.Conclusion: The changes in microglial phenotype and function from loss ofCYFIP1may contribute to pruning abnormalities observed inCYFIP1-associated neurodevelopmental disorders. Investigating risk genes in a range of CNS cell types may be required to fully understand the way in which common and rare variants intersect to yield neuropsychiatric disorders.
Loss of MLL3/4 decouples enhancer H3K4 monomethylation, H3K27 acetylation, and gene activation during ESC differentiation
Authors: Boileau Ryan M. , Chen Kevin X. , Blelloch Robert
Published: October 2022

Enhancers are essential in defining cell fates through the control of cell type specific gene expression. Enhancer activation is a multi-step process involving chromatin remodelers and histone modifiers including the monomethylation of H3K4 (H3K4me1) by MLL3 (KMT2C) and MLL4 (KMT2D). MLL3/4 are thought to be critical for enhancer activation and cognate gene expression including through the recruitment of acetyltransferases for H3K27. Here we test this model by evaluating the impact of MLL3/4 loss on chromatin and transcription during early embryonic stem cell differentiation. We find that MLL3/4 activity is required at most if not all sites that gain or lose H3K4me1 but is largely dispensable at sites that remain stably methylated during this transition. This requirement extends to H3K27 acetylation (H3K27ac) at most transitional sites. However, many sites gain H3K27ac independent of MLL3/4 or H3K4me1 including enhancers regulating key factors in early differentiation. Furthermore, despite the failure to gain active histone marks at thousands of enhancers, transcriptional activation of nearby genes is largely unaffected, thus uncoupling the regulation of these chromatin events from transcriptional changes during this transition. These data challenge current models of enhancer activation and imply distinct mechanisms between stable and dynamically changing enhancers. Collectively, our study highlights gaps in knowledge about the steps and epistatic relationships of enzymes necessary for enhancer activation and cognate gene transcription.
Serum Amyloid A proteins reduce bone mass during mycobacterial infections
Authors: Gomes Ana Cordeiro , Sousa Daniela Monteiro , Oliveira Tiago Carvalho , Fonseca Óscar , Pinto Ricardo J. , Silvério Diogo , Fernandes Ana Isabel , Moreira Ana C. , Silva Tânia , Teles Maria José , Pereira Luísa , Saraiva Margarida , Lamghari Meriem , Gomes Maria Salomé
Published: October 2022

Osteopenia has been associated to several inflammatory conditions, including mycobacterial infections. How mycobacteria cause bone loss remains elusive, but direct bone infection may not be required. Using genetically engineered mice and morphometric, transcriptomic and functional analyses, we found that infection withMycobacterium aviumimpacts bone turnover by decreasing bone formation and increasing bone resorption, in a IFNg- and TNFa-dependent manner. IFNg produced during infection enhanced macrophage TNFa secretion, which in turn increased the production of serum amyloid A (SAA) 3.Saa3expression was upregulated in the bone of bothM. avium- andMycobacterium tuberculosis-infectedmice and SAA proteins were increased in the serum of patients with active tuberculosis. Furthermore, the increased SAA levels seen in active tuberculosis patients correlated with altered serum bone turnover markers. Additionally, human SAA proteins impaired bone matrix deposition and increased osteoclastogenesis in vitro. Overall, we report a novel crosstalk between the cytokine network operating in macrophages and bone homeostasis and disclose SAA proteins as potential biomarkers of bone loss during infection by mycobacteria.
Understanding the chronic kidney disease landscape using patient representation learning from electronic health records
Authors: Kapur Karen , Freidank Moritz , Rebhan Michael
Published: October 2022

Understanding various subpopulations in chronic kidney disease can improve patient care and aid in developing treatments targeted to patients’ needs. Due to the general slow disease progression, electronic health records, which comprise a rich source of longitudinal real-world patient-level information, offer an approach for generating insights into disease. Here we apply the open-source ConvAE framework to train an unsupervised deep learning network using a real-world kidney disease cohort consisting of 2.2 million US patients from the OPTUM® EHR database. Numerical patient representations derived from ConvAE are used to derive disease subtypes, inform comorbidities and understand rare disease populations. To identify patients at high risk to develop end-stage kidney disease, we extend a validated algorithm classifying disease severity to hypothesize subpopulations of rapid chronic kidney disease progressors. We demonstrate that using a combination of data-driven methods offers a powerful exploratory approach to understand disease heterogeneity and identify high-risk patients who could be targeted for early therapeutic intervention to prevent end-stage kidney disease.
Covid-19 pandemic has polarized the society toward negative and positive traits depending on a person’s resilience and certain predispositions
Authors: Attary Taraneh , Noorbala Leila , Ghazizadeh Ali
Published: October 2022

The Covid-19 pandemic has caused a major disruption affecting almost all aspects of health, social and economic dimensions of our lives on an almost unprecedented global scale. While Covid-19 itself is, first and foremost, a pernicious physical illness, its highly contagious nature has caused significant psychological stress with occasional dire mental health consequences which are still not fully understood. To address this issue, we have conducted a longitudinal study by administering standard self-reporting questionnaires covering five major personalities and six mental traits of subjects before and a few months after the outbreak. Results revealed the distribution of population scores to become more extreme in either positive or negative trait directions despite the stability of average trait scores across the population. Higher resilience was found to be positively correlated with improved trait scores post-pandemic. Further investigations showed that certain predispositions could have an effect on trait score change post-Covid depending on the subject’s pre-Covid scores. In particular, in the subjects with moderate scores, there was a significant negative correlation between the positive trait scores and the post minus pre-positive trait scores. By examining various traits and personalities, these findings depict a more thorough picture of the pandemic’s impact on society’s psychological well-being and reveal certain predispositions and vulnerabilities that shape the mental health landscape in the post-Covid period with implications for mental health policies in dealing with Covid-19.
Non-invasive three-dimensional 1H-MR Spectroscopic Imaging of human brain glucose and neurotransmitter metabolism using deuterium labeling at 3T
Authors: Niess Fabian , Hingerl Lukas , Strasser Bernhard , Bednarik Petr , Goranovic Dario , Niess Eva , Hangel Gilbert , Krššák Martin , Spurny-Dworak Benjamin , Scherer Thomas , Lanzenberger Rupert , Bogner Wolfgang
Published: October 2022

Objectives

Non-invasive, affordable, and reliable mapping of brain glucose metabolism is of critical interest for clinical research and routine application as metabolic impairment is linked to numerous pathologies e.g., cancer, dementia and depression. A novel approach to map glucose metabolism non-invasively in the human brain and separate normal oxidative from pathologic anaerobic pathways has been presented recently on experimental MR scanners using direct or indirect detection of deuterium-labeled glucose and downstream metabolites such as glutamate, glutamine and lactate.

The aim of this study was to demonstrate the feasibility to non-invasively detect deuterium labeled downstream glucose metabolites indirectly in the human brain via 3D proton (1H) MR spectroscopic imaging on a clinical 3T MR scanner without additional hardware.

Materials and Methods

This prospective, institutional review board approved study was performed in seven healthy volunteers (mean age, 31±4 years, 5 m/ 2 f) following written informed consent. After overnight fasting and oral deuterium-labeled glucose administration 3D metabolic maps were acquired every ∼4 min with ∼0.24 ml isotropic spatial resolution using real-time motion-, shim- and frequency-corrected echo-less 3D1H-MR Spectroscopic Imaging. Time courses were analyzed using linear regression and non-parametric statistical tests. Deuterium labeled glucose and downstream metabolites were detected indirectly via their respective signal decrease in dynamic1H MR spectra due to deuterium to proton exchange in the molecules.

Results

Sixty-five minutes after deuterium-labeled glucose administration, glutamate+glutamine (Glx) signal intensities decreased in gray/white matter (GM,WM) by -15±2%,(p=0.02)/-14±3%,(p=0.02), respectively. Strong negative correlation between Glx and time was observed in GM/WM (r=-0.71p<0.001)/(r=-0.67,p<0.001) with 38±18% (p=0.02) steeper slopes, indicating faster metabolic activity in GM compared to WM. Other non-labeled metabolites showed no significant changes.

Conclusion

Our approach translates deuterium metabolic imaging to widely available clinical routine MR scanners without specialized hardware offering a safe, affordable, and versatile (other substances than glucose can be labeled) approach for non-invasive imaging of glucose and neurotransmitter metabolism in the human brain.
Cardiovascular magnetic resonance imaging after normal echocardiography in myocardial infarction with nonobstructed coronary arteries
Authors: Sundqvist Martin G. , Sörensson Peder , Ekenbäck Christina , Lundin Magnus , Agewall Stefan , Bacsovics Brolin Elin , Cederlund Kerstin , Collste Olov , Daniel Maria , Jensen Jens , Y-Hassan Shams , Henareh Loghman , Hofman-Bang Claes , Lyngå Patrik , Maret Eva , Sarkar Nondita , Spaak Jonas , Winnberg Oscar , Caidahl Kenneth , Ugander Martin , Tornvall Per
Published: October 2022

Background

In patients with myocardial infarction with nonobstructive coronary arteries (MINOCA), cardiovascular magnetic resonance imaging (CMR) can often establish a causal diagnosis. It is unknown if CMR is warranted in patients with normal echocardiographic findings, or if measurement of high-sensitive troponin T (hs-TnT) and NT-pro-BNP can be of value in selecting patients for further imaging.

Objectives

To assess the diagnostic accuracy of echocardiography and hs-TnT and NT-pro-BNP for identifying patients receiving any diagnosis using CMR.

Methods

We included patients (n = 123) from the SMINC2 study who underwent same day CMR and echocardiography, at a median of 3 days after hospital admission for MINOCA. Normal echocardiography was defined as left ventricular ejection fraction ≥ 55%, absolute global longitudinal strain ≥ 17%, E/e′ ≤ 14, and no regional wall motion abnormalities. Logistic regression models were fitted to assess the probability of CMR diagnosis at increasing levels of hs-TnT and NT-pro-BNP.

Results

Of patients with a normal echocardiographic examination, 23/33 (70%) received a diagnosis using CMR. Pathological echocardiography identified patients with a diagnosis using CMR with a sensitivity of 77%, specificity 38%, positive predictive value 82%, and negative predictive value 30%, respectively. There was no level of hs-TnT or NT-pro-BNP below which a CMR diagnosis could be reliably excluded.

Conclusions

The majority of patients with MINOCA and a normal echocardiogram will receive a diagnosis by CMR. A CMR diagnosis was common even among patients with low levels of biomarkers. CMR should be recommended regardless of echocardiographic findings and hs-TnT or NT-pro-BNP levels in patients with MINOCA.
Bacterial Etiology of Urinary Tract Infections In patients treated at Kenyan Health Facilities And their resistance towards commonly used antibiotics
Authors: Kiiru Susan , Maina John , Katana Japhet , Mwaniki John , Asiimwe Benon B , Mshana Stephen E , Keenan Katherine , Gillespie Stephen H. , Stelling John , Kiiru John , Holden Matthew T G ,   HATUA Consortium
Published: October 2022

1.0

Background

Evidence-based empirical antibiotic prescribing requires knowledge of local antimicrobial resistance patterns. The spectrum of pathogens and their susceptibility strongly influences guidelines for empirical therapies for urinary tract infections (UTI) management.

Objective

This study aimed to determine the prevalence of UTI causative bacteria and their corresponding antibiotic resistance profiles in in three counties of Kenya. Such data could be used to determine the optimal empirical therapy.

Methods

In this cross-sectional study, urine samples were collected from patients who presented with symptoms suggestive of UTI in the following healthcare facilities; Kenyatta National Hospital, Kiambu Hospital, Mbagathi, Makueni, Nanyuki, Centre for Microbiology Research, and Mukuru Health Centres. Urine cultures were done on Cystine Lactose Electrolyte Deficient (CLED) to isolate UTI bacterial etiologies, while antibiotic sensitivity testing was done using the Kirby-Bauer disk diffusion using CLSI guidelines and interpretive criteria.

Results

A total of 1,027(54%) uropathogens were isolated from the urine samples of 1898 participants. Staphylococcus spp. and Escherichia coli were the main uropathogens at 37.6% and 30.9 %, respectively. The percentage resistance to commonly used drugs for the treatment of UTI were as follows: trimethoprim (64%), sulfamethoxazole (57%), nalidixic acid(57%), ciprofloxacin (27%), amoxicillin-clavulanic acid (5%), and nitrofurantoin (9%) and cefixime (9%). Resistance rates to broad-spectrum antimicrobials, such as ceftazidime, gentamicin, and ceftriaxone, were 15%, 14%, and 11%, respectively. Additionally, the proportion of Multidrug-resistant (MDR) bacteria was 66%.

Conclusion

High resistance rates toward fluoroquinolones, sulfamethoxazole, and trimethoprim were reported. These antibiotics are commonly used drugs as they are inexpensive and readily available. Based on these findings, more robust standardised surveillance is needed to confirm the patterns observed while recognizing the potential impact of sampling biases on observed resistance rates.
For She had Eyes and Chose Preprints -– Social Media Impact, Citation and Publication rates of Ophthalmology preprints
Authors: Menshawey Rahma , Menshawey Esraa , Massoud Maryam
Published: October 2022

Background

Preprinting, is the sharing of non-peer reviewed, unpublished scholarly manuscripts. Across many fields of medicine, an exponential rise of manuscripts being posted to preprint servers has been observed. This has exploded during the COVID19 pandemic where early dissemination of information was critical, or where COVID19 priority disrupted the publication dynamics and priorities in other areas. We examined the characteristics of ophthalmology related preprints in this study.

Methods

We searched the bioRxiv and medRxiv servers for preprints relating to field of ophthalmology. Preprints were screened by title and abstract to ensure they were related to the field of ophthalmology. Outcomes included number of tweets, upper bound followers of tweeters, number of citations, news outlets reports and dates posted/published. If a preprint was published the same outcomes were collected for the published version to allow for comparisons, as well as journal publisher and cite score.

Results

After screening, a total of 720 preprints met our inclusion criteria. 420 of the preprints went on to be published. The publication rate of the preprints was 58.3%. The median number of tweets received on preprints was 3.5, IQR 5.5. 98.75% of preprints were tweeted about. Citation rate was 40.14%. The average number of days from date posted on server to date published was 180.5±124 days. Regression analysis revealed that tweets as a preprint predicts tweets as a published article, P=0.0135. citations as a preprint predicts citations as a published article, P<0.001. The average cite score was 8.5±6.2 among those preprints that we published in journals. 16.66% of papers were published by Elsevier (n = 70). 3.19% of preprints were COVID19 related, with significant differences found between them and non-COVID19 preprints in terms of number of tweets and number of citations.

Conclusions

Ophthalmology preprints are increasing across preprint servers. This maybe to bypass publication times and allow early dissemination of work, as well as increase visibility and citations. We identified that preprint citations and tweets predict published version citation and tweets.