bluuebunny/crossref_metadata_2025 huggingface dataset:
Controlled enzyme cargo loading in engineered bacterial microcompartment shells
Authors: Tefft Nicholas M. , Wang Yali , Jussupow Alexander , Feig Michael , TerAvest Michaela A.
Published: October 2024

Bacterial microcompartments (BMCs) are nanometer-scale organelles with a protein-based shell that serve to co-localize and encapsulate metabolic enzymes. They may provide a range of benefits to improve pathway catalysis, including substrate channeling and selective permeability. Several groups are working toward using BMC shells as a platform for enhancing engineered metabolic pathways. The microcompartment shell ofHaliangium ochraceum(HO) has emerged as a versatile and modular shell system that can be expressed and assembled outside its native host and with non-native cargo. Further, the HO shell has been modified to use the engineered protein conjugation system SpyCatcher-SpyTag for non-native cargo loading. Here, we used a model enzyme, triose phosphate isomerase (Tpi), to study non-native cargo loading into four HO shell variants and begin to understand maximal shell loading levels. We also measured activity of Tpi encapsulated in the HO shell variants and found that activity was determined by the amount of cargo loaded and was not strongly impacted by the predicted permeability of the shell variant to large molecules. All shell variants tested could be used to generate active, Tpi-loaded versions, but the simplest variants assembled most robustly. We propose that the simple variant is the most promising for continued development as a metabolic engineering platform.
Pathogen priming alters host transmission potential and predictors of transmissibility in a wild songbird species
Authors: Leon A.E. , Fleming-Davies A. , Adelman J.S. , Hawley D.M.
Published: October 2024

Pathogen reinfections occur widely, but the extent to which reinfected hosts contribute to ongoing transmission is often unknown despite its implications for host-pathogen dynamics. House finches (Haemorhous mexicanus) acquire partial protection from initial exposure to the bacterial pathogenMycoplasma gallisepticum(MG), with hosts readily reinfected with homologous or heterologous strains on short timescales. However, the extent to which reinfected hosts contribute to MG transmission has not been tested. We used three pathogen priming treatments– none, intermediate (repeated low-dose priming), or high (single high-dose priming)– to test how prior pathogen priming alters the likelihood of transmission to a cagemate during index bird reinfection with a homologous or heterologous MG strain. Relative to unprimed control hosts, the highest priming level strongly reduced maximum pathogen loads and transmission success of index birds during reinfections. Reinfections with the heterologous strain, previously shown to be more virulent and transmissible than the homologous strain used, resulted in higher pathogen loads within high-primed index birds, and showed higher overall transmission success regardless of host priming treatment. This suggests that inherent differences in strain transmissibility are maintained in primed hosts, leading to the potential for ongoing transmission during reinfections. Finally, among individuals, transmission was most likely from hosts harboring higher within-host pathogen loads, while associations between disease severity and transmission probability were dependent on a given bird’s priming treatment. Overall, our results indicate that reinfections can result in ongoing transmission, particularly where reinfections result from heterologous and highly transmissible strains, with key implications for virulence evolution.

Importance

As Covid-19 dramatically illustrated, humans and other animals can become infected with the same pathogen multiple times. Because individuals already have defenses against pathogen their immune systems have encountered before, reinfections are typically less severe, and are thought to be less contagious, but this is rarely directly tested. We used a songbird species and two strains of its common bacterial pathogen to study how contagious hosts are when their immune systems have some degree of prior experience with a pathogen. We found that reinfected hosts are not as contagious as initially infected ones. However, the more transmissible of the two strains, which also causes more harm to its hosts, was able to multiply more readily than the other strain within reinfected hosts, and was more contagious in both reinfected and first-infected hosts. This suggests that reinfections might favor more harmful pathogen strains that are better able to overcome immune defenses.
RDAforest: identifying environmental drivers of polygenic adaptation.
Authors: Matz Mikhail V , Black Kristina Leilani
Published: October 2024

Identifying environmental gradients driving genetic adaptation is one of the major goals of ecological genomics. We present RDAforest, a methodology that leverages the predominantly polygenic nature of adaptation and harnesses the versatility of random forest regression to solve this problem. Instead of computing individual SNP-environment associations, RDAforest seeks to explain the overall genetic covariance structure based on multiple environmental predictors. By relying on random forest instead of linear regression, this method can detect non-linear and non-monotonous dependencies as well as all possible interactions between predictors. It also incorporates a novel procedure to select the best predictor out of several correlated ones, and uses jackknifing to model uncertainty of genetic structure determination. Lastly, our methodology incorporates delineation and plotting of adaptive neighborhoods - areas on the landscape that are predicted to harbor differentially adapted individuals. Such maps can be used as a guide for planning conservation and ecological restoration efforts. We demonstrate the use of RDAforest in two simulated scenarios and one real dataset (North American gray wolves).
Fluorescent Antibody-Based Detection and Ultrastructural Analysis ofStreptococcus pneumoniaein Human Sputum
Authors: Jop Vidal Ana G. , Francis Meg , Chitanvis Maneesha , Frame Ithiel J. , Sharma Poonam , Vidal Patricio , Lanata Claudio F. , Grijalva Carlos , Daley William , Vidal Jorge E.
Published: October 2024

Background

Pneumococcal pneumonia continues to be a significant global health burden, affecting both children and adults. Traditional diagnostic methods for sputum analysis remain challenging. The objective of this study was twofold: to develop a rapid and easy-to-perform assay for the identification ofStreptococcus pneumoniae(Spn) directly in sputum specimens using fluorescence microscopy, and to characterize with high-resolution confocal microscopy the ultrastructure of pneumococci residing in human sputum.

Methods

We fluorescently labeled antibodies against the pneumococcal capsule (Spn-FLUO). The specificity and sensitivity of Spn-FLUO for detecting Spn was evaluatedin vitroandin vivousing mouse models of carriage and disease, human nasopharyngeal specimens, and sputum from patients with pneumococcal pneumonia. Spn was confirmed in the specimens using culture and a species-specific qPCR assays. Confocal microscopy and Imaris software analysis were utilized to resolve the ultrastructure of pneumococci in human sputum.

Results

Compared with cultures and qPCR, Spn-FLUO demonstrated high sensitivity (78-96%) in nasopharyngeal samples from mice and humans. The limit of detection (LOD) in nasopharyngeal samples was ≥1.6×10⁴ GenEq/ml. The specificity in human nasopharyngeal specimens was 100%. In lung specimens from mice infected with pneumococci, Spn-FLUO reached 100% sensitivity with a LOD of ≥1.39×10⁴ GenEq/ml. In human sputum, the sensitivity for detecting Spn was 92.7% with a LOD of 3.6×10³ GenEq/ml. Ultrastructural studies revealed that pneumococci are expectorated as large aggregates with a median size of 1336 µm².

Conclusions

Spn-FLUO is a rapid and sensitive assay for detecting Spn in human sputum within 30 min. The study highlights that most pneumococci form aggregates in human sputum.
Syzygium cumini(L.) Skeels has Thermostable and Selective Anti-Bacillus anthracisActivity
Authors: Kaur Rajinder , Singh Ashish Kumar , Maurya Indresh Kumar , Singh Samer
Published: October 2024

Introduction

Gastrointestinal (GI) anthrax caused byBacillus anthracisremains a neglected disease in many parts of the Americas, Asia, and Africa. The symptoms include dysentery, stomachache, bloating of the stomach, vomiting, fever, chills,etc.Current study evaluated several edible plants traditionally indicated for GI disease/symptoms in the Indian subcontinent for their anti-B. anthracisactivity.

Materials & Methods

Aqueous extracts of plant parts were assessed for anti-B. anthracisactivity using standard antimicrobial susceptibility testing assays. Most promising extracts were evaluated for desirable activity under conditions relevant to their usage, including extremes of temperature, pH, presence of bile salt, impact on gut microflora, and interaction with FDA-approved drugs for anthrax treatment. The bioactive components separated by bioactivity-guided thin-layer-chromatography were subjected to GC-MS characterization.

Results

AqueousSyzygium cumini(L.) Skeels or ‘Jamun’ extract (AJE) was most potent and reduced the viable colony-forming units (CFU) by 6-logs within 2 hours of exposure at ≥1.9%w/v concentration. It displayed both desirable selectivity towards gut microflora and thermostability (>90% and ∼80% of anti-B. anthracisactivity were retained on incubation at 50°C for 20 days and at 95°C for 12h, respectively). AJE and FDA-approved antibiotics for anthrax displayed synergy. GC-MS analysis of AJE identified various previously-identified antimicrobials belonging to categories of alkaloids, flavonoids, phenols,etc.

Conclusion

AJE has potent and selective anti-B. anthracisactivity with the desired degree of thermotolerance, compatibility with gut microflora, and recommended antibiotics. Further studies exploring the bioactive components in AJE and their potential application in preventing anthrax and anthrax-like diseases may be undertaken.
α-Synuclein Strain Dynamics Correlate with Cognitive Shifts in Parkinson’s Disease
Authors: Gadhave Kundlik , Xu Enquan , Wang Ning , Zhang Xiaodi , Deyell Jacob , Yang Jun , Wang Anthony , Cha Youngjae , Kumbhar Ramhari , Liu Haiqing , Niu Lili , Chen Rong , Zhang Shu , Bakker Catherine C. , Jin Lingtao , Liang Yajie , Ying Mingyao , Dawson Valina L. , Dawson Ted M. , Rosenthal Liana S. , Mao Xiaobo
Published: October 2024

α-Synuclein (α-syn) strains can serve as discriminators between Parkinson’s disease (PD) from other α-synucleinopathies. The relationship between α-syn strain dynamics and clinical performance as patients transition from normal cognition (NC) to cognitive impairment (CI) is not known. Here, we show that the biophysical properties and neurotoxicity of α-syn strains change as PD cognitive status transitions from NC to mild cognitive impairment (PD-MCI) and dementia (PD-D). Both cross-sectional and longitudinal analyses reveal distinct α-syn strains in PD patients correlating to their level of cognitive impairment. This study presents evidence that individuals with PD have different α-syn strains that change in accordance with their cognitive status and highlights the potential of α-syn strain dynamics to guide future diagnosis, management, and stratification of PD patients.

One Sentence Summary

Distinct features of α-syn strains change with cognitive decline in Parkinson’s disease.
Comparative proteomics of biofilm development inPseudoalteromonas tunicatadiscovers a distinct family of Ca2+-dependent adhesins
Authors: Ali Sura , Stavropoulos Alexander , Jenkins Benjamin , Graves Sadie , Che Geoffrey , Cheng Jiujun , Tan Huagang , Wei Xin , Egan Suhelen , Neufeld Josh D. , Eckhard Ulrich , Charles Trevor C. , Doxey Andrew C.
Published: October 2024

The marine bacterium,Pseudoalteromonas tunicata, is a useful model for studying mechanisms of biofilm development due to its ability to colonize and form biofilms on a variety of marine and eukaryotic host-associated surfaces. However, the pathways responsible forP. tunicatabiofilm formation are still incompletely understood, in part due to a lack of functional information for a large proportion of its proteome. Here, we used comparative shotgun proteomics to examineP. tunicatabiofilm development throughout the planktonic phase to three stages of biofilm development at 24, 48, and 72 h. Proteomic analysis identified 232 proteins that were up-regulated during different stages of biofilm development, including many hypothetical proteins as well as proteins known to be important forP. tunicatabiofilm development such as the autocidal enzyme AlpP, violacein proteins, S-layer protein SLR4, and various pili proteins. We further investigated the top identified biofilm-associated protein (Bap), a previously uncharacterized 1600 amino acid protein (EAR30327), which we designated as “BapP”. Based on AlphaFold modeling and genomic context analysis, we predicted BapP as a distinct Ca2+-dependent biofilm adhesin. Consistent with this prediction, a ΔbapPknockout mutant was defective in forming both pellicle and surface-associated biofilms, which was rescued by re-insertion ofbapPinto the genome. Similar to mechanisms of RTX adhesins, BapP-mediated biofilm formation was influenced by Ca2+levels, and BapP is likely exported by a type 1 secretion system. Ultimately, our work not only provides a useful proteomic dataset for studying biofilm development in an ecologically relevant organism, but it also adds to our knowledge of bacterial adhesin diversity, emphasizing Bap-like proteins as widespread determinants of biofilm formation in bacteria.
The LPP Indexes Baseline and Treatment-Related Changes in Anxiety Sensitivity
Authors: Butler Devin , Pavuluri Asha , Fix Spencer , Schmidt Norman B. , Bernat Edward
Published: October 2024

Development of neurophysiological treatment targets has been an important way to validate and advance treatment implementations. Anxiety Sensitivity (AS), described as a fear of fear, is one of the most well-researched transdiagnostic risk factors for psychopathology and has been demonstrated to be associated with a number of different INT symptoms and disorders, making it an ideal intervention target for treatment of anxiety and mood pathology. Currently, there exists a gap in terms of understanding underlying neural mechanisms of AS and treatment-related change in AS. The current study sought to examine the impact of 2 brief computerized interventions on AS in order to assess the P300 and late positive potential (LPP) event-related potential (ERP) components as an index of both baseline and treatment change in the transdiagnostic anxiety sensitivity construct. Participants received one of the following, with a 1-month follow-up: an anxiety reduction intervention of cognitive anxiety sensitivity treatment (CAST) alone, a mood intervention of cognitive bias modification interpretation (CBM-I), a combined CAST and CBM-I intervention, or a repeated contact control group. Baseline AS was significantly related to baseline P3/LPP, such that higher P3/LPP amplitude (heightened emotional reactivity) is associated with higher AS at intake. Further, treatment-related reductions in AS were associated with higher baseline reactivity: greater AS reductions at month one were associated with higher P3/LPP activity. Heightened emotional response was predictive of better treatment outcomes. Analyses also showed evidence for different mechanisms associated with CAST and CBM-I groups. Specifically, the CAST group evidenced predictions of treatment outcome in parietal areas, where the CBM-I group evidenced predictions in frontal areas. The Combined group evidenced both frontal and parietal activations, consistent with combining the effects from the CAST and CBM-I groups. These findings suggest that the P3/LPP is an index of cognitive-affective processes underlying AS at baseline and has predictive ability in assessing AS treatment outcome in that our observed treatment types engage different neural mechanisms.
COVID-19 Booster Doses Reduce Sex Disparities in Antibody Responses among Nursing Home Residents
Authors: Oyebanji Oladayo A. , Yin Anna , Sundheimer Nicholas , Ragavapuram Vaishnavi , Shea Patrick , Cao Yi , Chan Phillip A. , Nanda Aman , Tyagi Rohit , Raza Sakeena , Mujahid Nadia , Abul Yasin , Balazs Alejandro Benjamin , Bosch Jurgen , King Christopher L. , Klein Sabra , Gravenstein Stefan , Canaday David H. , Wilson Brigid M.
Published: October 2024

Background Data suggests that antibody responses following COVID-19 vaccines are a correlate of protection. Some studies, including the clinical trials of COVID-19 mRNA vaccines, did not stratify and evaluate whether antibody responses to COVID-19 vaccines differed between the sexes or with aging. This gap in research is particularly relevant for older populations such as nursing home residents (NHR). We hypothesized that sex differences in vaccine-induced antibody responses may intersect with age and be diminished among older adults residing in nursing homes. Methods We analyzed serum samples from 638 NHRs collected serially after the primary two-dose series and three subsequent booster doses of mRNA SARS-CoV-2 vaccinations. We analyzed anti-Spike IgG and neutralizing antibody titers to the Wuhan and Omicron BA.4/5 variant strains. Mixed-effects models predicting log-transformed titers were estimated to compare responses across vaccine doses, focusing on sex-differential responses. For detected post-dose sex differences, additional sample times were analyzed to assess the duration of the difference. Results Following the primary series, female NHRs with a prior history of SARS-CoV-2 infection had significantly higher Wuhan anti-Spike antibodies and neutralizing antibody titers than male NHRs with differences persisting up to nine months post-vaccination. Subsequent monovalent booster doses and a bivalent booster dose eliminated this disparity. We did not detect any differential response to the Omicron BA.4/5 variant. Conclusions The blunting of sex differences in antibody response observed following the primary series by the 1st booster dose underscores the importance of booster vaccination in this population.
Immunohistochemical profiles of dermatofibroma and dermatofibrosarcoma protuberans: A scoping review
Authors: Hardy Céline S. C. , Razavi Ali , Nunez Natalie , Fitzmaurice William , Dave Loma , Slutzky Amy R. , Vanderbeck Kaitlin , Farah Ramsay
Published: October 2024

This review summarizes the immunohistochemical profiles of dermatofibroma (DF) and dermatofibrosarcoma protuberans (DFSP) as reported by primary literature in the past 10 years. 63 studies were included in the review, with staining information for a total of 99 unique IHC markers reported. The most commonly reported stains were CD34, SMA, S100, and FXIIIa. Most studies applied IHC either to explore descriptive features of DF or DFSP or to determine their utility in diagnostic identification of the lesions. A number of studies applied novel biomarkers which may hold promise for distinguishing DF and DFSP, namely WT1, Cx43, LSP-1, and PHH3, which demonstrated considerable expression differences between the two lesions. This review highlights the need for validation of existing and emerging IHC markers for the diagnosis of DF and DFSP.
LUNAR: A Deep Learning Model to Predict Glioma Recurrence Using Integrated Genomic and Clinical Data
Authors: Patricoski-Chavez Jessica A. , Nagpal Seema , Singh Ritambhara , Warner Jeremy L. , Gamsiz Uzun Ece D.
Published: October 2024

Gliomas account for approximately 25.5% of all primary brain and central nervous system tumors, with a striking 80.8% of these being malignant. The prognosis varies significantly; low-grade gliomas (LGGs) can exhibit 5-year survival rates of up to 80%, while higher-grade gliomas (HGGs) often see rates below 5%. Recurrence is a common challenge, occurring in 52%-62% of LGGs and 90% of HGGs, complicating clinical management and treatment planning. Currently, no widely available models exist for predicting glioma recurrence, which is critical for optimizing patient outcomes. Machine learning (ML) and deep learning (DL) techniques have shown promise in predicting recurrence for various cancers, most using Electronic Health Records (EHR). This study introduces gLioma recUrreNceAttention-based classifieR(LUNAR), a DL-based model to predict early versus late glioma recurrence by integrating clinical, genomic, and mRNA expression data from patients with primary grade II-IV gliomas. The data was obtained from The Cancer Genome Atlas and the Glioma Longitudinal Analysis Consortium (GLASS).
Psilocybin Reduces Grooming in the SAPAP3 Knockout Mouse Model of Compulsive Behaviour
Authors: Gattuso James J , Wilson Carey , Hannan Anthony J , Renoir Thibault
Published: October 2024

Psilocybin is a serotonergic psychedelic compound which shows promise for treating compulsive behaviours. This is particularly pertinent as compulsive disorders require research into new pharmacological treatment options as the current frontline treatments such as selective serotonin reuptake inhibitors, require chronic administration, have significant side effects, and leave almost half of the clinical population refractory to treatment.

In this study, we investigated psilocybin administration in male and female SAPAP3 knockout (KO) mice, a well-validated mouse model of obsessive compulsive and related disorders. We assessed the effects of acute psilocybin (1 mg/kg, intraperitoneal) administration on head twitch and locomotor behaviour as well as anxiety- and compulsive-like behaviours at multiple time-points (1-, 3- and 8-days post-injection).

While psilocybin did not have any effect on anxiety-like behaviours, we revealed for the first time that acute psilocybin administration led to enduring reductions in compulsive behaviour in male SAPAP3 KO mice and reduced grooming behaviour in female WT and SAPAP3 KO mice. We also found that psilocybin increased locomotion in wild-type littermates but not in SAPAP3 KO mice, suggestingin vivoserotonergic dysfunctions in KO animals. On the other hand, the typical head-twitch response following acute psilocybin (confirming its hallucinogenic-like effect at this dose) was observed in both genotypes.

Our novel findings suggest that acute psilocybin may have potential to reduce compulsive-like behaviours (up to 1 week after a single injection). Our study can inform future research directions as well as supporting the utility of psilocybin as a novel treatment option for compulsive disorders.
Distinct optimization of motor control and learning: Self-paced motor learning achieves different motor patterns from overtrained
Authors: Hayashi Takuji , Takiyama Ken
Published: October 2024

Self-paced movement, resulting from extensive training and optimization, serves as an ideal model for investigating internal objectives without external constraints within the sensorimotor system. Previous studies have shown that the self-paced movement is consistent within individuals but inconsistent across individuals, highlighting a robust, unique optimization in motor control. Although motor learning is similarly an optimization process, it is unknown whether the internal objectives are shared with motor control and learning, i.e., whether it replicates the motor patterns identified by self-paced motor control. As the optimality principles typically address redundancy, a human behavioral experiment was designed to equate movement distance for motor control and learning, comparing redundant motion parameters, movement velocity, and duration, through detailed analysis that accommodates their nonlinear interaction and significant inter-individual baseline differences. Participants, instructed to use their preferred velocities and duration, exhibited minimal intra-individual variability in motion parameters. Notably, visuomotor shift perturbations exclusively affected velocity, while changes in target distances affected both velocity and duration. These findings suggest that the sensorimotor system employs distinct optimization mechanisms for motor control and learning to resolve redundancy.

Significance statement

Our natural behaviors are thought to be well-optimized. Self-paced movements, a major form of the behaviors, demonstrate significant stability within individuals but vary across individuals, suggesting that the sensorimotor system in the central nervous system operates a unique and robust optimization involved in self-paced motor control. Self-paced motor control is further refined during the motor learning process. However, it is unknown whether motor control and learning share a common objective function. We demonstrated that laboratory-based motor learning never resulted in identical motor patterns from the overtrained movements with natural instruction. Thus, the sensorimotor system would employ distinct optimization mechanisms for motor control and learning, suggesting that these processes are not contiguous.
Preemptive minocycline decreases allodynia and depressive-like behaviors in a peripheral neuropathy rat model: a preliminary study
Authors: Le Anh Cong Tuan , Sousa Ângela , Alves Nuno Dinis , Leite-Almeida Hugo
Published: October 2024

Background and Objective

The neuroimmune system plays a critical role at all phases of chronic pain including at its onset. We therefore hypothesized that preemptive immunomodulation could decrease susceptibility and/or offer protection to pain.

Materials and Methods

Six days before the spared nerve injury (SNI), Wistar Han rats were treated with either the immunomodulator minocycline (MIN) or vehicle (VEH). After that, half of the animals from each group switch treatments for additional 7 days, resulting in 4 groups: continuous treatment (MIN/MIN), pretreatment (MIN/VEH), early treatment (VEH/MIN) and the control (VEH/VEH). Mechanical allodynia was recorded using Von Frey test until 4 weeks after SNI where depressive-like behaviors of the animals were also assessed using sucrose preference test.

Results

The continuous treatment provided sustained protection against mechanical allodynia, with rats in this group showing a significantly higher threshold to pain sensitivity compared to those in VEH/VEH. In contrast, pain relief effects were not observed with MIN/VEH and VEH/MIN. Additionally, animals in MIN/MIN, and VEH/MIN exhibited decreased anhedonic-like behavior at 30 days after SNI, relative to the control.

Conclusions

The exposure to an anti-inflammatory drug circa the installation of a neuropathic lesion had a positive impact on allodynia and on anhedonic behavior for a relatively long period after treatment cessation. The results support the assertions that pain trajectories can be altered at pain early stages by targeting the neuroimmune system. This proof-of-concept has the potential to be broadened to other drugs and/or therapeutical schemes.

Highlights

Chronic pain susceptibility varies across individuals.

(endo)phenotypes of susceptibility manifest prior/circa pain onset.

Preemptive minocycline treatment transiently decreases allodynia.

Preemptive minocycline treatment provides sustained reduction of depressive-like behavior.

Immune system modulation prior to pain onset or at early stages have beneficial outcomes.
Sex-biased effect of sodium leak channel NALCN deletion in striatalDrd2spiny projection neurons
Authors: Castell Laia , Naon Claire , Rogliardo Angelina , Makrini Leila , Avrillon Maëlle , Mignon Audrey , Bernat Claire , Lory Philippe , Bertaso Federica , Monteil Arnaud , Bosch-Bouju Clémentine , Valjent Emmanuel
Published: October 2024

The sodium leak channel NALCN is an important modulator of neuronal excitability, yet its specific role in striatal medium-sized spiny neurons remains largely unexplored. In this study, considering thatNalcntranscripts are enriched in the dorsal and ventral striatum ofDrd2-SPNs, we investigated the functional impact of NALCN deletion inDrd2-expressing SPNs in both male and female mice. Electrophysiological recordings revealed significant sex differences, with male SPNs exhibiting altered membrane properties and increased excitability, while females showed more subtle changes. Interestingly, eticlopride-induced intracellular signaling was selectively enhanced in female SPNs lacking NALCN. Behaviorally, male mice exhibited reduced motivation in food-seeking tasks and impaired discrimination of threat cues. Our findings uncover an important, sex-specific role for NALCN in regulating striatal function and behavior and underscore its significance in maintaining normal striatal function.
Twelve phosphomimetic mutations induce the assembly of recombinant full-length human tau into paired helical filaments
Authors: Lövestam Sofia , Wagstaff Jane L. , Katsinelos Taxiarchis , Freund Stefan M.V. , Goedert Michel , Scheres Sjors H.W.
Published: October 2024

The assembly of tau into amyloid filaments is associated with more than twenty neurodegenerative diseases, collectively termed tauopathies. Cryo-EM structures of brain-derived tau filaments revealed that specific structures define different diseases, triggering a quest for the development of experimental model systems that replicate the structures of disease. Here, we describe twelve phosphomimetic, serine/threonine to aspartate, mutations in tau, which we termed PAD12, that collectively induce thein vitroassembly of full-length tau into filaments with the same structure as that of paired helical filaments extracted from the brains of individuals with Alzheimer’s disease. Solution-state nuclear magnetic resonance spectroscopy suggests that phosphomimetic mutations in the carboxy-terminal domain of tau may facilitate filament formation by disrupting an intramolecular interaction between two IVYK motifs. PAD12 tau can be used for both nucleation-dependent and multiple rounds of seeded assemblyin vitro, as well as for the seeding of tau biosensor cells. PAD12 tau can be assembled into paired helical filaments under various shaking conditions, with the resulting filaments being stable for extended periods of time. They can be labelled with fluorophores and biotin. Tau filaments extracted from the brains of individuals with Alzheimer’s disease brains have been known to be made of hyperphosphorylated and abnormally phosphorylated full-length tau, but it was not known if the presence of this post-translational modification is more than a mere correlation. Our findings suggest that hyperphosphorylation of tau may be sufficient for the formation of the Alzheimer tau fold. PAD12 tau will be a useful tool for the study of molecular mechanisms of neurodegeneration.
Pre-existing H1N1 immunity reduces severe disease with bovine H5N1 influenza virus
Authors: Le Sage Valerie , Werner Bailee D. , Merrbach Grace A. , Petnuch Sarah E. , O’Connell Aoife K , Simmons Holly C. , McCarthy Kevin R. , Reed Douglas S. , Moncla Louise H. , Bhavsar Disha , Krammer Florian , Crossland Nicholas A. , McElroy Anita K. , Duprex W. Paul , Lakdawala Seema S.
Published: October 2024

The emergence of highly pathogenic H5N1 avian influenza in dairy cattle herds across the United States has caused multiple mild human infections. There is an urgent need to understand the risk of spillover into humans. Here, we show that pre-existing immunity from the 2009 H1N1 pandemic influenza virus provided protection from mortality and severe clinical disease to ferrets intranasally infected with bovine H5N1. H1N1 immune ferrets exhibited a differential tissue tropism with little bovine H5N1 viral dissemination to organs outside the respiratory tract and significantly less H5N1 virus found in nasal secretions and the respiratory tract. Additionally, ferrets with H1N1 prior immunity produced antibodies that cross-reacted with H5N1 neuraminidase protein. Taken together, these results suggest that mild disease in humans may be linked to prior immunity to human seasonal influenza viruses.
Over supplementation of folic acid reduces survival 24 hours after hypoxia in male and femaleDrosophila melanogaster
Authors: Gunnala Siddarth , Harrison Alisha , Juba Amber , Ashcraft Paula , Bottiglieri Teodoro , Buhlman Lori M , Jadavji Nafisa M.
Published: October 2024

Hypoxia is a major component of ischemic stroke. Nutrition has been established as a modifiable risk factor for ischemic stroke. Over-supplementation of folic acid (FA) has become an increasing problem in the U.S and other countries as more people are consuming at or above the recommended daily amount of FA. The impact of over-supplementation of FA on hypoxia is not well understood. This study aimed to investigate how FA over-supplementation impacts hypoxia outcomes usingDrosophila melanogasteras a model. Adultw1118Drosophila melanogasterwere placed on control and 100 µM folic acid supplemented diets (FASD). Progeny 5 to 6 days old were exposed to hypoxia for two hours prior to returning to normoxic conditions to model reperfusion. Using liquid chromatography-tandem mass spectrometry, elevated FA levels were observed in FASD flies. Escape behavior was also demonstrated in hypoxia larvae, and increased hypoxia-induced mortality was exacerbated in FASD flies; however, diet did not influence hypoxia-medicated reductions in climbing motivation and ability. Data obtained suggests that hypoxia has a negative effect on survival and climbing behavior in the flies, and that FA over-supplementation has selected negative health outcomes after hypoxia.
Interplay of Virulence Factors and Signaling Molecules: Albumin and Calcium-Mediated Biofilm Regulation inBordetella bronchiseptica
Authors: Mugni Sabrina Laura , Ambrosis Nicolás , O’Toole George A. , Sisti Federico , Fernández Julieta
Published: October 2024

Bordetella bronchiseptica, a respiratory pathogen capable of infecting various mammals, including humans, is associated with chronic infections, contrasting with the acute infections caused byBordetella pertussis. Both pathogens can form biofilm-like structuresin vivo, providing tolerance against environmental stresses. Biofilm formation byB. bronchisepticais regulated by the BvgAS two-component system, with intermediate concentrations of certain modulators inducing a phase favoring biofilm formation. Recent studies have highlighted the role of cyclic diguanylate monophosphate (c-di-GMP) in this process: elevated c-di-GMP levels stimulate biofilm formation, whereas phosphodiesterase (PDE) activation reduces biofilms. Respiratory secretions, which contain albumin and calcium at higher concentrations than standard growth media, promote an increase in the amount and extracellular localization of the adenylate cyclase toxin (ACT), an importantBordetella spp. virulence factor. Secreted ACT present in the extracellular media or attached to the outer membrane inhibits biofilm formation. Based on these observations, we hypothesized that serum albumin and calcium together inhibit biofilm formation and explored the potential role of c-di-GMP in this process. Our findings demonstrate that serum albumin and calcium inhibitB. bronchisepticabiofilm formation by two apparently independent mechanisms, increasing AC secretion and inducing c-di-GMP degradation. This study contributes to the understanding of the mechanisms governingB. bronchisepticabiofilm formation and its modulation by host factors.
Variable Presence of an Evolutionarily New Brain Structure is Related to Trait Impulsivity
Authors: Willbrand Ethan H. , Maboudian Samira A. , Elliott Matthew V. , Kellerman Gabby M. , Johnson Sheri L. , Weiner Kevin S.
Published: October 2024

Background

Impulsivity is a multidimensional construct reflecting poor constraint over one’s behaviors. Clinical psychology research identifies separable impulsivity dimensions that are each unique transdiagnostic indicators for psychopathology. Yet, despite this apparent clinical importance, the shared and unique neuroanatomical correlates of these factors remain largely unknown. Concomitantly, neuroimaging research identifies variably present human brain structures implicated in cognition and disorder: the folds (sulci) of the cerebral cortex located in the latest developing and most evolutionarily expanded hominoid-specific association cortices.

Methods

We tethered these two fields to test whether variability in one such structure in anterior cingulate cortex (ACC)—the paracingulate sulcus (PCGS)—was related to individual differences in trait impulsivity. 120 adult participants with internalizing or externalizing psychopathology completed a magnetic resonance imaging scan and the Three-Factor Impulsivity Index. Using precision imaging techniques, we manually identified the PCGS, when present, and acquired quantitative folding metrics (PCGS length and ACC local gyrification index).

Results

Neuroanatomical-behavioral analyses revealed that participants with leftward or symmetrical PCGS patterns had greater severity of Lack of Follow Through (LFT)—which captures inattention and lack of perseverance—than those with rightward asymmetry. Neuroanatomical-functional analyses identified that the PCGS co-localized with a focal locus found in a neuroimaging meta-analysis on a feature underlying LFT. Both quantitative folding metrics did not relate to any impulsivity dimension.

Conclusions

This study advances understanding of the neuroanatomical correlates of impulsivity and establishes the notion that the topographical organization of distinct, hominoid-specific cortical expanses underlie separable impulsivity dimensions with robust, transdiagnostic implications for psychopathology.
Complex genetic interactions affect susceptibility to Alzheimer's disease risk in the BIN1 and MS4A6A loci
Authors: Nazarian Alireza , Morado Marissa , Kulminski Alexander M.
Published: October 2024

Genetics is the second strongest risk factor for Alzheimer's disease (AD) after age. More than 70 loci have been implicated in AD susceptibility so far, and the genetic architecture of AD entails both additive and nonadditive contributions from these loci. To better understand nonadditive impact of single-nucleotide polymorphisms (SNPs) on AD risk, we examined individual, joint, and interacting (SNPxSNP) effects of 139 and 66 SNPs mapped to the BIN1 and MS4A6A AD-associated loci, respectively. The analyses were conducted by fitting three respective dominant allelic-effect models using data from four independent studies. Joint effects were analyzed by considering pairwise combinations of genotypes of the selected SNPs, i.e., compound genotypes (CompG). The individual SNP analyses showed associations of 18 BIN1 SNPs and 4 MS4A6A SNPs with AD. We identified 589 BIN1 and 217 MS4A6A SNP pairs associated with AD in the CompG analysis, although their individual SNPs were not linked to AD independently. Notably, 34 BIN1 and 10 MS4A6A SNP pairs exhibited both significant SNPxSNP interaction effects and significant CompG effects. The vast majority of nonadditive effects were captured through the CompG analysis. These results expand the current understanding of the contributions of the BIN1 and MS4A6A loci to AD susceptibility. The identified nonadditive effects suggest a significant genetic modulation mechanism underlying the genetic heterogeneity of AD in these loci. Our findings highlight the importance of considering nonadditive genetic impact on AD risk beyond the traditional SNPxSNP approximation, as they may uncover critical mechanisms not apparent when examining SNPs individually.
PD-1/PD-L1 Blockade Combined with AbnobaViscum®Therapy is Linked to Improved Survival in Advanced or Metastatic NSCLC Patients, an ESMO-GROW Related Real-World Data Registry Study
Authors: Schad Friedemann , Thronicke Anja , Hofheinz Ralf-Dieter , Klein Reinhild , Grabowski Patricia , Oei Shiao-Li , Wüstefeld Hannah , Grah Christian
Published: October 2024

Background

Recent advancements in cancer treatment have shown the potential of PD-1/PD-L1 inhibitor (ICB) plusViscum albumL. (VA) therapy in improving survival rates for patients with advanced or metastasized non-small cell lung cancer (NSCLC). The objective of this study was to investigate factors associated with improved survival in NSCLC patients treated with a combination of ICB and VA.

Methods

Patients with advanced or metastasized NSCLC from the accredited national Network Oncology registry were included in the real-world data study adhering to ESMO-GROW criteria. The study was conducted with ethics approval. Survival and the impact on hazard were compared between patients receiving PD-1/PD-L1 inhibitor therapy alone versus combinational PD-1/PD-L1 inhibitors and abnobaViscum®therapy. Adjusted multivariate Cox proportional hazard analysis was utilized to examine factors linked to survival.

Results

Enrolled patients (n = 300) had stage III or stage IV NSCLC, had a 1.19 male/female ratio and were 68 years old (median). Two hundred and twenty-two patients (74%) were in the control (CTRL, PD-1/PD-L1 inhibitor therapy) and seventy-eight patients (26%) in the combinational (COMB, PD-1/PD-L1 inhibitor plus abnobaViscum®therapy) group. The three-year survival was significantly prolonged by 7 months when abnobaViscum®therapy was added to the anti-PD-1/PD-L1 therapy (Comb: 13.8 months vs. Control: 6.8 months, p = 0.005). The three-year survival rate was 16.5% in the COMB group and two times higher than the three-year survival rate in the CTRL group (8.0%). Adjusted multivariable Cox regression analysis was performed for patients with PD-L1 positive (≥1%) NSCLC treated with a first-line PD-1 inhibitor and revealed that the addition of abnobaViscum®therapy to anti-PD-1 significantly lowered the hazard of death by 75% in (aHR: 0.25; 95%CI: 0.11-0.60, p=0.002).

Conclusions

Our results indicate that addition of abnobaViscum®therapy is significantly linked to enhanced survival in patients with advanced or metastasized NSCLC who are undergoing treatment with standard PD-1/PD-L1 inhibitor therapy irrespective of their age, tumor stage, ECOG status, surgery or radiation. The mechanisms could involve a synergistic modulation of the immune response, reduced primary PD-1/PD-L1 inhibitor resistance via immunogenic cell death and/or modification of the tumor microenvironment by combinational PD-1/PD-L1 inhibitor and abnobaViscum®therapy. Our findings should be complemented with analyses of RCT or R-RCT.

Trial registration

The study was registered retrospectively (DRKS00013335).
Associations between out of home food sector outlet menu healthiness scores, menu characteristics and energy consumed by customers in 2021-2022
Authors: Finlay Amy , Huang Yuru , Adams Jean , Jones Andrew , Evans Rebecca , Robinsona Eric
Published: October 2024

Greater consumption of food prepared outside of the home (OOH) is associated with higher energy intake. Strategies are needed to make eating OOH food less harmful to health. Identifying menu characteristics that contribute to higher energy consumption OOH could aid characterisation of OOH outlets by their relative healthiness and inform future policy intervention in the OOH food sector.

Customers (N=3718) were asked to recall their food orders upon exiting a range of OOH outlets across four local authorities in England during 2021 and 2022. For each outlet, universal health rating scores were calculated based on select menu characteristics and deep learning healthiness scores were calculated based on outlet name. Random forest models and robust linear regression models clustered by outlet were used to identify whether outlet healthiness scores and individual menu characteristics were associated with kcal consumed.

Universal health rating scores, but not deep learning scores, were predictive of energy consumed during OOH outlet visits (-28.27; 95% CI -44.76 to -11.77; p=.003). Menu characteristics with the greatest importance for predicting energy consumed were the percent of savoury main menu items over 600kcal and 1345kcal, the number of desserts, the number of unique vegetables, and the percent of drinks over 100kcal. Menu characteristics accounted for 29% of variance in energy consumed by customers.

Universal health rating scores may be a useful tool to characterise the healthiness of OOH outlets in England. Investigating the potential impact of OOH outlet health ratings on consumer and business behaviour is now warranted.
Possible molecules of triple-heavy pentaquarks within the extended local hidden gauge formalism
Authors: Wang Zhong-Yu , Xiao Chu-Wen , Sun Zhi-Feng , Liu Xiang
Published: October 2024

In this study, we explore the interactions between mesons and baryons in the open heavy sectors to identify potential triple-heavy molecular pentaquarks. We derive the meson-baryon interaction potentials using the vector meson exchange mechanism within the extended local hidden gauge formalism. The scattering amplitudes are computed by solving the coupled-channel Bethe-Salpeter equation, revealing several bound systems. By analyzing the poles of these amplitudes in the complex plane, we determine the masses and widths of these bound states. Additionally, we evaluate the couplings and compositeness of different channels within each bound system to assess their molecular characteristics. Our predictions include 4 Ωccc-like states, 4 Ωbbb-like states, 14 Ωbcc-like states, and 10 Ωbbc-like states, which could be targets for future experimental investigations.

Published by the American Physical Society
2024
Scattering on the worldvolume: Amplitude relations in Brower-Goddard string models
Authors: Bjerrum-Bohr N. Emil J. , Jepsen Christian Baadsgaard
Published: October 2024

We investigate the Brower-Goddard extension of the Veneziano and Virasoro-Shapiro four-point amplitudes obtained by generalizing the Koba-Nielsen integrals to d-dimensional conformally invariant integrals. The amplitudes derived from this framework exhibit polynomial residues and can be shown to adhere to polynomial bounds at high energies. In odd dimensions, the amplitudes decompose into sums of three partial amplitudes, enabling the formulation of general amplitude relations that subsume the Kawai-Lewellen-Tye (KLT) formula as a particular case. The amplitudes contain multiple tachyons in their spectra. Still, we demonstrate that their residues comply with the positivity conditions mandated by unitarity for spacetime dimensions at or below critical values Dcrit(d), where Dcrit(6)=26 and Dcrit(∞)=10. In closing, we contemplate physical applications for membranes and potential extensions of the formalism.

Published by the American Physical Society
2024