bluuebunny/crossref_metadata_2025 huggingface dataset:
War Discourse and Disaster Premium: 160 Years of Evidence from the Stock Market
Authors: Hirshleifer David , Mai Dat , Pukthuanthong Kuntara
Published: November 2024

Using a semisupervised topic model on 7 million New York Times articles spanning 160 years, we test whether topics of media discourse predict future stock market excess returns to test rational and behavioral hypotheses about market valuation of disaster risk. Media discourse data address the challenge of sample size even when disasters are rare. Our methodology avoids look-ahead bias and addresses semantic shifts. Our discourse topics positively predicts market excess returns, with War having an out-of-sample $R^{2}$ of 1.35%. We call this effect the war return premium. The war return premium has increased in more recent time periods.
Why, with whom, and how to conduct interdisciplinary research? A review from a researcher’s perspective
Authors: Vladova Gergana , Haase Jennifer , Friesike Sascha
Published: November 2024

Many complex problems and emerging phenomena require joint research efforts across academic disciplines. Interdisciplinary research (IDR) is therefore widely considered a promising approach to knowledge production. At the same time, however, this form of research poses significant challenges for those involved. In this paper, we review the literature on IDR from the perspective of individual researchers engaging in or considering this type of research. We conducted a broad literature review covering the past 35 years of research on IDR. The review is structured along four typical questions that researchers have regarding IDR: “Why bother?” (Reasons for considering IDR); “Is it for me?” (The profile of IDR researchers); “How do I work with ‘them’?” (Obstacles of interdisciplinary collaboration); “What am I getting myself into?” (Challenges for IDR researchers). We analyzed the literature so that we could distill answers to those questions. We conclude our paper by emphasizing the inherent ambiguities of interdisciplinary research and proposing a set of self-reflective questions to help navigate the complexities of this research approach.
A Double-edged Sword: Evolutionary Novelty along Deep-time Diversity Oscillation in An Iconic Group of Predatory Insects (Neuroptera: Mantispoidea)
Authors: Li Hongyu , Zhuo De , Wang Bo , Nakamine Hiroshi , Yamamoto Shûhei , Zhang Weiwei , Jepson James E , Ohl Michael , Aspöck Ulrike , Aspöck Horst , Tin Nyunt Thet , Engel Michael S , Benton Michael J , Donoghue Philip , Liu Xingyue
Published: November 2024

Evolutionary novelties are commonly identified as drivers of lineage diversification, with key innovations potentially triggering adaptive radiation. Nevertheless, testing hypotheses on the role of evolutionary novelties in promoting diversification through deep time has proven challenging. Here we unravel the role of the raptorial appendages, with evolutionary novelties for predation, in the macroevolution of a predatory insect lineage, the Superfamily Mantispoidea (mantidflies, beaded lacewings, thorny lacewings, and dipteromantispids), based on a new dated phylogeny and quantitative evolutionary analyses on modern and fossil species. We demonstrate a single origin of the raptorial foreleg and its associated novelties as key innovations triggering an early radiation of raptorial mantispoids from the Late Triassic to the Early Jurassic. Subsequently, the evolution of the raptorial foreleg influenced the diversification in different modes among lineages. At times, it might have limited the morphological diversity of other body parts and lead to lineage constraint by intensifying competition and lowering environmental resilience, e.g., in thorny lacewings, whose extant diversity is meagre. Conversely, in mantidflies, reduced emphasis on foreleg novelties and increased plasticity in other body parts may lead to better adaptation to predator-prey interactions and environmental shifts, thus maintaining a stable or accelerated level of diversification. We also reveal how major environmental change and lineage interactions interplayed with raptorial novelties in shaping the significant oscillations of mantispoid diversification over deep time, especially the abrupt shift near the mid-Cretaceous. However, by excluding a substantial portion of samples from the mid-Cretaceous of Myanmar, these shifts of some evolutionary parameters, such as morphological disparity, body size, and diversification rates, became inconspicuous and might be overestimated due to sampling bias. Our results uncover the intricate evolutionary patterns and profound significance of raptorial specializations, providing new insights into the role of novelties in forming evolutionary trajectories, both for the better and worse. [evolutionary novelty; macroevolution; diversification; raptorial foreleg; fossil; insect; Mantispoidea]
Molecular diagnosis and duration of eschar swab sample positivity post-doxycycline therapy in scrub typhus patients
Authors: Kanaujia Rimjhim , Singh Harpreet , Bisht Kamlesh , Goel Shriya , Selvam Suresh , Kaur Jasleen , Nallasamy Karthi , Sharma Navneet , Biswal Manisha
Published: November 2024

Background

An eschar is not always present in all scrub typhus patients. Furthermore, such patients may present to tertiary care hospitals after administration of doxycycline. The present study aimed to determine the usefulness of using the swab from eschar sites in the diagnosis of scrub typhus in patients who present post-doxycycline therapy.

Methods

Blood, eschar scraping and swab samples were collected daily until patient discharge/death. Real-time SYBR green PCR targeting the groEl gene, TaqMan probe PCR targeting the 47 kDa gene and nested PCR targeting the 56 kDa gene of Orientia tsutsugamushi were carried out. Partial sequences of the 56 kDa gene of O. tsutsugamushi were sequenced by the Sanger method and phylogenetic analysis was performed using Mega X.

Results

In total, 42 samples (19 eschar scraping and 23 eschar swab samples) were collected from 22 patients. A high positivity of eschar scraping samples (89.5%, 17/19) in comparison to blood (63.2%, 12/19) was observed. The nested PCR for eschar swab samples was positive in 10 (43.5%), 47 kDa gene in nine (39.1%) and groEl in three (13%) samples. The swabs remained positive for 1–4 d after doxycycline was started. The majority of the sequences clustered with Karp-like strains.

Conclusion

The eschar swab is a good alternative sample for the diagnosis and genotyping of scrub typhus. It also has the added advantage of persistent positivity despite doxycycline administration.
Combined use of pritelivir with acyclovir or foscarnet suppresses evolution of HSV-1 drug resistance
Authors: Schalkwijk Hanna Helena , Andrei Graciela , Snoeck Robert
Published: November 2024

The widespread use of antivirals in immunocompromised individuals has led to frequent occurrences of drug-resistant herpes simplex virus 1 (HSV-1) infections. Current antivirals target the viral DNA polymerase (DP), resulting in cross-resistance patterns that emphasize the need for novel treatment strategies. In this study, we assessed whether combining antivirals with different targets affects drug resistance emergence by passaging wild-type HSV-1 under increasing concentrations of acyclovir (ACV), foscarnet (phosphonoformic acid, PFA), or the helicase–primase inhibitor pritelivir (PTV), individually or in combination (ACV + PTV or PFA + PTV). The resistance selection procedure was initiated from two different drug concentrations for each condition. Deep sequencing and subsequent phenotyping showed the rapid acquisition of resistance mutations under monotherapy pressure, whereas combination therapy resulted in either no mutations or mutations conferring ACV and/or PFA resistance. Notably, mutations associated with PTV resistance were not detected after five passages under combination pressure. Strains resistant to both ACV and PTV were eventually obtained upon further passaging under ACV + PTV pressure initiated from lower drug concentrations. PFA + PTV dual treatment induced PFA resistance mutations in the DP, but PTV resistance mutations were not acquired, even after 15 passages. Our data suggest that combining the helicase–primase inhibitor PTV with a DP inhibitor may be an effective strategy to prevent drug resistance evolution in HSV-1.
Trajectories of depressive symptoms in a population-based cohort of Black and White women from late reproductive age through the menopause transition: a 30-year analysis
Authors: Chirinos Diana A. , Yin Zhe , Schreiner Pamela J. , Appiah Duke , Wellons Melissa F. , Lewis Cora E. , Huddleston Heather G. , Kim Catherine
Published: November 2024

Objective

The aim of this study was to examine how depressive symptoms change in midlife and across the menopause transition.

Methods

We conducted a secondary analysis of data from a prospective population-based cohort, the Coronary Artery Risk Development in Young Adults study. We included women (n = 2,160) with ≥3 responses to the Center for Epidemiologic Studies Depression Scale (CES-D) beginning at examination year 5, at approximately 30 years of age, and again at years 10, 15, 20, 25, 30, and 35 (ages 35 through 60 years). We modeled trajectories of CES-D by chronologic age and compared these to trajectories of depressive symptoms by relation to age at menopause.

Results

We identified three trajectories of depressive symptoms: women with minimal (n = 1,328, 61%, mean CES-D 8.1); intermediate (n = 675, 31%, mean CES-D 15.6); or persistent depressive symptoms (n = 157, 7%, mean CES-D 26.1). Trajectories were stable over time, among women who had undergone natural menopause (n = 1,153), Black race (odds ratio [OR], 1.85; 95% confidence interval [CI], 1.43 to 2.40), less than a high school education (OR, 1.83; 95% CI, 1.38 to 2.41), and low income (OR, 1.60; 95% CI, 1.18 to 2.18), along with tobacco use (OR, 1.35; 95% CI, 1.04 to 1.77), alcohol consumption (OR, 1.01; 95% CI, 1.004 to 1.02), estrogen use for vasomotor symptoms (OR, 1.71; 95% CI, 1.06 to 2.77), and higher body mass index (OR, 1.03; 95% CI, 1.01 to 1.05) that were also associated with persistent depressive symptoms. Hormonal contraceptive use at year 2 was associated with lower odds of persistent depressive symptoms (OR, 0.69; 95% CI, 0.51 to 0.93). Similar patterns were observed among women who underwent surgical menopause.

Conclusions

Depressive symptoms in the premenopause were similar to those in postmenopause, and risk factors could be identified early in reproductive life. Studies with more frequent assessments of depressive symptoms during the menopause transition are needed.
Use of Lecanemab and Donanemab in the Canadian Healthcare System: Evidence, Challenges, and Areas for Future Research
Authors: Smith Eric E. , Phillips Natalie , Feldman Howard H. , Borrie Michael , Ganesh Aravind , Henri-Bhargava Alexandre , Desmarais Philippe , Frank Andrew , Badhwar AmanPreet , Barlow Laura , Bartha Robert , Best Sarah , Bethell Jennifer , Bhangu Jaspreet , Black Sandra E. , Bocti Christian , Bronskill Susan E. , Burhan Amer M. , Calon Frederic , Camicioli Richard , Campbell Barry , Collins D. Louis , Dadar Mahsa , DeMarco Mari L. , Ducharme Simon , Duchesne Simon , Einstein Gillian , Fisk John D. , Gawryluk Jodie R. , Grossman Linda , Ismail Zahinoor , Itzhak Inbal , Joshi Manish , Harrison Arthur , Kroger Edeltraut , Kumar Sanjeev , Laforce Robert , Lanctot Krista L. , Lau Meghan , Lee Linda , Masellis Mario , Massoud Fadi , Mitchell Sara B. , Montero-Odasso Manuel , Myers Karen , Nygaard Haakon B. , Pasternak Stephen H. , Peters Jody , Rajah M. Natasha , Robillard Julie M. , Rockwood Ken , Rosa-Neto Pedro , Seitz Dallas P. , Soucy Jean-Paul , Trenaman Shanna C. , Wellington Cheryl L. , Zadem Aicha , Chertkow Howard
Published: November 2024

Lecanemab and donanemab are monoclonal antibody therapies that remove amyloid-beta from the brain. They are the first therapies that alter a fundamental mechanism, amyloid-beta deposition, in Alzheimer disease (AD). To inform Canadian decisions on approval and use of these drugs, the Canadian Consortium on Neurodegeneration in Aging commissioned Work Groups to review evidence on the efficacy, and safety of these new therapies, as well as their projected impacts on Canadian dementia systems of care. We included persons with lived experience with Alzheimer disease in the discussion about the benefits and harms. Our review of the trial publications found strong support for statistically significant group differences, but also recognized that there are mixed views on the clinical relevance of the observed differences and the value of therapy for individual patients. The drugs are intended for persons with early AD, at a stage of mild cognitive impairment or mild dementia. If patients are treated, then confirmation of AD by positron emission tomography or cerebrospinal fluid analysis and monitoring for risk of amyloid-related imaging abnormalities was recommended, as done in the clinical trials, although it would strain Canadian resource capacity. More data are needed to determine the size of the potentially eligible treatment population in Canada.
Cortical effects of dopamine replacement account for clinical response variability in Parkinson’s disease
Authors: Wiesman Alex I. , Vinding Mikkel C. , Tsitsi Panagiota , Svenningsson Per , Waldthaler Josefine , Lundqvist Daniel
Published: November 2024

Individual variability in clinical response to dopaminergic replacement therapy (DRT) is a key barrier to efficacious treatment for patients with Parkinson’s disease (PD). A better understanding of the neurobiological sources of such inter-individual differences is necessary to inform future clinical interventions and motivate translational research. One potential source of this variability is an unintended secondary activation of extra-nigrostriatal dopamine systems by DRT, particularly in the neocortex. In this study, we use magnetoencephalography data collected from patients with PD before and after DRT to map their individual cortical neurophysiological responses to dopaminergic pharmacotherapy. By combining these DRT response maps with normative atlases of cortical dopamine receptor and transporter densities, we link the variable enhancement of rhythmic beta activity by DRT to dopamine-rich cortical regions. Importantly, patients who exhibited a larger dopaminergic beta cortical enhancement showed a smaller clinical improvement from DRT, indicating a potential source of individual variability in medication response for patients with PD. We conclude that these findings inform our understanding of the dopaminergic basis of neurophysiological variability often seen in patients with PD, and indicate that our methodological approach may be useful for data-driven contextualization of medication effects on cortical neurophysiology in future research and clinical applications.
The heterogeneity of youth at risk of diabetes and prediabetes: a latent class analysis of a national sample
Authors: McDonough Catherine , Li Yan Chak , Pandey Gaurav , Vangeepuram Nita , Liu Bian
Published: November 2024

Objectives

To identify youth subgroups based on lifestyle, BMI, and sociodemographic characteristics and examine the association between group membership and prediabetes/diabetes (preDM/DM) status.

Methods

We analyzed data from 1,278 adolescents (ages 12-17) from the 2011-2018 National Health and Nutrition Examination Surveys. PreDM/DM was defined using hemoglobin A1c (≥5.7 mg/dL) and/or fasting plasma glucose (≥100 mg/dL). Latent class analysis of physical activity, diet quality, screen time, and BMI identified subgroups, adjusted for sociodemographic factors. Associations between class membership and preDM/DM were assessed using survey-weighted logistic regression.

Results

Four classes emerged: High BMI and unhealthy lifestyle (37.5%), Healthy BMI and physically active (25.3%), Healthy BMI and lifestyle (16.0%), and Average BMI and lifestyle (21.8%). Youth in other classes had lower odds of preDM/DM compared to the High BMI and unhealthy lifestyle class, especially the Healthy BMI and active class (aOR=0.556, 95% CI=0.327-0.946).

Conclusions

Youth at risk of preDM/DM were from heterogeneous groups with varied lifestyle, health, and socioeconomic characteristics.
Estimates of SARS-CoV-2 infections and population immunity after the COVID-19 pandemic in Austria: Analysis of national wastewater data
Authors: Riedmann Uwe , Chalupka Alena , Richter Lukas , Sprenger Martin , Rauch Wolfgang , Schenk Hannes , Krause Robert , Willeit Peter , Oberacher Herbert , Høeg Tracy Beth , Ioannidis John PA , Pilz Stefan
Published: November 2024

Background

Post-pandemic surveillance data on COVID-19 infections may help inform future public health policies regarding SARS-CoV-2 testing, vaccinations or other COVID-19 measures. We estimate the total SARS-CoV-2 infections in Austria after the end of the pandemic (May 5, 2023, per WHO) up to May 2024 from wastewater data. Those estimates are used in an agent-based model (ABM) to estimate average national levels of SARS-CoV-2 infection protection (IP) and COVID-19 death protection (DP).

Methods

We use a previously published model estimating total infections in Austria from wastewater data and extrapolate the approach up to May 2024. Utilizing those estimates in an ABM, we estimate daily national average IP and DP. These estimates are based on waning immunity estimates of previous literature and incorporate documented vaccinations.

Findings

We estimate approximately 3·2 million infections between May 6, 2023, and May 23, 2024, with a total of 17·8 million infections following May 12, 2020. The ABM estimates that 95% of people in Austria were infected with SARS-CoV-2 at least once. It also shows very high levels of national average DP a year after the end of the pandemic. National IP remained relatively low after the onset of Omicron.

Interpretation

The estimated high number of SARS-CoV-2 infections since the end of the COVID-19 pandemic in Austria has kept the national average DP very high. These findings should be considered for public health decisions on SARS-CoV-2 testing practices and vaccine booster administrations.

Funding

Austrian Science Fund (FWF) KLI 1188.
Novel multiplex tools in an epidemic panel improve prediction of RSV infection dynamics and disease burden – a RESPINOW analysis
Authors: Harries Manuela , Klett-Tammen Carolina J. , Rodiah Isti , Dulovic Alex , Jaeger Veronika K , Krepel Jessica , Contreras Sebastian , Maak Katrin , Marsall Patrick , Möller Annette , Heise Jana-Kristin , Castell Stefanie ,   RESPINOW study group, Schneiderhan-Marra Nicole , Karch André , Lange Berit
Published: November 2024

Respiratory Syncytial Virus (RSV) is one of the leading causes of morbidity and mortality among infants and adult risk groups worldwide. Substantial case-underdetection and gaps in the understanding of reinfection dynamics of RSV limit reliable projection estimates.

Here, we use a novel RSV multiplex serological assay in a population-based panel to estimate season and age-specific probability of reinfection and combine it with sentinel and notification data to parameterize a mathematical model tailored to project RSV dynamics in Germany from 2020 to 2023.

Our reinfection estimates, based on a 20% post-F and a 45% N antibody increase in the assay over consecutive periods, were 5·7% (95%CI: 4·7-6·9) from 2020 to 2022 and 12·7% (95%CI: 10·5-15·2) from 2022 to 2023 in adults. In 2021, 30-39 year olds had a higher risk of reinfection, whereas in 2022, all but the 30-39 age group had an increased risk of reinfection. This suggests age-differential infection acquisition in the two seasons, e.g. due to still stronger public health measures in place in 2021 than in 2022.

Model-based projections that include the population-based reinfection estimations predicted the onset and peak for the 23/24 RSV season better than those only based on surveillance estimates.

Rapid, age-specific reinfection assessments and models incorporating this data will be critical for understanding and predicting RSV dynamics, especially with changing post-pandemic patterns and new prevention strategies e.g. monoclonal antibody.

Helmholtz Association, EU Horizon 2020 research and innovation program, Federal Ministry of Education and Research, and German Research supported this work.
Impact of Left Ventricular Venting on Acute Brain Injury in Patients with Cardiogenic Shock: An Extracorporeal Life Support Organization Registry Analysis
Authors: Feng Shi Nan , Liu Winnie L. , Kang Jin Kook , Kalra Andrew , Kim Jiah , Zaqooq Akram , Vogelsong Melissa A. , Kim Bo Soo , Brodie Daniel , Brown Patricia , Whitman Glenn J. R. , Keller Steven , Cho Sung-Min
Published: November 2024

Background

While left ventricular (LV) venting reduces LV distension in cardiogenic shock patients on venoarterial extracorporeal membrane oxygenation (VA-ECMO), it may also amplify risk of acute brain injury (ABI). We investigated the hypothesis that LV venting is associated with increased risk of ABI. We also compared ABI risk of the two most common LV venting strategies, percutaneous microaxial flow pump (mAFP) and intra-aortic balloon pump (IABP).

Methods

The Extracorporeal Life Support Organization registry was queried for patients on peripheral VA-ECMO for cardiogenic shock (2013-2024). ABI was defined as hypoxic-ischemic brain injury, ischemic stroke, or intracranial hemorrhage. Secondary outcome was hospital mortality. We compared no LV venting with 1) LV venting, 2) mAFP, and 3) IABP using multivariable logistic regression. To compare ABI risk of mAFP vs. IABP, propensity score matching was performed.

Results

Of 13,276 patients (median age=58.2, 69.9% male), 1,456 (11.0%) received LV venting (65.5% mAFP and 29.9% IABP), and 525 (4.0%) had ABI. After multivariable regression, LV-vented patients had increased odds of ABI (adjusted odds ratio (aOR)=1.76, 95% CI=1.29, 2.37, p<0.001) but no difference in mortality (aOR=1.08, 95% CI=0.91-1.28, p=0.39) compared to non-LV-vented patients. In the propensity- matched cohort of IABP (n=231) vs. mAFP (n=231) patients, there was no significant difference in odds of ABI (aOR=1.35, 95%CI=0.69-2.71, p=0.39) or mortality (aOR=0.88, 95%CI=0.58-1.31, p=0.52).

Conclusions

LV venting was associated with increased odds of ABI but not mortality in patients receiving peripheral VA-ECMO for cardiogenic shock. There was no difference in odds of ABI or mortality for IABP vs. mAFP patients.

Clinical Perspective

In patients receiving peripheral venoarterial extracorporeal membrane oxygenation (VA-ECMO) for cardiogenic shock, left ventricular venting is associated with increased odds of acute brain injury (ABI) but not mortality. However, mode of venting—intra-aortic balloon pump (IABP) or percutaneous microaxial flow pump (mAFP)—does not appear to impact either odds of ABI or mortality. These findings highlight a link between venting strategies and neurological outcomes in this high-risk population. Clinicians must weigh the benefits of venting against ABI risk when managing neurocritically ill patients, though our findings provide reassurance clinicians that both IABP and mAFP may offer comparable neurologic safety profiles.
Sustainable and portable CRISPR-based diagnostics for high-sensitivity Mpox detection
Authors: Hirano Rika , Yoshimi Kazuto , Asano Koji , Takeshita Kohei , Ishii Ken J. , Sato Kei , Mashimo Tomoji
Published: November 2024

Mpox has emerged as a critical public health challenge, creating an urgent need for rapid, reliable, and field-deployable diagnostic tools for outbreak settings. Here, we present Kairo-CONAN, a novel CRISPR-Cas3-based point-of-care (POC) diagnostic platform for Mpox, engineered for sustainability and portability. This system leverages a disposable hand warmer (Kairo) as a stable heat source and incorporates freeze-dried reagents for ambient temperature stability, enabling device-free, sensitive detection through lateral flow assay strips. Utilizing CRISPR-Cas3’s unique DNA-targeting and cleavage properties, we optimized probe DNA configurations for high specificity and designed clade-specific target crRNAs. Kairo-CONAN demonstrated rapid, high-sensitivity, and specific detection of Mpox virus (MPXV) DNA across multiple clades, including Clade Ia (Congo), Clade Ib (synthetic DNA), and Clade IIb (Tokyo). By addressing logistical and environmental challenges, Kairo-CONAN offers a sustainable, cost-effective, and field-adapted solution for infectious disease diagnostics, aligning with the 100-day mission framework to enhance global outbreak response efforts.
Observing picomolar protein unfolding using resonance light scattering
Authors: Alvarez Alain Bolaño , Arvesen Kristian B. , Hjuler Kasper F. , Bjerring Peter , Petersen Steffen B.
Published: November 2024

We here present a novel and sensitive methodology for determining the melting point (MP) of Bovine Serum Albumin (BSA) from micromolar to picomolar concentration levels under label free conditions. At 1 pM we could model the melting with a sharp gaussian. However, from the transient state observed during the melting process by using a simple exponential decay model we determined a time constant of 67 seconds. We applied this methodology by studying a 3.3 pM sample of a botulinum toxin A (BoNT-A) (stabilized with 2.8 nanomolar denatured Human Serum Albumin (HSA)). We were able to determine the Tm of BoNT-A in the presence of the approximately 1000-fold more concentrated HSA.

Entry for the Table of Contents

Protein label-free melting point (MP) determination at ultralow concentrations is a huge problem which concern to the biopharmaceutical industry. Here, we present a novel method to determine the MP of bovine serum albumin (BSA) from 1μM to 1pM under label-free conditions. The benefits of this study match the purposes of stability studies in formulations, in which the protein active component is successful at very low concentrations, such as botulinum toxin A (BoNT-A). We used BOCOUTRE, a commercially available pharmaceutical product based on BoNT-A, and Human Serum Albumin (HSA) as a stabilizer. Our method can detect the MP of the stabilizer protein, even if its concentration is markedly different from that of the active component protein (1000-fold) in the case of BOCOUTRE.
Antigen flexibility supports the avidity of hemagglutinin-specific antibodies at low antigen densities
Authors: Benegal Ananya , He Yuanyuan , Ho Katilyn , Groff Giselle , Guo Zijian , Vahey Michael D.
Published: November 2024

The receptor-binding protein of influenza A virus, hemagglutinin (HA), is the most abundant protein on the viral surface. While high densities of HA are thought to improve cellular attachment by increasing avidity for the viral receptor, they may also increase the avidity of neutralizing antibodies. The tradeoff between these two competing effects of avidity is not well understood. To better understand how features of the viral surface influence antibody avidity, we developed fluorescence-based assays to measure dissociation kinetics and steady-state binding of antibodies to intact virions. Focusing on two antibodies that bind to the HA head domain (S139/1 and C05), we confirm that binding orientations that favor bivalent attachment of antibodies to the viral surface can offset weak monovalent affinity by facilitating crosslinking. By modulating HA density in both engineered viruses and synthetic nanoparticles, we find that bivalent antibody binding remains resilient down to one-tenth the HA density on the viral surface and, in the case of C05, that antibody occupancy increases at these lowest densities. Finally, using a combination of structure-guided modeling and antibodies that lock HA in a tilted conformation, we identify flexibility of the HA ectodomain as an additional determinant of antibody avidity. Together, these results establish features of the viral surface that help support or suppress the binding of neutralizing antibodies.
Co-delivery of neurotrophic factors and a zinc chelator substantially promotes axon regeneration in the optic nerve crush model
Authors: Dieu Nguyen Huynh Quang , Nam Mi-hyun , Vigh Jozsef , Brzezinski Joseph , Duncan Lucas , Park Daewon
Published: November 2024

Traumatic optic neuropathies cause the death of retinal ganglion cells (RGCs) and axon degeneration. This is a result of the blockage of neurotrophic factor (NTF) supply from the brain and a vicious cycle of neurotoxicity, possibly mediated by increased levels of retinal Zn2+. Ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF) are two NTFs that are known to support RGC survival and promote axon regeneration. Dipicolylamine (DPA) has a strong affinity to Zn2+and can selectively chelate this ion. To continuously supply NTFs and reduce elevated retinal Zn2+, we developed poly(serinol hexamethylene urea)-based sulfonated nanoparticles (S-PSHU NPs), that co-delivers CNTF, BDNF, and DPA. Anin vitrorelease study was performed using the NTF-DPA-loaded S-PSHU NPs, demonstrating a sustained release of CNTF and BDNF for up to 8 weeks, while DPA was released for 4 weeks. In a rat optic nerve crush (ONC) model, DPA-loaded S-PSHU NPs exhibited dose-dependent elimination of retinal Zn2+. Similarly,in vitroprimary RGC culture demonstrated that the activity of RGCs and axon growth were dependent on the dosage of CNTF and BDNF. In addition, the NTF-DPA-loaded S-PSHU NPs significantly improved RGC survival and axon regeneration following ONC in rats, with the regenerated axons extending to the distal segment of the brain, including the suprachiasmatic nucleus, lateral geniculate nucleus, and superior colliculus.
Metabolic Adaptations To Acute Glucose Uptake Inhibition Converge Upon Mitochondrial Respiration For Leukemia Cell Survival
Authors: Komza Monika , Khatun Jesminara , Gelles Jesse D. , Trotta Andrew P. , Abraham-Enachescu Ioana , Henao Juan , Elsaadi Ahmed , Kotini Andriana G. , Clementelli Cara , Arandela JoAnn , El Ghaity-Beckley Sebastian , Barua Agneesh , Chen Yiyang , Marcellino Bridget K. , Papapetrou Eirini P. , Poyurovsky Masha V. , Chipuk Jerry Edward
Published: November 2024

One hallmark of cancer is the upregulation and dependency on glucose metabolism to fuel macromolecule biosynthesis and rapid proliferation. Despite significant pre-clinical effort to exploit this pathway, additional mechanistic insights are necessary to prioritize the diversity of metabolic adaptations upon acute loss of glucose metabolism. Here, we investigated a potent small molecule inhibitor to Class I glucose transporters, KL-11743, using glycolytic leukemia cell lines and patient-based model systems. Our results reveal that while several metabolic adaptations occur in response to acute glucose uptake inhibition, the most critical is increased mitochondrial oxidative phosphorylation. KL-11743 treatment efficiently blocks the majority of glucose uptake and glycolysis, yet markedly increases mitochondrial respiration via enhanced Complex I function. Compared to partial glucose uptake inhibition, dependency on mitochondrial respiration is less apparent suggesting robust blockage of glucose uptake is essential to create a metabolic vulnerability. When wild-type and oncogenic RAS patient-derived induced pluripotent stem cell acute myeloid leukemia (AML) models were examined, KL-11743 mediated induction of mitochondrial respiration and dependency for survival associated with oncogenic RAS. Furthermore, we examined the therapeutic potential of these observations by treating a cohort of primary AML patient samples with KL-11743 and witnessed similar dependency on mitochondrial respiration for sustained cellular survival. Together, these data highlight conserved adaptations to acute glucose uptake inhibition in diverse leukemic models and AML patient samples, and position mitochondrial respiration as a key determinant of treatment success.
Natural killer cell dysfunction drives keloid pathogenesis
Authors: Zhao Ying , Wei Qin , Zeng Rui , Wang Yan , Yang Yong , Wang Yetao
Published: November 2024

Keloids, characterized by excessive scar tissue resulting from abnormal wound healing, are primarily driven by hyperproliferative fibroblasts and overproduction of extracellular matrix. Although human natural killer (NK) cells are known for their role in inhibiting uncontrolled cell growth through cytokines like IFN-γ and TNF-α, they also produce amphiregulin (AREG), which paradoxically promotes cell proliferation and survival. The involvement of NK cells in keloid pathogenesis, however, remains largely unexplored. This study uncovers remarkable functional changes in NK cells within both lesional skin and the blood of keloid patients. In the skin, NK cell-produced IFN-γ plays a pivotal role in limiting keloid progression by inducing fibroblast apoptosis and curbing excessive extracellular matrix production, while NK cell-derived AREG actively opposes these protective effects. Notably, TGF-β-driven fibroblasts in keloid lesions further dampen NK cell IFN-γ production, revealing a complex and dynamic cellular interplay. In the bloodstream of keloid patients, a distinct NK cell subset emerges, marked by elevated interferon-stimulated genes (ISGs) and diminished IFN-γ production, which correlates with increased plasma IFN-β levels. This elevated IFN-β serves as a key initiating factor, driving NK cell exhaustion through impaired mitochondrial function and metabolic disruption. These findings highlight a critical mechanism underlying the functional abnormalities of keloid-associated NK cells and emphasize the influence of both local and systemic factors in shaping NK cell responses in keloid pathogenesis.

Graphical abstract

Highlights

In the skin, NK cell-derived IFN-γ is crucial for suppressing keloid fibroblast proliferation and extracellular matrix production.

AREG from NK cells counteracts the inhibitory effects of IFN-γ on keloid progression.

In the blood, elevated IFN-β in keloid patients drives the emergence of ISG+NK cells with reduced IFN-γ production.

IFN-β induces mitochondrial dysfunction and functional exhaustion in NK cells.
Study Protocol Efficacy, safety, and tolerability of ultra-high-caloric, fatty diet (UFD) in amyotrophic lateral sclerosis
Authors: Dorst Johannes , Ruckes Christian
Published: November 2024

The LIPCAL-ALS II study investigates the efficacy, safety, and tolerability of an ultra-high-caloric, fatty diet (UFD) in amyotrophic lateral sclerosis (ALS). It is a multicenter, 1:1-randomized, prospective, stratified, parallel-group, double-blind, placebo-controlled, confirmatory study with 392 patients conducted in 25 centers of the German network for motor neuron diseases (MND Net). Patients will be randomized to receive either the experimental intervention, consisting of an ultra-high-caloric fatty dietary supplement for drinking (100% lipid, 4.5 kcal/ml) 140 ml/day (630 kcal) or matching placebo (140 ml/day, <5% fat, <50 kcal) in addition to normal food intake. The primary endpoint is survival after 18 months of intervention. Patients with possible, probable (clinically or laboratory supported) or definite ALS according to revised El Escorial criteria with a disease duration of <36 months and a loss of ALS functional rating scale revised (ALSFRS-R) ≥0.33 points/months will be included.

Synopsis
FGF14repeat length and mosaic interruptions: modifiers of SCA27B?
Authors: Laß Joshua , Thomsen Mirja , Borsche Max , Lüth Theresa , Prietzsche Julia C. , Schaake Susen , Milovanović Andona , Macpherson Hannah , Gustavsson Emil K. , Awad Paula Saffie , Dragašević-Mišković Nataša , Laabs Björn-Hergen , König Inke R. , Westenberger Ana , Pearson Christopher E. , Brüggemann Norbert , Klein Christine , Trinh Joanne
Published: November 2024

Deep intronicFGF14repeat expansions have been identified as a frequent genetic cause of late-onset cerebellar ataxias, explaining up to 30% of patients. Interruptions between repeats have previously been identified to impact the penetrance in other repeat expansion disorders. Repeat interruptions withinFGF14have yet to be characterized in detail.

We utilized long-range PCR, Sanger sequencing, repeat-primed PCR, Nanopore, and PacBio sequencing to distinguish the repeat motifs, mosaicism, and number of repeat interruptions present inFGF14-related ataxia patients and unaffected individuals.

A total of 304 patients with late-onset ataxia and 190 unaffected individuals were previously screened for repeat expansions in theFGF14gene by long-range PCR, identifying 37 individuals with expanded repeat lengths (≥250 repeats). These, along with three newly identified expansion carriers were included in the present study, and advanced genetic methods were applied to investigate the repeat composition in 27 patients and 13 unaffected individuals. The expansions, based on Nanopore data, ranged from 236 to 486 repeats (SD = 60), with 20 individuals showing repeat interruptions, including complex motifs such asGAG, GAAGGA, GAAGAAAGAA, GAAAAGAAGAAGGAAGAAGGAA, GAAAAGAAGAAGGAA, andGCAGAAGAAGAAGAA. We calculated the longest pure GAA length from the long-read data for all 40 individuals. When comparing the pure GAA tract between patients and unaffected individuals, clusters were apparent based on greater or less than 200 repeats. Five ataxia patients with interruptions still had a remaining pure GAA expansion >200. We observed an association of the pure GAA length with age at onset (p=0.016,R2=0.256). Somatically-incurred mosaic divergent repeat interruptions were discovered that affect motif length and sequence (mDRILS), which varied in number and mosaicism (frequency: 0.37-0.93). The mDRILS correlated with pure GAA length (p=0.022,R2=0.334), with a higher mosaic frequency of interruptions in unaffected individuals compared to patients (unaffected: 0.90; patients: 0.67;p=0.010).

We demonstrate that i) long-read sequencing is required to detect complex repeat interruptions accurately; ii) repeat interruptions inFGF14are mosaic, have various lengths and start positions in the repeat tract, and can thereby be annotated as mDRILS, which iii) enabled us to establish a categorization based on remaining pure GAA repeats quantifying the impact of mDRILS on pathogenicity or age at onset, dependent on the interruption length and position, with high accuracy. Finally, we iv) provide evidence that mosaicism stabilizes pure GAA repeats in interruptedFGF14repeat expansions.
A rapid CRISPR/Cas12a-based assay for the detection of HIV-1 Indian Clade-C infections
Authors: Gaur Anjli , Bhakhri Harsh , Mishra Nitesh , Sharma Shaifali , Bansal Tanu , Kalaivani Mani , Brijwal Megha , Das Bimal Kumar , Lodha Rakesh , Sinha Subrata , Luthra Kalpana
Published: November 2024

Early detection of HIV-1 infection is crucial to initiate anti-retroviral therapy (ART) to suppress viremia and disease progression. Herein, we developed a CRISPR/Cas12a-based HIV-1 detection assay by optimizing components for a coupled isothermal preamplification by recombinase polymerase amplification (RPA). The HIV-1 Indian Clade-C-specific conserved pol region was targeted by crRNA designed for Clade-specific detection. The CRISPR/Cas12a cleavage of the viral cDNA input is displayed as a single visually detectable outcome due to the collateral cleavage of the ssDNA-FAM-BQ reporter, enabling the rapid detection of HIV-1. The performance of the assay was evaluated by testing sera of 41 Indian Clade C HIV-1 seropositive individuals, which included 28 HIV-1 infected infant samples, HIV-1 Indian clade C genome plasmid, viral disease control DNA/RNA samples (Influenza, RSV, Parvovirus, HPIV, CMV, and HBV), and 31 healthy donor sera samples. With 96% sensitivity and 92.65% specificity for HIV-1C detection, with fluorescence and visual readout, and a capability of detection using lateral flow dipsticks, our CRISPR/Cas12a-based HIV-1 C detection assay demonstrates the potential to be developed into a robust point-of-care molecular diagnostic test for HIV-1C. Moreover, it may serve as a potential rapid NAT alternative in detecting mother-to-child transmission (MCT) of HIV-1C in infants (<2 years of age), where rapid antibody-based serology tests are rendered ineffective due to the presence of maternal antibodies.
Deep learning classification of MRI differentiates brain changes in genetic and idiopathic Parkinson’s disease
Authors: Courtman Megan , Thurston Mark , Wang Hongrui , Banerjee Sube , Streeter Adam , McGavin Lucy , Hall Stephen , Sun Lingfen , Ifeachor Emmanuel , Mullin Stephen
Published: November 2024

Background

The prospect of neuroprotective treatments for Parkinson’s disease highlights the need for early diagnostic tests. Specialised MRI sequences suggest changes related to Parkinson’s disease may be detectable.

Objectives

We used the Parkinson’s Progression Markers Initiative dataset to investigate whether deep learning can detect early brain MRI changes of idiopathic and GBA/LRRK2 prodromal Parkinson’s disease.

Methods

Pairs of matched cohorts were used to train convolutional neural networks to classify T2 axial images. Explainability methods were used to visualise drivers of model predictions.

Results

Models built to distinguish between idiopathic Parkinson’s disease scans (n=504) and matched controls exhibited good classification performance for scans taken more than four years after diagnosis, with a Receiver Operating Characteristic area-under-the-curve of 0.89 (n=98). Model performance deteriorated as time since diagnosis reduced. Models built to distinguish non-manifesting carriers ofLRRK2(area-under-the-curve 0.92, 90% accuracy,n=115) andGBA(area-under-the-curve 0.94, 92% accuracy,n=109) from controls exhibited excellent classification performance. All models demonstrated foci of interest in cerebrospinal fluid spaces surrounding the brainstem. Models usingGBAscans also identified foci of interest in occipital lobes.

Conclusions

Deep learning models appear able to reproducibly detect changes in the brains of those with established but not early Parkinson’s disease. Conversely changes in at risk genetic cohorts are detectable at all stages, including in those who have not developed Parkinson’s disease. This implies a distinct pathological process ongoing within the brains of carriers of Parkinson’s disease genetic risk factors compared to those with sporadic Parkinson’s disease.
Scaling-up Cervical Cancer Services for Women Living with HIV in Mozambique, October 2018–September 2023
Authors: Correia Della , Bay Zurnaid , Wate Argentina , Nhanguiombe Herminio , Manhica Pinto , Bila Erica , Tualufo Sheila , Mate Celina , Amado Celeste , Lorenzoni Cesaltina
Published: November 2024

Background

Cervical cancer is the most common cancer among women in Mozambique. Women living with HIV (WLHIV) have a six times greater risk of developing cervical cancer. National guidelines call for annual screening of all HIV-positive women aged 20-49 years or below 20 years if she is sexually active and HIV-negative women aged 25-49 years, with follow-up after 1 year for HIV-positive and 3 years for HIV-negative women that screen negative. Women screened positive are referred to treatment with cryotherapy, thermal ablation, or loop electrosurgical excision procedure (LEEP). In 2021, HIV prevalence among women aged 15–49 years was estimated at 15.4%. We analyzed routine program data to describe the expansion of cervical cancer services and identify gaps in screening and treatment coverage among WLHIV since 2018.

Methods

We analyzed semi-annual, routinely collected programmatic data on cervical cancer screening and treatment services reported between 21 September 2018 to 20 March 2019 (585 sites reported) and 21 March to 20 September 2023 (610 sites reported). We verify rates of screening coverage (WLHIV screened divided by WLHIV on ART aged ≥15 years), screen positivity (WLHIV screened positive divided by number screened), and treatment (WLHIV treated for precancerous lesions divided by number screened positive).

Results

The screening coverage improved from 1.4% (10,596 screened/731,572 WLHIV on ART) in October 2018–March 2019 to 36.2% (395,609/1,094,033) in March–September 2023. In the same period, screen positivity rates increased from 8.1% (861/10,596) to 10.9% (43,290/395,614), and treatment rates increased from 59.9% (516/861) to 94.0% (40,677/43,290).

Conclusion

Access to cervical cancer services has improved dramatically for a large population of WLHIV. With increased screening, more WLHIV with pre-cancerous lesions have been found and treated, averting morbidity and mortality due to cervical cancer. Quality improvement strategies may further improve service delivery as the program expands to reach all eligible WLHIV in Mozambique.
Knowledge, attitudes and practices relating to HIV self-testing following its introduction in the Bas-Sassandra region of Côte d’Ivoire: the case of the ATLAS project
Authors: Simo Fotso Arlette , Koukobo Christian , Silhol Romain , Kra Arsène Kouassi , Boily Marie-Claude , Vautier Anthony , Larmarange Joseph
Published: November 2024

Background

Awareness of HIV status is crucial for accessing HIV care and prevention but remains suboptimal in West Africa. The ATLAS initiative, launched in Côte d’Ivoire, Mali, and Senegal, addressed this gap by distributing approximately 380,000 HIV self-testing (HIVST) kits from 2019 to 2021, primarily to key populations and their social networks. This study assessed levels and correlates of Knowledge, Attitudes, and Practices (KAP) related to HIVST in the Bas-Sassandra region of Côte d’Ivoire following ATLAS’s introduction.

Method

A cross-sectional population-based survey was conducted in the Bas-Sassandra region in 2021 among individuals aged 15-49. Bivariate statistics and multivariable logistic regressions were used to assess KAP levels and the associated factors.

Results

Although few participants reported having heard about HIVST (11%) or having used it (3%), most of them reported that if it were freely available, they would be interested/very interested in using it for themselves (76%), as well as for their sexual partners (75%). Education and wealth were positively associated with knowledge and positive attitudes towards HIVST among both men and women, whereas age was positively correlated to knowledge and use of HIVST among men only. The number of sexual partners over the last 12 months was positively associated with knowledge of HIVST and willingness to use HIVST for themselves or their sexual partners among both sexes. We also found that high HIV-related knowledge and low levels of stigma were positively associated with positive attitudes towards HIVST, while exposure to the media appeared to be correlated to knowledge of HIVST.

Conclusion

The high level of positive attitudes towards HIVST calls for a scaling up of access to HIVST in the region. Specific attention to groups with the worst KAP, such as the less educated, the poor or groups that are highly stigmatised, could enhance the success of such initiatives.