bluuebunny/crossref_metadata_2025 huggingface dataset:
Disentangling the effects of hearing loss and age on amplitude modulation frequency selectivity
Authors: Regev Jonathan , Relaño-Iborra Helia , Zaar Johannes , Dau Torsten
Published: July 2023

The processing and perception of amplitude modulation (AM) in the auditory system reflect a frequency-selective process, often described as a modulation filterbank. Previous studies on perceptual AM masking reported similar results for older listeners with hearing impairment (HI) and young listeners with normal hearing (NH), suggesting no effects of age or hearing loss on AM frequency selectivity. However, recent evidence has shown that age, independently of hearing loss, adversely affects AM frequency selectivity. Hence, this study aimed to disentangle the effects of hearing loss and age. A simultaneous AM masking paradigm was employed, utilizing a sinusoidal carrier at 2.8 kHz, narrow-band noise modulation maskers, and target modulation frequencies of 4, 16, 64, and 128 Hz. The results obtained from young (n=3, 24-30 years) and older (n=10, 63-77 years) HI listeners were compared to previously obtained data from young and older NH listeners. Notably, the HI listeners generally exhibited lower (unmasked) AM detection thresholds and greater AM frequency selectivity than their NH counterparts in both age groups. Overall, the results suggest that age negatively affects AM frequency selectivity for both NH and HI listeners, while hearing loss improves AM detection and AM selectivity, likely due to the loss of peripheral compression.
EpiGePT: a Pretrained Transformer model for epigenomics
Authors: Gao Zijing , Liu Qiao , Zeng Wanwen , Jiang Rui , Wong Wing Hung
Published: July 2023

The inherent similarities between natural language and biological sequences have given rise to great interest in adapting the transformer-based large language models (LLMs) underlying recent breakthroughs in natural language processing (references), for applications in genomics. However, current LLMs for genomics suffer from several limitations such as the inability to include chromatin interactions in the training data, and the inability to make prediction in new cellular contexts not represented in the training data. To mitigate these problems, we propose EpiGePT, a transformer-based pretrained language model for predicting context-specific epigenomic signals and chromatin contacts. By taking the context-specific activities of transcription factors (TFs) and 3D genome interactions into consideration, EpiGePT offers wider applicability and deeper biological insights than models trained on DNA sequence only. In a series of experiments, EpiGePT demonstrates superior performance in a diverse set of epigenomic signals prediction tasks when compared to existing methods. In particular, our model enables cross-cell-type prediction of long-range interactions and offers insight on the functional impact of genetic variants under different cellular contexts. These new capabilities will enhance the usefulness of LLM in the study of gene regulatory mechanisms. We provide free online prediction service of EpiGePT throughhttp://health.tsinghua.edu.cn/epigept/.
Brain aromatase and its relationship with parental experience and behavior in male mice
Authors: Duarte-Guterman Paula , Skandalis Dimitri A. , Merkl Ariane , Geissler Diana B. , Ehret Günter
Published: July 2023

In most mammals, paternal care is not mandatory for raising offspring. In house mice, experience with pups governs the extent and quality of paternal care. First-time fathers undergo a dramatic transition from ignoring or killing pups to caring for pups. The behavioral shift occurs together with changes in brain estrogen signaling as indicated by changes in estrogen receptor presence and distribution in multiple areas regulating olfaction, emotion, and motivation. Here, we report changes in the expression of aromatase, the enzyme converting testosterone into estrogen, as an indirect measure of estrogen synthesis. The amount of paternal experience (5 or 27 days) was associated with increased numbers of immunocytochemically-identified aromatase expressing cells in the medial and cortical amygdala, posterior piriform cortex, and ventromedial hypothalamus. Functionally, these changes can be related to the disappearance of aggression or neglect towards pups when first-time fathers or, even more, well-experienced fathers are handling their own pups. In the lateral septum, the anterior piriform cortex and to some extent in the medial preoptic area, parental experience increased the number of aromatase-positive cells only in fathers with 27 days of experience, and only in the right hemisphere. This is a new case of brain-functional lateralization due to experience that has activated certain instinctive behavior. Nuclei/areas associated with maternal care (medial preoptic area, bed nucleus of stria terminalis, nucleus accumbens) exhibited a left-hemisphere advantage in aromatase expressing cells, both in pup-naïve and pup-experienced males. This newly found lateralization may contribute to the left-hemisphere dominant processing and perception of pup calls to release parental behavior. In general, the experience-dependent changes in aromatase expression we observed in most brain areas did not mirror the previously reported changes in estrogen receptors (ERα) when pup-naïve males became pup-caring fathers. Hence, paternal behavior may depend in a brain area-specific way on the differential action of estrogen through its receptors and/or direct local modulation of neural processing.
Contextual protein and antibody encodings from equivariant graph transformers
Authors: Mahajan Sai Pooja , Ruffolo Jeffrey A. , Gray Jeffrey J.
Published: July 2023

The optimal residue identity at each position in a protein is determined by its structural, evolutionary, and functional context. We seek to learn the representation space of the optimal amino-acid residue in different structural contexts in proteins. Inspired by masked language modeling (MLM), our training aims to transduce learning of amino-acid labels from non-masked residues to masked residues in their structural environments and from general (e.g., a residue in a protein) to specific contexts (e.g., a residue at the interface of a protein or antibody complex). Our results on native sequence recovery and forward folding with AlphaFold2 suggest that the amino acid label for a protein residue may be determined from its structural context alone (i.e., without knowledge of the sequence labels of surrounding residues). We further find that the sequence space sampled from our masked models recapitulate the evolutionary sequence neighborhood of the wildtype sequence. Remarkably, the sequences conditioned on highly plastic structures recapitulate the conformational flexibility encoded in the structures. Furthermore, maximum-likelihood interfaces designed with masked models recapitulate wildtype binding energies for a wide range of protein interfaces and binding strengths. We also propose and compare fine-tuning strategies to train models for designing CDR loops of antibodies in the structural context of the antibody-antigen interface by leveraging structural databases for proteins, antibodies (synthetic and experimental) and protein-protein complexes. We show that pretraining on more general contexts improves native sequence recovery for antibody CDR loops, especially for the hypervariable CDR H3, while fine-tuning helps to preserve patterns observed in special contexts.
Two Decades of Endemic Dengue in Bangladesh (2000-2022): Trends, Seasonality, and impact of Temperature and Rainfall Patterns on transmission dynamics
Authors: Hasan Mohammad Nayeem , Khalil Ibrahim , Chowdhury Muhammad Abdul Baker , Rahman Mahbubur , Asaduzzaman Md , Billah Masum , Banu Laila Arjuman , Alam Mahbub-ul , Ahsan Atik , Traore Tieble , Uddin Md. Jamal , Galizi Roberto , Russo Ilaria , Zumla Alimuddin , Haider Najmul
Published: July 2023

Background

The objectives of this study were to compare the dengue virus (DENV) infection, deaths, case-fatality ratio, as well as meteorological parameters between the first and and the recent decade (2000-2010 vs. 2011-2022) and to understand the trends, seasonality, and impact of change of temperature and rainfall pattern on transmission dynamics of Dengue in Bangladesh

Methods

For the period 2000-2022, dengue cases and death data from Bangladesh’s Ministry of Health and Family Welfare’s website, and meteorological data from the Bangladesh Meteorological Department were analyzed. Mann-Kendall and Sen’s slop tests were used for trends and variations and fitted a time series Poisson regression model to identify the impact of meteorological parameters on the incidence of dengue cases. A forecast of dengue cases was performed using an autoregressive integrated moving average model.

Results

Over the past 22 years, a total of 244,246 dengue cases were reported including 849 deaths (Case fatality ratio [CFR] =0.34%). The mean annual number of dengue cases increased eight-fold during the second decade, with 2216 cases during 2000-2011 vs. 18,321 during 2012-2022. The mean annual deaths have doubled (21 vs. 46) although the overall CFR had decreased to one-third (0.69 vs 0.24). Between the periods, the annual temperature increased by 0.49 °C, and rainfall decreased by 314 mm despite increasing unusual rainfall in the pre-and-post monsoon period. An increasing trend of dengue cases is observed with a much stiffer rise after 2018. Monthly mean temperature (Incidence risk ratio [IRR]: 1.26), first-lagged rainfall (IRR: 1.08), and second-lagged rainfall (IRR: 1.17) were significantly associated with monthly dengue incidence.

Conclusions

The increased local temperature and unusual rainfall might have contributed to the increased incidence of DENV infection in Bangladesh. Community engagement, vector control, and destruction of mosquito habitats are key to controlling dengue.
The historical fingerprint and future impact of climate change on childhood malaria in Africa
Authors: Carlson Colin J. , Carleton Tamma A. , Odoulami Romaric C. , Molitor Cullen D. , Trisos Christopher H.
Published: July 2023

Health-related risks from climate change are growing exponentially1, but direct attribution of health outcomes to human influence on the climate remains challenging2,3. Here, we leverage a comprehensive dataset of 50,425 population surveys4to investigate whether human-caused climate change has increased the burden of childhood malaria across sub-Saharan Africa. In historical data, we find that prevalence shows a robust response to temperature and extreme precipitation, consistent with expectations from previous empirical and epidemiological work. Comparing historical climate reconstructions to counterfactual simulations without anthropogenic climate forcings, we find two-to-one odds that human-caused climate change has increased the overall prevalence of childhood malaria across sub-Saharan Africa since 1901. We estimate that by 2014, human-caused climate change was responsible for an average of 87 excess cases of malaria per 100,000 children ages 2 to 10, with higher elevation and cooler regions in southern and east Africa experiencing greater increases. Under future climate change, we project that increasing temperatures could accelerate the elimination of malaria in west and central Africa, where the present-day burden is highest, with an average overall reduction of 94 (low greenhouse gas emissions, SSP1-RCP2.6) to 1,890 (high emissions, SSP5-RCP8.5) cases per 100,000 children in sub-Saharan Africa by the end of the century. However, we find that limiting future global warming to under 2°C (SSP1-RCP2.6) compared to 3°C (SSP2-RCP4.5) could prevent an average of 505 excess cases in southern Africa, and 33 excess cases in east Africa, per 100,000 children by 2100. Our study resolves a decades-old debate about one of the first suspected health impacts of climate change, and provides a template for future work measuring its true global burden.
Evaluation of the impact of COVID-19 pandemic on hospital admission related to common infections
Authors: Fahmi Ali , Palin Victoria , Zhong Xiaomin , Yang Ya-Ting , Watts Simon , Ashcroft Darren M , Goldacre Ben , Mackenna Brian , Fisher Louis , Massey Jon , Mehrkar Amir , Bacon Seb ,   OpenSAFELY collaborative, Hand Kieran , Staa Tjeerd Pieter van
Published: July 2023

Background

Antimicrobial resistance (AMR) is a multifaceted global challenge, partly driven by inappropriate antibiotic prescribing. The COVID-19 pandemic impacted antibiotic prescribing for common bacterial infections. This highlights the need to examine risk of hospital admissions related to common infections, excluding COVID-19 infections during the pandemic.

Methods

With the approval of NHS England, we accessed electronic health records from The Phoenix Partnership (TPP) through OpenSAFELY platform. We included patients with primary care diagnosis of common infections, including lower respiratory tract infection (LRTI), upper respiratory tract infections (URTI), and lower urinary tract infection (UTI), from January 2019 to August 2022. We excluded patients with a COVID-19 record 90 days before to 30 days after the infection diagnosis. Using Cox proportional-hazard regression models, we predicted risk of infection-related hospital admission in 30 days follow-up period after the diagnosis.

Results

We found 12,745,165 infection diagnoses from January 2019 to August 2022. Of them, 80,395 (2.05%) cases were admitted to hospital in the follow-up period. Counts of hospital admission for infections dropped during COVID-19, e.g., LRTI from 3,950 in December 2019 to 520 in April 2020. Comparing those prescribed an antibiotic to those without, reduction in risk of hospital admission were largest with LRTI (adjusted odds ratio (OR) of 0.35; 95% CI, 0.35-0.36) and UTI (adjusted OR 0.45; 95% CI, 0.44-0.46), compared to URTI (adjusted OR 1.04; 95% CI, 1.03-1.06).

Conclusion

Large effectiveness of antibiotics in preventing complications related to LRTI and UTI can support better targeting of antibiotics to patients with higher complication risks.

Key messages

- The main drivers of infection-related hospital admission are age, Charlson comorbidity index, and history of prior antibiotics.

- Antibiotics are more effective in preventing hospital admission related to infections such as lower respiratory tract infection and urinary tract infection, rather than upper respiratory tract infection.

- Common antibiotic types are associated with more reduction in the risk of infection-related hospital admission.
Perception of the consumption of legal and illegal substances in the Honduran population
Authors: Espinoza-Turcios Eleonora , Sosa-Mendoza Carlos Antonio , Zambrano Lysien Ivania , Castro Ramos Henry Noel , Armada José , Mejia Christian R.
Published: July 2023

Introduction

Substance use affects physical health, mental health, causes social, economic damage in their family environment and society. In recent decades this has changed.

Aim

To determine the perception of the consumption of legal and illegal substances and related factors in the general Honduran population.

Methodology

Analytical cross-sectional study, through an active search, the information was provided by a suitable informant ≥ 18 years of age, both sexes. Direct questions were asked about consumption, this was associated to influential variables, through descriptive and analytical statistics. Results: Of the 3309 participants distributed nationally, When multivariate analysis was performed, it was found that there was a greater perception of problematic drug use when there was a history of previous violence (aPR: 1.53; 95%CI: 1.22-1.92; p-value<0.001), if cannabis had been consumed in the last quarter (aPR: 1.29; 95%CI: 1.05-1.58; p-value=0.016), if she stopped doing what was expected (aPR : 7.05; 95%CI: 5.00-9.95; p-value<0.001) or if she worried a friend or family member (aPR: 1.49; 95%CI: 1.20-1.86; p-value<0.001), on the contrary, there was less concern among those with university studies (aPR: 0.70; 95%CI: 0.49-0.99; p-value=0.048), adjusted for six variables.

Discussion

An association was found between the perception of problematic substance use according to sex, academic grade, history of previous violence, use of tobacco, cannabis, cocaine, opioids, hallucinogens, whether the person stopped doing what was expected, whether a friend or relative was concerned, or whether the person injected.

Conclusion

The most reported legal substance of use among the Honduran population was tobacco, followed by marijuana and cocaine among illegal substances.
Inter-scanner Aβ-amyloid PET harmonization using barrel phantom spatial resolution matching
Authors: Ruwanpathirana Gihan P. , Williams Robert C. , Masters Colin L. , Rowe Christopher C. , Johnston Leigh A. , Davey Catherine E.
Published: July 2023

The standardized uptake value ratio (SUVR) is used to measure Aβ uptake in PET images of the brain. Variations in PET scanner technologies and image reconstruction techniques can lead to variability in images acquired from different scanners. This poses a challenge for Aβ-PET studies conducted across multiple centers. The aim of harmonization is to achieve consistent Aβ-PET measurements across scanners. In this study, the procedure of matching the spatial resolution of a barrel phantom measured in each PET scanner is proposed as a method of Aβ-PET harmonization, validated using subject data.

Methods

Three different PET scanners were used: the Siemens Biograph Vision 600, Siemens Biograph mCT, and Philips Gemini TF64. A total of five, eight, and five subjects were each scanned twice with [18F]-NAV4694 across Vision-mCT, mCT-Philips, and Vision-Philips scanner pairs. The Vision and mCT scans were reconstructed using various iterations, subsets, and post-reconstruction Gaussian smoothing, while one reconstruction configuration was used for the Philips scans. The full-width at half-maximum (FWHM) of each reconstruction configuration was calculated using [18F]-filled barrel phantom scans with the SNMMI phantom analysis toolkit. Regional SUVRs were calculated from 72 brain regions using the AAL3 atlas for each subject and reconstruction configuration. Statistical similarity between SUVRs was assessed using paired (within subject) t-tests for each pair of reconstructions across scanners; the higher the p-value, the greater the similarity between the SUVRs.

Results

Vision-mCT harmonization

maximal statistical similarity (i.e.,p-value) between regional SUVRs was achieved using a 4.10 mm FWHM Vision reconstruction with a 4.30 mm FWHM mCT reconstruction.

Philips-mCT harmonization

maximal statistical similarity between regional SUVRs was achieved using an 8.2 mm FWHM Philips reconstruction with a 9.35 mm FWHM mCT reconstruction.

Philips-Vision harmonization

a 9.1 mm FWHM Vision reconstruction had maximum statistical similarity with regional SUVRs from an 8.2mm FWHM Philips reconstruction. Reconstruction pairs that maximized statistical similarity, and supported a null hypothesis of being drawn from the same distribution, were selected as harmonised for each scanner pair.

Conclusion

Using data obtained from three sets of participants, each scanned on a different pair of PET scanners, using reconstruction configurations with matched barrel phantom spatial resolutions, we have demonstrated that Aβ-PET quantitation can be harmonised across scanners, producing SUVR values statistically likely to be drawn from the same distribution. This finding is encouraging for the use of different PET scanners in multi-centre trials, or updates during longitudinal studies.
A binding site for phosphoinositides described by multiscale simulations explains their modulation of voltage gated sodium channels
Authors: Lin Yiechang , Tao Elaine , Champion James P , Corry Ben
Published: July 2023

Voltage gated sodium channels (Nav) are membrane proteins which open to facilitate the inward flux of sodium ions into excitable cells. In response to stimuli, Navchannels transition from the resting, closed state to an open, conductive state, before rapidly inactivating. Dysregulation of this functional cycle due to mutations causes diseases including epilepsy, pain conditions and cardiac disorders, making Navchannels a significant pharmacological target. Phosphoinositides are important lipid cofactors for ion channel function. The phosphoinositide PI(4,5)P2decreases Nav1.4 activity by increasing the difficulty of channel opening, accelerating fast inactivation and slowing recovery from fast inactivation. Using multiscale molecular dynamics simulations, we show that PI(4,5)P2binds stably to inactivated Navat a conserved site within the DIV S4-S5 linker, which couples the voltage sensing domain (VSD) to the pore. As the Nav C-terminal domain is proposed to also bind here during recovery from inactivation, we hypothesise that PI(4,5)P2prolongs inactivation by competitively binding to this site. In atomistic simulations, PI(4,5)P2reduces the mobility of both the DIV S4-S5 linker and the DIII-IV linker, responsible for fast inactivation, slowing the conformational changes required for the channel to recover to the resting state. We further show that in a resting state Navmodel, phosphoinositides bind to VSD gating charges, which may anchor them and impede VSD activation. Our results provide a mechanism by which phosphoinositides alter the voltage dependence of activation and the rate of recovery from inactivation, an important step for the development of novel therapies to treat Nav-related diseases.

Significance

Voltage-gated sodium channels form pores in the membrane to mediate electrical activity in nerve and muscle cells. They play critical roles throughout the human body and their dysfunction leads to diseases including epilepsy, cardiac arrhythmias and pain disorders. Membrane lipids called phosphoinositides have recently been shown to reduce the activity of a voltage-gated sodium channel, but the molecular basis of this mechanism is not known. Here we use simulations to reveal where these lipids bind to the channels and how they reduce channel activity by making it harder for the pores to open and slower to subsequently recover to the closed resting state.
A monochromatically excitable green-red dual-fluorophore fusion incorporating a new large Stokes shift fluorescent protein
Authors: Ejike J. Obinna , Sadoine Mayuri , Shen Yi , Ishikawa Yuuma , Sunal Erdem , Hänsch Sebastian , Hamacher Anna B. , Frommer Wolf B. , Wudick Michael M. , Campbell Robert E. , Kleist Thomas J.
Published: July 2023

Genetically encoded sensors enable quantitative imaging of analytes in live cells. State-of-the-art sensors are commonly constructed by combining ligand-binding domains with one or more sensitized fluorescent protein (FP) domains. Sensors based on a single FP are susceptible to artifacts caused by differing expression levels or sensor distributionin vivo. Hence, our lab developed dual-FP Matryoshka technology introduced by a single cassette that contains a stable large Stokes shift (LSS) reference FP nested within a reporter FP (cpEGFP), allowing simple construction of intensiometric sensors with the capacity for ratiometric quantification. The first-generation Green-Orange (GO) Matryoshka cassette established proof of concept but required custom optical setups to maximize achievable dynamic range. Here, we present a genetically encoded calcium sensor that employs optimized second-generation Green-Apple (GA) Matryoshka technology that incorporates a newly designed red LSSmApple fluorophore. LSSmApple provides improved excitation spectrum overlap with cpEGFP, allowing for monochromatic co-excitation with blue light. The exceptionally large Stokes shift of LSSmApple results in improved emission spectrum separation from cpEGFP, which minimizes fluorophore bleed-through and facilitates imaging using standard dichroics and red fluorescent protein (RFP) emission filters. We developed an image analysis pipeline for yeast (Saccharomyces cerevisiae) timelapse imaging that utilizes LSSmApple to segment and track cells for high-throughput quantitative analysis. In summary, we engineered a new fluorescent protein, constructed a genetically encoded calcium indicator (GA-MatryoshCaMP6s), and performed calcium imaging in yeast as a demonstration.
Reactivating and Reorganizing Activity-Silent Working Memory Through Two Distinct Mechanisms After Pinging the Brain
Authors: Yang Can , He Xianhui , Cai Ying
Published: July 2023

Recent studies have proposed that visual information can be maintained in an activity-silent state during working memory (WM), which can be reactivated by task-irrelevant high-contrast visual impulses (i.e., “pinging the brain”). Although pinging the brain has become a popular tool for exploring activity-silent WM in recent years, its underlying mechanisms remain unclear. In the current study, we directly compared the behavioral consequences and neural reactivation effects of context-independent and context-dependent pings to distinguish the noise-reduction and target-interaction hypotheses of pinging the brain. At first, in a behavioral study, we found that, compared with the baseline condition (no ping), only the horizontal context-dependent pings impaired recall performance. In a follow-up electroencephalogram study, our neural decoding results showed that the context-independent pings reactivated activity-silent WM transiently without changing the original WM representations or recall performance. In contrast, the context-dependent pings reactivated activity-silent WM more durably and further reorganized WM information by decreasing the dynamics of items’ neural representations. Notably, only the reactivation strength of the context-dependent pings correlated with recall performance and was modulated by the location of memorized items, with neural representations only being reactivated when both items and pings were presented horizontally. Together, our results provided evidence for two distinct mechanisms underlying pinging the brain, and the ping’s context played a critical role in reactivating and reorganizing activity-silent WM.
One session of prism adaptation training does not increase immediate engagement in occupational therapy in people with spatial neglect early after stroke: a proof-of-concept study nested within a phase II RCT
Authors: Checketts Matthew , Turton Ailie , Woodward-Nutt Kate , Longley Verity , Stocking Katie , Vail Andy , Bamford Ann , Bowen Audrey
Published: July 2023

Objectives

Spatial neglect, a debilitating cognitive syndrome and predictor of poor functional outcome, affects attention and awareness after stroke. Early rehabilitation is essential but neglect itself may impede participation in therapy. In a proof-of-concept study nested within an RCT, we investigated whether the oft-reported immediate effects of prism adaptation training (PAT) might enable engagement if introduced at the start of an occupational therapy session.

Methods

Early after stroke we video-recorded in-patients carrying out a standardised activity in their first RCT occupational therapy session, before and after PAT (or a control therapy activity). Level of engagement was later scored by a video-rater, experienced in therapy, blind to arm allocation (intervention/control) and whether randomly presented videos were recorded pre-or post-therapy. The rater recorded engagement scores on a 100mm visual analogue scale. Treating therapists also reported, on a 3-point Likert scale, whether or not engagement changed.

Results

49 of the RCT’s 53 patients were recruited (37 PAT, 12 control), 43 of whom consented to be video-recorded. Regression analysis did not suggest improvement in engagement following one session of PAT, using the blinded expert video scoring method: mean difference (95% CI) = −0.5 (−7.4 to 6.4) mm;p=0.89). Similarly, post-hoc re-rating of engagement scores (the video-rater viewed paired pre- and post-therapy recordings but remained blind to arm allocation) excluded any material difference in engagement following PAT: mean difference (95% CI) = 1.2 (−2.5 to 4.9) mm;p=.52). Impressions of level of engagement provided by the treating occupational therapists also suggested no change: OR (95% CI) = 1.3 (0.13 to 13);p=0.81).

Conclusions

Despite the need to enable neglect patients to engage in the therapy they are offered, we are confident that a single session of PAT at the start of a therapy session does not enhance immediate engagement in occupational therapy early after stroke. Our study does not address the alternative definition of engagement as a longitudinal, rapport-building process which could meaningfully be explored.
A zebrafish knock-in reporter line for the Foxo1a transcription factor
Authors: Suñer Inés Garteizgogeascoa , Singh Sumeet Pal
Published: July 2023

Zebrafish is a powerful model organism for in vivo live imaging. However, protein visualization relies to this date on the overexpression of fluorescently tagged proteins from a specific promoter which very often does not recapitulate endogenous patterns of expression and dynamics. Tagging proteins in the endogenous locus is not widely used in the field due to its technical inefficiency and difficulty. Here we developed a knock-in reporter line for the Foxo1a transcription factor by inserting an EGFP-pA cassette in frame at the C-terminal generating a fusion protein. Foxo1a has been involved in the regulation of many biological processes regarding metabolism, stress response, longevity, cell differentiation and others and its functions are conserved from invertebrates to vertebrates. Using in-vivo live imaging at early developmental stages, we validated the expression in the cardiovascular network, CNS, olfactory epithelium, spinal cord, retina, skeletal muscle, and myocardium. Our line opens the way for imaging studies aiming to characterize the expression and localization of this transcription factor in a tissue and context specific manner. Also, the knock-in line can be used in combination with other modern techniques to determine the transcriptional targets of Foxo1a, many of which remain unknown.
A 7T interleaved fMRS and fMRI study on visual contrast dependency in the human brain
Authors: Schrantee Anouk , Najac Chloe , Jungerius Chris , van der Zwaag Wietske , Jbabdi Saad , Clarke William T , Ronen Itamar
Published: July 2023

Introductions

Functional magnetic resonance spectroscopy (fMRS) is a non-invasive technique for measuring dynamic changes in neurometabolites. While previous studies have observed concentration changes in metabolites during neural activation, the relationship between neurometabolite response and stimulus intensity and timing requires further investigation. To address this, we conducted an interleaved fMRS and functional magnetic resonance imaging (fMRI) experiment using a visual stimulus with varying contrast levels.

Methods

A total of 20 datasets were acquired on a 7T MRI scanner. The visual task consisted of two STIM blocks (30s/20s ON/OFF, four minutes), with 10% or 100% contrast, interleaved with a four minutes REST block. A dynamic fitting approach was used for fMRS data analysis. For metabolite level changes, the STIM conditions were modeled in two different ways: either considering the full STIM block as active condition (full-block model) or only modeling the ON blocks as active condition (sub-block model). For linewidth changes due to the BOLD effect, STIM conditions were modeled using the sub-block model.

Results

For both models, we observed significant increases in glutamate levels for both the 10% and 100% visual contrasts, but no significant difference between the contrasts. Decreases in aspartate, and glucose, and increases in total N-acetylaspartate and total creatine were also detected, although less consistently across both 10% and 100% visual contrasts. BOLD-driven linewidth decreases and fMRI-derived BOLD increases within the MRS voxel were observed at both 10% and 100% contrasts, with larger changes at 100% compared to 10% in the fMRI-derived BOLD only. We observed a non-linear relation between visual contrast, the BOLD response, and the glutamate response.

Conclusion

Our study highlights the potential of fMRS as a complementary technique to BOLD fMRI for investigating the complex interplay between visual contrast, neural activity, and neurometabolism. Future studies should further explore the temporal response profiles of different neurometabolites and refine the statistical models used for fMRS analysis.
ReprogrammingYarrowia lipolyticametabolism for efficient synthesis of itaconic acid from flask to semi-pilot scale
Authors: Fu Jing , Zaghen Simone , Lu Hongzhong , Konzock Oliver , Poorinmohammad Naghmeh , Kornberg Alexander , Koseto Deni , Wentzel Alexander , Di Bartolomeo Francesca , Kerkhoven Eduard J
Published: July 2023

Itaconic acid is an emerging platform chemical with extensive applications. It is currently produced byAspergillus terreusthrough biological fermentation. However,A. terreusis a fungal pathogen and needs additional morphology controls, and therefore the production remains problematic. Here, we reprogrammed the GRAS yeastYarrowia lipolyticametabolism for competitive itaconic acid production. After redirecting the flux of lipid accumulation as carbon sink, we evaluated itaconic acid production both inside and outside the mitochondria, and fine modulated its synthetic pathway. We then mimicked the regulation of nitrogen limitation in nitrogen replete conditions through down regulation of IDH by weak promoter changing, RNAi, or CRISPRi. Ultimately, we optimized fermentation parameters for fed-batch cultivations, and produced itaconic acid with titres of 130.1 g/L in 1L bioreactors and 94.8 g/L in a 50L bioreactor on semi-pilot scale. Our finds provide effective approaches for harnessing GRAS microorganism for competitive industrial itaconic acid production.
Simultaneous multi-site editing of individual genomes using retron arrays
Authors: González-Delgado Alejandro , Lopez Santiago C. , Rojas-Montero Matías , Fishman Chloe B. , Shipman Seth L.
Published: July 2023

Our understanding of genomics is limited by the scale of our genomic technologies. While libraries of genomic manipulations scaffolded on CRISPR gRNAs have been transformative, these existing approaches are typically multiplexed across genomes. Yet much of the complexity of real genomes is encoded within a genome across sites. Unfortunately, building cells with multiple, non-adjacent precise mutations remains a laborious cycle of editing, isolating an edited cell, and editing again. Here, we describe a technology for precisely modifying multiple sites on a single genome simultaneously. This technology – termed a multitron – is built from a heavily modified retron, in which multiple donor-encoding msds are produced from a single transcript. The multitron architecture is compatible with both recombineering in prokaryotic cells and CRISPR editing in eukaryotic cells. We demonstrate applications for this approach in molecular recording, genetic element minimization, and metabolic engineering.
Evaluating evidence for co-geography in theAnopheles-Plasmodiumhost-parasite system
Authors: Rehmann Clara T. , Ralph Peter L. , Kern Andrew D.
Published: July 2023

The often tight association between parasites and their hosts means that under certain scenarios, the evolutionary histories of the two species can become closely coupled both through time and across space. Using spatial genetic inference, we identify a potential signal of common dispersal patterns in theAnopheles gambiaeandPlasmodium falciparumhost-parasite system as seen through a between-species correlation of the differences between geographic sampling location and geographic location predicted from the genome. This correlation may be due to coupled dispersal dynamics between host and parasite, but may also reflect statistical artifacts due to uneven spatial distribution of sampling locations. Using continuous-space population genetics simulations, we investigate the degree to which uneven distribution of sampling locations leads to bias in prediction of spatial location from genetic data and implement methods to counter this effect. We demonstrate that while algorithmic bias presents a problem in inference from spatio-genetic data, the correlation structure betweenA. gambiaeandP. falciparumpredictions cannot be attributed to spatial bias alone, and is thus likely a genetic signal of co-dispersal in a host-parasite system.
Loss of epigenetic suppression of retrotransposons with oncogenic potential in aging mammary luminal epithelial cells
Authors: Senapati Parijat , Miyano Masaru , Sayaman Rosalyn W. , Basam Mudaser , Leung Amy , LaBarge Mark A. , Schones Dustin E.
Published: July 2023

A primary function of DNA methylation in mammalian genomes is to repress transposable elements (TEs). The widespread methylation loss that is commonly observed in cancer cells results in the loss of epigenetic repression of TEs. The aging process is similarly characterized by changes to the methylome. However, the impact of these epigenomic alterations on TE silencing and the functional consequences of this have remained unclear. To assess the epigenetic regulation of TEs in aging, we profiled DNA methylation in human mammary luminal epithelial cells (LEps)—a key cell lineage implicated in age-related breast cancers—from younger and older women. We report here that several TE subfamilies function as regulatory elements in normal LEps, and a subset of these display consistent methylation changes with age. Methylation changes at these TEs occurred at lineage-specific transcription factor binding sites, consistent with loss of lineage specificity. Whereas TEs mainly showed methylation loss, CpG islands (CGIs) that are targets of the Polycomb repressive complex 2 (PRC2) show a gain of methylation in aging cells. Many TEs with methylation loss in aging LEps have evidence of regulatory activity in breast cancer samples. We furthermore show that methylation changes at TEs impact the regulation of genes associated with luminal breast cancers. These results indicate that aging leads to DNA methylation changes at TEs that undermine the maintenance of lineage specificity, potentially increasing susceptibility to breast cancer.
Organizational cybersecurity readiness in the ICT sector: a quanti-qualitative assessment
Authors: Neri Martina , Niccolini Federico , Martino Luigi
Published: July 2023

Purpose

Cyberattacks are becoming increasingly widespread, and cybersecurity is therefore increasingly important. Although the technological aspects of cybersecurity are its best-known characteristics, the cybersecurity phenomenon goes beyond the detection of technological impacts, and encompasses all the dimensions of an organization. This study thus focusses on an additional set of organizational elements. The key elements of cybersecurity organizational readiness depicted here are cybersecurity awareness, cybersecurity culture and cybersecurity organizational resilience (OR). This study aims to qualitatively assess small and medium enterprises’ (SMEs) overall level of organizational cybersecurity readiness.

Design/methodology/approach

This study focused on conducting a cybersecurity organizational readiness assessment using a sample of 53 Italian SMEs from the information and communication technology sector. Informed mixed method research, this study was conducted consistent with the principles of the explanatory sequential mixed method design, and adopting a quanti-qualitative methodology. The quantitative data were collected through a questionnaire. Qualitative data were subsequently collected through semi-structured interviews.

Findings

Although many elements of the technical aspects of cybersecurity OR have yielded very encouraging results, there are still some areas that require improvement. These include those facets that constitute the foundation of cybersecurity awareness, and, thus, a cybersecurity culture. This result highlights that the areas in need of improvement are exactly those that are most important in fighting against cyber threats via organizational cybersecurity readiness.

Originality/value

Although the importance of SMEs is obvious, evidence of such organizations’ attitudes to cybersecurity are still limited. This research is an attempt to depict the organizational issue related to cybersecurity, i.e. overall cybersecurity organizational readiness.
Finding post-colonial identity through vernacular and climate responsive adaptations: the architecture of Bangladesh from 1947 to 1971
Authors: Ahmed Iftekhar , Khan Tanjina
Published: July 2023

Purpose

Fresh out of the two-century-old British legacy, Bangladesh, formerly known as East Pakistan from 1947 to 1971, was searching for a post-colonial architectural style. Colonial architecture in the region in general often imposed imported European elements, ignoring the preceding legacies of the Sultanate and the Mughals. The critical challenge was to find a balance between the prevailing high modernism in architecture and the local vernacular and climatic forces. The Pakistani government invited international architects to fill the gap left by a non-existent local architectural industry. Unfortunately, their work has rarely been properly analyzed. With selected case studies, this paper analyzes their work in an attempt to explore their contribution to creating a national architectural identity.

Design/methodology/approach

This study uses a case study approach with selected architectural projects from the period. It uses research tools such as systematic analysis of drawings, volumes and photographs and archival research.

Findings

The international architects took inspiration from the strong vernacular and climatic forces of the region. The resultant expressions of the two-decade-long search in their combined body of work are some of the finest examples of vernacular and climate-responsive architecture in the region. They transcended the regular international style and became context-specific and unique. The quest for East Pakistan's post-colonial architectural identity was partially met by the newly found identity through vernacular and climate-responsive adaptation in architecture.

Originality/value

This study explores how a unified vernacular and climate-responsive adaptations potentially shaped the post-colonial architectural identity of the region. No prior study exists on this issue for the time period.
CATS: A high‐performance software framework for simulating plant migration in changing environments
Authors: Gattringer Andreas , Wessely Johannes , Hülber Karl , Moser Dietmar , Dullinger Stefan
Published: July 2023

Considering local population dynamics and dispersal is crucial to project species' range adaptations in changing environments. Dynamic models including these processes are highly computer intensive, with consequent restrictions on spatial extent and/or resolution.

We present CATS, an open‐source, extensible modelling framework for simulating spatially and temporarily explicit population dynamics of plants. It can be used in conjunction with species distribution models, or via direct parametrisation of vital rates and allows for fine‐grained control over the demographic and dispersal processes' models.

The performance and flexibility of CATS is exemplified (i) by modelling the range shift of four plant species under three future climate scenarios across Europe at a spatial resolution of 100 m., and (ii) by exploring consequences of demographic compensation for range expansion on artificial landscapes.

The presented software attempts to leverage the availability of computational resources and lower the barrier of entry for large‐extent, fine‐resolution simulations of plant range shifts in changing environments.
Consultation is the new C‐word
Authors: Stolte Gretchen
Published: July 2023

The neoliberal turn has had significant impacts across Australian universities and First Nations communities, especially since the emergence of the global pandemic. These developments have highlighted the inherent flaws of the consultation process in developing programs and policies. Here, the weaknesses of the consultation process are analyzed using an anti‐politics framework together with two comparative case studies. The first case study concerns the consultation process that Australian universities conducted after the global pandemic, and the second case study pertains to consultation processes commonly experienced by First Nation communities with mining companies and museums. The weaknesses of these processes have been understood by First Nations communities for generations, but they are only recently coming to light in mainstream thinking. It is time to recognize consultation as a failed system and to start calling for collaboration and accountability.
Is social media use for math learning beneficial for ethnic minority students' math identity? A socialization perspective
Authors: Hu Xiang , Zuo Haode , Lai Chun , Zhu Gaoxia , Guo Jiesi , Tan Huiling
Published: July 2023

Although the educational potential of social media has been widely acknowledged, it remains unclear whether social media use might present opportunities for the development of math identity. This study drew on the socialization framework of math identity to examine the relationships between social media use for math learning, bicultural identity integration, ethnic‐math beliefs and math identity among ethnic minority high school students in China. Structural equation modelling results showed that (a) social media use was positively related to math identity; (b) high bicultural identity integration was positively associated with math identity, while biased ethnic‐math beliefs were negatively related to math identity and (c) social media use suppressed the socialization process of math identity, weakening the maladaptive roles of low bicultural identity integration and biased ethnic‐math beliefs in shaping math identity. Our findings highlight the beneficial role of social media use in student math learning. Theoretical and practical implications are discussed.

Practitioner notes

What is already known about this topic

Social media use for learning is associated with students' academic motivation, engagement and academic achievement.

Social media use may have affordances for identity development, especially for ethnic minorities.

The formation of ethnic minority students' math identity is intertwined with their math and ethnic socialization.

What this paper adds

Social media use for math learning was directly and positively related to ethnic minorities' math identity.

This study quantitatively confirmed the associations of bicultural identity integration and ethnic‐math beliefs with math identity.

Social media use suppressed the relations of bicultural identity integration and ethnic‐math beliefs with math identity.

Implications for practice and/or policy

Promoting social media use for math learning benefits ethnic minority students' math identity.

Social media use for math learning could alleviate the maladaptive role of low bicultural identity integration and biased ethnic‐math beliefs in math identity development.

Ethnic minority students' math identity socialization processes merit attention.