bluuebunny/crossref_metadata_2025 huggingface dataset:
Children and Pedometers: A Study in Reactivity and Knowledge
Authors: Prewitt Steven L. , Hannon James C. , Brusseau Timothy A.
Published: September 2024

Pedometers are simple inexpensive tools that are widely used for the measurement of physical activity. Reactivity is always a concern when using pedometers. An issue not yet addressed is the role previous knowledge has on the impact of reactivity. The primary purpose of this study was to examine if reactivity exists in 4th-6th grade students and if prior knowledge about pedometers had an effect on reactivity. Participants included 109 (54 females) 4th- 6th grade students from a suburban charter school. Prior to data collection, students completed a questionnaire to measure their knowledge of pedometers. Pedometers were worn from after-school until before school each day for two weeks with half of the students wearing sealed devices the first week, then switching to unsealed. Steps were counted and pedometers were redistributed each afternoon. Repeated measures ANOVA results showed no significant differences in step counts between unsealed and sealed conditions, or when knowledge and experience regarding pedometers was included as a covariate. Pedometers are inexpensive and reliable tools that researchers and educators can use to measure physical activity. In this study reactivity did not occur with older elementary students and a student’s knowledge of pedometers did not affect reactivity.
The Impact of Smart Work Environment on Working Moms' Job Performance: Dual Mediating Effects of Job Autonomy and Job Satisfaction
Authors:   Korean Health & Behavior Analysis Association, An Yejin , Park Junseong , Jung Taeyun
Published: September 2024

This study aimed to empirically confirm the dual mediating effects of job autonomy and job satisfaction in the relationship between the smart work environment of working moms and their job performance. To validate these research questions, a survey was conducted with 200 working moms aged 20 to 50, residing nationwide and raising children while employed. The data collected were analyzed using SPSS 28.0 and SPSS PROCESS Macro(v4.2). The results of the analysis are as follows: First, a significant positive influence was confirmed among the smart work environment, job autonomy, job satisfaction, and job performance. Second, it was found that job autonomy significantly mediated the impact of the smart work environment on job performance. Third, job satisfaction was also found to be a significant mediator in the relationship between the smart work environment and job performance. The sequential mediating effects of job autonomy and job satisfaction in the impact of the smart work environment on job performance were confirmed as significant. Based on the results of the study, the implications of this study were discussed.
Pain KAP Study - Assessment of Knowledge, Attitude and Practice in Cancer Pain Management in North India
Authors: Shirsath K  , Bangar N  , Mossarat S  , Valame S  , Kumar R  , Yelne V  , KD Datta , Singhal M  , Gaikwad U
Published: September 2024

Background: Pain management is critical in the everyday job of healthcare professionals who encounter patients who are in pain on a regular basis. To provide efficient pain treatment, these healthcare professionals must acquire extensive training and have a solid grasp of cancer-related pain. Regrettably, adherence to the World Health Organization's (WHO) treatment recommendations is frequently poor. Our research aims to analyze cancer patients' pain management understanding and practices, as well as medical oncologists' attitudes, knowledge, and practices in the context of pain treatment. Methodology: The study involved the distribution of pain management tool questionnaires to oncologists (Consultant Oncologists, senior registrars) during their outpatient department (OPD) visits. The questionnaire comprised a total of 27 questions, which were a mix of multiple-choice and short-answer format. Results: Despite the fact that many oncologists are acquainted with the WHO pain ladder and grading system, barely half of them use it on a regular basis. Only a few oncologists are knowledgeable with opioid dose, maximum dosage, and conversion formulas, while the others are only vaguely acquainted. In terms of hospital resources, the majority of oncologists have access to a pain management team; however, only a few of them engage with this team on a regular basis, and the vast majority never involve the pain management team in patient care choices. Conclusion: Our findings indicate a lack of both knowledge and training in pain treatment. Because good pain management is a vital component of successful cancer therapy, we believe that pain management training should be prioritized within the oncology curriculum
Evaluación del empleo de estacas de madera como puntos de atracción para la liebre europea Lepus europaeus Pallas, 1778 en Navarra
Authors: Fernández Alfonso , Soriguer Ramón C.
Published: September 2024

Se ha estudiado el uso que hacen las liebres europeas Lepus europaeus de puntos de atracción colocados en sus áreas de campeo en el valle de Atez, Navarra, así como el patrón anual de deposición de excrementos en la zona. Los puntos de atracción consistieron en estacas de madera. Las densidades de excrementos en las parcelas marcadas con estacas fueron estadísticamente superiores a las densidades en parcelas no marcadas. Este uso parece estar relacionado con un comportamiento social de marcaje del territorio. El patrón de variación de la abundancia de excrementos a lo largo del año presentó una oscilación muy marcada con valores máximos en el periodo estival. Finalmente se discute el empleo de esta metodología para llevar a cabo trabajos de distribución y estimaciones de abundancia en áreas de baja densidad de liebres.
Robustness paradox of cascading dynamics in interdependent networks
Authors: Wang Jian-Wei , Zhao Nai-Xuan , Wang Chu-Pei , Xiang Ling-Hui , Wen Ting-Xin ,   School of Business Administration, Liaoning Technical University, Huludao 125105, China,   School of Business Administration, Northeastern University, Shenyang 110167, China
Published: September 2024

Cascading failure process in interdependent networks has always been an important field of network cascading analysis. Unlike the previous studies, we take people’s demand for minimizing travel costs into consideration in this article and propose a network dynamics model based on the cost constraint. On this basis, we pay attention to the characteristics of different layers in the interdependent network, and taking the real-world traffic network for example, we define different load propagation modes for different layers. Then, we carry out the simulation experiment on cascade failure in the artificial network. By changing the structure of the network and the parameters in the model, such as the capability value of the network side and the connectivity of the network, we are able to focus on the effects of traditional protection strategies during the simulation and obtain some interesting conclusions. It is generally believed that increasing the quantity of connections in the network or improving the quality of edges will enhance the network robustness effectively. However, our experimental results show that these methods may actually reduce network robustness in some cases. On the one hand, we find that the resurrection of some special edges in the network is the main reason for the capacity paradox, as these edges will destroy the stable structure of the original network. On the other hand, neither improving the internal connectivity of a single-layer network nor enhancing the coupling strength between interdependent networks will effectively improve network robustness. This is because as the number of edges increases, some critical edges may appear in the network, attracting a large amount of the network load and leading the network robustness to decrease. These conclusions remind us that blindly investing resources in network construction cannot achieve the best protection effect. Only by scientifically designing the network structures and allocating network resources reasonably can the network robustness be effectively improved.
Studying near-field propagation of generalized parabolic beams by virtual source method
Authors: Li Jia-Ning , Liu Wen , Ren Zhi-Jun ,   Key Laboratory of Optical Information Detecting and Display Technology, Zhejiang Normal University, Jinhua 321004, China
Published: September 2024

Generalized parabolic beams have various optical morphologies. They can be used in different research fields, such as component design, aero-optics, and microwave wireless power transmission. Studying the near-field transmission characteristics of these beams is important for improving utilization efficiency. We develop a more accurate theoretical framework to precisely understand the propagation behaviors of complex light fields in the near-field range, especially to break through the limitations of conventional near-axis approximation. This framework fully reveals the propagation mechanism of parabolic beams and their energy transmission modes. Here, based on the principle of independent propagation and the virtual source method, a group of virtual sources are introduced to analyze generalized parabolic beams. These beams can be expanded into the superposition of infinite continuous integer Bessel beams. Then, by combining the Weber integral formula and the Fourier Bessel transform, we rigorously derive an integral expression for generalized parabolic beams during near-field propagation. This expression breaks through the limitation of the traditional paraxial approximation and contains all the key propagation parameters of the family of beams. Based on this integral expression, the intensity distribution and phase characteristics of the generalized parabolic beam along the optical axis are further calculated and analyzed to reveal its energy transfer mode and phase characteristics. By comparing the paraxial approximate solution with the nonparaxial corrected solution for generalized parabolic beams, the far-field propagation of generalized parabolic beams is found to be the same when the propagation distance is sufficiently long. Such simulation results indirectly confirm the correctness of the obtained theoretical solution. The simple paraxial approximation theory can be used conveniently to calculate the far-field propagation of generalized parabolic beams. However, large errors exist when paraxial theory is used to calculate the near-field distribution of generalized parabolic beams. Although calculating nonparaxial propagation is especially complex, the nonparaxial correction solution is necessary when generalized parabolic beams are used in near-field research. Such research results not only deepen the understanding of the propagation mechanism of generalized parabolic beams but also lay a theoretical foundation for studying the precise propagation behaviors of other complex light fields in near-field optics.
NMDA receptor antagonist memantine selectively affects recurrent processing during perceptual inference
Authors: Noorman Samuel , Stein Timo , Zantvoord Jasper , Fahrenfort Johannes J , van Gaal Simon
Published: September 2024

Perceptual inference requires the integration of visual features through recurrent processing, the dynamic exchange of information between higher and lower level cortical regions. While animal research has demonstrated a crucial role of NMDA receptors in recurrent processing, establishing a causal link between NMDA-mediated recurrent processing and human perception has remained challenging. Here, we report two pharmacological studies with randomized, double-blind, crossover designs in which we administered the NMDA antagonist memantine, while collecting human electroencephalography (EEG). We trained and tested EEG classiﬁers to reflect the processing of speciﬁc stimulus features with increasing levels of complexity, namely differences in stimulus contrast, collinearity between local line elements, and illusory surfaces of a Kanizsa triangle. In two experiments involving different participants and visual tasks, we found that memantine selectively affected decoding of the Kanizsa illusion, known to depend on recurrent processing, while leaving decoding of contrast and collinearity largely unaffected. Interestingly, the results from an attentional blink (experiment 1) and task-relevance manipulation (experiment 2) showed that memantine was only effective when the stimulus was attended and consciously accessed. These ﬁndings demonstrate that NMDA inhibition selectively affects recurrent processing, especially for attended objects, and thereby provide a crucial step toward bridging animal and human research, shedding light on the neural mechanisms underpinning perceptual inference and conscious perception.
Stabilization of GTSE1 by cyclin D1-CDK4/6 promotes cell proliferation: relevance in cancer prognosis
Authors: García-Vázquez Nelson , González-Robles Tania J , Lane Ethan , Spasskaya Daria , Zhang Qingyue , Kerzhnerman Marc , Jeong YeonTae , Collu Marta , Simoneschi Daniele , Ruggles Kelly V , Rona Gergely , Pagano Michele , Kaisari Sharon
Published: September 2024

Cyclin D1 is the activating subunit of the cell cycle kinases CDK4 and CDK6, and its dysregulation is a well-known oncogenic driver in many human cancers. The biological function of cyclin D1 has been primarily studied by focusing on the phosphorylation of the retinoblastoma (RB) gene product. Here, using an integrative approach combining bioinformatic analyses and biochemical experiments, we show that GTSE1 (G2 and S phases expressed protein 1), a protein positively regulating cell cycle progression, is a previously unknown substrate of cyclin D1-CDK4/6. The phosphorylation of GTSE1 mediated by cyclin D1-CDK4/6 inhibits GTSE1 degradation, leading to high levels of GTSE1 also during the G1 phase of the cell cycle. Functionally, the phosphorylation of GTSE1 promotes cellular proliferation and is associated with poor prognosis within a pan-cancer cohort. Our findings provide insights into cyclin D1’s role in cell cycle control and oncogenesis beyond RB phosphorylation.
Ultraslow serotonin oscillations in the hippocampus delineate substates across NREM and waking
Authors: Cooper Claire , Parthier Daniel , Sibille Jérémie , Tukker John , Tritsch Nicolas X , Schmitz Dietmar
Published: September 2024

Beyond the vast array of functional roles attributed to serotonin (5-HT) in the brain, changes in 5-HT levels have been shown to accompany changes in behavioral states, including WAKE, NREM and REM sleep. Whether 5-HT dynamics at shorter time scales can be seen to delineate substates within these larger brain states remains an open question. Here, we performed simultaneous recordings of extracellular 5-HT using a recently-developed G Protein–Coupled Receptor-Activation–Based 5-HT sensor (GRAB5-HT3.0) and local field potential (LFP) in the hippocampal CA1, which revealed the presence of prominent ultraslow (<0.05 Hz) 5-HT oscillations both during NREM and WAKE states. Interestingly, the phase of these ultraslow 5-HT oscillations was found to distinguish substates both within and across larger behavioral states. Hippocampal ripples occurred preferentially on the falling phase of ultraslow 5-HT oscillations during both NREM and WAKE, with higher power ripples concentrating near the peak specifically during NREM. By contrast, hippocampal-cortical coherence was strongest and microarousals and EMG peaks were most prevalent during the rising phase in both wake and NREM. Overall, ultraslow 5-HT oscillations delineate substates within the larger behavioral states of NREM and WAKE, thus potentially temporally segregating internal memory consolidation processes from arousal-related functions.
The penetration ring is a novel infection structure formed by the penetration peg for invading plant cell membrane in rice blast fungus
Authors: Fang Wenqin , Zai Xiaoyu , Chen Jia , Abubakar Yakubu Saddeeq , Wu Qiuqiu , Fang Zhenyu , Huang Xiuwei , Gan Xiang , Ebbole Daniel J , Wang Zonghua , Zheng Wenhui
Published: September 2024

Many fungal pathogens develop specialized infection structures such as appressoria to penetrate plant cells. However, it is not clear whether special structures are formed after cell wall penetration before invading host cytoplasm membrane in hemibiotrophic pathogens. Here, we showed that a penetration ring consisting of Ppe1 secreted proteins is formed after appressorium-mediated cell wall penetration and remained at the base of penetration site after invading plant cytoplasm membrane in the rice blast fungus
Magnaporthe oryzae
. The same persistent Ppe1 ring is formed after the penetration of neighboring cells by transpressoria.
PPE1
is specifically expressed during plant infection and the Δ
ppe1
mutant is defective in penetration and invasive growth. Blockage of penetration peg formation impedes the development of the Ppe1 ring. Close examinations showed that the penetration ring is formed at the collar of penetration pegs between plant cell wall and cytoplasm membrane and it is persistent as a fixed ring even after invasive hyphae invaded neighboring cells. Furthermore, Ppe1 is a member of an expanded family of secreted proteins that are unique to fungal pathogens using extreme appressorium turgor for plant penetration. Other members of the Ppe1 family also localize to the penetration ring for anchoring on cytoplasm membrane during plant infection. Taken together, a penetration ring consisting of a family of secreted proteins is formed between plant cell wall and cytoplasm membrane, which may function as a novel physical structure at the interface between the tip of penetration pegs and plant cytoplasm membrane before the differentiation of invasive hyphae.
MLCK/MLCP regulates mammalian axon regeneration via the redistribution of the growth cone F-actin
Authors: Saijilafu  , Wang Wei-Hua , Ma Jin-Jin , Yin Yin , Ma Yan-Xia
Published: September 2024

Axon regrowth is a key determinant of the restoration of the biological function of the nervous system after trauma. However, mature mammalian neurons have limited capacity for axon regeneration. We have previously demonstrated that neuronal axon growth both in the central and the peripheral nervous systems is markedly enhanced when non-muscle myosin II (NMII) is inhibited with blebbistatin. The activity of NMII is primarily regulated by MLCK and MLCP
via
the phosphorylation and dephosphorylation of its light chain, respectively; however, the functional roles of MLCK and MLCP in mammalian axonal regeneration remain unknown. In the present study, we provide strong evidence that the inhibition of MLCK activity significantly blocks axon regeneration in the mouse. Conversely, inhibition of MLCP promotes axon regrowth of both peripheral and central nervous system. Our findings further indicate that the MLCK/MLCP regulates axon regeneration via the reorganization of F-actin distribution in the growth cone, and this result suggests that direct regulation of the growth cone machinery is a potential strategy to promote axon regeneration.
Endogenous Precision of the Number Sense
Authors: Prat-Carrabin Arthur , Woodford Michael
Published: September 2024

The behavioral variability in psychophysical experiments and the stochasticity of sensory neurons have revealed the inherent imprecision in the brain’s representations of environmental variables
1–6
. Numerosity studies yield similar results, pointing to an imprecise ‘number sense’ in the brain
7–13
. If the imprecision in representations reflects an optimal allocation of limited cognitive resources, as suggested by efficient-coding models
14–26
, then it should depend on the context in which representations are elicited
25,27
. Through an estimation task and a discrimination task, both involving numerosities, we show that the scale of subjects’ imprecision increases, but sublinearly, with the width of the prior distribution from which numbers are sampled. This sublinear relation is notably different in the two tasks. The double dependence of the imprecision — both on the prior and on the task — is consistent with the optimization of a tradeoff between the expected reward, different for each task, and a resource cost of the encoding neurons’ activity. Comparing the two tasks allows us to clarify the form of the resource constraint. Our results suggest that perceptual noise is endogenously determined, and that the precision of percepts varies both with the context in which they are elicited, and with the observer’s objective.
ARID1A governs the silencing of sex-linked transcription during male meiosis in the mouse
Authors: Menon Debashish U , Chakraborty Prabuddha , Murcia Noel , Magnuson Terry
Published: September 2024

We present evidence implicating the BAF (BRG1/BRM Associated Factor) chromatin remodeler in meiotic sex chromosome inactivation (MSCI). By immunofluorescence (IF), the putative BAF DNA binding subunit, ARID1A (AT-rich Interaction Domain 1a), appeared enriched on the male sex chromosomes during diplonema of meiosis I. Those germ cells showing a Cre-induced loss of ARID1A were arrested in pachynema and failed to repress sex-linked genes, indicating a defective MSCI. Consistent with this defect, mutant sex chromosomes displayed an abnormal presence of elongating RNA polymerase II coupled with an overall increase in chromatin accessibility detectable by ATAC-seq. By investigating potential mechanisms underlying these anomalies, we identified a role for ARID1A in promoting the preferential enrichment of the histone variant, H3.3, on the sex chromosomes, a known hallmark of MSCI. Without ARID1A, the sex chromosomes appeared depleted of H3.3 at levels resembling autosomes. Higher resolution analyses by CUT&RUN revealed shifts in sex-linked H3.3 associations from discrete intergenic sites and broader gene-body domains to promoters in response to the loss of ARID1A. Several sex-linked sites displayed ectopic H3.3 occupancy that did not co-localize with DMC1 (DNA Meiotic Recombinase 1). This observation suggests a requirement for ARID1A in DMC1 localization to the asynapsed sex chromatids. We conclude that ARID1A-directed H3.3 localization influences meiotic sex chromosome gene regulation and DNA repair.
PITAR, a DNA damage-inducible cancer/testis long noncoding RNA, inactivates p53 by binding and stabilizing TRIM28 mRNA
Authors: Jana Samarjit , Mondal Mainak , Mahale Sagar , Gupta Bhavana , Prasasvi Kaval Reddy , Kandasami Lekha , Jha Neha , Chowdhury Abhishek , Santosh Vani , Kanduri Chandrasekhar , Somasundaram Kumaravel
Published: September 2024

In tumors with WT p53, alternate mechanisms of p53 inactivation are reported. Here, we have identified a long noncoding RNA, PITAR (p53 Inactivating TRIM28 Associated RNA), as an inhibitor of p53. PITAR is an oncogenic Cancer/testis lncRNA and is highly expressed in glioblastoma (GBM) and glioma stem-like cells (GSC). We establish that TRIM28 mRNA, which encodes a p53-specific E3 ubiquitin ligase, is a direct target of PITAR. PITAR interaction with TRIM28 RNA stabilized TRIM28 mRNA, which resulted in increased TRIM28 protein levels and reduced p53 steady-state levels due to enhanced p53 ubiquitination. DNA damage activated PITAR, in addition to p53, in a p53-independent manner, thus creating an incoherent feedforward loop to inhibit the DNA damage response by p53. While PITAR silencing inhibited the growth of WT p53 containing GSCs in vitro and reduced glioma tumor growth in vivo, its overexpression enhanced the tumor growth in a TRIM28-dependent manner and promoted resistance to Temozolomide. Thus, we establish an alternate way of p53 inactivation by PITAR, which maintains low p53 levels in normal cells and attenuates the DNA damage response by p53. Finally, we propose PITAR as a potential GBM therapeutic target.
Cryo-EM structures of Kv1.2 potassium channels, conducting and non-conducting
Authors: Wu Yangyu , Yan Yangyang , Yang Youshan , Bian Shumin , Rivetta Alberto , Allen Ken , Sigworth Fred J
Published: September 2024

We present near-atomic-resolution cryo-EM structures of the mammalian voltage-gated potassium channel Kv1.2 in open, C-type inactivated, toxin-blocked and sodium-bound states at 3.2 Å, 2.5 Å, 3.2 Å, and 2.9Å. These structures, all obtained at nominally zero membrane potential in detergent micelles, reveal distinct ion-occupancy patterns in the selectivity filter. The first two structures are very similar to those reported in the related Shaker channel and the much-studied Kv1.2-2.1 chimeric channel. On the other hand, two new structures show unexpected patterns of ion occupancy. First, the toxin α-Dendrotoxin, like Charybdotoxin, is seen to attach to the negatively-charged channel outer mouth, and a lysine residue penetrates into the selectivity filter, with the terminal amine coordinated by carbonyls, partially disrupting the outermost ion-binding site. In the remainder of the filter two densities of bound ions are observed, rather than three as observed with other toxin-blocked Kv channels. Second, a structure of Kv1.2 in Na
+
solution does not show collapse or destabilization of the selectivity filter, but instead shows an intact selectivity filter with ion density in each binding site. We also attempted to image the C-type inactivated Kv1.2 W366F channel in Na
+
solution, but the protein conformation was seen to be highly variable and only a low-resolution structure could be obtained. These findings present new insights into the stability of the selectivity filter and the mechanism of toxin block of this intensively studied, voltage-gated potassium channel.
Early Steps of Protein Disaggregation by Hsp70 Chaperone and Class B J-Domain Proteins are Shaped by Hsp110
Authors: Sztangierska Wiktoria , Wyszkowski Hubert , Pokornowska Maria , Kochanowicz Klaudia , Rychłowski Michał , Liberek Krzysztof , Kłosowska Agnieszka
Published: September 2024

Hsp70 is a key cellular system counteracting protein misfolding and aggregation, associated with stress, ageing and disease. Hsp70 solubilizes aggregates and aids protein refolding through substrate binding and release cycles regulated by co-chaperones: J-domain proteins (JDPs) and Nucleotide Exchange Factors (NEFs). Here, we elucidate the collaborative impact of Hsp110 NEFs and different JDP classes throughout Hsp70-dependent aggregate processing. We show that Hsp110 plays a major role at initial stages of disaggregation, determining its final efficacy. The NEF catalyses the recruitment of thick Hsp70 assemblies onto aggregate surface, which modifies aggregates into smaller species more readily processed by chaperones. Hsp70 stimulation by Hsp110 is much stronger with Class B than Class A JDPs and requires the auxiliary interaction between Class B JDP and the Hsp70 EEVD motif. Furthermore, we demonstrate for the first time that Hsp110 disrupts the JDP-Hsp70 interaction. Such destabilisation of chaperone complexes at the aggregate surface might improve disaggregation, but also lead to the inhibition above the substoichiometric Hsp110 optimum. Thus, balanced interplay between the co-chaperones and Hsp70 is critical to unlock its disaggregating potential.
Sensitivity to vocal emotions emerges in newborns at 37 weeks gestational age
Authors: Hou Xinlin , Zhang Peng , Mo Licheng , Peng Cheng , Zhang Dandan
Published: September 2024

Emotional responsiveness in neonates, particularly their ability to discern vocal emotions, plays an evolutionarily adaptive role in human communication and adaptive behaviors. The developmental trajectory of emotional sensitivity in neonates is crucial for understanding the foundations of early social-emotional functioning. However, the precise onset of this sensitivity and its relationship with gestational age (GA) remain subjects of investigation. In a study involving 120 healthy neonates categorized into six groups based on their GA (ranging from 35 and 40 weeks), we explored their emotional responses to vocal stimuli. These stimuli encompassed disyllables with happy and neutral prosodies, alongside acoustically matched nonvocal control sounds. The assessments occurred during natural sleep states using the odd-ball paradigm and event-related potentials. The results reveal a distinct developmental change at 37 weeks GA, marking the point at which neonates exhibit heightened perceptual acuity for emotional vocal expressions. This newfound ability is substantiated by the presence of the mismatch response, akin to an initial form of adult mismatch negativity, elicited in response to positive emotional vocal prosody. Notably, this perceptual shift’s specificity becomes evident when no such discrimination is observed in acoustically matched control sounds. Neonates born before 37 weeks GA do not display this level of discrimination ability. This developmental change has important implications for our understanding of early social-emotional development, highlighting the role of gestational age in shaping early perceptual abilities. Moreover, while these findings introduce the potential for a valuable screening tool for conditions like autism, characterized by atypical social-emotional functions, it is important to note that the current data are not yet robust enough to fully support this application. This study makes a substantial contribution to the broader field of developmental neuroscience and holds promise for future research on early intervention in neurodevelopmental disorders.
Dynamic chromatin architecture identifies new autoimmune-associated enhancers for IL2 and novel genes regulating CD4+ T cell activation
Authors: Pahl Matthew C , Sharma Prabhat , Thomas Rajan M , Thompson Zachary , Mount Zachary , Pippin James A , Morawski Peter A , Sun Peng , Su Chun , Campbell Daniel , Grant Struan FA , Wells Andrew D
Published: September 2024

Genome-wide association studies (GWAS) have identified hundreds of genetic signals associated with autoimmune disease. The majority of these signals are located in non-coding regions and likely impact cis-regulatory elements (cRE). Because cRE function is dynamic across cell types and states, profiling the epigenetic status of cRE across physiological processes is necessary to characterize the molecular mechanisms by which autoimmune variants contribute to disease risk. We localized risk variants from 15 autoimmune GWAS to cRE active during TCR-CD28 co-stimulation of naïve human CD4+ T cells. To characterize how dynamic changes in gene expression correlate with cRE activity, we measured transcript levels, chromatin accessibility, and promoter–cRE contacts across three phases of naive CD4+ T cell activation using RNA-seq, ATAC-seq, and HiC. We identified ~1200 protein-coding genes physically connected to accessible disease-associated variants at 423 GWAS signals, at least one-third of which are dynamically regulated by activation. From these maps, we functionally validated a novel stretch of evolutionarily conserved intergenic enhancers whose activity is required for activation-induced IL2 gene expression in human and mouse, and is influenced by autoimmune-associated genetic variation. The set of genes implicated by this approach are enriched for genes controlling CD4+ T cell function and genes involved in human inborn errors of immunity, and we pharmacologically validated eight implicated genes as novel regulators of T cell activation. These studies directly show how autoimmune variants and the genes they regulate influence processes involved in CD4+ T cell proliferation and activation.
The evolutionary history of the ancient weevil family Belidae (Coleoptera: Curculionoidea) reveals the marks of Gondwana breakup and major floristic turnovers, including the rise of angiosperms
Authors: Li Xuankun , Marvaldi Adriana E , Oberprieler Rolf G , Clarke Dave , Farrell Brian D , Sequeira Andrea , Ferrer M Silvia , O’Brien Charles , Salzman Shayla , Shin Seunggwan , Tang William , McKenna Duane D
Published: September 2024

The rise of angiosperms to ecological dominance and the breakup of Gondwana during the Mesozoic marked major transitions in the evolutionary history of insect-plant interactions. To elucidate how contemporary trophic interactions were influenced by host plant shifts and palaeogeographical events, we integrated molecular data with information from the fossil record to construct a timetree for ancient phytophagous weevils of the beetle family Belidae. Our analyses indicate that crown-group Belidae originated approximately 138 Ma ago in Gondwana, associated with Pinopsida (conifer) host plants, with larvae likely developing in dead/decaying branches. Belids tracked their host plants as major plate movements occurred during Gondwana’s breakup, surviving on distant, disjunct landmasses. Some belids shifted to Angiospermae and Cycadopsida when and where conifers declined, evolving new trophic interactions, including brood-pollination mutualisms with cycads and associations with achlorophyllous parasitic angiosperms. Extant radiations of belids in the genera
Rhinotia
(Australian region) and
Proterhinus
(Hawaiian Islands) have relatively recent origins.
DTX3L ubiquitin ligase ubiquitinates single-stranded nucleic acids
Authors: Dearlove Emily L , Chatrin Chatrin , Buetow Lori , Ahmed Syed F , Schmidt Tobias , Bushell Martin , Smith Brian O , Huang Danny T
Published: September 2024

Ubiquitination typically involves covalent linking of ubiquitin (Ub) to a lysine residue on a protein substrate. Recently, new facets of this process have emerged, including Ub modification of non-proteinaceous substrates like ADP-ribose by the DELTEX E3 ligase family. Here we show that the DELTEX family member DTX3L expands this non-proteinaceous substrate repertoire to include single-stranded DNA and RNA. Although the N-terminal region of DTX3L contains single-stranded nucleic acid binding domains and motifs, the minimal catalytically competent fragment comprises the C-terminal RING and DTC domains (RD). DTX3L-RD catalyses ubiquitination of the 3’-end of single-stranded DNA and RNA, as well as double-stranded DNA with a 3’ overhang of two or more nucleotides. This modification is reversibly cleaved by deubiquitinases. NMR and biochemical analyses reveal that the DTC domain binds single-stranded DNA and facilitates the catalysis of Ub transfer from RING-bound E2-conjugated Ub. Our study unveils the direct ubiquitination of nucleic acids by DTX3L, laying the groundwork for understanding its functional implications.
Dimer-monomer transition defines a hyper-thermostable peptidoglycan hydrolase mined from bacterial proteome by lysin-derived antimicrobial peptide-primed screening
Authors: Zhang Li , Hu Fen , Zhao Zirong , Li Xinfeng , Zhong Mingyue , He Jiajun , Yao Fangfang , Zhang Xiaomei , Mao Yuxuan , Wei Hongping , He Jin , Yang Hang
Published: September 2024

Phage-derived peptidoglycan hydrolases (i.e., lysins) are considered promising alternatives to conventional antibiotics due to their direct peptidoglycan degradation activity and low risk of resistances. However, the discovery of these enzymes is often hampered by the limited availability of phage genomes. Herein, we report a new strategy to mine active peptidoglycan hydrolases from bacterial proteomes by lysin-derived antimicrobial peptide-primed screening. As a proof-of-concept, five
p
eptidoglycan
h
ydrolases from the

A
cinetobacter
b
aumannii

proteome (PHAb7-PHAb11) were identified using PlyF307 lysin-derived peptide as a template. Among them, PHAb10 and PHAb11 showed potent bactericidal activity against multiple pathogens even after treatment at 100°C for 1 hour, while the other three were thermosensitive. We solved the crystal structures of PHAb8, PHAb10, and PHAb11 and unveiled that hyper-thermostable PHAb10 underwent a unique folding-refolding thermodynamic scheme mediated by the dimer-monomer transition, while thermosensitive PHAb8 formed a monomer. Two mouse models of bacterial infection further demonstrated the safety and efficacy of PHAb10. In conclusion, our antimicrobial peptide-primed strategy provides new clues for the discovery of promising antimicrobial drugs.
Cryo-electron tomographic investigation of native hippocampal glutamatergic synapses
Authors: Matsui Aya , Spangler Cathy J , Elferich Johannes , Shiozaki Momoko , Jean Nikki , Zhao Xiaowei , Qin Maozhen , Zhong Haining , Yu Zhiheng , Gouaux Eric
Published: September 2024

Chemical synapses are the major sites of communication between neurons in the nervous system and mediate either excitatory or inhibitory signaling [1]. At excitatory synapses, glutamate is the primary neurotransmitter and upon release from presynaptic vesicles, is detected by postsynaptic glutamate receptors, which include ionotropic AMPA and NMDA receptors [2, 3]. Here we have developed methods to identify glutamatergic synapses in brain tissue slices, label AMPA receptors with small gold nanoparticles (AuNPs), and prepare lamella for cryo-electron tomography studies. The targeted imaging of glutamatergic synapses in the lamella is facilitated by fluorescent pre- and postsynaptic signatures, and the subsequent tomograms allow for identification of key features of chemical synapses, including synaptic vesicles, the synaptic cleft and AuNP-labeled AMPA receptors. These methods pave the way for imaging brain regions at high resolution, using unstained, unfixed samples preserved under near-native conditions.
Phylogeny of neocortical-hippocampal projections provides insight in the nature of human memory
Authors: Reznik Daniel , Majka Piotr , Rosa Marcello GP , Witter Menno P , Doeller Christian F
Published: September 2024

Throughout mammalian evolution, the hippocampal region, unlike the neocortex, largely preserved its cytoarchitectural organization and its role in mnemonic functions. This contrast raises the possibility that the hippocampal region receives different types of cortical input across species, which may be reflected in species-specific memory-related differences. To test this hypothesis, we examined differences in unimodal and transmodal cortical input to the hippocampal region in the rat, marmoset, macaque and human. Our results demonstrate that unlike unimodal cortical input, transmodal cortical input to the hippocampal region was selectively preserved during mammalian evolution. These findings suggest that memory-related processes in different species likely operate on different types of sensory information. Our observations provide a comparative anatomical framework elucidating the process of dimensionality reduction underlying the formation of human memory.
Ultrastructural sublaminar-specific diversity of excitatory synaptic boutons in layer 1 of the adult human temporal lobe neocortex
Authors: Rollenhagen Astrid , Sadeghi Akram , Walkenfort Bernd , Hilgetag Claus C , Sätzler Kurt , Lübke Joachim HR
Published: September 2024

Layer (L)1, beside receiving massive cortico-cortical, commissural and associational projections, is the termination zone of tufted dendrites of pyramidal neurons and the area of Ca
2+
spike initiation. However, its synaptic organization in humans is not known. Quantitative 3D-models of synaptic boutons (SBs) in L1 of the human temporal lobe neocortex were generated from non-epileptic neocortical biopsy tissue using transmission electron microscopy, 3D-volume reconstructions and TEM tomography. Particularly, the size of active zones (AZs) and the readily releasable, recycling and resting pool of synaptic vesicles (SVs) were quantified.The majority of SBs contained numerous mitochondria comprising ∼7% of the total volume of SBs, had a large macular, non-perforated AZs (∼0.20 µm
2
) and were predominantly located on dendritic spines. SBs had a total pool of ∼3500 SVs, a comparably large readily releasable (∼4 SVs), recycling (∼470 SVs) and resting (∼2900 SVs) pool. Astrocytic coverage of SBs suggests both synaptic cross talk or removal of spilled glutamate by astrocytic processes at synaptic complexes.The structural composition of SBs in L1 may underlie the function of L1 networks that mediate, integrate and synchronize contextual and cross-modal information, enabling flexible and state-dependent processing of feedforward sensory inputs from other layers of the cortical column.
Diagnostic performance of serum metabolites biomarker associated with colorectal adenoma: a systematic review
Authors: Abu Bakar Maryam Fatimah , Chin Siok Fong , Makpol Suzana , Tan Jen Kit , Mohammed Nawi Azmawati
Published: September 2024

Evidence on serum biomarkers as a non-invasive tool to detect colorectal adenoma (CRA) in the general population is quite promising. However, the sensitivity and specificity of these serum biomarkers in detecting disease are still questionable. This study aimed to systematically review the evidence on the diagnostic performance of serum biomarkers associated with CRA. Database searches on PubMed, Scopus, and WoS from January 2014 to December 2023 using PRISMA guidelines resulted in 4,380 citations, nine of which met inclusion criteria. The quality of these studies was assessed using the QUADOMICS tool. These studies reported on 77 individual/panel biomarkers which were further analysed to find associated altered pathways using MetaboAnlyst 5.0. Diagnostic accuracy analysis of these biomarkers was conducted by constructing a receiver operating characteristic (ROC) curve using their reported sensitivity and specificity. This review identified six potential serum metabolite biomarkers with 0.7<AUC<1. Benzoic acid, acetate, and lactate significantly differentiate CRA vs. normal, while adenosine, pentothenate, and linoleic acid are highly remarkable for CRA vs. CRC. The five most affected pathways for CRA vs. normal are glycoxylate and dicarboxylate metabolism; alanine, aspartate, and glutamate metabolism; aminoacyl-tRNA biosynthesis; D-glutamine and D-glutamate metabolism; and nitrogen metabolism. Meanwhile, pyruvate metabolism, glycolysis/gluconeogenesis, glycerolipid metabolism, citrate/TCA cycle, and alanine, aspartate, and glutamate metabolism were found to be altered in CRA vs. CRC. However, the association of suggested serum metabolites and altered pathways is still unknown. Despite promising emerging evidence, further validation studies in a diverse population with standardized methodology are needed to validate the findings.
In-silico and In-vitro Evaluation of Acetylcholinesterase Activity of Methanolic Extract of Vitex negundo
Authors: Devi S Shobana , Anusha D , Karthika K , Ramasamy Kavitha
Published: September 2024

Introduction: Vitex negundo has a myriad of medicinal uses, such as antioxidant, analgesic and anthelminthic properties, and it is used for dysmenorrhoea. The plant contains various phytochemicals, such as flavonoids, vitamins and casticin. All components of the plant are utilised medicinally due to the minimal occurrence of adverse drug reactions, making it a potential drug target for various chronic diseases. However, the role of this plant in neurodegenerative disorders, such as Alzheimer’s Disease (AD), has not yet been extensively studied. Aim: To evaluate the in-silico and in-vitro activity of the antiAlzheimer properties of the Methanolic Extract of Vitex negundo (MEVN) leaves. Materials and Methods: The present in-silico docking study and in-vitro study were conducted in the Department of Pharmacology at Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, Tamil Nadu, India, over a period of two months. The in-silico analysis was performed to determine the intermolecular interactions between the ligand and protein of the top five scored molecules using PyMol software. To assess the Acetylcholinesterase (AChE) inhibitory property, the findings were presented as docking scores. Cell viability and cytotoxicity were evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay, with results expressed as percentages for various concentrations: 6.25 μg/mL, 12.5 μg/ mL, 25 μg/mL, 50 μg/mL, 75 μg/mL, and 100 μg/mL of MEVN. Results: The MEVN exhibited competitive inhibition of the AChE enzyme. There were active interactions between Agnuside, Isochlorogenic Acid B, Isochlorogenic Acid C, Kaempferol-3- O-rutinoside, and Quercetin found in the MEVN with AChE. The percentage of cell viability for the concentrations of 6.25 μg/ mL, 12.5 μg/mL, 25 μg/mL, 50 μg/mL, 75 μg/mL, and 100 μg/ mL, as determined by the MTT assay, was 98.62%, 98.86%, 97.19%, 96.66%, 91.86%, and 78.82%, respectively. The results indicated that MEVN does not exhibit any toxicity. Conclusion: The findings demonstrated that MEVN possesses AChE inhibitory properties and maintains cell viability, both of which are indicative of anti-Alzheimer activity. Therefore, MEVN can be further evaluated for its potential in preventing cell cytotoxicity and treating AD.
Graft Salvage in Management of Septic Knee Post-ACL Reconstruction: A Case Report
Authors: Pawar Raj Vinay , Deshmukh Ashwin , Salunkhe Rahul
Published: September 2024

The frequency of Anterior Cruciate Ligament Reconstructions (ACLR) has risen in recent years and is projected to continue increasing. Knee-joint infections consequent to this procedure, although rare, present a significant concern due to their potential severity. Hence, comprehending the progression of this complication and its detrimental effects if not promptly addressed is crucial. The impact of infection on the joint can vary depending on the duration between onset, diagnosis, and initiation of appropriate treatment. In some cases, the infection may have minimal consequences for the joint, while in others, it could lead to compromised viability of the Anterior Cruciate Ligament (ACL) graft, damage to the articular cartilage, or even premature onset of osteoarthritis. In the present case, a 42-year-old male had presented to the Orthopaedics Outpatient Department (OPD) six weeks postoperatively following an ACL reconstruction with clinical and laboratory findings pointing towards a septic knee. Lab findings suggested a raised ESR-71 mm/hr, CRP-127 mg/dL, and TLC-10,200/microL. The decision for immediate arthroscopic debridement with synovectomy was taken to achieve decompression all the while preserving the graft. This was followed by antibiotic saline irrigation for two days with strict antibiotic coverage following it.
Assessing the Utility of Oxygen Desaturation Index as a Diagnostic Tool for Obstructive Sleep Apnoea: A Cross-sectional Study
Authors: Thamilan Arularasu Paari , Sakthivel Nagarjun , Balasubramanian Karniha , Suriyan Subramanian , Nagesh Nalini Jayanthi , Assain Shaz
Published: September 2024

Introduction: Obstructive Sleep Apnoea (OSA) is a common yet underdiagnosed condition with serious medical consequences if not recognised early. Despite its limitations, the ApnoeaHypopnoea Index (AHI) remains the most studied parameter for assessing the severity of OSA. This situation has created a need for a preliminary, alternative diagnostic tool for the early diagnosis and severity assessment of OSA in resource-limited settings. Aim: To determine whether the Oxygen Desaturation Index (ODI) could serve as a simple yet equally effective diagnostic tool compared to the AHI in assessing the severity of OSA. Materials and Methods: A cross-sectional study was conducted in SRM Medical College, Chennai, Tamil Nadu, India, involving 100 patients who underwent Level III polysomnography for suspected OSA. The study spanned one year, from May 2023 to May 2024. Ethical clearance for the study was obtained from the Institutional Review Board (IRB). Pearson’s correlation coefficient was applied to assess the relationship between AHI and ODI scores. Cohen’s weighted Kappa analysis BlandAltman plot, ROC curve analysis, and Youden’s J Statistic were performed to determine the best ODI threshold for OSA severity. Statistical analysis was conducted using Statistical Package for Social Sciences (SPSS) version 22.0, ensuring robust and reliable results. Results: Analysis of the obtained parameters suggested a strong correlation (r=0.94, p-value<0.001) between AHI and ODI scores. ROC curve analysis indicated that an ODI >32 had good effectiveness in detecting severe OSA. Conclusion: The strong positive correlation and significant agreement between AHI values and ODI scores indicate that ODI could be reliable in diagnosing and assessing the severity of OSA, especially in resource-limited environments.