bluuebunny/crossref_metadata_2025 huggingface dataset:
Theta mediated dynamics of human hippocampal-neocortical learning systems in memory formation and retrieval
Authors: Gattas Sandra , Larson Myra Sarai , Mnatsakanyan Lilit , Sen-Gupta Indranil , Vadera Sumeet , Swindlehurst A. Lee , Rapp Paul E. , Lin Jack J. , Yassa Michael A.
Published: December 2023

Episodic memory arises as a function of dynamic interactions between the hippocampus and the neocortex, yet the mechanisms have remained elusive. Here, using human intracranial recordings during a mnemonic discrimination task, we report that 4-5 Hz (theta) power is differentially recruited during discrimination vs. overgeneralization, and its phase supports hippocampal-neocortical when memories are being formed and correctly retrieved. Interactions were largely bidirectional, with small but significant net directional biases; a hippocampus-to-neocortex bias during acquisition of new information that was subsequently correctly discriminated, and a neocortex-to-hippocampus bias during accurate discrimination of new stimuli from similar previously learned stimuli. The 4-5 Hz rhythm may facilitate the initial stages of information acquisition by neocortex during learning and the recall of stored information from cortex during retrieval. Future work should further probe these dynamics across different types of tasks and stimuli and computational models may need to be expanded accordingly to accommodate these findings.
BACH1 controls hepatic insulin signaling and glucose homeostasis in mice
Authors: Jin Jiayu , He Yunquan , Guo Jieyu , Pan Qi , Wei Xiangxiang , Xu Chen , Qi Zhiyuan , Li Qinhan , Ma Siyu , Lin Jiayi , Jiang Nan , Ma Jinghua , Wang Xinhong , Jiang Lindi , Ding Qiurong , Osto Elena , Zhi Xiuling , Meng Dan
Published: December 2023

Hepatic insulin resistance is central to the metabolic syndrome. Here we investigate the role of BTB and CNC homology 1 (BACH1) in hepatic insulin signaling. BACH1 is elevated in the hepatocytes of individuals with obesity and patients with non-alcoholic fatty liver disease (NAFLD). Hepatocyte-specific Bach1 deletion in male mice on a high-fat diet (HFD) ameliorates hyperglycemia and insulin resistance, improves glucose homeostasis, and protects against steatosis, whereas hepatic overexpression of Bach1 in male mice leads to the opposite phenotype. BACH1 directly interacts with the protein-tyrosine phosphatase 1B (PTP1B) and the insulin receptor β (IR-β), and loss of BACH1 reduces the interaction between PTP1B and IR-β upon insulin stimulation and enhances insulin signaling in hepatocytes. Inhibition of PTP1B significantly attenuates BACH1-mediated suppression of insulin signaling in HFD-fed male mice. Hepatic BACH1 knockdown ameliorates hyperglycemia and improves insulin sensitivity in diabetic male mice. These results demonstrate a critical function for hepatic BACH1 in the regulation of insulin signaling and glucose homeostasis.
Hypothalamic CRH neurons represent physiological memory of positive and negative experience
Authors: Füzesi Tamás , Rasiah Neilen P. , Rosenegger David G. , Rojas-Carvajal Mijail , Chomiak Taylor , Daviu Núria , Molina Leonardo A. , Simone Kathryn , Sterley Toni-Lee , Nicola Wilten , Bains Jaideep S.
Published: December 2023

Recalling a salient experience provokes specific behaviors and changes in the physiology or internal state. Relatively little is known about how physiological memories are encoded. We examined the neural substrates of physiological memory by probing CRHPVN neurons of mice, which control the endocrine response to stress. Here we show these cells exhibit contextual memory following exposure to a stimulus with negative or positive valence. Specifically, a negative stimulus invokes a two-factor learning rule that favors an increase in the activity of weak cells during recall. In contrast, the contextual memory of positive valence relies on a one-factor rule to decrease activity of CRHPVN neurons. Finally, the aversive memory in CRHPVN neurons outlasts the behavioral response. These observations provide information about how specific physiological memories of aversive and appetitive experience are represented and demonstrate that behavioral readouts may not accurately reflect physiological changes invoked by the memory of salient experiences.
Unique adipose tissue invariant natural killer T cell subpopulations control adipocyte turnover in mice
Authors: Han Sang Mun , Park Eun Seo , Park Jeu , Nahmgoong Hahn , Choi Yoon Ha , Oh Jiyoung , Yim Kyung Min , Lee Won Taek , Lee Yun Kyung , Jeon Yong Geun , Shin Kyung Cheul , Huh Jin Young , Choi Sung Hee , Park Jiyoung , Kim Jong Kyoung , Kim Jae Bum
Published: December 2023

Adipose tissue invariant natural killer T (iNKT) cells are a crucial cell type for adipose tissue homeostasis in obese animals. However, heterogeneity of adipose iNKT cells and their function in adipocyte turnover are not thoroughly understood. Here, we investigate transcriptional heterogeneity in adipose iNKT cells and their hierarchy using single-cell RNA sequencing in lean and obese mice. We report that distinct subpopulations of adipose iNKT cells modulate adipose tissue homeostasis through adipocyte death and birth. We identify KLRG1+ iNKT cells as a unique iNKT cell subpopulation in adipose tissue. Adoptive transfer experiments showed that KLRG1+ iNKT cells are selectively generated within adipose tissue microenvironment and differentiate into a CX3CR1+ cytotoxic subpopulation in obese mice. In addition, CX3CR1+ iNKT cells specifically kill enlarged and inflamed adipocytes and recruit macrophages through CCL5. Furthermore, adipose iNKT17 cells have the potential to secrete AREG, and AREG is involved in stimulating adipose stem cell proliferation. Collectively, our data suggest that each adipose iNKT cell subpopulation plays key roles in the control of adipocyte turnover via interaction with adipocytes, adipose stem cells, and macrophages in adipose tissue.
Solvent-pair surfactants enabled assembly of clusters and copolymers towards programmed mesoporous metal oxides
Authors: Xie Wenhe , Ren Yuan , Jiang Fengluan , Huang Xin-Yu , Yu Bingjie , Liu Jianhong , Li Jichun , Chen Keyu , Zou Yidong , Hu Bingwen , Deng Yonghui
Published: December 2023

Organic-inorganic molecular assembly has led to numerous nano/mesostructured materials with fantastic properties, but it is dependent on and limited to the direct interaction between host organic structure-directing molecules and guest inorganic species. Here, we report a “solvent-pair surfactants” enabled assembly (SPEA) method to achieve a general synthesis of mesostructured materials requiring no direct host-guest interaction. Taking the synthesis of mesoporous metal oxides as an example, the dimethylformamide/water solvent pairs behave as surfactants and induce the formation of mesostructured polyoxometalates/copolymers nanocomposites, which can be converted into metal oxides. This SPEA method enables the synthesis of functional ordered mesoporous metal oxides with different pore sizes, structures, compositions and tailored pore-wall microenvironments that are difficult to access via conventional direct organic-inorganic assembly. Typically, nitrogen-doped mesoporous ε-WO3 with high specific surface area, uniform mesopores and stable framework is obtained and exhibits great application potentials such as gas sensing.
Atroposelective hydroarylation of biaryl phosphines directed by phosphorus centres
Authors: Li Zexian , Wang Minyan , Yang Youqing , Liang Yong , Chen Xiangyang , Zhao Yue , Houk K. N. , Shi Zhuangzhi
Published: December 2023

Prized for their ability to generate chemical complexity rapidly, catalytic carbon–hydrogen (C–H) activation and functionalization reactions have enabled a paradigm shift in the standard logic of synthetic chemistry. Directing group strategies have been used extensively in C–H activation reactions to control regio- and enantioselectivity with transition metal catalysts. However, current methods rely heavily on coordination with nitrogen and/or oxygen atoms in molecules and have therefore been found to exhibit limited generality in asymmetric syntheses. Here, we report enantioselective C–H activation with unsaturated hydrocarbons directed by phosphorus centres to rapidly construct libraries of axially chiral phosphines through dynamic kinetic resolution. High reactivity and enantioselectivity are derived from modular assembly of an iridium catalyst with an endogenous phosphorus atom and an exogenous chiral phosphorus ligand, as confirmed by detailed experimental and computational studies. This reaction mode significantly expands the pool of enantiomerically enriched functional phosphines, some of which have shown excellent efficiency for asymmetric catalysis.
Redox-enabled electronic interrogation and feedback control of hierarchical and networked biological systems
Authors: Wang Sally , Chen Chen-Yu , Rzasa John R. , Tsao Chen-Yu , Li Jinyang , VanArsdale Eric , Kim Eunkyoung , Zakaria Fauziah Rahma , Payne Gregory F. , Bentley William E.
Published: December 2023

Microelectronic devices can directly communicate with biology, as electronic information can be transmitted via redox reactions within biological systems. By engineering biology’s native redox networks, we enable electronic interrogation and control of biological systems at several hierarchical levels: proteins, cells, and cell consortia. First, electro-biofabrication facilitates on-device biological component assembly. Then, electrode-actuated redox data transmission and redox-linked synthetic biology allows programming of enzyme activity and closed-loop electrogenetic control of cellular function. Specifically, horseradish peroxidase is assembled onto interdigitated electrodes where electrode-generated hydrogen peroxide controls its activity. E. coli’s stress response regulon, oxyRS, is rewired to enable algorithm-based feedback control of gene expression, including an eCRISPR module that switches cell-cell quorum sensing communication from one autoinducer to another—creating an electronically controlled ‘bilingual’ cell. Then, these disparate redox-guided devices are wirelessly connected, enabling real-time communication and user-based control. We suggest these methodologies will help us to better understand and develop sophisticated control for biology.
Spatiotemporal signaling underlies progressive vascular rarefaction in myocardial infarction
Authors: Tung Lin Wei , Groppa Elena , Soliman Hesham , Lin Bruce , Chang Chihkai , Cheung Chun Wai , Ritso Morten , Guo David , Rempel Lucas , Sinha Sarthak , Eisner Christine , Brassard Julyanne , McNagny Kelly , Biernaskie Jeff , Rossi Fabio
Published: December 2023

Therapeutic angiogenesis represents a promising avenue to revascularize the ischemic heart. Its limited success is partly due to our poor understanding of the cardiac stroma, specifically mural cells, and their response to ischemic injury. Here, we combine single-cell and positional transcriptomics to assess the behavior of mural cells within the healing heart. In response to myocardial infarction, mural cells adopt an altered state closely associated with the infarct and retain a distinct lineage from fibroblasts. This response is concurrent with vascular rarefaction and reduced vascular coverage by mural cells. Positional transcriptomics reveals that the infarcted heart is governed by regional-dependent and temporally regulated programs. While the remote zone acts as an important source of pro-angiogenic signals, the infarct zone is accentuated by chronic activation of anti-angiogenic, pro-fibrotic, and inflammatory cues. Together, our work unveils the spatiotemporal programs underlying cardiac repair and establishes an association between vascular deterioration and mural cell dysfunction.
Within-host genetic diversity of extended-spectrum beta-lactamase-producing Enterobacterales in long-term colonized patients
Authors: Aguilar-Bultet Lisandra , García-Martín Ana B. , Vock Isabelle , Maurer Pekerman Laura , Stadler Rahel , Schindler Ruth , Battegay Manuel , Stadler Tanja , Gómez-Sanz Elena , Tschudin-Sutter Sarah
Published: December 2023

Despite recognition of the immediate impact of infections caused by extended-spectrum beta-lactamase (ESBL)-producing Enterobacterales (ESBL-PE) on human health, essential aspects of their molecular epidemiology remain under-investigated. This includes knowledge on the potential of a particular strain to persist in a host, mutational events during colonization, and the genetic diversity in individual patients over time. To investigate long-term genetic diversity of colonizing and infecting ESBL-Klebsiella pneumoniae species complex and ESBL-Escherichia coli in individual patients over time, we performed a ten-year longitudinal retrospective study and extracted clinical and microbiological data from electronic health records. In this investigation, 76 ESBL-K. pneumoniae species complex and 284 ESBL-E. coli isolates were recovered from 19 and 61 patients. Strain persistence was detected in all patients colonized with ESBL-K. pneumoniae species complex, and 83.6% of patients colonized with ESBL-E. coli. We frequently observed isolates of the same strain recovered from different body sites associated with either colonization or infection. Antimicrobial resistance genes, plasmid replicons, and whole ESBL-plasmids were shared between isolates regardless of chromosomal relatedness. Our study suggests that patients colonized with ESBL-producers may act as durable reservoirs for ongoing transmission of ESBLs, and that they are at prolonged risk of recurrent infection with colonizing strains.
Physics-aware differentiable design of magnetically actuated kirigami for shape morphing
Authors: Wang Liwei , Chang Yilong , Wu Shuai , Zhao Ruike Renee , Chen Wei
Published: December 2023

Shape morphing that transforms morphologies in response to stimuli is crucial for future multifunctional systems. While kirigami holds great promise in enhancing shape-morphing, existing designs primarily focus on kinematics and overlook the underlying physics. This study introduces a differentiable inverse design framework that considers the physical interplay between geometry, materials, and stimuli of active kirigami, made by soft material embedded with magnetic particles, to realize target shape-morphing upon magnetic excitation. We achieve this by combining differentiable kinematics and energy models into a constrained optimization, simultaneously designing the cuts and magnetization orientations to ensure kinematic and physical feasibility. Complex kirigami designs are obtained automatically with unparalleled efficiency, which can be remotely controlled to morph into intricate target shapes and even multiple states. The proposed framework can be extended to accommodate various active systems, bridging geometry and physics to push the frontiers in shape-morphing applications, like flexible electronics and minimally invasive surgery.
A broad-spectrum gas sensor based on correlated two-dimensional electron gas
Authors: Hong Yuhao , Wei Long , Zhang Qinghua , Deng Zhixiong , Liao Xiaxia , Zhou Yangbo , Wang Lei , Li Tongrui , Liu Junhua , Xiao Wen , Hu Shilin , Wang Lingfei , Li Lin , Huijben Mark , Gan Yulin , Chen Kai , Koster Gertjan , Rijnders Guus , Liao Zhaoliang
Published: December 2023

Designing a broad-spectrum gas sensor capable of identifying gas components in complex environments, such as mixed atmospheres or extreme temperatures, is a significant concern for various technologies, including energy, geological science, and planetary exploration. The main challenge lies in finding materials that exhibit high chemical stability and wide working temperature range. Materials that amplify signals through non-chemical methods could open up new sensing avenues. Here, we present the discovery of a broad-spectrum gas sensor utilizing correlated two-dimensional electron gas at a delta-doped LaAlO3/SrTiO3 interface with LaFeO3. Our study reveals that a back-gating on this two-dimensional electron gas can induce a non-volatile metal to insulator transition, which consequently can activate the two-dimensional electron gas to sensitively and quantitatively probe very broad gas species, no matter whether they are polar, non-polar, or inert gases. Different gas species cause resistance change at their sublimation or boiling temperature and a well-defined phase transition angle can quantitatively determine their partial pressures. Such unique correlated two-dimensional electron gas sensor is not affected by gas mixtures and maintains a wide operating temperature range. Furthermore, its readout is a simple measurement of electric resistance change, thus providing a very low-cost and high-efficient broad-spectrum sensing technique.
Pervasive epistasis exposes intramolecular networks in adaptive enzyme evolution
Authors: Buda Karol , Miton Charlotte M. , Tokuriki Nobuhiko
Published: December 2023

Enzyme evolution is characterized by constant alterations of the intramolecular residue networks supporting their functions. The rewiring of these network interactions can give rise to epistasis. As mutations accumulate, the epistasis observed across diverse genotypes may appear idiosyncratic, that is, exhibit unique effects in different genetic backgrounds. Here, we unveil a quantitative picture of the prevalence and patterns of epistasis in enzyme evolution by analyzing 41 fitness landscapes generated from seven enzymes. We show that >94% of all mutational and epistatic effects appear highly idiosyncratic, which greatly distorted the functional prediction of the evolved enzymes. By examining seemingly idiosyncratic changes in epistasis along adaptive trajectories, we expose several instances of higher-order, intramolecular rewiring. Using complementary structural data, we outline putative molecular mechanisms explaining higher-order epistasis along two enzyme trajectories. Our work emphasizes the prevalence of epistasis and provides an approach to exploring this phenomenon through a molecular lens.
A human lower-limb biomechanics and wearable sensors dataset during cyclic and non-cyclic activities
Authors: Scherpereel Keaton , Molinaro Dean , Inan Omer , Shepherd Max , Young Aaron
Published: December 2023

Tasks of daily living are often sporadic, highly variable, and asymmetric. Analyzing these real-world non-cyclic activities is integral for expanding the applicability of exoskeletons, protheses, wearable sensing, and activity classification to real life, and could provide new insights into human biomechanics. Yet, currently available biomechanics datasets focus on either highly consistent, continuous, and symmetric activities, such as walking and running, or only a single specific non-cyclic task. To capture a more holistic picture of lower limb movements in everyday life, we collected data from 12 participants performing 20 non-cyclic activities (e.g. sit-to-stand, jumping, squatting, lunging, cutting) as well as 11 cyclic activities (e.g. walking, running) while kinematics (motion capture and IMUs), kinetics (force plates), and electromyography (EMG) were collected. This dataset provides normative biomechanics for a highly diverse range of activities and common tasks from a consistent set of participants and sensors.
Improved chromosome-level genome assembly of Indian sandalwood (Santalum album)
Authors: Zhang Xinhua , Li MingZhi , Bian Zhan , Chen Xiaohong , Li Yuan , Xiong Yuping , Fang Lin , Wu Kunlin , Zeng Songjun , Jian Shuguang , Wang Rujiang , Ren Hai , Teixeira da Silva Jaime A. , Ma Guohua
Published: December 2023

Santalum album is a well-known aromatic and medicinal plant that is highly valued for the essential oil (EO) extracted from its heartwood. In this study, we present a high-quality chromosome-level genome assembly of S. album after integrating PacBio Sequel, Illumina HiSeq paired-end and high-throughput chromosome conformation capture sequencing technologies. The assembled genome size is 207.39 M with a contig N50 of 7.33 M and scaffold N50 size of 18.31 M. Compared with three previously published sandalwood genomes, the N50 length of the genome assembly was longer. In total, 94.26% of the assembly was assigned to 10 pseudo-chromosomes, and the anchor rate far exceeded that of a recently released value. BUSCO analysis yielded a completeness score of 94.91%. In addition, we predicted 23,283 protein-coding genes, 89.68% of which were functionally annotated. This high-quality genome will provide a foundation for sandalwood functional genomics studies, and also for elucidating the genetic basis of EO biosynthesis in S. album.
Discovery of 1-(5-bromopyrazin-2-yl)-1-[3-(trifluoromethyl)benzyl]urea as a promising anticancer drug via synthesis, characterization, biological screening, and computational studies
Authors: Mohammed Yasser Hussein Issa , Shamkh Israa M. , Alharthi Nahed S. , Shanawaz Mohammed A. , Alzahrani Hind A. , Jabbar Basit , Beigh Saba , Alghamdi Saad , Alsakhen Nada , Khidir Elshiekh B. , Alhuthali Hayaa M. , Karamalla Taqwa Hafiz Elamin , Rabie Amgad M.
Published: December 2023

Cancer and different types of tumors are still the most resistant diseases to available therapeutic agents. Finding a highly effective anticancer drug is the first target and concern of thousands of drug designers. In our attempts to address this concern, a new pyrazine derivative, 1-(5-bromopyrazin-2-yl)-1-[3-(trifluoromethyl)benzyl]urea (BPU), was designed via structural optimization and synthesized to investigate its anticancer/antitumor potential. The in-vitro anticancer properties of BPU were evaluated by MTT assay using selected cell lines, including the Jurkat, HeLa, and MCF-7 cells. The Jurkat cells were chosen to study the effect of BPU on cell cycle analysis using flow cytometry technique. BPU exhibited an effective cytotoxic ability in all the three cell lines assessed. It was found to be more prominent with the Jurkat cell line (IC50 = 4.64 ± 0.08 µM). When it was subjected to cell cycle analysis, this compound effectively arrested cell cycle progression in the sub-G1 phase. Upon evaluating the antiangiogenic potential of BPU via the in-vivo/ex-vivo shell-less chick chorioallantoic membrane (CAM) assays, the compound demonstrated very significant findings, revealing a complementary supportive action for the compound to act as a potent anticancer agent through inhibiting blood vessel formation in tumor tissues. Moreover, the docking energy of BPU computationally scored − 9.0 kcal/mol with the human matrix metalloproteinase 2 (MMP-2) and − 7.8 kcal/mol with the human matrix metalloproteinase 9 (MMP-9), denoting promising binding results as compared to the existing drugs for cancer therapy. The molecular dynamics (MD) simulation outcomes showed that BPU could effectively bind to the previously-proposed catalytic sites of both MMP-2 and MMP-9 enzymes with relatively stable statuses and good inhibitory binding abilities and parameters. Our findings suggest that the compound BPU could be a promising anticancer agent since it effectively inhibited cell proliferation and can be selected for further in-vitro and in-vivo investigations. In addition, the current results can be extensively validated by conducting wet-lab analysis so as to develop novel and better derivatives of BPU for cancer therapy with much less side effects and higher activities.
Prognostic utility and characterization of left ventricular hypertrophy using global thickness
Authors: Lundin Magnus , Heiberg Einar , Nordlund David , Gyllenhammar Tom , Steding-Ehrenborg Katarina , Engblom Henrik , Carlsson Marcus , Atar Dan , van der Pals Jesper , Erlinge David , Borgquist Rasmus , Khoshnood Ardavan , Ekelund Ulf , Nickander Jannike , Themudo Raquel , Nordin Sabrina , Kozor Rebecca , Bhuva Anish N. , Moon James C. , Maret Eva , Caidahl Kenneth , Sigfridsson Andreas , Sörensson Peder , Schelbert Erik B. , Arheden Håkan , Ugander Martin
Published: December 2023

Cardiovascular magnetic resonance (CMR) can accurately measure left ventricular (LV) mass, and several measures related to LV wall thickness exist. We hypothesized that prognosis can be used to select an optimal measure of wall thickness for characterizing LV hypertrophy. Subjects having undergone CMR were studied (cardiac patients, n = 2543; healthy volunteers, n = 100). A new measure, global wall thickness (GT, GTI if indexed to body surface area) was accurately calculated from LV mass and end-diastolic volume. Among patients with follow-up (n = 1575, median follow-up 5.4 years), the most predictive measure of death or hospitalization for heart failure was LV mass index (LVMI) (hazard ratio (HR)[95% confidence interval] 1.16[1.12–1.20], p < 0.001), followed by GTI (HR 1.14[1.09–1.19], p < 0.001). Among patients with normal findings (n = 326, median follow-up 5.8 years), the most predictive measure was GT (HR 1.62[1.35–1.94], p < 0.001). GT and LVMI could characterize patients as having a normal LV mass and wall thickness, concentric remodeling, concentric hypertrophy, or eccentric hypertrophy, and the three abnormal groups had worse prognosis than the normal group (p < 0.05 for all). LV mass is highly prognostic when mass is elevated, but GT is easily and accurately calculated, and adds value and discrimination amongst those with normal LV mass (early disease).
BOO-ST and CBCEC: two novel hybrid machine learning methods aim to reduce the mortality of heart failure patients
Authors: Sutradhar Ananda , Al Rafi Mustahsin , Shamrat F M Javed Mehedi , Ghosh Pronab , Das Subrata , Islam Md Anaytul , Ahmed Kawsar , Zhou Xujuan , Azad A. K. M. , Alyami Salem A. , Moni Mohammad Ali
Published: December 2023

Heart failure (HF) is a leading cause of mortality worldwide. Machine learning (ML) approaches have shown potential as an early detection tool for improving patient outcomes. Enhancing the effectiveness and clinical applicability of the ML model necessitates training an efficient classifier with a diverse set of high-quality datasets. Hence, we proposed two novel hybrid ML methods ((a) consisting of Boosting, SMOTE, and Tomek links (BOO-ST); (b) combining the best-performing conventional classifier with ensemble classifiers (CBCEC)) to serve as an efficient early warning system for HF mortality. The BOO-ST was introduced to tackle the challenge of class imbalance, while CBCEC was responsible for training the processed and selected features derived from the Feature Importance (FI) and Information Gain (IG) feature selection techniques. We also conducted an explicit and intuitive comprehension to explore the impact of potential characteristics correlating with the fatality cases of HF. The experimental results demonstrated the proposed classifier CBCEC showcases a significant accuracy of 93.67% in terms of providing the early forecasting of HF mortality. Therefore, we can reveal that our proposed aspects (BOO-ST and CBCEC) can be able to play a crucial role in preventing the death rate of HF and reducing stress in the healthcare sector.
Clinical characterisation of women with persistent genital arousal disorder: the iPGAD-study
Authors: Kümpers Franziska M. L. M. , Sinke Christopher , Schippert Cordula , Kollewe Katja , Körner Sonja , Raab Peter , Meyer Bernhard , Maschke Sabine , Karst Matthias , Sperling Christian , Dalkeranidis Eleni , Krüger Tillmann H. C.
Published: December 2023

Persistent Genital Arousal Disorder (PGAD) is a rare condition—mostly in women—where patients perceive prolonged genital arousal without any sexual desire or stimulation. Etiopathological considerations reach from peripheral to central issues over local disturbance of the pudendal nerve to neuropathy, psychosocial, and pharmacological theories. Since well controlled clinical studies about PGAD in conjunction with a mental and somatic health status are missing, this study is a detailed clinical investigation of PGAD patients compared to healthy controls. 26 women who fulfilled diagnostic criteria for PGAD were compared to 26 age matched healthy controls. Investigations included comparison of vegetative, gynaecological and sexual history, psychiatric features as well as a (neuro-)radiological, neurophysiological and gynaecological examination. Moreover, a detailed clinical characterisation of PGAD symptoms was performed. PGAD symptoms were mostly characterised as tingling or prickling and were permanently present. In over 80%, PGAD symptoms were located in the clitoris. Almost 70% reported radiations to other regions of the body. Most frequent trigger factors were tight clothes, mental stress, driving a car/bus/bicycle and sexual intercourse. Relieving factors were mainly distraction, relaxation, physical exercise, masturbation and swimming. In group comparisons, PGAD presented with significant higher rates of sexual dysfunctions, spontaneous orgasms, swelling of the genitals, extraordinary lubrication as well as higher rates in depression, agoraphobia, generalized anxiety disorder and lifetime panic disorder. Significantly more PGAD patients were diagnosed with restless legs symptoms. In contrast childhood traumatization, somatization disorder, suicidality, gynaecological as well as neurophysiological examination of the pudendal nerve were not different between the groups. MRI of the brain, pelvis and spinal cord was unsuspicious and incidental findings - including Tarlov cysts or pelvic venous congestion - were equally distributed among the groups. In summary, our study provides a careful characterization of women with PGAD highlighting a serious mental burden, most probably as a consequence of PGAD. With the current set of clinical investigations there was no evidence of a clear causal relationship to a specific clinical finding as it has been previously discussed. Future studies and additional techniques will have to further explore where and how in the peripheral or central nervous systems PGAD develops.
Cervical vestibular evoked myogenic potential (cVEMP) findings in adults with sensorineural hearing loss (SNHL): comparisons between 500 Hz tone burst and narrowband CE-Chirp stimuli
Authors: Zakaria Mohd Normani , Salim Rosdan , Abdul Wahat Nor Haniza , Md Daud Mohd Khairi , Wan Mohamad Wan Najibah
Published: December 2023

There has been a growing interest in studying the usefulness of chirp stimuli in recording cervical vestibular evoked myogenic potential (cVEMP) waveforms. Nevertheless, the study outcomes are debatable and require verification. In view of this, the aim of the present study was to compare cVEMP results when elicited by 500 Hz tone burst and narrowband (NB) CE-Chirp stimuli in adults with sensorineural hearing loss (SNHL). Fifty adults with bilateral SNHL (aged 20–65 years) underwent the cVEMP testing based on the established protocol. The 500 Hz tone burst and NB CE-Chirp (centred at 500 Hz) stimuli were presented to each ear at an intensity level of 120.5 dB peSPL. P1 latency, N1 latency, and P1–N1 amplitude values were analysed accordingly. The NB CE-Chirp stimulus produced significantly shorter P1 and N1 latencies (p < 0.001) with large effect sizes (d > 0.80). In contrast, both stimuli elicited cVEMP responses with P1–N1 amplitude values that were not statistically different from one another (p = 0.157, d = 0.15). Additionally, age and hearing level were found to be significantly correlated (r = 0.56, p < 0.001), as were age and cVEMP amplitude for each stimulus (p < 0.001). To conclude, since both stimuli were presented at an equivalent intensity level (in dB peSPL), the shorter P1 and N1 latencies of cVEMP produced by the NB CE-Chirp stimulus (centred at 500 Hz) were unlikely due to enhanced saccular stimulation. Another more sensible reason is the temporal adjustment of the chirp stimulus.
Significance of LHCGR polymorphisms in polycystic ovary syndrome: an association study
Authors: Singh Sukhjashanpreet , Kaur Mandeep , Beri Archana , Kaur Anupam
Published: December 2023

This study was conducted to analyze the association of Luteinizing Hormone/Choriogonadotropin Receptor (LHCGR) gene rs4953616 and rs7371084 polymorphisms with the risk of polycystic ovary syndrome (PCOS) in Punjab, India. A total of 823 women (443 PCOS cases and 380 healthy controls) were enrolled in the present study. The polymerase chain reaction-restriction fragment length polymorphism technique (PCR–RFLP) was used for genotyping. Anthropometric parameters, lipid and hormonal profiles, were compared between the two groups. Demographic features were compared using Mann Whitney U test while the Chi-square test and odds ratios (ORs) were used to assess the genetic association and risk towards PCOS, respectively. A one-way analysis of variance (ANOVA) test was employed to analyze the correlation of genotypes with baseline parameters in PCOS cases. A statistically significant difference was revealed in the genotypic and allelic frequencies of rs4953616 polymorphism between PCOS cases and controls (p = 0.01 and p = 0.004, respectively). The mutant genotype (TT), mutant allele (T), and recessive model of rs4953616 polymorphism conferred 1.77, 1.3, and 1.5 times risk towards PCOS, respectively. No significant distribution for genotypes and alleles was found for rs7371084 in both groups (p = 0.25 and p = 0.26, respectively). In addition to dyslipidemia, PCOS women also had significantly higher body mass index (BMI) and waist-to-hip ratio (WHR), testosterone (T), and luteinizing hormone (LH). Upon haplotype analysis, the TT haplotype was found to be significantly associated with the increased risk of PCOS. Our results demonstrated a significant role of LHCGR rs4953616 polymorphism in the development of PCOS.
Intestinal dysbiosis as an intraoperative predictor of septic complications: evidence from human surgical cohorts and preclinical models of peritoneal sepsis
Authors: Spari Daniel , Zwicky Simone N. , Yilmaz Bahtiyar , Salm Lilian , Candinas Daniel , Beldi Guido
Published: December 2023

Major surgery exposes the intestinal microbiota to inflammatory and antibiotic stressors, which alter the microbiota composition of the intestinal lumen and fecal contents. However, it is not sufficiently understood, if such dysbiosis develops already during surgery and if alterations in microbiota may be the cause of surgical complications. End-of-surgery composition of the microbiota in the rectum was assessed in 41 patients undergoing either rectal or duodenopancreatic resection and was compared to baseline before surgery using 16S-rRNA sequencing. A subset of patients developed severe dysbiosis at the end of surgery, which was characterized by an overgrowth of the Proteobacteria phylum that includes the facultative pathogen E. coli. To test if dysbiosis impacts on surgical outcomes, dysbiosis was modeled in mice by a single oral administration of vancomycin prior to cecal ligation and puncture. Dysbiosis was associated with impaired post-surgical survival, dysregulation of the host’s immune response, elevated bacterial virulence and reduced bacterial metabolism of carbon sources. In conclusion, dysbiosis can be detected already at the end of surgery in a fraction of patients undergoing major surgery. Modelling surgery-associated dysbiosis in mice using single-shot administration of vancomycin induced dysbiosis and resulted in elevated mortality.
Investigation of SARS-CoV-2 individual proteins reveals the in vitro and in vivo immunogenicity of membrane protein
Authors: Haystead Timothy , Lee Eric , Cho Kirstin , Gullickson Gail , Hughes Philip , Krafsur Greta , Freeze Robert , Scarneo Scott
Published: December 2023

Evidence in SARS-CoV-2 patients have identified that viral infection is accompanied by the expression of inflammatory mediators by both immune and stromal cells within the pulmonary system. However, the immunogenicity of individual SARS-CoV-2 proteins has yet to be evaluated. The SARS-CoV-2 virus consists of 29 proteins, categorized either as nonstructural proteins (NSP’s), structural proteins (SP’s) or accessory proteins. Here we sought to evaluate the immunogenicity of NSP 1, 7, 8, 9, 10, 12, 14, 16 and the SP’s spike protein (full length, S1, S2 and receptor binding domain subunits), nucleocapsid and membrane SARS-CoV-2 proteins against THP-1 and human peripheral blood mononuclear cells (PBMCs). Our results indicate that various SARS-CoV-2 proteins elicit a proinflammatory immune response indicated by increases in cytokines TNF, IL-6 and IL-1β. Our results support that SARS-CoV-2 membrane protein induced a robust increase of TNF, IL-6, IL-1β and IL-10 expression in both THP-1 and human PBMC’s. Further evaluation of intranasal membrane protein challenge in male and female BALB/c mice show increases in BALF (bronchalveolar lavage fluid) proinflammatory cytokine expression, elevated cellularity, predominantly neutrophilic, and concomitant peribronchiolar and perivascular lymphomononuclear and neutrophilic inflammation. Our results suggest that individual membrane associated SARS-CoV-2 proteins induce a robust immune response that may contribute to viral induced cytokine release syndrome (CRS) in the lungs of moderate to severe COVID-19 patients. We posit that SARS-CoV-2 membrane challenges in immune-competent mice can serve as an adequate surrogate for the development of novel treatments for SARS-CoV-2 induced pulmonary inflammation, thereby avoiding expensive live virus studies under BSL-3 conditions.
A reliable benchmark of the last 640,000 years millennial climate variability
Authors: Rousseau Denis-Didier , Bagniewski Witold , Cheng Hai
Published: December 2023

How often have past climates undergone abrupt transitions? While our understanding of millennial variability during the past 130,000 years is well established, with precise dates available, such information on previous climate cycles is limited. To address this question, we identified 196 abrupt transitions in the δ18O record of the well-dated Chinese composite speleothem for the last 640,000 years. These results correspond to abrupt changes in the strength of the East Asian Monsoon, which align with the Greenland stadials and interstadials observed in the North Atlantic region during the last 130,000 years before present. These precise dates of past abrupt climate changes constitute a reliable and necessary benchmark for Earth System models used to study future climate scenarios.
Number agreement processing in adolescents with and without developmental language disorder (DLD): evidence from event-related brain potentials
Authors: Courteau Émilie , Royle Phaedra , Steinhauer Karsten
Published: December 2023

In morphologically richer languages, including French, one must learn the specific properties of number agreement in order to understand the language, and this learning process continues into adolescence. This study examined similarities and differences between French-speaking adolescents with and without developmental language disorder (DLD) when processing number agreement, and investigated how morpho-syntactic regularity affected language processing. Using event-related potentials (ERP) and only grammatical sentences with audio-visual mismatches, we studied ERP correlates to three types of number agreement: (1) regular determiner agreement in noun phrases, (2) regular subject-verb plural liaison, and (3) irregular subject-verb agreement. We also included a lexico-semantic mismatch condition to investigate lexico-semantic processing in our participants. 17 adolescents with DLD (M = 14.1 years) and 20 (pre)teens with typical language (TL, M = 12.2 years) participated in the study. Our results suggest three patterns. First, French-speaking teenagers without DLD are still consolidating their neurocognitive processing of morpho-syntactic number agreement and generally display ERP profiles typical of lower language proficiency than adult native speakers. Second, differences in morphosyntactic processing between teenagers with and without DLD seem to be limited to rule-based (regular) number agreement. Third, there is little evidence for corresponding differences in lexico-semantic processing.
Identification of differences in CD4+ T-cell gene expression between people with asthma and healthy controls
Authors: Tutino Mauro , Hankinson Jenny , Murray Clare , Lowe Lesley , Kerry Gina , Rattray Magnus , Custovic Adnan , Johnston Sebastian L. , Shi Chenfu , Orozco Gisela , Eyre Stephen , Martin Paul , Simpson Angela , Curtin John A.
Published: December 2023

Functional enrichment analysis of genome-wide association study (GWAS)-summary statistics has suggested that CD4+ T-cells play an important role in asthma pathogenesis. Despite this, CD4+ T-cells are under-represented in asthma transcriptome studies. To fill the gap, 3'-RNA-Seq was used to generate gene expression data on CD4+ T-cells (isolated within 2 h from collection) from peripheral blood from participants with well-controlled asthma (n = 32) and healthy controls (n = 11). Weighted Gene Co-expression Network Analysis (WGCNA) was used to identify sets of co-expressed genes (modules) associated with the asthma phenotype. We identified three modules associated with asthma, which are strongly enriched for GWAS-identified asthma genes, antigen processing/presentation and immune response to viral infections. Through integration of publicly available eQTL and GWAS summary statistics (colocalisation), and protein–protein interaction (PPI) data, we identified PTPRC, a potential druggable target, as a putative master regulator of the asthma gene-expression profiles. Using a co-expression network approach, with integration of external genetic and PPI data, we showed that CD4+ T-cells from peripheral blood from asthmatics have different expression profiles, albeit small in magnitude, compared to healthy controls, for sets of genes involved in immune response to viral infections (upregulated) and antigen processing/presentation (downregulated).
Early diagnosis and meta-agnostic model visualization of tuberculosis based on radiography images
Authors: Natarajan Sasikaladevi , Sampath Pradeepa , Arunachalam Revathi , Shanmuganathan Vimal , Dhiman Gaurav , Chakrabarti Prasun , Chakrabarti Tulika , Margala Martin
Published: December 2023

Despite being treatable and preventable, tuberculosis (TB) affected one-fourth of the world population in 2019, and it took the lives of 1.4 million people in 2019. It affected 1.2 million children around the world in the same year. As it is an infectious bacterial disease, the early diagnosis of TB prevents further transmission and increases the survival rate of the affected person. One of the standard diagnosis methods is the sputum culture test. Diagnosing and rapid sputum test results usually take one to eight weeks in 24 h. Using posterior-anterior chest radiographs (CXR) facilitates a rapid and more cost-effective early diagnosis of tuberculosis. Due to intraclass variations and interclass similarities in the images, TB prognosis from CXR is difficult. We proposed an early TB diagnosis system (tbXpert) based on deep learning methods. Deep Fused Linear Triangulation (FLT) is considered for CXR images to reconcile intraclass variation and interclass similarities. To improve the robustness of the prognosis approach, deep information must be obtained from the minimal radiation and uneven quality CXR images. The advanced FLT method accurately visualizes the infected region in the CXR without segmentation. Deep fused images are trained by the Deep learning network (DLN) with residual connections. The largest standard database, comprised of 3500 TB CXR images and 3500 normal CXR images, is utilized for training and validating the recommended model. Specificity, sensitivity, Accuracy, and AUC are estimated to determine the performance of the proposed systems. The proposed system demonstrates a maximum testing accuracy of 99.2%, a sensitivity of 98.9%, a specificity of 99.6%, a precision of 99.6%, and an AUC of 99.4%, all of which are pretty high when compared to current state-of-the-art deep learning approaches for the prognosis of tuberculosis. To lessen the radiologist’s time, effort, and reliance on the level of competence of the specialist, the suggested system named tbXpert can be deployed as a computer-aided diagnosis technique for tuberculosis.
Deep learning framework for automated goblet cell density analysis in in-vivo rabbit conjunctiva
Authors: Jang Seunghyun , Kim Seonghan , Lee Jungbin , Choi Wan Jae , Yoon Chang Ho , Yang Sejung , Kim Ki Hean
Published: December 2023

Goblet cells (GCs) in the conjunctiva are specialized epithelial cells secreting mucins for the mucus layer of protective tear film and playing immune tolerance functions for ocular surface health. Because GC loss is observed in various ocular surface diseases, GC examination is important for precision diagnosis. Moxifloxacin-based fluorescence microscopy (MBFM) was recently developed for non-invasive high-contrast GC visualization. MBFM showed promise for GC examination by high-speed large-area imaging and a robust analysis method is needed to provide GC information. In this study, we developed a deep learning framework for GC image analysis, named dual-channel attention U-Net (DCAU-Net). Dual-channel convolution was used both to extract the overall image texture and to acquire the GC morphological characteristics. A global channel attention module was adopted by combining attention algorithms and channel-wise pooling. DCAU-Net showed 93.1% GC segmentation accuracy and 94.3% GC density estimation accuracy. Further application to both normal and ocular surface damage rabbit models revealed the spatial variations of both GC density and size in normal rabbits and the decreases of both GC density and size in damage rabbit models during recovery after acute damage. The GC analysis results were consistent with histology. Together with the non-invasive high-contrast imaging method, DCAU-Net would provide GC information for the diagnosis of ocular surface diseases.
Development and implementation of the frog-in-maze game to study upper limb movement in people with Parkinson’s disease
Authors: Virmani Tuhin , Kemp Aaron S. , Pillai Lakshmi , Glover Aliyah , Spencer Horace , Larson-Prior Linda
Published: December 2023

Upper-limb bradykinesia occurs early in Parkinson’s disease (PD) and bradykinesia is required for diagnosis. Our goal was to develop, implement and validate a game “walking” a frog through a maze using bimanual, alternating finger-tapping movements to provide a salient, objective, and remotely monitorable method of tracking disease progression and response to therapy in PD. Twenty-five people with PD and 16 people without PD participated. Responses on 5 different mazes were quantified and compared to spatiotemporal gait parameters and standard disease metrics in these participants. Intertap interval (ITI) on maze 2 & 3, which included turns, was strongly inversely related to stride-length and stride-velocity and directly related to motor UPDRS scores. Levodopa decreased ITI, except in maze 4. PD participants with freezing of gait had longer ITI on all mazes. The responses quantified on maze 2 & 3 were related to disease severity and gait stride-length, were levodopa responsive, and were worse in people with freezing of gait, suggesting that these mazes could be used to quantify motor dysfunction in PD. Programming our frog-in-maze game onto a remotely distributable platform could provide a tool to monitor disease progression and therapeutic response in people with PD, including during clinical trials.