bluuebunny/crossref_metadata_2025 huggingface dataset:
The First Reported Case of a Child with Two Different Rare Metabolic Disorders: Very Long-Chain Acyl-CoA Dehydrogenase Deficiency and Encephalomyopathic Mitochondrial DNA Depletion Syndrome 13
Authors: Alotaibi Maha , Alqasmi Amal , Albassam Faisal , Alkahtani Turki , Alqahtany Muath , Alkhaldi Mohammed
Published: October 2023

One of the most common inborn errors in fatty acid β oxidation (FAO) is a very long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency. It is autosomal recessive. The enzyme used in the first phase of FAO is VLCAD. The enzyme is responsible for β oxidation spiral pathway's initial step, the dehydrogenation process of long-chain fatty acyl-CoA. The phenotypes include hypoglycemia, hepatomegaly, cardiomyopathy, and occasionally abrupt mortality. Most VLCAD deficiencies in newborns are now detected during the neonatal period due to the development of newborn screening programs. Mitochondrial DNA depletion syndromes (MTDPS) are one of the rarest metabolic disorders. It is an autosomal recessive disease caused by defects in genes necessary for the maintenance of mitochondrial DNA (mtDNA). One of these FBXL4 (F-box and leucine-rich repeat protein 4) variants causes encephalomyopathic mtDNA depletion syndrome 13 (MTDPS13), which presents as a failure to thrive, severe global developmental delay, hypotonia, early infantile onset of encephalopathy, and lactic acidosis. We report here the case of a Saudi infant born to consanguineous parents who presented to us with severe failure to thrive, profound neurodevelopmental delays, and facial dysmorphic features. Whole-exome sequencing (WES) showed the infants had MTDPS13. The FBXL4 variant c.1698A > G p. (Ile566Met) has previously been described as a disease that causes developmental delay and lactic acidosis, and another variant has also been detected in the patient. The ACADVL variant c.134C > A p. (Ser45*) has previously been described to cause VLCAD deficiency. A comprehensive literature review showed our patient to be the first case of MTDPS13 and VLCAD reported to date worldwide.
Mountain Lodges of Peru and Huacahuasi Community – A Joint Venture in the Sacred Valley
Authors: Seixas Jakeline Cibelle Santos
Published: October 2023

Incorporating local communities into tourism is key to the sector’s sustainable development. In some Andean communities of Peru, initiatives have been implemented to promote local development, protect the environment, and diversify the tourist offer, directly involving traditional communities in regions close to the trails that lead to Machu Picchu. One example is the partnership between the Huacahuasi community, located in the Lares region, and Mountain Lodges of Peru (MLP), a family-owned Peruvian company created in 2005. The joint venture between the Huacahuasi community and MLP gave rise to the Huacahuasi Lodge.

The activities related to the lodge play a significant role in the social and economic development of regional residents. This case study aims to shed light on the MLP integration and profit-sharing model with the Huacahuasi community, addressing the inception of the luxury lodges to the participation of the community, challenges, partnerships, initiatives, and prospects for the enterprise, the community, and tourism in Peru.

The content of this case study is the result of material obtained from interviews with MLP’s Sales and Marketing Manager in North America, Nadia Le Bon, who was happy to be named in this case study, research on the Adventure Travel Trade Association and Mountain Lodges of Peru websites, and other sources mentioned in the references.

Information

© The Author 2023
Near-zero-adhesion-enabled intact wafer-scale resist-transfer printing for high-fidelity nanofabrication on arbitrary substrates
Authors: Shu Zhiwen , Feng Bo , Liu Peng , Chen Lei , Liang Huikang , Chen Yiqin , Yu Jianwu , Duan Huigao
Published: October 2023

There is an urgent need for novel processes that can integrate different functional nanostructures onto specific substrates, so as to meet the fast-growing need for broad applications in nanoelectronics, nanophotonics, and flexible optoelectronics. Existing direct-lithography methods are difficult to use on flexible, nonplanar, and biocompatible surfaces. Therefore, this fabrication is usually accomplished by nanotransfer printing. However, large-scale integration of multiscale nanostructures with unconventional substrates remains challenging because fabrication yields and quality are often limited by the resolution, uniformity, adhesivity, and integrity of the nanostructures formed by direct transfer. Here, we proposed a resist-based transfer strategy enabled by near-zero adhesion, which was achieved by molecular modification to attain a critical surface energy interval. This approach enabled the intact transfer of wafer-scale, ultrathin-resist nanofilms onto arbitrary substrates with mitigated cracking and wrinkling, thereby facilitating the in situ fabrication of nanostructures for functional devices. Applying this approach, fabrication of three-dimensional-stacked multilayer structures with enhanced functionalities, nanoplasmonic structures with ∼10 nm resolution, and MoS2-based devices with excellent performance was demonstrated on specific substrates. These results collectively demonstrated the high stability, reliability, and throughput of our strategy for optical and electronic device applications.
Case Report: concurrent myocardial and cerebral infarction due to aortic thrombus
Authors: Thurston Alexander J F , Chapman Andrew R , Bing Rong
Published: October 2023

Background

Aortic mural thrombus is a rare acute aortic syndrome that can present with embolism to a distal organ. No guidelines or randomized evidence exist to guide therapy for patients with aortic mural thrombus. Cardiac and cerebral embolism is a particularly unusual presentation of aortic thrombus but has significant implications for patient management.

Case summary

We present an unusual case of a young patient with simultaneous embolization of aortic thrombus to the coronary and cerebral vasculature, causing cerebral infarcts and a myocardial infarction. He presented with chest pain, slurred speech, right homonymous hemianopia, and inferior ST-elevation on electrocardiogram (ECG). Bedside echocardiography identified an inferoseptal regional wall motion abnormality. Emergent computerised tomography (CT) brain and aorta showed acute cerebral infarcts and aortic mural thrombus. He was managed medically with anticoagulation and discharged without disability after a period of rehabilitation.

Discussion

This case demonstrates the value of careful clinical assessment in the setting of ST-elevation prior to transferring a patient for invasive angiography, as well as highlighting the role of echocardiography and CT imaging in the diagnosis of acute aortic syndromes. We describe the various management options for aortic mural thrombus, the role of multi-disciplinary decision-making, and our rationale for selecting a strategy of anticoagulation.
Green LED irradiation promotes the quality of cabbage through delaying senescence and regulating glucosinolate metabolism
Authors: Guo Feng , Zhou Hongsheng , Hu Huali , Zhang Yingtong , Ling Jun , Liu Xuesong , Luo Shufen , Li Pengxia
Published: October 2023

Light-emitting diode (LED) irradiation can affect postharvest vegetable and fruit shelf life and nutritional quality. In this study, 11 kinds of glucosinolates (GLS) and 6 types of GLS breakdown products were identified in cabbage leaves. To investigate the effects of LED irradiation on quality and GLS metabolism, postharvest cabbage was irradiated with 25 μmol/(m2·s) green LED (GL) light at room temperature for 12 d. The dark condition and natural light were used as controls. GL irradiation inhibited the respiration rate and the accumulation of malondialdehyde, and maintained higher cabbage sensory score, chlorophyll content, and antioxidant enzyme activities, thus extending its postharvest shelf life. Additionally, GL irradiation promoted GLS profile accumulation, including glucoraphanin, glucoiberin, gluconapin, gluconasturtiin, glucobrassicin, and sinigrin, which could have resulted from upregulated expression of the transcription factors MYB28 and MYB51, and the key genes involved in GLS biosynthesis (CYP83A1, CYP83B1, ST5b, and UGT74B1). Furthermore, GLS degradation was promoted by this treatment during the late stage of shelf life, as higher myrosinase activity and relative MYR and ESM expression levels were found in treated cabbage leaves, resulting in higher isothiocyanate (ITC) and indole-3-carbinol contents after day 6. Therefore, GL irradiation was beneficial for cabbage preservation.
How Did COVID-19 Affect Mental Health and Access to Care in Persons With Inflammatory Bowel Disease
Authors: Shaffer Seth R
Published: October 2023

The coronavirus disease pandemic globally affected public health and the world economy, leading to an increase in mental health symptoms, thought to be due in part to periods of quarantining, restrictions, and other interventions used to curb ongoing transmission of the virus. It is well established that persons with inflammatory bowel disease (IBD) have significantly higher rates of depression and anxiety than the general population and that mental health symptoms can exacerbate disease severity. For persons with IBD, psychological distress was correlated with challenges in accessing medical care. In the early stages of the pandemic, endoscopy suites were closed, leading to fewer colonoscopies, although this rebounded the following year. This likely led to fewer diagnoses of IBD initially as people avoided the health care system, and also a reduction in IBD-related dysplasia being detected during colonoscopy. Many hospitals and health care clinics adjusted by delivering telemedicine for ambulatory care. Persons with IBD had increased stress about accessing both their health care provider and gastroenterologist during the pandemic, although many had increased satisfaction with the level of care they received virtually. Telemedicine is now being used in most clinics in conjunction with in-person care, to help deliver care, and can be cost-effective. Additional research is needed to assess whether heightened levels of mental health symptoms have led to worsening disease activity, and further, if a delay in health care access including colonoscopies and surgeries, or the perceived decreased access to health care professionals for some will have detrimentally affected the disease course for persons with IBD.
Factors Associated With Serial Lipase Measurement in Hospitalized Patients With Acute Pancreatitis
Authors: Gurakar Merve , Faghih Mahya , Akshintala Venkata S. , Bhullar Furqan A. , Kanthasamy Kavin , Khashab Mouen A. , Kamal Ayesha , Zaheer Atif , He Jin , Afghani Elham , Singh Vikesh K.
Published: October 2023

Objectives

To determine the factors associated with serial lipase measurement in patients with acute pancreatitis (AP).

Methods

Patients admitted to Johns Hopkins Health System between September 2019 and August 2020 with lipase ≥3 times upper limit normal were prospectively identified. Acute pancreatitis was defined using revised Atlanta criteria. Serial lipase measurement was defined as >2 lipase measurements on consecutive days within 7 days of presentation.

Results

There were 294 patients with AP with mean age 52.4 ± 16 years (SD), and 155 (52.7%) were male. A total of 227 (77.2%) were admitted to a medical service. There were 111 (37.7%) who underwent serial lipase measurements. There were 89 (30.8%), 36 (12.2%), 6 (1%), and 40 (13.6%) patients with systemic inflammatory response syndrome at time of initial lipase measurement, persistent organ failure, necrosis on admission, and intensive care unit admission. Serial lipase measurements were more likely to be obtained in patients admitted to surgical services (odds ratio, 4.3; 95% confidence interval, 1.4–13.2; P = 0.01) and nontertiary hospitals (odds ratio, 1.8; 95% confidence interval, 1.0–2.9; P = 0.04).

Conclusion

More than one-third of AP patients undergo serial lipase measurements. This practice is more likely to occur on surgical services and in nontertiary hospitals.
Effect of exercise on fatigue in patients receiving maintenance hemodialysis treatment: A systematic review and network meta-analysis
Authors: Lu Xianying , Yang Jing , Bai Dingxi , Wu Chenxi , Cai Mingjin , Wang Wei , He Jiali , Gong Xiaoyan , Gao Jing , Hou Chaoming
Published: October 2023

Objective

This study aimed to evaluate the effect of different exercises for improving fatigue in maintenance hemodialysis patients.

Design

PubMed, Embase, Web of Science, Cochrane, PEDro, CNKI, VIP, Wanfang data, CBM, and CINAHL were conducted from the establishment of the database to July 2023. We independently screened the literature, evaluated the quality, analyzed the data using Stata 15.0, and performed subgroup analysis on intervention time and exercise intervention adherence.

Results

Twenty-three studies were analyzed, with 1,867 patients and nine interventions. Based on the surface under cumulative ranking curves (SUCRA) and pairwise comparisons effects, overall long-term, short-term, and exercise intervention adherence >90% effects have all presented that during dialysis aerobic-resistance combined exercise (DDAR) was ranked as the most effective compared with routine care (SUCRC: 83.9%, SMD = -1.45, 95% CI (-2.23, -0.67); SUCRC: 85.9%, SMD = -1.38, 95% CI (-2.24, -0.52); SUCRC: 86.6%, SMD = -1.54, 95%CI (-2.58, -0.49); SUCRC: 83.6%, SMD = -1.45, 95% CI (-2.25, -0.66), respectively), followed by interdialytic period muscle relaxation exercise, interdialytic period aerobic-resistance combined exercise, interdialytic period aerobic exercise, and interdialytic period Baduanjin.

Conclusion

DDAR may be considered in practice when resources allow. However, high-quality, multi-center, and large-sample randomized control trials must further verify this conclusion.
Reciprocal regulation of NagC and quorum sensing systems and their roles in hmsHFRS expression and biofilm formation in Yersinia pseudotuberculosis
Authors: Wiechmann Anja , Garcia Vanina , Elton Linzy , Williams Paul , Atkinson Steve
Published: October 2023

Biofilm formation by

Yersinia pseudotuberculosis

is regulated by quorum sensing (QS) and dependent on the haemin storage locus hms, required for the extracellular polysaccharide poly-N-acetylglucosamine (poly-GlcNAc) production. In

Escherichia coli

NagC regulates both GlcNAc biosynthesis and metabolism with GlcNAc acting as a signal that co-ordinates these and other activities. However, the contribution of NagC and GlcNAc to biofilm development in

Y. pseudotuberculosis

is not known. Here we show that a Y. pseudotuberculosis nagC mutant is impaired for biofilm production on abiotic (glass) and biotic (Caenorhabitis elegans) surfaces. Genetic complementation restored poly-GlcNAc production and biofilm formation on C. elegans. Using lux-based promoter fusions, hmsHFRS expression was found to be nagC dependent. Given that NagC and QS both regulate aggregation and biofilm formation, we investigated their regulatory relationship using lux-based promoter fusions. These revealed that (i) nagC is negatively autoregulated, but expression can be partially restored in the nagC mutant by exogenous GlcNAc, (ii) NagC negatively regulates the ytbI and ypsI QS genes and (iii) nagC expression is reduced in the ytbI, ypsI and ypsR mutants but not the ytbR mutant. These data establish the existence of a reciprocal regulatory relationship between NagC and QS, which in the case of the luxRI pair ytbRI, is also GlcNAc-dependent. NagC and GlcNAc are therefore components of a regulatory system involving QS that modulates biofilm formation and aggregation.
The human LIN28B nucleosome is inherently pre-positioned for efficient binding of multiple OCT4s without H3 K27 acetylation
Authors: Lian Tengfei , Guan Ruifang , Zhou Bing-Rui , Bai Yawen
Published: October 2023

Pioneer transcription factors possess the unique ability to access DNA within tightly packed chromatin structures, playing pivotal roles in cell differentiation and reprogramming. However, their precise mechanism for recognizing nucleosomes has remained mystery. Recent structural and biochemical investigations into the binding interactions between the human pioneer factor OCT4 and the LIN28B nucleosome by Sinha et al.1and Guan et al.2have yielded conflicting results regarding nucleosome positioning, nucleosomal DNA unwrapping, binding cooperativity, and the role of N-terminal tail of OCT4. In this study, we undertook a comparative analysis of these two research efforts and delved into the factors contributing to the observed discrepancies. Our investigation unveiled that the utilization of human and Xenopus laevis core histones, along with a discrete two-step salt dialysis method, led to distinct positioning of DNA within reconstituted LIN28B nucleosomes. Additionally, our reanalysis of the electrophoretic mobility shift assay data showed that H3 K27 acetylation did not increase OCT4 binding to the internal sites of the nucleosome when normalized to input; instead, it promoted sample aggregation. Thus, the available experimental data support the notion that the human LIN28B nucleosome is pre-positioned for efficient binding with multiple OCT4s, and there is no compelling evidence for its regulation by histone modifications.
Merging-limited coarsening governs long-term stability of nanoscale condensates
Authors: Chen Feipeng , Zhang Yaojun , Shum Ho Cheung
Published: October 2023

Droplet coarsening occurs in a variety of fields, characterized by the spontaneous growth of smaller droplets into larger ones to minimize their interfacial free energy and achieve global thermodynamic equilibrium. However, recent studies revealed that the coarsening is much suppressed in living cells where nanoscale biomolecular condensates with droplet-like behaviors maintain stable sizes over extended time periods. The mechanism underpinning such long-term stability of condensates remains poorly understood. Here, we experimentally observe that coacervate droplets of small sizes (tens to hundreds of nanometers) remain stable over hours with significantly slower coarsening rates than predicted by classic theories. Using scaling analysis and Monte Carlo simulations, we demonstrate that the anomalously stable coacervates can be explained by a merging-limited coarsening (MLC), in which merging probability among coacervates of sizes smaller than a critical valuebecomes markedly low, whereηis the internal viscosity and γ is the interfacial tension of droplets. We further develop an analytical model that quantitatively captures the coarsening dynamics of coacervates across different experimental conditions. More broadly, by constructing a viscosity-interfacial tension diagram, we find that many biological condensates intrinsically exhibit large critical sizes, making them prone to undergo slow coarsening through the MLC mechanism. Such merging-limited coarsening may represent a universal mechanism underlying condensate size control in synthetic systems and living cells.
Transposon-triggered epigenetic chromatin dynamics modulate EFR-related pathogen response
Authors: Mencia Regina , Arce Agustín L. , Houriet Candela , Xian Wenfei , Contreras Adrián , Shirsekar Gautam , Weigel Detlef , Manavella Pablo A.
Published: October 2023

Infectious diseases drive the evolution of wild plants and impact yield in crop plants. Like animals, plants can sense biotic threats via conserved pathogen-associated patterns (PAMPs). Since an overly robust immune response can harm plants, understanding the mechanisms for tuning defense responses to the appropriate level is vital as we endeavor to develop pathogen-resistant crops. In this paper, we studied the Arabidopsis pattern recognition receptor (PRR) EFR, which senses bacterial EF-Tu. An inverted-repeat transposon (Ea-IR) betweenEFRand the neighboringXI-klocus controls local chromatin organization, promoting the formation of a repressive chromatin loop. Upon pathogen infection, the chromatin landscape aroundEFRandXl-kdynamically changes to allow for increasedEFRtranscription. Chromatin opening facilitates the passage of RNA polymerase II across the neighboringXI-kgene termination site, leading to a longerXI-ktranscript that includesEa-IRsequences. Dicer-like (DCL) enzymes process the longer Xl-k transcript into small RNAs (sRNAs), which reset chromatin topology to a repressive state, attenuating, in turn, the immune response, reminiscent of attenuation of receptor signaling in other systems. From an evolutionary point of view, we found that natural Arabidopsis accessions missingEa-IRhave a constitutive "EFR-open" chromatin configuration that correlates with higher basal EFR levels and higher background resistance to pathogens. Collectively, our study offers evidence for a scenario in which a transposon, chromatin organization, and gene expression interact to fine-tune immune responses, both during the course of infection and in the course of evolution. Similar gene-associated IRs in crops could provide valuable non-coding targets for genome editing or assisted plant breeding programs.
Combinatorial cooperativity can facilitate epithelial-mesenchymal transition in a miR200-Zeb feedback network
Authors: Rashid Mubasher , Devi Brasanna M , Banerjee Malay
Published: October 2023

Carcinoma cells often utilize epithelial-mesenchymal transition (EMT) programs for cancer progression and metastasis. Numerous studies point to the SNAIL-induced miR200/Zeb feedback circuit as crucial in regulating EMT by shifting cancer cells to at least three (epithelial (E), hybrid (h E/M), mesenchymal (M)) phenotypic states arrayed along the epithelial-mesenchymal phenotypic spectrum. However, a coherent molecular-level understanding of how such a tiny circuit controls carcinoma cell entrance into and residence in various states is lacking. Here, we use molecular binding data and mathematical modeling to report that miR200/Zeb circuit can essentially utilize combinatorial cooperativity to control E-M phenotypic plasticity. We identify minimal combinatorial cooperativities that give rise to E, hybrid-E/M, and M phenotypes. We show that disrupting a specific number of miR200 binding sites on Zeb as well as Zeb binding sites on miR200 can have phenotypic consequences – the circuit can dynamically switch between two (E, M) and three (E, hybrid-E/M, M) phenotypes. Further, we report that in both SNAIL-induced and SNAIL knock-out miR200/Zeb circuits, cooperative transcriptional feedback on Zeb as well as Zeb translational inhibition due to miR200 are essential for the occurrence of intermediate hybrid-E/M phenotype. Finally, we demonstrate that SNAIL can be dispensable for EMT, and in the absence of SNAIL, the transcriptional feedback can control cell state transition from E to hybrid-E/M, to M state. Our results thus highlight molecular-level regulation of EMT in miR200/Zeb circuit and we expect these findings to be crucial to future efforts aiming to prevent EMT-facilitated dissemination of carcinomas.
NOXA/MCL-1 axis determines cell-death decision between apoptosis and pyroptosis and the inflammatory secretome of breast cancer cells treated with anti-mitotics
Authors: Dumont Alison , Gautier Fabien , Batard Quentin , Guette Catherine , Guillonneau François , Campone Mario , Juin Philippe , Barillé-Nion Sophie
Published: October 2023

Understanding how the malignant cells respond to chemotherapy is essential to prevent the development of resistance and to improve the efficiency of anti-cancer drugs. Recently, we established that, by intrinsic and paracrine mechanisms, taxol treatment in breast tumor cells increases NOXA a pro-apoptotic protein functioning as an endogenous inhibitor of survival protein MCL-1, thereby enhancing cytotoxic load on the compensatory survival protein BCL-xL. We herein sought to define the contribution of NOXA/MCL-1 to the modality of cell death secretome composition upon anti-mitotic treatment associated with a BCL-xL antagonist.

We observed that genetic inactivation of NOXA (enforcing MCL-1 pro-survival activity) in cancer cells not only delays their death when exposed to taxol in combination with the BCL-xL antagonist A1331852, but also alters its morphological characteristics with the apparition of features evoking pyroptosis. We identified the Caspase3-GSDME axis as regulating pyroptotic-like features suggesting that NOXA may act as a negative regulator of this cell death process (and MCL-1 as a positive regulator for it). Furthermore, comparative analysis of secretomes from the NOXA proficient or deficient cancer cells treated by taxol reveals variations in inflammatory cytokine production including those of IL-1β and IL-18.

Thus, our results show that anti-mitotic treatments are able to induce death by apoptosis and/or pyroptosis depending on BCL-2 family balance in breast cancer cells. Furthermore, NOXA/MCL-1 ratio appears to control the communication between these two types of cell death and their associated extracellular inflammatory signals in coordination with the pore-forming gasdermin GSDME.
Microglia facilitate and stabilize the response to general anesthesia
Authors: He Yang , Liu Taohui , He Quansheng , Ke Wei , Li Xiaoyu , Du Jinjin , Deng Suixin , Shu Zhenfeng , Wu Jialin , Yang Baozhi , Wang Yuqing , Mao Ying , Rao Yanxia , Shu Yousheng , Peng Bo
Published: October 2023

General anesthesia leads to a loss of consciousness and an unarousable state in patients. Although general anesthetics are widely used in clinical practice, their underlying mechanisms remain elusive. The potential involvement of nonneuronal cells is unknown. Microglia are important immune cells in the central nervous system (CNS) that play critical roles in CNS function and dysfunction. We unintentionally observed delayed anesthesia induction and early anesthesia emergence in microglia-depleted mice. We found that microglial depletion differentially regulates neuronal activities by suppressing the neuronal network of anesthesia-activated brain regions and activating emergence-activated brain regions. Thus, microglia facilitate and stabilize the anesthesia status. This influence is not mediated by dendritic spine plasticity. Instead, it relies on the activation of microglial P2Y12 and subsequent calcium influx, which facilitates the general anesthesia response. Together, we elucidate the regulatory role of microglia in general anesthesia, extending our knowledge of how nonneuronal cells modulate neuronal activities.
A metagenomics pipeline reveals insertion sequence-driven evolution of the microbiota
Authors: Kirsch Joshua M. , Hryckowian Andrew J. , Duerkop Breck A.
Published: October 2023

Insertion sequence (IS) elements are mobile genetic elements in bacterial genomes that support adaptation. We developed a database of IS elements coupled to a computational pipeline that identifies IS element insertions in the microbiota. We discovered that diverse IS elements insert into the genomes of intestinal bacteria regardless of human host lifestyle. These insertions target bacterial accessory genes that aid in their adaptation to unique environmental conditions. Using IS expansion inBacteroides, we show that IS activity leads to insertion “hot spots” in accessory genes. We show that IS insertions are stable and can be transferred between humans. Extreme environmental perturbations force IS elements to fall out of the microbiota and many fail to rebound following homeostasis. Our work shows that IS elements drive bacterial genome diversification within the microbiota and establishes a framework for understanding how strain level variation within the microbiota impacts human health.
Suppression of epithelial proliferation and tumourigenesis by immunoglobulin A
Authors: Donaldson Gregory P. , Reis Gabriella L. , Saad Marwa , Wichmann Christopher , Mamede Izabela , Chen Guo , DelGaudio Nicole L. , Zhang Dayu , Aydin Begüm , Harrer Caroline E. , Castro Tiago B.R. , Grivennikov Sergei , Reis Bernardo S. , Stadtmueller Beth M. , Victora Gabriel D. , Mucida Daniel
Published: October 2023

Immunoglobulin A (IgA) is the most abundant antibody isotype produced across mammals and plays a specialized role in mucosal homeostasis1. Constantly secreted into the lumen of the intestine, IgA binds commensal microbiota to regulate their colonization and function2,3with unclear implications for health. IgA deficiency is common in humans but is difficult to study due to its complex aetiology and comorbidities4–8. Using genetically and environmentally controlled mice, here we show that IgA-deficient animals have increased susceptibility to endogenous colorectal tumours. Cellular and molecular analyses revealed that, in the absence of IgA, colonic epithelial cells induce antibacterial factors and accelerate cell cycling in response to the microbiota. Oral treatment with IgA was sufficient to both reduce steady-state proliferation and protect mice from tumours, but this function was due to antibody structure rather than binding specificity. In both organoid and monolayer culture systems, IgA directly suppressed epithelial growth. Co-immunoprecipitation mass spectrometry and a targeted CRISPR screen identified DMBT1 as an IgA-binding epithelial surface protein required for IgA-mediated suppression of proliferation. Together, IgA and DMBT1 regulate Notch signalling and tune the normal cycling of absorptive colonocyte progenitors. In mice, deleting the transmembrane and cytoplasmic signalling portions of DMBT1 or blocking Notch signalling was sufficient to reverse both the increased proliferation and tumour susceptibility of IgA knockouts. These experiments establish a homeostatic function for IgA in tempering physiological epithelial responses to microbiota to maintain mucosal health.
A coarse-grained model of glycosaminoglycans for biomolecular simulations
Authors: Shivgan Aishwary T. , Marzinek Jan K. , Krah Alexander , Matsudaira Paul , Verma Chandra S. , Bond Peter J.
Published: October 2023

Proteoglycans contain glycosaminoglycans (GAGs), negatively charged linear polymers made of repeating disaccharide units of uronic acid and hexosamine units. They play vital roles in numerous physiological and pathological processes, particularly governing cellular communication and attachment. Depending on their sulphonation state, acetylation, and glycosidic linkages, GAGs belong to different families. The high molecular weight, heterogeneity, and flexibility of GAGs hampers their characterization at atomic resolution, but this may be circumvented via coarse-grained (CG) approaches. In this work, we report a CG model for a library of common GAG types in their isolated or proteoglycan-linked states compatible with the widely popular CG Martini forcefields (versions 2.2 and 3.0). The model reproduces conformational and thermodynamic properties for a wide variety of GAGs, as well as matching structural and binding data for selected proteoglycan test systems. The parameters developed here may thus be employed to study a range of GAG-containing biomolecular systems, benefitting from the efficiency and broad applicability of the Martini framework.
YY2/BUB3 axis-mediated SAC hyperactivity determines tumor cell fate through chromosomal instability
Authors: Hosea Rendy , Duan Wei , Meliala Ian Timothy Sembiring , Li Wenfang , Wei Mankun , Hillary Sharon , Zhao Hezhao , Miyagishi Makoto , Wu Shourong , Kasim Vivi
Published: October 2023

Spindle assembly checkpoint (SAC) is a crucial safeguard mechanism of mitosis fidelity, which is fundamental for equal division of duplicated chromosomes to the two progeny cells. Impaired SAC can lead to chromosomal instability (CIN), a well-recognized hallmark of cancer that facilitates tumor progression; paradoxically, high CIN levels are associated with better drug sensitivity and prognosis. However, the mechanism by which CIN determines tumor cell fates and drug sensitivity remain poorly understood. In this study, using a cross-omics approach, we identified YY2 as a mitotic regulator that peaks at M phase and promotes SAC activity by positively regulating the transcriptional activity ofbudding uninhibited by benzimidazole 3(BUB3), a component of SAC. While inducing CIN, YY2/SAC activity defect enhanced mitosis and tumor growth, whereas YY2/SAC hyperactivation, as a result ofYY2overexpression, triggered mitotic delay and growth suppression. Furthermore, we revealed that excessive CIN, caused by eitherYY2overexpression or further inhibiting SAC activity inYY2-knocked out cells, leads to higher cell death rates. However, residual tumor cells that survived DNA damage-based therapy had moderate CIN and increased drug resistance; meanwhileYY2overexpression in these cells sensitizes them to DNA-damage agents. Hence, this study provides insights into the regulatory mechanism of SAC activity as well as the role of YY2/BUB3 axis, SAC activity, and CIN levels in determining tumor cell fate. Furthermore, this study also links up tumor cells drug resistance with moderate CIN, and suggest a novel anti-tumor therapeutic strategy that combines SAC activity modulators and DNA-damage agents.

Significance

This study identifies the novel role of YY2/BUB3 axis as a SAC modulator, as well as emphasizing the role of YY2-mediated SAC activity and CIN levels in determining tumor cell fates.
Genetic Association ofCYP1A2Gene Variant (rs762551) with Caffeine Induced-Hypertension Susceptibility and Cytochrome P450 1A2 Protein Analyses
Authors: Amjad Gulsher , Saif Rashid , Hussain Mehnaz Ghulam
Published: October 2023

High blood pressure is one of the most common illnesses affecting the Pakistani population due to, but not limited to, dietary habits, sedentary lifestyle and socio-economic aspects which have devastating effects on human health and general well-being. Caffeine is metabolized by CYP1A2 which results in lowered blood pressure while its retention in case of low metabolism may lead to hypertension. This phenomenon occurs because caffeine and its metabolites block A1 receptors in the kidney lowering the function of adenosine in blood pressure regulation. Current research aimed to demonstrate the genetic association ofCYP1A2gene variant 15:74749576C>A (C allele lowering CYP1A2 activity) within caffeine induced hypertensive individuals of Pakistani origin using ARMS-PCR. This pilot scale study revealed that overall, 8%, 56% and 36% sampled population (n=50) is homozygous wild-type (C/C), heterozygous (C/A) and homozygous mutant (A/A) respectively. Similarly, alternative allele frequency is 0.28 and 0.48 in cases and controls. Chi-square (χ2) association test using PLINK data analysis toolset was applied which showed significant results of χ2(2,N= 50) = 4.244,p= 0.039. Hardy Weinberg Equilibrium analysis was also applied which establishes that sampled population is obeying the principle withp-valueof 0.241. Moreover, odds-ratio depicts that the mutant allele is 0.42 times less prevalent in cases vs. controls. A few bioinformatics tools were employed e.g., ProtParam, PsiPred, PDB-RCSB, Motif finder, CTU-TMHMM-2.0, ScanProsite, GPS PAIL2.0, PRmePRed, NetOGlyc4.0, NetPhos3, SIFT analysis and STRING database in order to predict physicochemical properties, secondary structure, 3-dimensional structure, conserved motifs, transmembrane structure, post-translational modifications, protein variants impact on its function and protein-protein interactions respectively. The current endeavor attempted to provide the genetic architecture of the aforementioned variant in this case-control study in Pakistani individuals, which can pave paths of preventive medicine initiatives through genetic counsel of the masses.
Multiunit frontal eye field activity codes the visuomotor transformation, but not gaze prediction or target memory, in a delayed saccade task
Authors: Seo Serah , Bharmauria Vishal , Schütz Adrian , Yan Xiaogang , Wang Hongying , Crawford J. Douglas
Published: October 2023

Single-unit (SU) activity − action potentials isolated from one neuron — has traditionally been employed to relate neuronal activity to behavior. However, recent investigations have shown that multi-unit (MU) activity − ensemble neural activity recorded within the vicinity of one microelectrode − may also contain accurate estimations of task-related neural population dynamics. Here, using a well-established model-fitting approach, we compared the spatial codes of SU response fields with corresponding MU response fields recorded from the frontal eye fields (FEF) in head-unrestrained monkeys (Macaca mulatta) during a memory-guided saccade task. We focused on characterizing the visuomotor transformation from Target-in-Eye coordinates to future Gaze-in-Eye coordinates (Sajad et al., 2015). Most SUvisualresponse fields coded targets (with some predicting Gaze), whereas the MU population only coded targets. Most SUmotorresponses coded Gaze, but many still retained a target code. In contrast, MU motor activity predominantly coded Gaze with very little target coding. Finally, both SU and MU populations showed a progressive transition through intermediate ‘Target-to-Gaze’ codes during the delay period, but the MU activity showed a ‘smoother’ transition. These results confirm the theoretical and practical potential of MU activity recordings as a biomarker for fundamental sensorimotor transformations (e.g., Target-to-Gaze coding in the oculomotor system), while also highlighting the importance of SU activity for coding more cognitive (e.g., predictive / memory) aspects of sensorimotor behavior.

SIGNIFICANCE STATEMENT

Multi-unit recordings (undifferentiated signals from several neurons) are relatively easy to record and provide a simplified estimate of neural dynamics, but it is not clear which single-unit signals are retained, amplified, or lost. Here, we compared single-/multi-unit activity from a well-defined structure (the frontal eye fields) and behavior (memory-delay saccade task), tracking their spatial codes through time. The progressive transformation from target to gaze coding observed in single-unit activity was retained in multi-unit activity, but gaze prediction (in the visual response) and target memory (in the motor response) were lost. This suggests that multi-unit activity provides an excellent biomarker for healthy sensorimotor transformations, at the cost of missing more subtle cognitive signals.
Graphite: painting genomes using a colored De Bruijn graph
Authors: Beeloo Rick , Zomer Aldert L. , Dutilh Bas E.
Published: October 2023

The recent growth of microbial sequence data allows comparisons at unprecedented scales, enabling tracking of strains, mobile genetic elements, or genes. Querying a genome against a large reference database can easily yield thousands of matches that are tedious to interpret and pose computational challenges. We developed Graphite that uses a colored De Bruijn graph (cDBG) to paint query genomes, selecting the local best matches along the full query length. By focusing on the closest genomic match of each query region, Graphite reduces the number of matches while providing promising leads for genomic forensics. When applied to hundreds ofCampylobactergenomes we found extensive gene sharing, including a previously undetectedC. coliplasmid that matched aC. jejunichromosome. Together, genome painting using cDBGs as enabled by Graphite, can reveal new biological phenomena by mitigating computational hurdles. Graphite is implemented in Julia, available athttps://github.com/MGXlab/Graphite.
Thymically imprinted differential responsivity of naïve CD4 T cells to IL2 results in a heterogeneity of both Treg induction and subsequent effector functioning
Authors: Pennock Nathan D. , Qian Yamin , Ishihara Kazumi , Nakamura Yamami , Cross Eric , Sakaguchi Shimon , White Jason T.
Published: October 2023

Thymic selection predisposes naive T cells to particular outcomes when challenged later with cognate antigen, whether the antigen is self or foreign. This suggests that there is an inherent heterogeneity of functioning among T cells within the naive population (both CD4 and CD8s), and that each T cell, as part of its thymic development, is given a certain ‘programming’ which will affect its eventual fate decisions. In this project, we looked at the primary effects of this thymic imprinting on the conversion of naïve CD4 T cells into Tregs. Further, using an induced-Treg-reporter system, we exam the impact of thymic imprinted heterogeneity on effector functionality and identity stability. We report that naïve T cell differential responsivity to cytokines leads to the observed difference in Treg induction, and that the Tregs induced from T cells of different self-affinities maintain a heterogeneity of effector function and identity.
Genetic and pharmacologic alterations of claudin9 levels suffice to induce functional and mature inner hair cells
Authors: Chen Yingying , Lee Jeong Han , Li Jin , Park Seojin , Perez Flores Maria C. , Peguero Braulio , Kersigo Jennifer , Kang Mincheol , Choi Jinsil , Levine Lauren , Gratton Michael Anne , Fritzsch Bernd , Yamoah Ebenezer N.
Published: October 2023

Hearing loss is the most common form of sensory deficit. It occurs predominantly due to hair cell (HC) loss. Mammalian HCs are terminally differentiated by birth, making HC loss challenging to replace. Here, we show the pharmacogenetic downregulation ofCldn9, a tight junction protein, generates robust supernumerary inner HCs (IHCs) in mice. The ectopic IHC shared functional and synaptic features akin to typical IHCs and were surprisingly and remarkably preserved for at least fifteen months >50% of the mouse’s life cycle.In vivo,Cldn9knockdown using shRNA on postnatal days (P) P2-7 yielded analogous functional ectopic IHCs that were equally durably conserved. The findings suggest that Cldn9 levels coordinate embryonic and postnatal HC differentiation, making it a viable target for altering IHC development pre- and post-terminal differentiation.
Lethal COVID-19 Associates With RAAS-Induced Inflammation For Multiple Organ Damage Including Mediastinal Lymph Nodes
Authors: Guarnieri Joseph W. , Topper Michael J. , Beigel Katherine , Haltom Jeffrey A. , Chadburn Amy , Frere Justin , An Julia , Cope Henry , Borczuk Alain , Sinha Saloni , Lim Christine , Kim JangKeun , Park Jiwoon , Meydan Cem , Foox Jonathan , Mozsary Christopher , Bram Yaron , Richard Stephanie , Epsi Nusrat J. , Agan Brian , Chenoweth Josh , Simons Mark , Tribble David , Burgess Timothy , Dalgard Clifton , Heise Mark T. , Moorman Nathaniel J. , Baxter Victoria K. , Madden Emily A. , Taft-Benz Sharon A. , Anderson Elizabeth J. , Sanders Wes A. , Dickmander Rebekah J. , Widjaja Gabrielle A , Janssen Kevin , Lie Timmy , Murdock Deborah , Angelin Alessia , Albrecht Yentli Soto , Olali Arnold , Cen Zimu , Dybas Joseph , Priebe Waldemar , Emmett Mark R. , Best Sonja M. , Johnson Maya Kelsey , Trovao Nidia S. , Clark Kevin B. , Zaksas Victoria , Meller Rob , Grabham Peter , Schisler Jonathan C. , Moraes-Vieira Pedro M. , Pollett Simon , Mason Christopher E. , Wurtele Eve Syrkin , Taylor Deanne , Schwartz Robert E. , Beheshti Afshin , Wallace Douglas C. , Baylin Stephen B.
Published: October 2023

Lethal COVID-19 outcomes are most often attributed to classic cytokine storm and attendant excessive immune signaling. We re-visit this question using RNA sequencing in nasopharyngeal and 40 autopsy samples from COVID-19-positive and negative individuals. In nasal swabs, the top 100 genes which significantly correlated with COVID-19 viral load, include many canonical innate immune genes. However, 22 much less studied "non-canonical" genes are found and despite the absence of viral transcripts, subsets of these are upregulated in heart, lung, kidney, and liver, but not mediastinal lymph nodes. An important regulatory potential emerges for the non-canonical genes for over-activating the renin-angiotensin-activation-system (RAAS) pathway, resembling this phenomenon in hereditary angioedema (HAE) and its overlapping multiple features with lethal COVID-19 infections. Specifically, RAAS overactivation links increased fibrin deposition, leaky vessels, thrombotic tendency, and initiating the PANoptosis death pathway, as suggested in heart, lung, and especially mediastinal lymph nodes, with a tightly associated mitochondrial dysfunction linked to immune responses. For mediastinal lymph nodes, immunohistochemistry studies validate the transcriptomic findings showing abnormal architecture, excess fibrin and collagen deposition, and pathogenic fibroblasts. Further, our findings overlap findings in SARS-CoV-2 infected hamsters, C57BL/6 and BALB/c mouse models, and importantly peripheral blood mononuclear cell (PBMC) and whole blood samples from COVID-19 patients infected with early variants and later SARS-CoV-2 strains. We thus present cytokine storm in lethal COVID-19 disease as an interplay between upstream immune gene signaling producing downstream RAAS overactivation with resultant severe organ damage, especially compromising mediastinal lymph node function.
Identification of CFAP52 as a novel diagnostic target of male infertility with defects of sperm head-tail connection and flagella development
Authors: Jin Hui-Juan , Ruan Tie-Chao , Dai Si-Yu , Geng Xin-Yan , Yang Yi-Hong , Shen Ying , Chen Su-Ren
Published: October 2023

Male infertility is a worldwide population health concern. Asthenoteratozoospermia is a common cause of male infertility, but its etiology remains incompletely understood. No evidence indicates the relevance ofCFAP52mutations to human male infertility. Our whole-exome sequencing identified compound heterozygous mutations inCFAP52recessively cosegregating with male infertility status in a non-consanguineous Chinese family. Spermatozoa ofCFAP52-mutant patient mainly exhibited abnormal head-tail connection and deformed flagella.Cfap52-knockout mice resembled the human infertile phenotype, showing a mixed acephalic spermatozoa syndrome (ASS) and multiple morphological abnormalities of the sperm flagella (MMAF) phenotype. The ultrastructural analyses further revealed a failure of connecting piece formation and a serious disorder of ‘9+2’ axoneme structure. CFAP52 interacts with a head-tail coupling regulator SPATA6 and is essential for its stability. Expression of microtubule inner proteins and radial spoke proteins were reduced after the CFAP52 deficiency. Moreover, CFAP52-associated male infertility in humans and mice could be overcome by ICSI. The study reveals a prominent role for CFAP52 in sperm development, suggesting that CFAP52 might be a novel diagnostic target for male infertility with defects of sperm head-tail connection and flagella development
Unlocking DNA Damage Sensitivity of Cancer Cells: The Potential of Splicing Inhibitors
Authors: Anufrieva Ksenia S. , Lukina Maria M. , Ivanova Olga M. , Kazakova Anastasia N. , Shnaider Polina V. , Klimina Ksenia M. , Veselovsky Vladimir A. , Luzhin Artem V. , Velichko Artem K. , Kantidze Omar L. , Mochalova Elizaveta N. , Nikitin Maxim P. , Kashina Aleksandra V. , Vasilchikova Ekaterina A. , Deev Roman V. , Emelin Alexey M. , Turchin Anton N. , Liu Zhaojian , Wang Zixiang , Boichenko Veronika S. , Markina Nadezhda M. , Lagarkova Maria A. , Govorun Vadim M. , Arapidi Georgij P. , Shender Victoria O.
Published: October 2023

Despite the growing interest in pre-mRNA alternative splicing (AS) as a therapeutic anticancer target, the potential of splicing inhibitors in treating solid tumors remains largely unexplored. We conducted a meta-analysis of transcriptome data from six different tumor types and revealed that splicing inhibitors induced similar patterns of AS, resulting in widespread exon-skipping and intron retention events that often lead to nonsense-mediated decay of the transcripts. Interestingly, in many cases exon skipping is induced by a compensatory cellular response to splicing inhibitor treatment. It involves an upregulation of multiple splicing factors and incomplete recognition of branch points by U2 snRNP. These post transcriptional changes downregulate one-third of essential DNA repair genes, thereby creating a therapeutic vulnerability that can be exploited for cancer treatment. To harness this vulnerability, we proposed a new approach to cancer treatment consisting of sequential addition of a splicing inhibitors followed by a DNA-damaging agent. Ourin vitroandin vivoexperiments demonstrated that this strategy exhibits promising therapeutic potential for a wide range of tumors.