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Paper mulberry (Broussonetia papyrifera) is a well-known woody tree historically used for Cai Lun papermaking, one of the four great inventions of ancient China. More recently, Paper mulberry has also been used as forage to address the shortage of feedstuff because of its digestible crude fiber and high protein contents. In this study, we obtained a chromosome-scale genome assembly for Paper mulberry using integrated approaches, including Illumina and PacBio sequencing platform as well as Hi-C, optical, and genetic maps. The assembled Paper mulberry genome consists of 386.83 Mb, which is close to the estimated size, and 99.25% (383.93 Mb) of the assembly was assigned to 13 pseudochromosomes. Comparative genomic analysis revealed the expansion and contraction in the flavonoid and lignin biosynthetic gene families, respectively, accounting for the enhanced flavonoid and decreased lignin biosynthesis in Paper mulberry. Moreover, the increased ratio of syringyl-lignin to guaiacyl-lignin in Paper mulberry underscores its suitability for use in medicine, forage, papermaking, and barkcloth making. We also identified the root-associated microbiota of Paper mulberry and found that Pseudomonas and Rhizobia were enriched in its roots and may provide the source of nitrogen for its stems and leaves via symbiotic nitrogen fixation. Collectively, these results suggest that Paper mulberry might have undergone adaptive evolution and recruited nitrogen-fixing microbes to promote growth by enhancing flavonoid production and altering lignin monomer composition. Our study provides significant insights into genetic basis of the usefulness of Paper mulberry in papermaking and barkcloth making, and as forage. These insights will facilitate further domestication and selection as well as industrial utilization of Paper mulberry worldwide., (Copyright © 2019 The Author. Published by Elsevier Inc. All rights reserved.)

Risk-assessing and controlling virus transmission from soil-rich post-washing water (PWW) are crucial during harvesting raw vegetables. However, viruses are normally difficult to concentrate because of their low concentrations and complex backgrounds. Here, ultrafiltration (UF), virus adsorption-elution (VIRADEL), and optimized paper filtration-coupled ultrafiltration (PFC-UF) methods were employed to evaluate the recovery of non-enveloped murine norovirus (MNV-1), hepatitis A virus (HAV), and enveloped human coronavirus 229E (HCoV-229E) from soil-rich PWW. Among the three methods, PFC-UF outperformed the other methods in the recovery of viruses from PWW with soil content. Under the highest soil condition with virus seeded at a titer of 10 2 plaque-forming unit (PFU) or TCID 50 , the PFC-UF method exhibited an exceedingly consistent recovery rate of 78.8 ± 13.3 (MNV-1) and 44.4 ± 25.2% (HAV). However, the recovery of enveloped HCoV-229E was inferior to non-enveloped viruses. Overall, PFC-UF provided a reliable method for recovering viruses in soil-rich PWW., Competing Interests: Z.W. and C.C. are co-inventors on related intellectual property., (© 2022 The Author(s).)

Publishing a primary research article is typically the result of a collaborative effort between a variety of researchers across differing career stages. STAR Protocols can complement a research article and empower authors to share the expertise they contributed to the larger study. In this Backstory, we interview members of the Gennarino lab, who published a Cell paper and four protocols, covering bioinformatics, culturing of patient-derived cell lines, neuroimaging from mouse brain sections and primary neurons, and mouse seizure recordings. For more information on the protocols related to this backstory, please refer to (Gennarino et al., 2018)., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Fifteen percent of couples of reproductive age suffer from infertility globally and the burden of infertility disproportionately impacts residents of developing countries. Assisted reproductive technologies (ARTs), including in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), have been successful in overcoming various reasons for infertility including borderline and severe male factor infertility which consists of 20%-30% of all infertile cases. Approximately half of male infertility cases stem from suboptimal sperm parameters. Therefore, healthy/normal sperm enrichment and sorting remains crucial in advancing reproductive medicine. Microfluidic technologies have emerged as promising tools to develop in-home rapid fertility tests and point-of-care (POC) diagnostic tools. Here, we review advancements in fabrication methods for paper-based microfluidic devices and their emerging fertility testing applications assessing sperm concentration, sperm motility, sperm DNA analysis, and other sperm functionalities, and provide a glimpse into future directions for paper-based fertility microfluidic systems., Competing Interests: The authors declare the following competing financial interest(s): S.T. is a co-founder of and has equity interest in GetDeHealth, a company that is developing microfluidic technologies for point-of-care diagnostic and wellness solutions. The interests of S.T. were viewed and managed in accordance with the conflict of interest policies. Author S.T. is a member of the iScience Editorial Board. B.A. is a member of ART Fertility Clinics, a company working on human reproductive medicine. The interests of B.A. were viewed and managed in accordance with the conflict of interest policies. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed., (© 2022 The Author(s).)

Immunogenicity has imposed a challenge to efficacy and safety evaluation of adeno-associated virus (AAV) vector-based gene therapies. Mild to severe adverse events observed in clinical development have been implicated with host immune responses against AAV gene therapies, resulting in comprehensive evaluation of immunogenicity during nonclinical and clinical studies mandated by health authorities. Immunogenicity of AAV gene therapies is complex due to the number of risk factors associated with product components and pre-existing immunity in human subjects. Different clinical mitigation strategies have been employed to alleviate treatment-induced or -boosted immunogenicity in order to achieve desired efficacy, reduce toxicity, or treat more patients who are seropositive to AAV vectors. In this review, the immunogenicity risk assessment, manifestation of immunogenicity and its impact in nonclinical and clinical studies, and various clinical mitigation strategies are summarized. Last, we present bioanalytical strategies, methodologies, and assay validation applied to appropriately monitor immunogenicity in AAV gene therapy-treated subjects., Competing Interests: The authors declare no competing interests., (© 2022 The Authors.)

Paper substrate has many advantages, such as low cost, bendable, foldable, printable, and environmentally friendly recycling. Nowadays, paper has been further extended as a flexible platform to deliver electronic information with the integration of organic optoelectronic devices, such as organic thin-film transistor, organic solar cell, organic electrochromic device, and organic light-emitting device. It has great potential to become the new generation of flexible substrate. Given rough surface and porous of paper, many efforts have been underway in recent years to enable the compatibility between optoelectronics and paper substrate. In this review, we present the development history of paper and its physicochemical properties, and summarize the current development of paper-based organic optoelectronic devices. We also discuss the challenges that need to be addressed before practical uses of paper-based organic optoelectronic devices., Competing Interests: The authors declare no competing interests., (© 2022 The Authors.)

Most laboratories employ spin coating with application of antisolvent to achieve high efficiency in perovskite solar cells. However, this method wastes a lot of material and is not industrially usable. Conversely, large area coating techniques such as blade and slot-die require high precision engineering both for deposition of ink and for gas or for electromagnetic drying procedures that replace, out of necessity, anti-solvent engineering. Here we present a simple and effective method to deposit uniform high-quality perovskite films with a piece of paper as an applicator at low temperatures. We fabricated solar cells on flexible PET substrates manually with 11% power conversion efficiency. Deposition after soaking the sheet of paper in a green antisolvent improved the efficiency by 82% compared to when using dry paper as applicator. This new technique enables manual film deposition without any expensive equipment and has the potential to be fully automated for future optimization and exploitation., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

Skin-interfaced wearable electronics can find a broad spectrum of applications in healthcare, human-machine interface, robotics, and others. The state-of-the-art wearable electronics usually suffer from costly and complex fabrication procedures and nonbiodegradable polymer substrates. Paper, comprising entangled micro- or nano-scale cellulose fibers, is compatible with scalable fabrication techniques and emerges as a sustainable, inexpensive, disposable, and biocompatible substrate for wearable electronics. Given various attractive properties (e.g., breathability, flexibility, biocompatibility, and biodegradability) and rich tunability of surface chemistry and porous structures, paper offers many exciting opportunities for wearable electronics. In this review, we first introduce the intriguing properties of paper-based wearable electronics and strategies for cellulose modifications to satisfy specific demands. We then overview the applications of paper-based devices in biosensing, energy storage and generation, optoelectronics, soft actuators, and several others. Finally, we discuss some challenges that need to be addressed before practical uses and wide implementation of paper-based wearable electronics., Competing Interests: The authors declare no competing interests., (© 2021 The Authors.)

Synthetic gene networks have wide-ranging uses in reprogramming and rewiring organisms. To date, there has not been a way to harness the vast potential of these networks beyond the constraints of a laboratory or in vivo environment. Here, we present an in vitro paper-based platform that provides an alternate, versatile venue for synthetic biologists to operate and a much-needed medium for the safe deployment of engineered gene circuits beyond the lab. Commercially available cell-free systems are freeze dried onto paper, enabling the inexpensive, sterile, and abiotic distribution of synthetic-biology-based technologies for the clinic, global health, industry, research, and education. For field use, we create circuits with colorimetric outputs for detection by eye and fabricate a low-cost, electronic optical interface. We demonstrate this technology with small-molecule and RNA actuation of genetic switches, rapid prototyping of complex gene circuits, and programmable in vitro diagnostics, including glucose sensors and strain-specific Ebola virus sensors.

This i3 is a data visualization based on the Cell Stem Cell tenth anniversary theme of lineage tracing. Using Scopus citations of Cell Stem Cell research papers, it illustrates both the evolution of the stem cell field and the way new research builds on work that came before. Users can navigate the graphic and the represented papers by stem cell type, organism, and author online at cell.com/i3/cell-stem-cell/lineage. To view this SnapShot, open or download the PDF., (Copyright © 2017. Published by Elsevier Inc.)

Tremendous progress has been made in the design and implementation of synthetic gene circuits, but real-world applications of such circuits have been limited. Cell-free circuits embedded on paper developed by Pardee et al. promise to deliver specific and rapid diagnostics on a low-cost, highly scalable platform. [ABSTRACT FROM AUTHOR]

An increasing number of publications include modeling. Often, such studies help us to gain a deeper insight into the phenomena studied and break down barriers between experimental and theoretical communities. However, combining experimental and theoretical work is challenging for authors, reviewers, and readers. To help maximize the usefulness and impact of combined theoretical and experimental research, this Primer describes the purpose, usefulness, and different types of models and addresses the practical aspect of integrated publications by outlining characteristics of good modeling, presentation, and fruitful collaborations., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Innovations in wearable technology and artificial intelligence have enabled consumer devices to process and transmit data about human mental states (cognitive, affective, and conative) through what this paper refers to as "cognitive biometrics." Devices such as brain-computer interfaces, extended reality headsets, and fitness wearables offer significant benefits in health, wellness, and entertainment through the collection and processing and cognitive biometric data. However, they also pose unique risks to mental privacy due to their ability to infer sensitive information about individuals. This paper challenges the current approach to protecting individuals through legal protections for "neural data" and advocates for a more expansive legal and industry framework, as recently reflected in the draft UNESCO Recommendation on the Ethics of Neurotechnology, to holistically address both neural and cognitive biometric data. Incorporating this broader and more inclusive approach into legislation and product design can facilitate responsible innovation while safeguarding individuals' mental privacy. Biometric data relating to human cognitive, affective, and conative states ("cognitive biometrics") are not adequately protected under existing privacy laws. The authors argue for an expansive approach that would treat neural and cognitive biometric data holistically as categories of "sensitive data" and provide them with analogous privacy protections. [ABSTRACT FROM AUTHOR]

The diverse etiologies of the genetic neurodegenerative disorder known as primary familial brain calcification have dimmed hopes for curative therapies. However, two new papers in Neuron 1,2 provide a reason for optimism by identifying mechanisms involved in brain phosphate transport and a promising target for restoring phosphate balance in the brain. The diverse etiologies of the genetic neurodegenerative disorder known as primary familial brain calcification have dimmed hopes for curative therapies. However, two new papers in Neuron provide a reason for optimism by identifying mechanisms involved in brain phosphate transport and a promising target for restoring phosphate balance in the brain. [ABSTRACT FROM AUTHOR]

A recent Nature paper 1 reveals that gut microbes metabolize N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) into the bladder carcinogen N- n -butyl-N-(3-carboxypropyl)-nitrosamine (BCPN) in the intestines, establishing a direct link between gut microbial activity and the development of bladder cancer. A recent Nature paper reveals that gut microbes metabolize N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) into the bladder carcinogen N- n -butyl-N-(3-carboxypropyl)-nitrosamine (BCPN) in the intestines, establishing a direct link between gut microbial activity and the development of bladder cancer. [ABSTRACT FROM AUTHOR]

Deploying anti-CRISPR proteins is a potent strategy used by phages to inhibit bacterial CRISPR-Cas defense. In a new Nature paper, Trost et al. 1 discover and characterize an exciting anti-CRISPR mechanism with possible implications beyond this microscopic arms race. Deploying anti-CRISPR proteins is a potent strategy used by phages to inhibit bacterial CRISPR-Cas defense. In a new Nature paper, Trost et al. discover and characterize an exciting anti-CRISPR mechanism with possible implications beyond this microscopic arms race. [ABSTRACT FROM AUTHOR]

The pre-fusion coronavirus HKU1 spike binds host sialoglycans and proteinaceous receptor TMPRSS2 for cell entry. In this issue of Cell , three papers by Fernández et al., McCallum et al., and Wang et al. provide structural information on HKU1 spike interactions with host receptors, providing insights into its multi-step opening. The pre-fusion coronavirus HKU1 spike binds host sialoglycans and proteinaceous receptor TMPRSS2 for cell entry. In this issue of Cell , three papers by Fernandez et al., McCallum et al., and Wang et al. provide structural information on HKU1 spike interactions with host receptors, providing insights into its multi-step opening. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide-1 (GLP-1) and N-methyl-D-aspartate (NMDA) receptors in the brain regulate metabolic homeostasis. In a paper published in Nature , Petersen et al. describe a bimodal molecule that conjugates a GLP-1 analog with MK-801 (NMDA receptor antagonist), which lowers feeding and body weight to a greater extent than the GLP-1R agonist alone. Glucagon-like peptide-1 (GLP-1) and N-methyl-D-aspartate (NMDA) receptors in the brain regulate metabolic homeostasis. In a paper published in Nature , Petersen et al. describe a bimodal molecule that conjugates a GLP-1 analog with MK-801 (NMDAR receptor antagonist), which lowers feeding and body weight to a greater extent than the GLP-1R agonist alone. [ABSTRACT FROM AUTHOR]

In their recent paper published in Nature , Luo et al. 1 investigate the cancer-cell-intrinsic roles of the PI3Kγ complex in leukemia. Their findings pinpoint PI3Kγ inhibition as a possible novel treatment avenue for a subset of acute leukemias. In their recent paper published in Nature , Luo et al.1 investigate the cancer-cell-intrinsic roles of the PI3Kγ complex in leukemia. Their findings pinpoint PI3Kγ inhibition as a possible novel treatment avenue for a subset of acute leukemias. [ABSTRACT FROM AUTHOR]

The ClinGen Hereditary Breast, Ovarian, and Pancreatic Cancer (HBOP) Variant Curation Expert Panel (VCEP) is composed of internationally recognized experts in clinical genetics, molecular biology, and variant interpretation. This VCEP made specifications for the American College of Medical Genetics and Association for Molecular Pathology (ACMG/AMP) guidelines for the ataxia telangiectasia mutated (ATM) gene according to the ClinGen protocol. These gene-specific rules for ATM were modified from the ACMG/AMP guidelines and were tested against 33 ATM variants of various types and classifications in a pilot curation phase. The pilot revealed a majority agreement between the HBOP VCEP classifications and the ClinVar-deposited classifications. Six pilot variants had conflicting interpretations in ClinVar, and re-evaluation with the VCEP's ATM -specific rules resulted in four that were classified as benign, one as likely pathogenic, and one as a variant of uncertain significance (VUS) by the VCEP, improving the certainty of interpretations in the public domain. Overall, 28 of the 33 pilot variants were not VUS, leading to an 85% classification rate. The ClinGen-approved, modified rules demonstrated value for improved interpretation of variants in ATM. This paper details ACMG/AMP-style guidelines for ataxia telangiectasia mutated (ATM) variant interpretation and shows the results of pilot classifications. Several phenotype-driven rules were omitted or modified due to low-penetrance and commonness of breast cancer. This work aims to harmonize the classification of ATM variants and avoid misinterpretation by using standard rules. [ABSTRACT FROM AUTHOR]

We talk to corresponding author Thomas Gonatopoulos-Pournatzis and co-first authors Arun Prasath Damodaran and Mei-Sheng Xiao about their paper "Genome-scale exon perturbation screens uncover exons critical for cell fitness" (in this issue of Molecular Cell) and get insights into their findings, career trajectories, and future directions in the pre-mRNA processing field. [ABSTRACT FROM AUTHOR]

In 1973, two papers from Bliss and Lømo and from Bliss and Gardner-Medwin reported that high-frequency synaptic stimulation in the dentate gyrus of rabbits resulted in a long-lasting increase in synaptic strength. This form of synaptic plasticity, commonly referred to as long-term potentiation (LTP), was immediately considered as an attractive mechanism accounting for the ability of the brain to store information. In this historical piece looking back over the past 50 years, we discuss how these two landmark contributions directly motivated a colossal research effort and detail some of the resulting milestones that have shaped our evolving understanding of the molecular and cellular underpinnings of LTP. We highlight the main features of LTP, cover key experiments that defined its induction and expression mechanisms, and outline the evidence supporting a potential role of LTP in learning and memory. We also briefly explore some ramifications of LTP on network stability, consider current limitations of LTP as a model of associative memory, and entertain future research orientations. Caya-Bissonnette and Béïque discuss the milestones that have shaped our current understanding of the molecular and cellular basis of long-term potentiation. [ABSTRACT FROM AUTHOR]

Anoctamins are a family of Ca2+-activated proteins that may act as ion channels and/or phospholipid scramblases with limited understanding of function and disease association. Here, we identified five de novo and two inherited missense variants in ANO4 (alias TMEM16D) as a cause of fever-sensitive developmental and epileptic or epileptic encephalopathy (DEE/EE) and generalized epilepsy with febrile seizures plus (GEFS+) or temporal lobe epilepsy. In silico modeling of the ANO4 structure predicted that all identified variants lead to destabilization of the ANO4 structure. Four variants are localized close to the Ca2+ binding sites of ANO4, suggesting impaired protein function. Variant mapping to the protein topology suggests a preliminary genotype-phenotype correlation. Moreover, the observation of a heterozygous ANO4 deletion in a healthy individual suggests a dysfunctional protein as disease mechanism rather than haploinsufficiency. To test this hypothesis, we examined mutant ANO4 functional properties in a heterologous expression system by patch-clamp recordings, immunocytochemistry, and surface expression of annexin A5 as a measure of phosphatidylserine scramblase activity. All ANO4 variants showed severe loss of ion channel function and DEE/EE associated variants presented mild loss of surface expression due to impaired plasma membrane trafficking. Increased levels of Ca2+-independent annexin A5 at the cell surface suggested an increased apoptosis rate in DEE-mutant expressing cells, but no changes in Ca2+-dependent scramblase activity were observed. Co-transfection with ANO4 wild-type suggested a dominant-negative effect. In summary, we expand the genetic base for both encephalopathic sporadic and inherited fever-sensitive epilepsies and link germline variants in ANO4 to a hereditary disease. This paper establishes missense variants in the anoctamin family member ANO4 (or TMEM16D) as a cause of distinct epileptic disorders. Resulting phenotypes depend on the location in the protein and the functional impact of the substitution such as loss of cation channel function and increased apoptosis signaling. [ABSTRACT FROM AUTHOR]

Anti-phage defenses must rapidly sense and respond to diverse viruses. A recent pair of papers in Nature reveal via structural and functional assays how the PARIS defense system, a recently discovered toxin-antitoxin system, senses phage-associated molecular patterns (PhAMPs), thereby activating an endonuclease toxin that cleaves tRNA to block phage replication. [ABSTRACT FROM AUTHOR]

Epigenetic inheritance of heterochromatin requires transfer of parental H3-H4 tetramers to both daughter duplexes during replication. Three recent papers exploit yeast genetics coupled to inheritance assays and AlphaFold2-multimer predictions coupled to biochemistry to reveal that a replisome component (Mrc1/CLASPIN) is an H3-H4 tetramer chaperone important for parental histone transfer to daughters. [ABSTRACT FROM AUTHOR]

A recent Nature paper by Xu et al. 1 describes an important link between RNA polymerase II promoter-proximal pausing and genome stability orchestrated by liquid droplet formation to reduce unwanted R-loop accumulation. A recent Nature paper by Xu et al.1 describes an important link between RNA polymerase II promoter-proximal pausing and genome stability orchestrated by liquid droplet formation to reduce unwanted R-loop accumulation. [ABSTRACT FROM AUTHOR]

Tardigrades withstand ionizing irradiation levels ∼500 times higher than humans can tolerate. Two recent papers shed light on how this might be achieved — via the transcriptional induction of DNA repair genes, the induction of a radioprotective DNA-binding protein, and possibly also the heightened capacity of repair proteins. [ABSTRACT FROM AUTHOR]

Sleep is a universal, essential biological process. It is also an invaluable window on consciousness. It tells us that consciousness can be lost but also that it can be regained, in all its richness, when we are disconnected from the environment and unable to reflect. By considering the neurophysiological differences between dreaming and dreamless sleep, we can learn about the substrate of consciousness and understand why it vanishes. We also learn that the ongoing state of the substrate of consciousness determines the way each experience feels regardless of how it is triggered—endogenously or exogenously. Dreaming consciousness is also a window on sleep and its functions. Dreams tell us that the sleeping brain is remarkably lively, recombining intrinsic activation patterns from a vast repertoire, freed from the requirements of ongoing behavior and cognitive control. The paper by Tononi et al. discusses what sleep reveals about the substrate of consciousness, how experience can vanish during sleep, and how dreams can be supported by a brain largely disconnected from the environment, unreflective, and forgetful. [ABSTRACT FROM AUTHOR]

We spoke with authors co-first authors Jayoung Ku, Keonyong Lee, and lead author Yoosik Kim about their paper "Alternative polyadenylation determines the functional landscape of inverted Alu repeats" (this issue of Molecular Cell), finding renewed energy from attending scientific meetings, and the open questions they are most interested in investigating next. [ABSTRACT FROM AUTHOR]

Sex-biased admixture can be inferred from ancestry-specific proportions of X chromosome and autosomes. In a paper published in the American Journal of Human Genetics , Micheletti et al. 1 used this approach to quantify male and female contributions following the transatlantic slave trade. Using a large dataset from 23andMe, they concluded that African and European contributions to gene pools in the Americas were much more sex biased than previously thought. We show that the reported extreme sex-specific contributions can be attributed to unassigned genetic ancestry as well as the limitations of simple models of sex-biased admixture. Unassigned ancestry proportions in the study by Micheletti et al. ranged from ∼1% to 21%, depending on the type of chromosome and geographic region. A sensitivity analysis illustrates how this unassigned ancestry can create false patterns of sex bias and that mathematical models are highly sensitive to slight sampling errors when inferring mean ancestry proportions, making confidence intervals necessary. Thus, unassigned ancestry and the sensitivity of the models effectively prohibit the interpretation of estimated sex biases for many geographic regions in Micheletti et al. Furthermore, Micheletti et al. assumed models of a single admixture event. Using simulations, we find that violations of demographic assumptions, such as subsequent gene flow and/or sex-specific assortative mating, may have confounded the analyses of Micheletti et al., but unassigned ancestry was likely the more important confounding factor. Our findings underscore the importance of using complete ancestry information, sufficiently large sample sizes, and appropriate models when inferring sex-biased patterns of demography. This Matters Arising paper is in response to Micheletti et al., 1 published in American Journal of Human Genetics. See also the response by Micheletti et al., 2 published in this issue. [ABSTRACT FROM AUTHOR]