bluuebunny/crossref_metadata_2025 huggingface dataset:
Yeast surface display-based identification of ACE2 mutations that modulate SARS-CoV-2 spike binding across multiple mammalian species
Authors: Heinzelman Pete , Greenhalgh Jonathan C , Romero Philip A
Published: January 2022

Understanding how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) interacts with different mammalian angiotensin-converting enzyme II (ACE2) cell entry receptors elucidates determinants of virus transmission and facilitates development of vaccines for humans and animals. Yeast display-based directed evolution identified conserved ACE2 mutations that increase spike binding across multiple species. Gln42Leu increased ACE2-spike binding for human and four of four other mammalian ACE2s; Leu79Ile had an effect for human and three of three mammalian ACE2s. These residues are highly represented, 83% for Gln42 and 56% for Leu79, among mammalian ACE2s. The above findings can be important in protecting humans and animals from existing and future SARS-CoV-2 variants.
Discourses of Social Inclusion in Chilean Sexual and Reproductive Health Policy
Authors: Cubillos-Almendra Javiera
Published: January 2022

Sexual and reproductive health (SRH) policy raises important normative questions. Accordingly, this article—inspired by a discursive approach to public policy—uses social inclusion approach to analyze Chilean SRH policy (2000–2018). It argues that despite long decades of capitalist neoliberal modernization and four consecutive center/left-wing governments, Chilean SRH policy remains as conservative as under right-wing dictatorship, and focused mainly on fertile women. The proposed conceptual model that informs this analysis considers three features of the public policy: the normative referent that guides it, the vision of society that underlies its discourse, and the presupposed concept of subject. The methodology includes tracing Chile’s SRH policy, critical frame analysis of relevant political texts, and interviews with governmental and nongovernmental political stakeholders.
Stem Cell Therapies for Central Nervous System Trauma: The 4 Ws—What, When, Where, and Why
Authors: Li Xiaofei , Sundström Erik
Published: January 2022

Traumatic injury of the central nervous system (CNS) is a worldwide health problem affecting millions of people. Trauma of the CNS, that is, traumatic brain injury (TBI) and spinal cord injury (SCI), lead to massive and progressive cell loss and axonal degeneration, usually with very limited regeneration. At present, there are no treatments to protect injured CNS tissue or to replace the lost tissue. Stem cells are a cell type that by definition can self-renew and give rise to multiple cell lineages. In recent years, therapies using stem and progenitor cells have shown promising effects in experimental CNS trauma, particularly in the acute-subacute stage, but also in chronic injuries. However, the therapeutic mechanisms by which transplanted cells achieve the structural and/or functional improvements are often not clear. Stem cell therapies for CNS trauma can be categorized into 2 main concepts, transplantation of exogenous neural stem cells and neural progenitor cells and recruitment of endogenous stem and progenitor cells. In this review, focusing on the advances during the last decade, we will discuss the major cell therapies, the pros and cons of these 2 concepts for TBI and SCI, and the treatment strategies we believe will be successful.
Robust In Vitro and In Vivo Immunosuppressive and Anti-inflammatory Properties of Inducible Caspase-9-mediated Apoptotic Mesenchymal Stromal/Stem Cell
Authors: Romecín Paola Alejandra , Vinyoles Meritxell , López-Millán Belén , de la Guardia Rafael Diaz , Atucha Noemi M , Querol Sergi , Bueno Clara , Benitez Raquel , Gonzalez-Rey Elena , Delgado Mario , Menéndez Pablo
Published: January 2022

Mesenchymal stromal stem/cells (MSC) therapies are clinically used in a wide range of disorders based on their robust HLA-independent immunosuppressive and anti-inflammatory properties. However, the mechanisms underlying MSC therapeutic activity remain elusive as demonstrated by the unpredictable therapeutic efficacy of MSC infusions reported in multiple clinical trials. A seminal recent study showed that infused MSCs are actively induced to undergo apoptosis by recipient cytotoxic T cells, a mechanism that triggers in vivo recipient-induced immunomodulation by such apoptotic MSCs, and the need for such recipient cytotoxic cell activity could be replaced by the administration of ex vivo-generated apoptotic MSCs. Moreover, the use of MSC-derived extracellular vesicles (MSC-EVs) is being actively explored as a cell-free therapeutic alternative over the parental MSCs. We hypothesized that the introduction of a “suicide gene” switch into MSCs may offer on-demand in vivo apoptosis of transplanted MSCs. Here, we prompted to investigate the utility of the iCasp9/AP1903 suicide gene system in inducing apoptosis of MSCs. iCasp9/AP1903-induced apoptotic MSCs (MSCiCasp9+) were tested in vitro and in in vivo models of acute colitis. Our data show a very similar and robust immunosuppressive and anti-inflammatory properties of both “parental” alive MSCGFP+ cells and apoptotic MSCiCasp9+ cells in vitro and in vivo regardless of whether apoptosis was induced in vivo or in vitro before administering MSCiCasp9+ lysates. This development of an efficient iCasp9 switch may potentiate the safety of MSC-based therapies in the case of an adverse event and, will also circumvent current logistic technical limitations and biological uncertainties associated to MSC-EVs.
Rejuvenation of Tissue Stem Cells by Intrinsic and Extrinsic Factors
Authors: Cai Yusheng , Wang Si , Qu Jing , Belmonte Juan Carlos Izpisua , Liu Guang-Hui
Published: January 2022

Stem cell therapies, including stem cell transplantation and rejuvenation of stem cells in situ, are promising avenues for tackling a broad range of diseases. Stem cells can both self-renew and differentiate into other cell types, and play a significant role in the regulation of tissue homeostasis and regeneration after cell degeneration or injury. However, stem cell exhaustion or dysfunction increases with age and impedes the normal function of multiple tissues and systems. Thus, stem cell therapies could provide a solution to aging and age-associated diseases. Here, we discuss recent advances in understanding the mechanisms that regulate stem cell regeneration. We also summarize potential strategies for rejuvenating stem cells that leverage intrinsic and extrinsic factors. These approaches may pave the way toward therapeutic interventions aiming at extending both health and life span.
Umbilical Cord Blood and Cord Tissue-Derived Cell Therapies for Neonatal Morbidities: Current Status and Future Challenges
Authors: Zhou Lindsay , McDonald Courtney , Yawno Tamara , Jenkin Graham , Miller Suzanne , Malhotra Atul
Published: January 2022

Cell therapies are an emerging focus for neonatal research, with benefits documented for neonatal respiratory, neurological, and cardiac conditions in pre-clinical studies. Umbilical cord blood (UCB) and umbilical cord (UC) tissue-derived cell therapy is particularly appealing for preventative or regenerative treatment of neonatal morbidities; they are a resource that can be collected at birth and used as an autologous or allogeneic therapy. Moreover, UCB contains a diverse mix of stem and progenitor cells that demonstrate paracrine actions to mitigate damaging inflammatory, immune, oxidative stress, and cell death pathways in several organ systems. In the past decade, published results from early-phase clinical studies have explored the use of these cells as a therapeutic intervention in neonates. We present a systematic review of published and registered clinical trials of UCB and cord tissue-derived cell therapies for neonatal morbidities. This search yielded 12 completed clinical studies: 7 were open-label phase I and II safety and feasibility trials, 3 were open-label dose-escalation trials, 1 was a open-label placebo-controlled trial, and 1 was a phase II randomized controlled trial. Participants totaled 206 infants worldwide; 123 (60%) were full-term infants and 83 (40%) were preterm. A majority (64.5%) received cells via an intravenous route; however, 54 (26.2%) received cells via intratracheal administration, 10 (4.8%) intraoperative cardiac injection, and 9 (4.3%) by direct intraventricular (brain) injection. Assessment of efficacy to date is limited given completed studies have principally been phase I and II safety studies. A further 24 trials investigating UCB and UC-derived cell therapies in neonates are currently registered.
Gadd45g, A Novel Antidepressant Target, Mediates Metformin-Induced Neuronal Differentiation of Neural Stem Cells Via DNA Demethylation
Authors: Zhang Le , Li Qingfeng , Wang Huan , Wu Yuanfei , Ye Xiujuan , Gong Zhuo , Li Qingqing , Xuan Aiguo
Published: January 2022

Increased neurogenesis elicits antidepressive-like effects. The antidiabetic drug metformin (Met) reportedly promotes hippocampal neurogenesis, which ameliorates spatial memory deficits and depression-like behaviors. However, the precise molecular mechanisms underpinning Met-induced neuronal differentiation of neural stem cells (NSCs) remain unclear. We showed that Met enhanced neuronal differentiation of NSCs via Gadd45g but not Gadd45a and Gadd45b. We further found that Gadd45g increased demethylation of neurogenic differentiation 1 promoter by regulating the activity of passive and active DNA demethylation enzymes through an adenylate-activated protein kinase -independent mechanism in Met-treated NSCs. Importantly, genetic deficiency of Gadd45g decreased hippocampal neurogenesis, which could contribute to spatial memory decline, and depression-like behaviors in the adult mice, whereas forced expression of Gadd45g alleviated the depressive-like behaviors. Our findings provide a model that Gadd45g-mediated DNA demethylation contributes to Met-induced neuronal genesis and its antidepressant-like effects and propose the concept that targeting Gadd45g regulation of neurogenesis might serve as a novel antidepressant strategy.
DDX04+ Stem Cells in the Ovaries of Postmenopausal Women: Existence and Differentiation Potential
Authors: Wu Meng , Lu Zhiyong , Zhu Qingqing , Ma Lingwei , Xue Liru , Li Yan , Zhou Su , Yan Wei , Ye Wenlei , Zhang Jinjin , Luo Aiyue , Wang Shixuan
Published: January 2022

Ovarian aging is a pacemaker with multiple organ dysfunction. Recently, stem cells with the ability to generate new oocytes have been identified, which provides the possibility of stem cell therapy for ovarian aging. Several studies have revealed the existence of stem cells in the human postmenopausal ovary. In this study, we describe a new method using magnetic-activated cell sorting combined with differential adhesion to isolate DDX4+ stem cells from ovaries of postmenopausal women and show that the cells exhibit similar gene expression profiles and growth characteristics with primitive germ cells. Furthermore, the DDX4+ stem cells could enter the meiosis stage and differentiation into oocytes. The RNA-seq data of the differentiated oocytes shows that mitochondrial metabolism may play an important role in the oogenesis process of the DDX4+ stem cells. Through using the human ovarian cortical fragments transplantation model, we indicated that the GFP-DDX4+ stem cells differentiated into some GFP positive oocyte-like structure in vivo. Our study provided a new method for the isolation of DDX4+ stem cells from the ovaries of postmenopausal women and confirmed the ability of these stem cells to differentiate into oocytes.
Linc1548 Promotes the Transition of Epiblast Stem Cells Into Neural Progenitors by Engaging OCT6 and SOX2
Authors: Bai Mingliang , Li Guoping , Jiapaer Zeyidan , Guo Xudong , Xi Jiajie , Wang Guiying , Ye Dan , Chen Wen , Duan Baoyu , Kang Jiuhong
Published: January 2022

The transition of embryonic stem cells from the epiblast stem cells (EpiSCs) to neural progenitor cells (NPCs), called the neural induction process, is crucial for cell fate determination of neural differentiation. However, the mechanism of this transition is unclear. Here, we identified a long non-coding RNA (linc1548) as a critical regulator of neural differentiation of mouse embryonic stem cells (mESCs). Knockout of linc1548 did not affect the conversion of mESCs to EpiSCs, but delayed the transition from EpiSCs to NPCs. Moreover, linc1548 interacts with the transcription factors OCT6 and SOX2 forming an RNA-protein complex to regulate the transition from EpiSCs to NPCs. Finally, we showed that Zfp521 is an important target gene of this RNA-protein complex regulating neural differentiation. Our findings prove how the intrinsic transcription complex is mediated by a lncRNA linc1548 and can better understand the intrinsic mechanism of neural fate determination.
Histone Variant macroH2A1.1 Enhances Nonhomologous End Joining-dependent DNA Double-strand-break Repair and Reprogramming Efficiency of Human iPSCs
Authors: Giallongo Sebastiano , Řeháková Daniela , Biagini Tommaso , Lo Re Oriana , Raina Priyanka , Lochmanová Gabriela , Zdráhal Zbyněk , Resnick Igor , Pata Pille , Pata Illar , Mistrík Martin , de Magalhães João Pedro , Mazza Tommaso , Koutná Irena , Vinciguerra Manlio
Published: January 2022

DNA damage repair (DDR) is a safeguard for genome integrity maintenance. Increasing DDR efficiency could increase the yield of induced pluripotent stem cells (iPSC) upon reprogramming from somatic cells. The epigenetic mechanisms governing DDR during iPSC reprogramming are not completely understood. Our goal was to evaluate the splicing isoforms of histone variant macroH2A1, macroH2A1.1, and macroH2A1.2, as potential regulators of DDR during iPSC reprogramming. GFP-Trap one-step isolation of mtagGFP-macroH2A1.1 or mtagGFP-macroH2A1.2 fusion proteins from overexpressing human cell lines, followed by liquid chromatography-tandem mass spectrometry analysis, uncovered macroH2A1.1 exclusive interaction with Poly-ADP Ribose Polymerase 1 (PARP1) and X-ray cross-complementing protein 1 (XRCC1). MacroH2A1.1 overexpression in U2OS-GFP reporter cells enhanced specifically nonhomologous end joining (NHEJ) repair pathway, while macroH2A1.1 knock-out (KO) mice showed an impaired DDR capacity. The exclusive interaction of macroH2A1.1, but not macroH2A1.2, with PARP1/XRCC1, was confirmed in human umbilical vein endothelial cells (HUVEC) undergoing reprogramming into iPSC through episomal vectors. In HUVEC, macroH2A1.1 overexpression activated transcriptional programs that enhanced DDR and reprogramming. Consistently, macroH2A1.1 but not macroH2A1.2 overexpression improved iPSC reprogramming. We propose the macroH2A1 splicing isoform macroH2A1.1 as a promising epigenetic target to improve iPSC genome stability and therapeutic potential.
Telomerase Reverse Transcriptase Expression Marks a Population of Rare Adipose Tissue Stem Cells
Authors: Lynes Matthew D , Carlone Diana L , Townsend Kristy L , Breault David T , Tseng Yu-Hua
Published: January 2022

In adult tissues such as adipose tissue, post-mitotic cells like adipocytes can be replaced by differentiation of a population of tissue-resident stem cells. Expression of mouse telomerase reverse transcriptase (mTert) is a hallmark of stem cell populations, and previous efforts to identify tissue-resident adult stem cells by measuring mTert expression have increased our understanding of stem cell biology significantly. Here, we used a doxycycline-inducible mouse model to perform longitudinal, live-animal lineage-tracing of mTert-expressing cells for more than 1 year. We identified a rare (<2%) population of stem cells in different fat depots that express putative preadipocyte markers. The adipose-derived mTert-positive cells are capable of self-renewal and possess adipogenic potential. Finally, we demonstrate that high-fat diet (HFD) can initiate differentiation of these cells in vivo. These data identify a population of adipose stem cells that contribute to the depot-specific response to HFD.
Exploring Motor Neuron Diseases Using iPSC Platforms
Authors: Johns Alexandra E , Maragakis Nicholas J
Published: January 2022

The degeneration of motor neurons is a pathological hallmark of motor neuron diseases (MNDs), but emerging evidence suggests that neuronal vulnerability extends well beyond this cell subtype. The ability to assess motor function in the clinic is limited to physical examination, electrophysiological measures, and tissue-based or neuroimaging techniques which lack the resolution to accurately assess neuronal dysfunction as the disease progresses. Spinal muscular atrophy (SMA), spinal and bulbar muscular atrophy (SBMA), hereditary spastic paraplegia (HSP), and amyotrophic lateral sclerosis (ALS) are all MNDs with devastating clinical outcomes that contribute significantly to disease burden as patients are no longer able to carry out normal activities of daily living. The critical need to accurately assess the cause and progression of motor neuron dysfunction, especially in the early stages of those diseases, has motivated the use of human iPSC-derived motor neurons (hiPSC-MN) to study the neurobiological mechanisms underlying disease pathogenesis and to generate platforms for therapeutic discovery and testing. As our understanding of MNDs has grown, so too has our need to develop more complex in vitro models which include hiPSC-MN co-cultured with relevant non-neuronal cells in 2D as well as in 3D organoid and spheroid systems. These more complex hiPSC-derived culture systems have led to the implementation of new technologies, including microfluidics, multielectrode array, and machine learning which offer novel insights into the functional correlates of these emerging model systems.
Mst1/2 Is Necessary for Satellite Cell Differentiation to Promote Muscle Regeneration
Authors: Yang Jingjing , Wang Kezhi , An Yina , Wu Ran , Li Jiangbo , Wang Haidong , Dong Yanjun
Published: January 2022

The diminished ability for muscle to regenerate is associated with aging, diabetes, and cancers. Muscle regeneration depends on the activation and differentiation of satellite cells (SCs). Inactivation of Mst1/2 promotes cell proliferation by activating Yap, and that has been reported as a potential therapeutic target for improving many organ regeneration. However, the function of Mst1/2 in SCs fate decision and that effect on muscle regeneration remain unknown. By using inducible conditional knockout Mst1/2 in the SCs of mice and an inhibitor of Mst1/2, we found that inhibition of Mst1/2 in SCs significantly decrease Yap phosphorylation, thus causing Yap to accumulate in the nucleus and impairing SC differentiation; Mst1/2 were slightly elevated by irisin stimulation during SC differentiation; but inhibiting Mst1/2 in SCs significantly impaired irisin-induced muscle regeneration. These results indicate that Mst1/2 is necessary for SC differentiation and inhibiting Mst1/2 as a therapeutic target has potential risks for muscle regeneration.
Impaired Bone Fracture Healing in Type 2 Diabetes Is Caused by Defective Functions of Skeletal Progenitor Cells
Authors: Figeac Florence , Tencerova Michaela , Ali Dalia , Andersen Thomas L , Appadoo Dan Rémi Christiansen , Kerckhofs Greet , Ditzel Nicholas , Kowal Justyna M , Rauch Alexander , Kassem Moustapha
Published: January 2022

The mechanisms of obesity and type 2 diabetes (T2D)-associated impaired fracture healing are poorly studied. In a murine model of T2D reflecting both hyperinsulinemia induced by high-fat diet and insulinopenia induced by treatment with streptozotocin, we examined bone healing in a tibia cortical bone defect. A delayed bone healing was observed during hyperinsulinemia as newly formed bone was reduced by –28.4 ± 7.7% and was associated with accumulation of marrow adipocytes at the defect site +124.06 ± 38.71%, and increased density of SCA1+ (+74.99 ± 29.19%) but not Runx2+ osteoprogenitor cells. We also observed increased in reactive oxygen species production (+101.82 ± 33.05%), senescence gene signature (≈106.66 ± 34.03%), and LAMIN B1- senescent cell density (+225.18 ± 43.15%), suggesting accelerated senescence phenotype. During insulinopenia, a more pronounced delayed bone healing was observed with decreased newly formed bone to –34.9 ± 6.2% which was inversely correlated with glucose levels (R2 = 0.48, P < .004) and callus adipose tissue area (R2 = .3711, P < .01). Finally, to investigate the relevance to human physiology, we observed that sera from obese and T2D subjects had disease state-specific inhibitory effects on osteoblast-related gene signatures in human bone marrow stromal cells which resulted in inhibition of osteoblast and enhanced adipocyte differentiation. Our data demonstrate that T2D exerts negative effects on bone healing through inhibition of osteoblast differentiation of skeletal stem cells and induction of accelerated bone senescence and that the hyperglycemia per se and not just insulin levels is detrimental for bone healing.
L-DOPA-Induced Neurogenesis in the Hippocampus Is Mediated Through GPR143, a Distinct Mechanism of Dopamine
Authors: Kasahara Yuka , Masukawa Daiki , Kobayashi Kenta , Yamasaki Miwako , Watanabe Masahiko , Goshima Yoshio
Published: January 2022

Neurogenesis occurs in the hippocampus throughout life and is implicated in various physiological brain functions such as memory encoding and mood regulation. L-3,4-dihydroxyphenylalanine (L-DOPA) has long been believed to be an inert precursor of dopamine. Here, we show that L-DOPA and its receptor, GPR143, the gene product of ocular albinism 1, regulate neurogenesis in the dentate gyrus (DG) in a dopamine-independent manner. L-DOPA at concentrations far lower than that of dopamine promoted proliferation of neural stem and progenitor cells in wild-type mice under the inhibition of its conversion to dopamine; this effect was abolished in GPR143 gene-deficient (Gpr143−/y) mice. Hippocampal neurogenesis decreased during development and adulthood, and exacerbated depression-like behavior was observed in adult Gpr143−/y mice. Replenishment of GPR143 in the DG attenuated the impaired neurogenesis and depression-like behavior. Our findings suggest that L-DOPA through GPR143 modulates hippocampal neurogenesis, thereby playing a role in mood regulation in the hippocampus.
Hoxb1 Regulates Distinct Signaling Pathways in Neuromesodermal and Hindbrain Progenitors to Promote Cell Survival and Specification
Authors: Pazur Kristijan , Giannios Ioannis , Lesche Mathias , Rodriguez-Aznar Eva , Gavalas Anthony
Published: January 2022

Hox genes play key roles in the anterior-posterior (AP) specification of all 3 germ layers during different developmental stages. It is only partially understood how they function in widely different developmental contexts, particularly with regards to extracellular signaling, and to what extent their function can be harnessed to guide cell specification in vitro. Here, we addressed the role of Hoxb1 in 2 distinct developmental contexts; in mouse embryonic stem cells (mES)-derived neuromesodermal progenitors (NMPs) and hindbrain neural progenitors.

We found that Hoxb1 promotes NMP survival through the upregulation of Fgf8, Fgf17, and other components of Fgf signaling as well as the repression of components of the apoptotic pathway. Additionally, it upregulates other anterior Hox genes suggesting that it plays an active role in the early steps of AP specification. In neural progenitors, Hoxb1 synergizes with shh to repress anterior and dorsal neural markers, promote the expression of ventral neural markers and direct the specification of facial branchiomotorneuron (FBM)-like progenitors. Hoxb1 and shh synergize in regulating the expression of diverse signals and signaling molecules, including the Ret tyrosine kinase receptor. Finally, Hoxb1 synergizes with exogenous Glial cell line-derived neurotrophic factor (GDNF) to strengthen Ret expression and further promote the generation of FBM-like progenitors. Facial branchiomotorneuron-like progenitors survived for at least 6 months and differentiated into postmitotic neurons after orthotopic transplantation near the facial nucleus of adult mice. These results suggested that the patterning activity of Hox genes in combination with downstream signaling molecules can be harnessed for the generation of defined neural populations and transplantations with implications for neurodegenerative diseases.
CTGF-D4 Amplifies LRP6 Signaling to Promote Grafts of Adult Epicardial-derived Cells That Improve Cardiac Function After Myocardial Infarction
Authors: Rao Krithika S , Kloppenburg Jessica E , Marquis Taylor , Solomon Laura , McElroy-Yaggy Keara L , Spees Jeffrey L
Published: January 2022

Transplantation of stem/progenitor cells holds promise for cardiac regeneration in patients with myocardial infarction (MI). Currently, however, low cell survival and engraftment after transplantation present a major barrier to many forms of cell therapy. One issue is that ligands, receptors, and signaling pathways that promote graft success remain poorly understood. Here, we prospectively isolate uncommitted epicardial cells from the adult heart surface by CD104 (β-4 integrin) and demonstrate that C-terminal peptide from connective tissue growth factor (CTGF-D4), when combined with insulin, effectively primes epicardial-derived cells (EPDC) for cardiac engraftment after MI. Similar to native epicardial derivatives that arise from epicardial EMT at the heart surface, the grafted cells migrated into injured myocardial tissue in a rat model of MI with reperfusion. By echocardiography, at 1 month after MI, we observed significant improvement in cardiac function for animals that received epicardial cells primed with CTGF-D4/insulin compared with those that received vehicle-primed (control) cells. In the presence of insulin, CTGF-D4 treatment significantly increased the phosphorylation of Wnt co-receptor LRP6 on EPDC. Competitive engraftment assays and neutralizing/blocking studies showed that LRP6 was required for EPDC engraftment after transplantation. Our results identify LRP6 as a key target for increasing EPDC engraftment after MI and suggest amplification of LRP6 signaling with CTGF-D4/insulin, or by other means, may provide an effective approach for achieving successful cellular grafts in regenerative medicine.
Lactate Enhances Mouse ES Cell Differentiation Toward XEN Cells In Vitro
Authors: Gatie Mohamed I , Cooper Tyler T , Khazaee Reza , Lajoie Gilles A , Kelly Gregory M
Published: January 2022

Metabolism plays a crucial role for cell survival and function; however, recent evidence has implicated it in regulating embryonic development. In the embryo, the inner cell mass undergoes orchestrated cellular divisions resulting in the formation of pluripotent epiblast stem cells and primitive endoderm cells. However, both lineages can be captured in vitro as embryonic stem (ES) cells and extraembryonic endoderm (XEN) cells. Concomitantly, changes in the metabolic profile occurs during development, and are well documented in the embryonic lineages. However, a comprehensive multi-omic analysis of these features in XEN cells remains lacking. We observed that mouse XEN cells exhibited high sensitivity to glycolytic inhibition in addition to maintaining elevated intra- and extracellular lactate levels in vitro. Extraembryonic endoderm cells maintain high lactate levels by increased LDHA activity, and re-routing pyruvate away from the mitochondria resulting in reduced mitochondrial activity due to disruptions in electron transport chain stoichiometry. Importantly, exogenous lactate supplementation or promoting intracellular lactate accumulation enhances XEN differentiation in vitro. These results highlight how lactate contributes to XEN differentiation in vitro and may serve to enhance reprogramming efficiency of cells used for regenerative medicine.
ROR2 Downregulation Activates the MSX2/NSUN2/p21 Regulatory Axis and Promotes Dental Pulp Stem Cell Senescence
Authors: He Xin , Yang Zhan , Chu Xiao-Yang , Li Yun-Xia , Zhu Biao , Huang Yan-Xia , Wang Wei , Gao Chun-Yan , Chen Xu , Zheng Chun-Yan , Yang Kai , Zhang Dong-Liang
Published: January 2022

Cellular senescence severely limits the research and the application of dental pulp stem cells (DPSCs). A previous study conducted by our research group revealed a close implication of ROR2 in DPSC senescence, although the mechanism underlying the regulation of ROR2 in DPSCs remains poorly understood so far. In the present study, it was revealed that the expression of the ROR2-interacting transcription factor MSX2 was increased in aging DPSCs. It was demonstrated that the depletion of MSX2 inhibits the senescence of DPSCs and restores their self-renewal capacity, and the simultaneous overexpression of ROR2 enhanced this effect. Moreover, MSX2 knockdown suppressed the transcription of NOP2/Sun domain family member 2 (NSUN2), which regulates the expression of p21 by binding to and causing the 5-methylcytidine methylation of the 3ʹ- untranslated region of p21 mRNA. Interestingly, ROR2 downregulation elevated the levels of MSX2 protein, and not the MSX2 mRNA expression, by reducing the phosphorylation level of MSX2 and inhibiting the RNF34-mediated MSX2 ubiquitination degradation. The results of the present study demonstrated the vital role of the ROR2/MSX2/NSUN2 axis in the regulation of DPSC senescence, thereby revealing a potential target for antagonizing DPSC aging.
Toll-Like Receptor 5 Promotes the Neurogenesis From Embryonic Stem Cells and Adult Hippocampal Neural Stem Cells in Mice
Authors: Seong Kyung-Joo , Choi Seungho , Lee Hyun-Gwan , Rhee Joon Haeng , Lee Jin Ho , Koh Jeong-Tae , Kim Sun-Hun , Choi Won-Seok , Jung Ji-Yeon , Kim Won-Jae
Published: January 2022

Toll-like receptors (TLRs) make a crucial contribution to the innate immune response. TLR5 was expressed in embryoid body derived from mouse embryonic stem cells (mESCs) and βIII-tubulin-positive cells under all-trans retinoic acid-treated condition. TLR5 was upregulated during neural differentiation from mESCs and augmented the neural differentiation of mESCs via nuclear factor-κB and interleukin 6/CREB pathways. Besides, TLR5 was expressed in SOX2- or doublecortin-positive cells in the subgranular zone of the hippocampal dentate gyrus where adult neurogenesis occurs. TLR5 inhibited the proliferation of adult hippocampal neural stem cells (NSCs) by regulating the cell cycle and facilitated the neural differentiation from the adult hippocampal NSCs via JNK pathway. Also, TLR5 deficiency impaired fear memory performance in mice. Our data suggest that TLR5 is a crucial modulator of neurogenesis from mESCs and adult hippocampal NSCs in mice and represents a new therapeutic target in neurological disorders related to cognitive function.
Neural Stem Cell-Derived Extracellular Vesicles Counteract Insulin Resistance-Induced Senescence of Neurogenic Niche
Authors: Natale Francesca , Leone Lucia , Rinaudo Marco , Sollazzo Raimondo , Barbati Saviana Antonella , La Greca Francesco , Spinelli Matteo , Fusco Salvatore , Grassi Claudio
Published: January 2022

Neural stem and progenitor cell (NSPC) depletion may play a crucial role in the cognitive impairment observed in many age-related non-communicable diseases. Insulin resistance affects brain functions through a plethora of mechanisms that remain poorly understood. In an experimental model of insulin resistant NSPCs, we identified a novel molecular circuit relying on insulin receptor substrate-1 (IRS-1)/ Forkhead box O (FoxO) signaling cascade and inhibiting the recruitment of transcription factors FoxO1 and FoxO3a on the promoters of genes regulating proliferation and self-renewal. Insulin resistance also epigenetically increased the expression of cyclin-dependent kinase inhibitor 1 (p21) and accelerated NSPC senescence. Of note, we found that stimulation of NSPCs with NSPC-derived exosomes (exo-NSPC) rescued IRS-1/FoxO activation and counteracted both the reduced proliferation and senescence of stem cells. Accordingly, intranasal administration of exo-NSPC counteracted the high-fat diet-dependent impairment of adult hippocampal neurogenesis in mice by restoring the balance between proliferating and senescent NSPCs in the hippocampus. Our findings suggest a novel mechanism underlying the metabolic control of NSPC fate potentially involved in the detrimental effects of metabolic disorders on brain plasticity. In addition, our data highlight the role of extracellular vesicle-mediated signals in the regulation of cell fate within the adult neurogenic niche.
Estimating the direct Disability-Adjusted Life Years (DALYs) associated with SARS-CoV-2 (COVID-19) in the Republic of Ireland: The first full year
Authors: Moran Declan , Pires Sara Montero , Wyper Grant , Devleesschauwer Brecht , Cuschieri Sarah , Kabir Zubair
Published: January 2022

Objectives

Burden of Disease frameworks facilitate estimation of the health impact of diseases to be translated into a single measure, such as the Disability-Adjusted-Life-Year (DALY).

Methods

DALYs were calculated as the sum of Years of Life Lost (YLL) and Years Lived with Disability (YLD) directly associated with COVID-19 in the Republic of Ireland (RoI) from March 01, 2020, to February 28, 2021. Life expectancy is based on the Global Burden of Disease (GBD) Study life tables for 2019.

Results

There were 220,273 confirmed cases with a total of 4,500 deaths as a direct result of COVID-19. DALYs were estimated to be 51,532.1 (95% Uncertainty Intervals [UI] 50,671.6, 52,294.3). Overall, YLL contributed to 98.7% of the DALYs. Of total symptomatic cases, 6.5% required hospitalisation and of those hospitalised 10.8% required intensive care unit treatment. COVID-19 was likely to be the second highest cause of death over our study’s duration.

Conclusion

Estimating the burden of a disease at national level is useful for comparing its impact with other diseases in the population and across populations. This work sets out to standardise a COVID-19 BoD methodology framework for the RoI and comparable nations in the EU.
A Web-based Spatial Decision Support System of Wastewater Surveillance for COVID-19 Monitoring: A Case Study of a University Campus
Authors: Tang Wenwu , Chen Tianyang , Slocum Zachery , Lan Yu , Delmelle Eric , Chen Don , Mittal Neha , Rice-Boayue Jacelyn , Shukla Tarini , Lin Sophia , Akella Srinivas , Schlueter Jessica , Munir Mariya , Gibas Cynthia
Published: January 2022

The ongoing COVID-19 pandemic has produced substantial impacts on our society. Wastewater surveillance has increasingly been introduced to support the monitoring, and thus mitigation, of COVID-19 outbreaks and transmission. Monitoring of buildings and sub-sewershed areas via a wastewater surveillance approach has been a cost-effective strategy for mass testing of residents in congregate living situations such as universities. A series of spatial and spatiotemporal data are involved with wastewater surveillance, and these data must be interpreted and integrated with other information to better serve as guidance on response to a positive wastewater signal. The management and analysis of these data poses a significant challenge, in particular, for the need of supporting timely decision making. In this study, we present a web-based spatial decision support system framework to address this challenge. Our study area is the main campus of the University of North Carolina at Charlotte. We develop a spatiotemporal data model that facilitates the management of space-time data related to wastewater surveillance. We use spatiotemporal analysis and modeling to discover spatio-temporal patterns of COVID-19 virus abundance at wastewater collection sites that may not be readily apparent in wastewater data as they are routinely collected. Web-based GIS dashboards are implemented to support the automatic update and sharing of wastewater testing results. Our web-based SDSS framework enables the efficient and automated management, analytics, and sharing of spatiotemporal data of wastewater testing results for our study area. This framework provides substantial support for informing critical decisions or guidelines for the prevention of COVID-19 outbreak and the mitigation of virus transmission on campus.
Convalescent plasma improves overall survival in patients with B-cell lymphoid malignancies and COVID-19: a longitudinal cohort and propensity score analysis
Authors: Hueso Thomas , Godron Anne-Sophie , Lanoy Emilie , Pacanowski Jérôme , Levi Laura I. , Gras Emmanuelle , Surgers Laure , Guemriche Amina , Meynard Jean-Luc , Pirenne France , Idri Salim , Tiberghien Pierre , Morel Pascal , Besson Caroline , Duléry Rémy , Lamure Sylvain , Hermine Olivier , Gagneux-Brunon Amandine , Freymond Nathalie , Grabar Sophie , Lacombe Karine ,   the HEMOPLASM Study Group
Published: January 2022

Patients with hematological malignancies and COVID-19 display a high mortality rate. In such patients, immunosuppression due to underlying disease and previous specific treatment impair humoral response, limiting viral clearance. Thus, COVID-19 convalescent plasma (CCP) therapy appears as a promising approach through the transfer of neutralizing antibodies specific to SARS-CoV-2.

We report the effect of CCP in a cohort of 112 patients with hematological malignancies and COVID-19 and a propensity score analysis on subgroups of patients with B-cell lymphoid disease treated (n=81) or not (n=120) with CCP between 1 May 2020 and 1 April 2021. The overall survival of the whole cohort was 65% [56–74.9] and 77.5% [68.5–87.7] for patients with B-cell neoplasm. Prior anti-CD20 monoclonal antibodies therapy was associated with better overall survival whereas age, high blood pressure, and COVID-19 severity were associated with a poor outcome. After an inverse probability of treatment weighting approach, we observed in anti-CD20–exposed patients with B-cell lymphoid disease a decreased mortality of 63% (95% CI=31%–80%) in the CCP-treated group compared to the CCP-untreated subgroup, confirmed in the other sensitivity analyses.

Convalescent plasma may be beneficial in COVID-19 patients with B-cell neoplasm who are unable to mount a humoral immune response.
Humoral immune responses against SARS-CoV-2 variants including omicron in solid organ transplant recipients after three doses of a COVID-19 mRNA vaccine
Authors: Saharia Kapil K. , Husson Jennifer S. , Niederhaus Silke V. , Iraguha Thierry , Avila Stephanie V. , Yoo Youngchae J. , Hardy Nancy M. , Fan Xiaoxuan , Omili Destiny , Crane Alice , Carrier Amber , Xie Wen Y. , Vander Mause Erica , Hankey Kim , Bauman Sheri , Lesho Patricia , Mannuel Heather D. , Ahuja Ashish , Mathew Minu , Avruch James , Baddley John , Goloubeva Olga , Shetty Kirti , Dahiya Saurabh , Rapoport Aaron P. , Luetkens Tim , Atanackovic Djordje
Published: January 2022

Background

Solid organ transplant recipients (SOTR), who typically receive post-transplant immunosuppression, show increased COVID-19-related mortality. It is unclear whether an additional dose of COVID-19 vaccines in SOTR can overcome the reduced immune responsiveness against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants.

Methods

We performed a prospective cohort study of 53 SOTR receiving SARS-CoV-2 vaccination into a prospective cohort study performing detailed immunoprofiling of humoral immune responses against SARS-CoV-2 and its variants.

Results

Prior to the additional vaccine dose, 60.3% of SOTR showed no measurable neutralization and only 18.9% demonstrated neutralizing activity of >90% following two vaccine doses. More intensive immunosuppression, antimetabolites in particular, negatively impacted antiviral immunity. While absolute IgG levels were lower in SOTR than controls, antibody titers against microbial recall antigens were in fact higher. In contrast, SOTR showed reduced vaccine-induced IgG/IgA antibody titers against SARS-CoV-2 and its delta variants. Vaccinated SOTR showed a markedly fewer linear B cell epitopes, indicating reduced B cell diversity. Importantly, a third vaccine dose led to an increase in anti-SARS-CoV-2 antibody titers and neutralizing activity across alpha, beta and delta variants. However, we observed a significant decrease in anti-spike antibody titers with the omicron variant.

Conclusions

Only a small subgroup of SOTR generated functionally relevant antibodies after completing the initial vaccine series based on dysfunctional priming of immune responses against novel antigens. An additional dose of the vaccine results in dramatically improved antibody responses against all SARS-CoV-2 variants except omicron.
Immunoglobulin Replacement Therapy in Chronic Lymphocytic Leukaemia patients with hypogammaglobulinaemia and infection; analysis of total national utilisation data in Australia 2008-2013
Authors: Keegan Anastazia , Dennington Peta , Dhondy Nina , MULLIGAN Stephen P.
Published: January 2022

Objectives
To analyse total national utilisation of immunoglobulin (Ig) replacement therapy (IgRT) for Chronic Lymphocytic Leukaemia patients with acquired hypogammaglobulinaemia and severe and/or recurrent bacterial infections.

Methods
In 2007, the National Blood Authority first published Criteria for the clinical use of intravenous immunoglobulin in Australia. The Australian Red Cross Lifeblood assessed, approved, and recorded all supply with patient demographics, distribution data, intravenous Ig (IVIg) volumes and treatment episodes. IVIg was the sole product used in Australia from 2008-2013 inclusive.

Results
From 2008-2013 across Australia, 2,734 individual CLL patients received 48,870 treatment episodes using a total 1,324,926 grams of IVIg therapy. Six IVIg products were available, with domestically manufactured Intragam P accounting for 89.7% of supply. The average age for first dose was 74 years. Males received 60.6% of the total treatment episodes representing 20% more than females. The average pre-treatment IgG level was 4.03g/L +/- 2.03g/L (range 0.30-10.50g/L). A sustained average annual increased IVIg utilisation of 5.5% was observed. There was significant regional variation consistent with differences in prescriber preferences across states and territories.

Conclusion
This study provides a globally unique insight into IgRT supply and demand in CLL patients by analysis of total national use in Australia over a six year period.
Increased Risk of Poor Clinical Outcome in COVID-19 Patients with Diabetes Mellitus and in-hospital Mortality Predictors: A Retrospective Cohort from a Tertiary Hospital in Indonesia
Authors: Mokoagow Md Ikhsan , Harbuwono Dante Saksono , Kshanti Ida Ayu , Rumende C Martin , Subekti Imam , Harimurti Kuntjoro , Lie Khie Chen , Shatri Hamzah
Published: January 2022

Aim

To determine association between diabetes in confirmed cases of COVID-19 and intensive care admission and in-hospital mortality, evaluate several laboratory parameters as mortality predictor, and develop predictors of in-hospital mortality among diabetics with COVID-19.

Methods

This retrospective cohort recruited all cases of COVID-19 hospitalized in Fatmawati General Hospital during March to October 2020. Inclusion criteria was RT-PCR confirmed cases of COVID-19 who aged 18 years and older while exclusion criteria were incomplete medical record or cannot be found and pregnant women.

Results

We enrolled 506 participants to this study with median age of 51 years (IQR:22), female (56.32%), and diabetes (28.46%). Diabetes increased intensive care admission (adjusted OR:6.07;95%CI:3.52-10,43) and in-hospital mortality (adjusted OR:50;95%CI:1.61-3.89). In predicting in-hospital mortality, ferritin and lactate dehydrogenase offered an acceptable discrimination, AUC:0.71 (95%CI: 0.62-0.79) and AUC:0.70 (95%CI: 0.61-0.78), respectively. The optimal cut-off of predicting mortality for ferritin was 786 g/mL and for LDH was 514.94 u/L. Factors include age above 70 years old, RBGs level on admission above 250 mg/dL or below 140 mg/dL, ferritin level above 786 ng/mL, and presence of ARDS increased the odds of mortality among individuals with diabetes.

Conclusions

Diabetes increases risk of intensive care admission and in hospital mortality in COVID-19. Multivariate analysis showed that older age, RBG on admission, high ferritin level, presence of ARDS increased the odds of mortality among individuals with diabetes.
Identifying the critical time window for the association of the early-life gut microbiome and metabolome with childhood neurodevelopment
Authors: Sun Zheng , Lee-Sarwar Kathleen , Kelly Rachel S. , Lasky-Su Jessica A. , Litonjua Augusto A. , Weiss Scott T. , Liu Yang-Yu
Published: January 2022

It has been widely recognized that a critical time window for neurodevelopment occurs in early life, and that the host’s gut microbiome plays an important role in neurodevelopment. While murine models have demonstrated that the maternal gut microbiome also influences offspring brain development, for humans it is still unclear if the critical time window for the association between the gut microbiome and neurodevelopment is prenatal, postnatal or both. Here we leverage a large-scale human study and compare the associations between the gut microbiota and metabolites from mothers and their children with the children’s neurodevelopment. We show, for the first time, that the maternal gut microbiome is more relevant than the children’s gut microbiome to the children’s neurodevelopment in the first year of life. Interestingly, the roles of the same taxa with respect to neurodevelopment can be opposite at the two stages of fetal neurodevelopment. These findings shed light on potential therapeutic interventions to prevent neurodevelopmental disorders.
Sample Size Calculations for Variant Surveillance in the Presence of Biological and Systematic Biases
Authors: Wohl Shirlee , Lee Elizabeth C. , DiPrete Bethany L. , Lessler Justin
Published: January 2022

As demonstrated during the SARS-CoV-2 pandemic, detecting and tracking the emergence and spread of pathogen variants is an important component of monitoring infectious disease outbreaks. Pathogen genome sequencing has emerged as the primary tool for variant characterization, so it is important to consider the number of sequences needed when designing surveillance programs or studies, both to ensure accurate conclusions and to optimize use of limited resources. However, current approaches to calculating sample size for variant monitoring often do not account for the biological and logistical processes that can bias which infections are detected and which samples are ultimately selected for sequencing. In this manuscript, we introduce a framework that models the full process— including potential sources of bias—from infection detection to variant characterization, and we demonstrate how to use this framework to calculate appropriate sample sizes for sequencing-based surveillance studies. We consider both cross-sectional and continuous sampling, and we have implemented our method in a publicly available tool that allows users to estimate necessary sample sizes given a specific aim (e.g., variant detection or measuring variant prevalence) and sampling method. Our framework is designed to be easy to use, while also flexible enough to be adapted to other pathogens and surveillance scenarios.