bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anticoagulation and Thrombotic Events in the Multisystem Inflammatory Syndrome in Children: Experience of a Single-center Cohort and Review of the Literature
Authors: Pegoraro Francesco , Lasagni Donatella , Trapani Sandra , Mastrolia Maria V. , Simonini Gabriele , Indolfi Giuseppe , Resti Massimo 
Published: January 2023

The multisystem inflammatory syndrome in children (MIS-C) is a severe clinical entity affecting the coagulative system; although thromboembolic events (TEs) are not common, most patients receive anticoagulation.
We retrospectively assessed patients below 18 years admitted with MIS-C at Meyer Children’s Hospital (Florence, Italy). Data on baseline clinical and laboratory presentation, treatment, and outcome, including differences between patients with and without thrombotic prophylaxis, were analyzed.
Thirty-two children 1 to 15 years were included. Seventeen patients (53.1%) required intensive care admission, 2 (8.7%) had obesity, 7 (30.4%) a central venous catheter, and 14 (43.8%) an impaired cardiac function. Twelve patients (37.5%) received prophylactic anticoagulation: they had more frequent cardiac involvement (91.7 vs. 50%, P=0.02) and higher ferritin levels (median 1240 vs. 501.5 ng/mL, P<0.001). No differences were found in median d-dimers between the 2 groups. Twenty-one patients (65.6%) had d-dimers >5×upper limit of normal but the indication for anticoagulation was not driven by d-dimers. No patient had hemorrhagic events and only 1 patient (3.1%) had a superficial thrombotic event (under thromboprophylaxis).
Our series and the available literature data on MIS-C and thromboembolic events suggest that TEs are a rare complication of MIS-C that is frequently associated with high d-dimer values. However, also in MIS-C, the well-established risk factors of pediatric TEs (ie, older age, central venous catheter, obesity, and cancer) should guide thromboembolic risk assessment.
Implementing a Fall Prevention Initiative in Nurse-Facilitated Annual Wellness Visits
Authors: Quinlan Sharon , Ryer Suzanne 
Published: January 2023

Background:
Falls are the leading cause of injury-related death and disability in community-dwelling older adults.

Local Problem:
Evidence-based fall prevention activities in primary care, including nurse-facilitated wellness visits, have been limited. Barriers including patient engagement and adherence exist.

Method:
A quality improvement project integrating components of the Centers for Disease Control and Prevention's Stopping Elder Accidents, Deaths & Injury (STEADI) was introduced by registered nurses during older adult annual wellness visits.

Intervention:
Nurses assessed risk and implemented patient-centered fall prevention plans including follow-up.

Results:
A total of 522 patients were screened, with 21% (n = 111) having increased fall risk. Of these, 78% (n = 87) engaged in home safety, gait, strength, and balance assessments and the majority (n = 83; 95%) participated in fall prevention plans of care. At 2-week follow-up, patients' self-reported adherence was 74% for gait/strength/balance and 67% for home safety.

Conclusion:
An expanded primary care team model shows promise for promoting fall prevention behaviors.
Treatment Strategy for Condyle/Ramus Deficiency Using 3D Virtual Surgery and CAD/CAM Technologies; Total Joint Replacement or Inverted-L Osteotomy
Authors: Maeng Ji Youn , Ha Sung-Ho , Baek Seung-Hak , Choi Jin-Young 
Published: January 2023

Objective:
To introduce a guideline for selecting proper surgical modalities for correction of skeletal Class II malocclusion with moderate-to-severe vertical height deficiency (VHD) of the condyle/ramus complex (CRC) using bimaxillary surgery in conjunction with total joint replacement (TJR) or inverted-L osteotomy (ILO) assisted by 3D virtual surgical planning and CAD/CAM technologies.

Cases:
Four cases of severe skeletal Class II patients with moderate-to-severe VHD of CRC were presented. They underwent bimaxillary surgery using Le Fort I osteotomy in the maxilla and TJR or ILO in the mandible, with the help of virtual surgical planning (VSP) and computer-aided design/computer-aided manufacturing (CAD/CAM)-printed surgical guides and osteosynthesis plates. Guidelines are as follows: (1) if a patient has a moderate degree of VHD and the function of the temporomandibular joint (TMJ) is normal, ILO would be preferred for vertical elongation of the ramus; (2) if a patient has congenitally small condyle or severe condylar resorption, TJR would be preferred to resolve severe VHD of CRC; and (3) when a patient has a metal allergy, foreign body reaction or anatomic limitations (ie, thin cranial base cortex for fossa fixation), ILO would be a better option than TJR.

Results:
TJR or ILO using VSP and CAD/CAM-printed surgical guides, wafers, and customized plates can provide a proper selection of the surgical plan, accurate transfer of surgical plans to actual surgical procedures, and esthetic improvement of the facial profile.

Conclusion:
This guideline based on the degree of VHD and functional aspects of CRC might help clinicians to select effective surgical modality for correction of skeletal Class II malocclusion with moderate-to-severe VHD of CRC.
Robust single membrane protein tweezers
Authors: Kim Seoyoon , Lee Daehyo , Wijesinghe W.C. Bhashini , Min Duyoung 
Published: January 2023

AbstractSingle-molecule tweezers, such as magnetic tweezers, are powerful mechanical manipulation tools that can probe nm-scale structural changes in a single membrane protein under force. However, the weak molecular tethers used in the tweezers limit a long time, repetitive mechanical manipulation because of their force-induced bond breakage. Here, using the metal-free click chemistry of dibenzocyclooctyne (DBCO) cycloaddition and the rapid, strong binding of traptavidin to dual biotins (2xbiotin), we developed robust single-molecule tweezers that can perform thousands of force applications on a single membrane protein. By applying up to 50 pN for each cycle, which is sufficiently high for most biological processes, we were able to observe repetitive forced unfolding for a designer membrane protein up to approximately 1000 times on average. Monte Carlo simulations showed that the average error of the unfolding kinetic values rapidly decays to 1.8% at 200-time pulling, indicating that our method can quickly produce reliable statistics. The approach established here is also applicable to highly polar DNA molecules, permitting the nanomechanical manipulation of diverse biomolecular systems.
Hippocampal area CA2 controls seizure dynamics, interictal EEG abnormalities and social comorbidity in mouse models of temporal lobe epilepsy
Authors: Lisgaras Christos Panagiotis , Oliva Azahara , Mckenzie Sam , LaFrancois John , Siegelbaum Steven A. , Scharman Helen E. 
Published: January 2023

ABSTRACTTemporal lobe epilepsy (TLE) is characterized by spontaneous recurrent seizures, abnormal activity between seizures, and impaired behavior. CA2 pyramidal neurons (PNs) are potentially important because inhibiting them with a chemogenetic approach reduces seizure frequency in a mouse model of TLE. However, whether seizures could be stopped by timing inhibition just as a seizure begins is unclear. Furthermore, whether inhibition would reduce the cortical and motor manifestations of seizures are not clear. Finally, whether interictal EEG abnormalities and TLE comorbidities would be improved are unknown. Therefore, real-time optogenetic silencing of CA2 PNs during seizures, interictal activity and behavior were studied in 2 mouse models of TLE. CA2 silencing significantly reduced seizure duration and time spent in convulsive behavior. Interictal spikes and high frequency oscillations were significantly reduced, and social behavior was improved. Therefore, brief focal silencing of CA2 PNs reduces seizures, their propagation, and convulsive manifestations, improves interictal EEG, and ameliorates social comorbidities.HIGHLIGHTSReal-time CA2 silencing at the onset of seizures reduces seizure durationWhen CA2 silencing reduces seizure activity in hippocampus it also reduces cortical seizure activity and convulsive manifestations of seizuresInterictal spikes and high frequency oscillations are reduced by real-time CA2 silencingReal-time CA2 silencing of high frequency oscillations (>250Hz) rescues social memory deficits of chronic epileptic mice
Fcγ-receptor-independent controlled activation of CD40 canonical signaling by novel therapeutic antibodies for cancer therapy
Authors: Reitinger Carmen , Beckmann Karsten , Carle Anna , Blümle Eva , Jurkschat Nicole , Paulmann Claudia , Prassl Sandra , Kazandijan Linda V. , Nimmerjahn Falk , Fischer Stephan 
Published: January 2023

AbstractActivation of CD40-mediated signaling in antigen-presenting cells is a promising therapeutic strategy to promote immune responses against tumors. Agonistic anti-CD40 antibodies currently in development require Fcγ-receptor-mediated crosslinking of CD40 molecules for meaningful activation of CD40 signaling but have limitations due to dose-limiting toxicities. Here we describe the identification of CD40 antibodies which strongly stimulate antigen-presenting cells in an entirely Fc-independent manner. These novel Fc-silenced anti-CD40 antibodies induce upregulation of costimulatory receptors CD80 and CD86 and cytokine release by dendritic cells with an efficacy exceeding that of existing antibodies. Binding to the CD40L interaction region on CD40 appears to be a prerequisite to achieving such strong activities. Finally, the most active identified anti-CD40 antibody shows evidence of activity in terms of the expected markers of canonical CD40 signaling when injected in humanized mice. There are no signs of obvious toxicities whereas the clinical-stage anti-CD40 antibody CP-870,893 induced severe signs of toxicity in these animals despite a lower dose compared with the novel Fc-silenced canonical agonist. These studies thus demonstrate potent activation of antigen-presenting cells with anti-CD40 antibodies lacking Fcγ-receptor-binding activity and open the possibility of an efficacious and safe combination therapy for cancer patients.One Sentence SummaryTreatment of antigen-presenting cells and humanized mice with novel Fc-silenced CD40 antibodies demonstrates an Fcγ-receptor-independent canonical agonistic mode of action for therapeutic use.
Astrocytic control of extra-cellular GABA drives circadian time-keeping in the suprachiasmatic nucleus
Authors: Patton A. P. , Morris E.L. , McManus D. , Wang H. , Li Y. , Chin J.W. , Hastings M. H. 
Published: January 2023

SummaryThe hypothalamic suprachiasmatic nucleus (SCN) is the master mammalian circadian clock. Its cell-autonomous timing mechanism, a transcriptional/translational feedback loop (TTFL), drives daily peaks of neuronal electrical activity. Intercellular signals synchronize and amplify TTFL and electrical rhythms across the circuit. SCN neurons are GABAergic, but the role of GABA in circuit-level time-keeping is unclear. SCN slices expressing the GABA sensor iGABASnFR demonstrate a circadian oscillation of extracellular GABA ([GABA]e) that, counter-intuitively, runs in antiphase to neuronal activity, peaking in circadian night. Resolving this paradox, we found that [GABA]eis regulated by GABA transporters (GATs), uptake peaking during circadian day. This is mediated by the circadian-regulated, astrocytically expressed GAT3 (Slc6a11). Clearance of [GABA]ein circadian day facilitates neuronal firing, neuropeptide release and TTFL rhythmicity. Moreover, genetic complementation demonstrated that the astrocytic TTFL can alone drive [GABA]erhythms. Thus, astrocytic clocks maintain SCN circadian time-keeping by temporally controlling GABAergic inhibition of SCN neurons.
The chromatin modulating NSL complex regulates genes and pathways genetically linked to Parkinson’s disease
Authors: Hicks Amy R. , Reynolds Regina , O’Callaghan Ben , Ruiz Sonia Garcia , Martinez Ana Luisa Gil , Botia Juan , Plun-Favreau Helene , Ryten Mina 
Published: January 2023

AbstractGenetic variants conferring risk for Parkinson’s disease have been highlighted through genome-wide association studies, yet exploration of their specific disease mechanisms is lacking. Two Parkinson’s disease candidate genes,KAT8andKANSL1, identified through genome-wide studies and a PINK1-mitophagy screen, encode part of the histone acetylating non-specific lethal complex. This complex localises to the nucleus, where it has a role in transcriptional activation, and to mitochondria, where it has been suggested to have a role in mitochondrial transcription. In this study, we sought to identify whether the non-specific lethal complex has potential regulatory relationships with other genes associated with Parkinson’s disease in human brain.Correlation in the expression of non-specific lethal genes and Parkinson’s disease-associated genes was investigated in primary gene co-expression networks utilising publicly available transcriptomic data from multiple brain regions (provided by the Genotype-Tissue Expression Consortium and UK Brain Expression Consortium), whilst secondary networks were used to examine cell-type specificity. Reverse engineering of gene regulatory networks generated regulons of the complex, which were tested for heritability using stratified linkage disequilibrium score regression and then validatedin vitrousing the QuantiGene multiplex assay.Significant clustering of non-specific lethal genes was revealed alongside Parkinson’s disease-associated genes in frontal cortex primary co-expression modules. Both primary and secondary co-expression modules containing these genes were enriched for mainly neuronal cell types. Regulons of the complex contained Parkinson’s disease-associated genes and were enriched for biological pathways genetically linked to disease. When examined in a neuroblastoma cell line, 41% of prioritised gene targets showed significant changes in mRNA expression followingKANSL1orKAT8perturbation.In conclusion, genes encoding the non-specific lethal complex are highly correlated with and regulate genes associated with Parkinson’s disease. Overall, these findings reveal a potentially wider role for this protein complex in regulating genes and pathways implicated in Parkinson’s disease.
Novel orthotopic model of neuroblastoma in RNU homozygous rats
Authors: Sever ReidAnn , Rosenblum Lauren Taylor , Schmidt Lori , Hartwick Sean , Schwab Kristina , Wu Yijen , Raphael Itay , Reyes Miguel , Edwards Wilson Barry , Malek Marcus , Kohanbash Gary 
Published: January 2023

AbstractNeuroblastoma, the most common extracranial solid malignancy in children, accounts for 15% of pediatric cancer deaths despite multimodal therapy including surgical resection. Unfortunately, complete surgical resection remains challenging due to encasement of major neurovascular structures, unclear tumor margins, and remote nodal disease. While mouse models of neuroblastoma are extremely valuable for studying tumor biology and medical treatments, the small size renders the mouse model insufficient to evaluate novel surgical therapy.Here, we have developed a novel rat model of neuroblastoma to facilitate further development of surgical treatment. Human neuroblastoma cells (SK-N-BE(2)) were injected into the adrenal gland of RNU nude rats. They developed 2 cm xenograft tumors at 5 weeks which were easily identifiable on MRI imaging and on visual inspection. The rats began losing weight and neared end stage at 7 weeks, at which point surgical resection was attempted. While surgical resection was technically feasible, the rats were too frail to survive surgery at the late stage. The pathology of the tumors was consistent with neuroblastoma: small round blue cells with strong PHOX2B staining. Thus, we present a novel rat neuroblastoma model that can be used for development of surgical techniques, such as the use of intraoperative contrast agents.
A dual MTOR/NAD+ acting gerotherapy
Authors: Li Jinmei , Kumar Sandeep , Miachin Kirill , Bean Nicholas L. , Halawi Ornella , Lee Scott , Park JiWoong , Pierre Tanya H. , Hor Jin-Hui , Ng Shi-Yan , Wallace Kelvin J. , Rindtorff Niklas , Miller Timothy M. , Niehoff Michael L. , Farr Susan A. , Kletzien Rolf F. , Colca Jerry , Tanis Steven P. , Chen Yana , Griffett Kristine , McCommis Kyle S. , Finck Brian N. , Peterson Tim R. 
Published: January 2023

ABSTRACTThe geroscience hypothesis states that a therapy that prevents the underlying aging process should prevent multiple aging related diseases. The mTOR (mechanistic target of rapamycin)/insulin and NAD+ (nicotinamide adenine dinucleotide) pathways are two of the most validated aging pathways. Yet, it’s largely unclear how they might talk to each other in aging. In genome-wide CRISPRa screening with a novel class of N-O-Methyl-propanamide-containing compounds we named BIOIO-1001, we identified lipid metabolism centering on SIRT3 as a point of intersection of the mTOR/insulin and NAD+ pathways. In vivo testing indicated that BIOIO-1001 reduced high fat, high sugar diet-induced metabolic derangements, inflammation, and fibrosis, each being characteristic of non-alcoholic steatohepatitis (NASH). An unbiased screen of patient datasets suggested a potential link between the anti-inflammatory and anti-fibrotic effects of BIOIO-1001 in NASH models to those in amyotrophic lateral sclerosis (ALS). Directed experiments subsequently determined that BIOIO-1001 was protective in both sporadic and familial ALS models. Both NASH and ALS have no treatments and suffer from a lack of convenient biomarkers to monitor therapeutic efficacy. A potential strength in considering BIOIO-1001 as a therapy is that the blood biomarker that it modulates, namely plasma triglycerides, can be conveniently used to screen patients for responders. More conceptually, to our knowledge BIOIO-1001 is a first therapy that fits the geroscience hypothesis by acting on multiple core aging pathways and that can alleviate multiple conditions after they have set in.Brief SummaryThese studies characterize a novel gerotherapy, BIOIO-1001, that identifies lipid metabolism as an intersection of the mTOR and NAD+ pathways.
Fatty liver-mediated glycine restriction impairs glutathione synthesis and causes hypersensitization to acetaminophen
Authors: Ghrayeb Alia , Agranovich Bella , Peled Daniel , Finney Alexandra C. , Abramovich Ifat , Garcia Jonatan Fernandez , Traylor James , Drucker Shani , Fernandes Sara Isabelle , Weissman Natan , Chen Y. Eugene , Rom Oren , Mor Inbal , Gottlieb Eyal 
Published: January 2023

SummaryNon-alcoholic fatty liver disease (NAFLD) affects nearly one third of the population worldwide. Understanding metabolic pathways involved can provide insights into disease progression. Untargeted metabolomics of livers from mice with early-stage steatosis indicated a decrease in methylated metabolites suggesting altered one carbon metabolism. The levels of glycine, a central component of one carbon metabolism, were lower in steatotic mice, in line with clinical evidence. Isotope tracing studies demonstrated that increased synthesis of serine from glycine is the underlying cause for glycine limitation in fatty livers. Consequently, the low glycine availability in steatotic livers impaired glutathione (GSH) synthesis under oxidative stress induced by acetaminophen (APAP), enhancing hepatic toxicity. Glycine supplementation mitigated acute liver damage and overall toxicity caused by APAP in fatty livers by supportingde novoGSH synthesis. Thus, early metabolic changes in NAFLD that lead to glycine depletion sensitize mice to xenobiotic toxicity even at a reversible stage of NAFLD.
The absence of a neurogenic response to a repeated concussive-like injury in mice
Authors: Weingarten A. , Madjou T. M. , Yeturu S.N. , Samudrala N. , Villasana L.E. 
Published: January 2023

AbstractIn response to traumatic brain injury (TBI), the brain increases its generation of new neurons (neurogenesis) within the hippocampus, a brain region critical for learning and memory. Because neurogenesis plays important roles in learning and memory, post-traumatic neurogenesis may represent an adaptive response contributing to cognitive recovery. In contrast to increases in neurogenesis acutely after injury, levels of neurogenesis become impaired long after TBI. And although chronic deficits in neurogenesis after TBI have been reported by multiple groups, it is unknown whether the hippocampus remains capable of eliciting another neurogenic response to a repeated injury. To address this lack of knowledge, we used a closed head injury model that reflects a concussive-like injury or a mild TBI (mTBI) and assessed levels of neurogenesis in male and female adult mice. Mice received one or two mTBI or sham treatments 3 weeks apart. Compared to mice with a single mTBI, proliferation and neurogenesis were blunted in mice that received a second mTBI. This impaired response was unlikely due to a short recovery time between the two mTBIs as the proliferative response to a second mTBI was also impaired when two months were allowed between injuries. We further found that proliferation was impaired in the radial-glia like cells despite an intact pool. The mice that received two mTBIs also had a blunted intensity in their GFAP staining. In contrast to reports of aberrant post-TBI neurogenesis, we found that the neurons born after mTBI had normal dendritic branches. Lastly, we found that impairments in the inability to mount a neurogenic response after a second mTBI were associated with deficits in neurogenesisstrategy flexibility in the reversal water maze task. Our data suggests that a loss in the neurogenic response could in part contribute to worse cognitive recovery after a repeated concussion. These data may expose a novel target to help improve long-term cognitive outcome following repeated brain injury.
Smart utilization of betaine lipids in giant clamTridacna crocea
Authors: Sakai Ryuichi , Goto-Inoue Naoko , Yamashita Hiroshi , Aimoto Naoya , Kitai Yuto , Maruyama Tadashi 
Published: January 2023

AbstractThe giant clamTridacna croceainhabits shallow tropical seas with poorly nourished water and severe sun irradiation. They harbor symbiotic algae “zooxanthellae” (dinoflagellate family Symbiodiniaceae) in the mantle tissue and are thought to thrive in this extreme environment by utilizing photosynthetic products from the algae. However, there is no measure of the detailed metabolic flow between the host and symbiont to evaluate one of the most successful symbiotic relationships in nature. Here, we employed liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based lipidomics and Fourier-transform ion cyclotron resonance MS imaging onT. croceatissues, revealing a unique lipid composition and localization with their symbiont algae. We discovered that the non-phosphorous microalgal betaine lipid diacylglycerylcarboxy-hydroxymethylcholine (DGCC) was present in all tissues and organs ofT. croceato approximately the same degree as phosphatidylcholine (PC). The fatty acid composition of DGCC was similar to that of PC, which is thought to have physiological roles similar to that of DGCC. MS imaging showed co-localization of these lipids throughout the clam tissues. Glycerylcarboxy-hydroxymethylcholine (GCC), the deacylated derivative of DGCC, was found to be a free form of DGCC in the clams and was isolated and characterized from cultured Symbiodiniaceae strains that were isolated from giant clams. These results strongly suggest that giant clams have evolved to smartly utilize DGCCs, phosphorus-free polar lipids of symbiont algae, as essential membrane components to enable them to thrive in oligotrophic coral reef milieu.