bluuebunny/crossref_metadata_2025_split huggingface dataset:
Process intensification for generating and decomposing formic acid, a liquid hydrogen carrier
Authors: Egbert Jonathan D. , Grubel Katarzyna , Howe Daniel T. , Weber Robert S. , Agarwal Arun S. , Brix Todd 
Published: January 2022

AbstractWe preview two processes that facilitate using formic acid (HCOOH) as a liquid hydrogen carrier to store renewably‐generated electrical energy and then release it to generate electrical power cleanly for backup or emergency applications. First, we show that simultaneously oxidizing an organic solute (typically a waste stream) can assist the electrochemical synthesis of formic acid by lowering the cell potential. The electrolyser comprises a hybrid 3‐chamber PEM stack that reduces CO₂ via a gas‐diffusion cathode boosted by the oxidation of aqueous methanol. However, the extent of the boosting needs to be optimized across the whole operation of the cell. Next, we present results from an intensified reactor for decomposing formic acid back into H₂ and CO₂ at elevated pressure so that the H₂ can be used in a fuel cell. The reactor combines three operations: Vaporization of the formic acid, its decomposition, and separation of the product stream. Their close coupling affords energy savings and a compact design that could be mounted on a mobile skid. We briefly discuss the electrode catalyst that facilitates the first process and two thermally activated catalysts (Ir supported on covalent triazine framework and Pd supported on carbon) that enable the second process.
Biomimetic Diels–Alder Reactions in Natural Product Synthesis: A Personal Retrospect
Authors: Tang Yefeng , Liu Jingchun , Xi Shuang 
Published: January 2022

AbstractNature has been recognized for her super capability of constructing complex molecules with remarkable efficiency and elegancy. Among nature’s versatile synthetic toolkits, Diels–Alder reaction is particularly attractive since it allows for rapid generation of molecular complexity from simple precursors. For natural products biosynthetically formed through Diels–Alder reactions, the most straightforward way to access them should build on biomimetic Diels–Alder reactions. However, the implementation of biomimetic Diels–Alder reactions in a laboratory setting may encounter considerable challenges, particularly for those suffering from complicated reactivity and selectivity issues. Indeed, the translation of a biosynthetic hypothesis into a real biomimetic synthesis entails the orchestrated combination of nature’s inspiration and chemist’s rational design. In this Account, we will briefly summarize our recent progress on the application of biomimetic Diels–Alder reactions in natural product synthesis. As shown in the discussed stories, rational manipulation of the structures of biosynthetic precursors plays a crucial role for the successful implementation of biomimetic Diels–Alder reactions.1 Introduction2 Biomimetic Synthesis of Rossinone B3 Biomimetic Synthesis of Homodimericin A4 Biomimetic Synthesis of Polycyclic and Dimeric Xanthanolides5 Biomimetic Synthesis of Periconiasins and Pericoannosins6 Biomimetic Synthesis of Merocyctochalasans7 Conclusion and Outlook
Investigation into the thermal effect of the LIPS-200 ion thruster plume
Authors: CHEN Xinwei , HE Bijiao , GU Zuo , GENG Hai , GUO Ning , ZHAO Yong , SHI Kai , TIAN Kai , CHEN Tao , MA Yifan 
Published: January 2022

Abstract
The distribution of the thermal effects of the ion thruster plume are essential for estimating the influence of the thruster plume, improving the layout of the spacecraft, and for the thermal shielding of critical sensitive components. In order to obtain the heat flow distribution in the plume of the LIPS-200 xenon ion thruster, an experimental study of the thermal effects of the plume has been conducted in this work, with a total heat flow sensor and a radiant heat flow sensor over an axial distance of 0.5–0.9 m and a thruster angle of 0°–60°. Combined with a Faraday probe and a retarding potential analyzer, the thermal accommodation coefficient of the sensor surface in the plume is available. The results of the experiment show that the xenon ion thruster plume heat flow is mainly concentrated within a range of 15°. The total and radial heat flow of the plume downstream of the thruster gradually decreases along the axial and radial directions, with the corresponding values of 11.78 kW m−2 and 0.3 kW m−2 for the axial 0.5 m position, respectively. At the same position, the radiation heat flow accounts for a very small part of the total heat flow, approximately 3%–5%. The thermal accommodation factor is 0.72–0.99 over the measured region. Furthermore, the PIC and DSMC methods based on the Maxwell thermal accommodation coefficient model (EX-PWS) show a maximum error of 28.6% between simulation and experiment for LIPS-200 ion thruster plume heat flow, which, on the one hand, provides an experimental basis for studying the interaction between the ion thruster and the spacecraft, and on the other hand provides optimization of the ion thruster plume simulation model.
DISCOVERY OF IBD3540: A NOVEL GUT-RESTRICTED GLUTAMATE CARBOXYPEPTIDASE II INHIBITOR WITH ORAL ACTIVITY IN MOUSE COLITIS MODELS
Authors: Peters Diane , Norris Lauren , Tenora Lukas , Snajdr Ivan , Zhu Xiaolei , Sakamoto Shinji , Thomas Ajit , Majer Pavel , Rais Rana , Slusher Barbara 
Published: January 2022

Abstract

BACKGROUND & AIMS
Glutamate carboxypeptidase II (GCPII) is robustly overexpressed in both Crohn’s disease and ulcerative colitis and is a promising therapeutic target for IBD. We have previously published that systemically or enema administered small molecule GCPII inhibitors have efficacy in multiple mouse colitis models. While this is a highly encouraging activity profile for a candidate IBD drug, an oral dose route would be strongly preferred. Thus, here we develop and characterize a new class of GCPII inhibitors designed to be gut-restricted for oral administration, with the intention of selecting a lead inhibitor for further clinical development.

METHODS
Anti-inflammatory secondary bile acids lithocholic acid, deoxycholic acid and ursodeoxycholic acid were conjugated to GCPII inhibitor, 2-PMPA, yielding three novel constructs. These conjugates were screened for oral activity in murine dextran sulfate sodium (DSS) colitis, followed by detailed characterization of the most active inhibitor to: measure GCPII inhibition (IC50), confirm colon target engagement, evaluate plasma and colon pharmacokinetic profiles, compare efficacy versus standard-of-care agents, evaluate mechanisms of anti-inflammatory activity in vivo, confirm efficacy in a second colitis model (IL10-/-), and assess safety in standard preclinical assays.

RESULTS
The deoxycholic acid 2-PMPA conjugate, IBD3540, was identified as the lead inhibitor (IC50 = 4nM). Oral IBD3540 was robustly efficacious in acute DSS colitis, where it dose-dependently inhibited colon GCPII, attenuated both gross disease activity index and blinded colon histopathology scores, and exhibited improved efficacy relative to both sulfasalazine and tofacitinib when compared head-to-head. Mechanistically, we determined that IBD3540 attenuated pathogenic monocytic inflammation in the colon, as measured by flow cytometry, and also decreased colon pro-inflammatory cytokine content. We confirmed efficacy of IBD3540 in spontaneously occurring, chronic, IL10-/- colitis, where treatment initiated 4 weeks after the onset of colon inflammation improved multiple disease endpoints. Further, in preclinical safety screens, inclusive of CYP inhibition/induction assays, Eurofins SafetyScreen44, and AMES/hERG mutagenicity testing, no concerns were identified.

CONCLUSION
IBD3540 is a novel, gut-restricted, GCPII inhibitor with potent oral anti-colitis efficacy in both acute (DSS) and chronic (IL10-/-) mouse colitis models and a promising preclinical safety profile. Further development of this mechanistically unique candidate IBD drug is warranted.
POPULATION PHARMACOKINETICS AND PHARMACODYNAMICS OF OZANIMOD IN ULCERATIVE COLITIS
Authors: Tatosian Daniel , Shen Jun , Chen Lu , Lavigne Jean , Teuscher Nathan , Harris Sarah , Chitkara Denesh , Tirucherai Giridhar , Marta Cecilia 
Published: January 2022

Abstract

BACKGROUND
Ozanimod is an oral small molecule sphingosine 1-phosphate receptor modulator approved for relapsing forms of multiple sclerosis (RMS) and moderately to severely active ulcerative colitis (UC) and under development for Crohn’s disease. Ozanimod and its major active metabolites CC112273 and CC1084037 block lymphocyte egress from lymphoid tissues, reducing the absolute lymphocyte count (ALC) in blood. To characterise the influence of patient characteristics on ALC response, a population pharmacokinetic/pharmacodynamic (PK/PD) analysis was conducted.

METHODS
A nonlinear mixed-effects Emax model described the ALC time course and relationship to CC112273 concentrations in healthy subjects and patients with UC or RMS. The analysed data included 34,449 ALC values obtained from 4122 subjects enrolled in 11 Phase 1, 2, and 3 clinical studies. The effect of age, sex, smoking status, disease type, body weight, total bilirubin, and baseline ALC on the maximum ALC reduction (Emax) and half-maximal concentration (EC50) were investigated. Simulations of typical ALC reductions for healthy subjects and patients with UC or RMS receiving 0.5 or 1 mg ozanimod were conducted to explore the influence of smoking and assess the time for ALC recovery.

RESULTS
Increasing CC112273 concentrations were associated with reductions in ALC to a maximum of 74% from baseline, with an estimated EC50 of 2.8 nM CC112273. Healthy subjects, females, and higher body weights were associated with larger ALC Emax (Figure 1), while healthy subjects, increased age, nonsmokers and higher baseline ALC were associated with an increased EC50 (Figure 2). UC patients receiving 0.5 mg and 1 mg ozanimod HCl are predicted to have mean ALC reductions of 46.1% and 57.2%, respectively, with similar reductions for RMS patients of 48.0% and 57.4%. Smoking was associated with a 27.2% reduction in the ALC EC50, which partially offsets the reduced plasma CC112273 concentrations in smokers. Simulations show that 1 mg ozanimod has comparable ALC reductions of 57.4% in nonsmokers and 52.7% in smokers. Upon discontinuing ozanimod 1 mg in UC patients, a mean recovery time to normal (1 x 109/L ALC count) of 32.8 days was predicted, with 90% of the population recovering in 3 months. Overall results were consistent with findings from clinical trials.

CONCLUSION
Population analysis demonstrated a similar PK/PD relationship for ALC reductions in patients with RMS and UC. Smoking was not associated with substantial difference in ALC, consistent with no loss of efficacy in smokers. Upon discontinuation of ozanimod treatment, the majority of UC and RMS patients will recover lymphocyte counts to normal within 3 months.
NOVEL INSIGHTS INTO THE MECHANISM OF ACTION OF EXCLUSIVE ENTERAL NUTRITION IN CROHN’S DISEASE: PRE-CLINICAL STUDY IN A RODENT MODEL OF CROHN’S-LIKE COLITIS
Authors: Geesala Ramasatyaveni , Lin You-Min , Zhang Ke , M’Koma Amosy , Cohn Steven , Shi Xuan-Zheng 
Published: January 2022

Abstract

BACKGROUND AND AIMS
Exclusive enteral nutrition (EEN) is the only established dietary therapy for Crohn’s disease (CD). However, mechanisms of action of EEN in CD are not clear. CD is characterized by recurrent transmural inflammation in the gut. Mechanical stress, associated with inflammatory cell infiltration, edema, fibrosis, and obstruction, is inevitably present in CD tissue. We hypothesized that transmural inflammation causes mechanical stress, which induces expression of mechanosensitive genes such as IL-6 and COX-2 in the gut, and that EEN treatment attenuates inflammation by alleviating the effect of mechanical stress-induced expression of proinflammatory genes in CD.

METHODS
CD-like colitis was induced by intracolonic instillation of TNBS (65 mg/kg in 250 μL of 40% ethanol) into the distal colon of 8∼10 weeks old SD rats. Control rats were treated with intracolonic saline instillation. We fed the control and colitis rats with either normal pellet food or EEN with Ensure liquid diet ad lib. Rats were euthanized 7 days after treatments.

RESULTS
(1) TNBS colitis rats presented decreased body weight, increased disease activity and inflammation index of the colon in pellet food treated rats, which were dramatically improved by EEN treatment. (2) EEN did not significantly affect body weight in control rats, though it dramatically reduced fecal weight by 84.5(±4.3)%, and increased fecal water content by 29.8(±1.3)%. (3) In the solid food fed rats, TNBS treatment induced a localized transmural inflammation with narrowed lumen in the site of instillation (site I) (Figure 1). This led to a distended colon segment (site P) prior to site I, and a non-distended segment (site D) distal to site I. Expression of IL-6 and COX-2 mRNAs was increased significantly (p&lt;0.01) by 111(±44) and 13.1(±2.5)-fold in site I of CD rats, compared to controls. Importantly, the IL-6 and COX-2 mRNA expression was also significantly increased in the distended site P [228(±72) and 16.6(±4.3)-fold], but not in site D (Figure 2). The increased expression of IL-6 and COX-2 occurred mainly in the colonic smooth muscle cells (SMC). (4) However, EEN treatment with Ensure Regular prevented lumen distention in colitis rats. The increase of IL-6 and COX-2 expression in colitis was attenuated drastically in sites I and P (Figure 2). Treatment with other types of liquid diet (Ensure Clear or rodent liquid diet) had similar effects. (5) Expression of IL-6 and COX-2 was highly inducible by mechanical stretch in cultured colonic SMC in vitro and by lumen distention in colon obstruction.

CONCLUSIONS
Mechanical stress plays a critical role in gut inflammation by inducing expression of mechanosensitive proinflammatory mediators in CD-like colitis. EEN treatment reduces inflammation in CD by alleviating the effects of mechanical stress on expression of genes such as IL-6 and COX-2.
CLINICAL FEATURES AND OUTCOMES OF PAEDIATRIC PATIENTS WITH ISOLATED COLONIC CROHN’S DISEASE: A MULTICENTRE STUDY FROM THE PAEDIATRIC IBD PORTO GROUP OF ESPGHAN
Authors: Berger Tal , Lee Huey Miin , Padmanaban Lavenya Ramasamy , Wine Eytan , Yerushalmy-Feler Anat , Hojsak Iva , Kazeka Denis , Serban Daniela Elena , Yogev Dotan , Ledder Oren , Lionetti Paolo , Scarallo Luca , Gasparetto Marco , Croft Nicholas M , Miele Erasmo , Staiano Annamaria , Meredith Joseph , Aloi Marina , Alvisi Patrizia , Urlep Darja , Weiss Batia , Malham Mikkel , Matar Manar , Navas-López Víctor , Romano Claudio , Dipasquale Valeria , Norsa Lorenzo , Kolho Kaija-Leena , Shamir Raanan , Shouval Dror 
Published: January 2022

Abstract

BACKGROUND
Adult studies suggest that patients with isolated colonic Crohn’s disease (L2 CD) exhibit unique characteristics differentiating them from patients with ileo-cecal (L1) CD and ulcerative colitis (UC). We aimed to characterize clinical features and outcomes of paediatric patients with L2.

METHODS
Retrospective data was collected through the Porto IBD group of ESPGHAN on paediatric patients with L2, L1 or UC at different time-points. Outcome measures included time to 1st flare, hospital admissions, initiation of anti-TNFa drug, stricture and surgery.

RESULTS
Three hundred patients were included: 102 L1, 94 L2 and 104 UC. Rates of hematochezia at presentation were 14.7%, 44.7% and 95.2%, while rates of fever were 12.7%, 26.6% and 2.9%, for patients with L1, L2 and UC, respectively (P&lt;0.001 for all comparisons). Skip lesions were identified in 65% of patients with L2, and granulomas in 36%, similar to L1 patients. Rates of ASCA and pANCA positivity significantly differed between the groups: 25.4% and 16.7% for patients with L2, compared with 55.2% and 2.3%, and 1.8% and 52.9% for patients with L1 and UC, respectively. Response rates to exclusive enteral nutrition were comparable between L1 and L2 (78.3-82.4%), as was the response to oral steroids (70.4-76.5%) in the three groups. While times to 1st flare and admission were similar between groups, patients with L1 were commenced on anti-TNFa earlier. Moreover, stricturing phenotype and need for colectomy were very rare in patients with L2.

CONCLUSIONS
Significant differences are observed in the clinical presentation and outcomes of paediatric patients with L2, compared to patients with L1 and UC.
FEAR OF THE COVID-19 PANDEMIC IN ADOLESCENTS AND YOUNG ADULTS WITH INFLAMMATORY BOWEL DISEASE: RELATIONSHIP TO PSYCHOLOGICAL AND PHYSICAL OUTCOMES
Authors: Neiman Nicole , Anjur Kavya , Yeh Ann Ming , Bensen Rachel , Wren Anava 
Published: January 2022

Abstract

BACKGROUND
The fear of contracting COVID-19 has taken a significant toll on the psychological and physical health of adolescents and young adults (AYA), especially those with chronic health conditions. AYA with Inflammatory Bowel Disease (IBD) are at increased risk for poor psychological and physical well-being. However, to date, there is no published research examining the Fear of COVID-19 Scale (FCV-19S) in AYA with IBD.

AIMS
To assess: 1) the reliability of the Fear of COVID-19 Scale in AYA with IBD, and 2) how the fear of COVID-19 relates to key psychological (i.e., anxiety, depression) and physical (i.e., fatigue, pain, disease activity) outcomes in AYA with IBD.

METHODS
This ongoing study is a collaboration between Stanford University and ImproveCareNow. Participants included 64 AYA with IBD (M=18.7 years old; 52% Ulcerative Colitis; 60% female; 60% White). Participants completed a one-time online survey. Correlation analyses examined the association between fear of COVID-19, outcome variables (i.e., anxiety, depression, fatigue, pain, disease activity), and demographic variables. Multiple linear regression (MLR) analyses (using the F test) further examined the association between fear of COVID-19, outcome variables, and significant demographic variables (i.e., age, sex).

RESULTS
The internal reliability of FCV-19S was measured using Crohnbach’s alpha (α=0.88), indicating high internal consistency. Correlation analyses demonstrated that fear of COVID-19 was significantly associated with anxiety, depression, and fatigue (Table 1). The overall MLR models were significant for anxiety (P&lt;0.001), depression (P=0.002), and fatigue (P=0.031), but not for pain and disease activity. Fear of COVID-19, age, and sex accounted for 29% of the variance in anxiety, 27% of the variance in depression, and 17% of the variance in fatigue. Fear of COVID-19 was not a significant independent predictor of outcomes (Table 2). Female sex was a significant independent predictor for greater levels of anxiety (b=-0.31, P=0.016) and depression (b=-0.35, P=0.008). Older age was a significant independent predictor for greater levels of depression (b=0.29, P=0.031).

CONCLUSION
Preliminary results suggest that FCV-19S can be reliably assessed in AYA with IBD. Analyses indicate that fear of COVID-19 is associated with anxiety, depression, and fatigue in AYA with IBD. While COVID-19 fear may be important in explaining these outcomes, female sex independently predicted increased anxiety and depression, and older age independently predicted depression. This highlights the importance of assessing relevant demographic variables (e.g., female sex, young adults) when considering predictors of adjustment in AYA with IBD. Research should further investigate fear of COVID-19 in larger, more diverse IBD populations to better understand its relationship to key IBD outcomes.
BEZLOTOXUMAB THERAPY FOR RECURRENT CLOSTRIDIUM DIFFICILE INFECTION IN AN ULCERATIVE COLITIS PATIENT
Authors: Fein Aaron , Kern Cody , Mohamed Rana , Barrett Terrence , Perry Courtney 
Published: January 2022

Abstract

INTRODUCTION
Clostridium difficile infection (CDI) is the most common infectious cause of nosocomial diarrhea, comprising 10-20% of all cases. CDI is a significant complication for IBD patients. Not only can CDI induce IBD flare, IBD patients also experience significantly higher CDI recurrence when compared to the general population. New monoclonal antibody (mAB) therapies, such as bezlotoxumab, have improved management of recurrent CDI (rCDI). The MODIFY I/II trial included 44 patients with known IBD, 28 of which received bezlotoxumab. Among these 28 patients, there was a 27.2% absolute reduction in the incidence of rCDI. Encouraged by these results, we recently prescribed bezlotoxumab in a UC patient with rCDI and herein report our experience.

CASE REPORT
A 21-year-old female with a history of ulcerative colitis (UC) diagnosed in 2017 presented for treatment of rCDI. Her first episode of CDI occurred in 2019 during an active UC flare treated with steroids and infliximab induction. CDI was successfully treated with a four-week course of 125mg oral vancomycin twice daily followed by once daily for an additional four weeks. She had a recurrent episode of CDI one year after her initial infection while on vedolizumab for UC treatment. She was treated with 125mg oral vancomycin, four times daily, and tapered down by one dose over a four-month period. Two years after her initial CDI, she developed worsening non-bloody diarrhea, nausea, and anorexia with weight loss. She again tested positive for C. difficile via glutamate dehydrogenase antigen and PCR for toxin B. Fecal calprotectin was 2190 mg/g. She was treated with 14-day course fidaxomicin 200mg BID and a single infusion of bezlotoxumab 10mg/kg. Treatment for UC was not adjusted. At follow up one month later, her symptoms had resolved and fecal calprotectin normalized (17 mg/g). Six months later, she remains asymptomatic.

DISCUSSION
Recurrent CDI is a frequent culprit for inducing IBD flares, and is difficult to manage. Fecal transplant (FMT) is an option for rCDI, but often entails logistical challenges and risks cross-contamination of endoscopic facilities. Bezlotoxumab is an appealing option for rCDI as a single dose medication with few reported side effects in the MODIFY clinical trials. While the number of IBD patients in the MODIFY trial was small, results were promising. In our patient, bezlotoxumab quickly resolved her rCDI and IBD flare without need for alteration or escalation of her biologic therapy, and she has remained asymptomatic for six months. This case corroborates the prospect that bezlotoxumab positively affects the clinical outcomes of UC patients with rCDI compared to those on repetitive antimicrobial therapy and/or FMT without mAB therapy. Further investigation into the long-term efficacy of this therapy is merited for the IBD patient population in the real-world setting.