bluuebunny/crossref_metadata_2025_split huggingface dataset:
Changing the drug development and therapeutic paradigm with biologic drug combinations and bispecifics: How to choose between these two approaches?
Authors: Zheng Songmao , Prell Rodney , Sheng Jennifer , Wang Yow‐Ming , Hamuro Lora 
Published: May 2022

AbstractBiologics are increasingly being co‐developed in combination or as novel constructs like bispecific antibodies (BsAbs) with the goal of targeting multiple, non‐redundant mechanisms of action. Rational design of combinations and dual‐targeting approaches that consider disease complexities have the potential to improve efficacy and safety, to increase duration of clinical benefit, and to minimize clinical resistance mechanisms. Here we summarize examples of BsAbs and biologic combinations that have been approved by health authorities and present drug development considerations when deciding between these two strategies. These include an understanding of target biology, nonclinical safety risks, dose optimization strategies, the regulatory framework, pharmacokinetic, immunogenicity, and bioanalytical assay considerations. The disease biology, target dynamics, and pharmacology objectives were identified as important factors in early drug development to decide between a BsAb versus a combination. Nonclinical safety assessment and dose optimization strategies can also pose challenges for BsAb versus combinations. High unmet medical needs and lack of treatment options are often the common denominators for deciding to develop a BsAb or a combination. Future development of biologic triple combinations and BsAbs combinations with other biologics will further increase drug development complexities and hold promise for more effective treatment options for patients.
Renminbi Appreciation and China's Industrial Upgrading
Authors: Wong Chin‐Yoong , Eng Yoke‐Kee 
Published: May 2022

AbstractTo identify the macroeconomic environment that has enabled China's industrial upgrading during a period of persistent renminbi appreciation, we construct a two‐country New Keynesian model of industrial upgrading with a global production network, endogenous firm entry, and a directed quality frontier. We show that renminbi appreciation promotes industrial upgrading without hurting real economic growth in the longer run. This holds true especially through four channels. First, the quality threshold for firm entry is lower to allow for more firms participation and thus greater product varieties (quality threshold channel). Second, upstream skill‐based production uses more imported inputs of higher quality (imported input channel). Third, there is substantial global demand towards the exports of high‐quality inputs (global demand channel). Fourth, domestic inputs are competing against imported inputs to broaden the scope for competition in the upstream product market to incentivize quality upgrading (scope for competition channel).
The Threat of Financial Sanctions: What Safeguards Can Central Banks Build?
Authors: Ramaswamy Srichander 
Published: May 2022

AbstractThe sanctions imposed by the G10 countries on financial institutions in Russia, including on its central bank, will come under scrutiny by emerging market central banks. This will help them build appropriate safeguards against disruptions to cross‐border transactions and revise their investment mandates to reduce the risk of reserve asset freezes. Building new financial market infrastructure and cross‐border payment systems, or strengthening existing ones, will become the priority of emerging global powers. The goal will be to build systems that support democratic governance mechanisms, have oversight arrangements involving the central banks of trusted countries, and promote fair and safe access to clearing and settlement under well‐defined policy guidelines. The use of alternatives to the US dollar as the invoicing currency in international trade will gather momentum. Markets for energy and other commodities will be the change drivers. China has an important role to play.
Does College Location Affect the Location Choice of New College Graduates in China?
Authors: Huang Mian , Xing Chunbing , Cui Xiaoyong 
Published: May 2022

AbstractBased on a representative survey of new college graduates in China, we present a job location choice model that allows for a self‐selection effect in college regions by considering region‐dependent heterogeneous preference for job locations and unobservable location features. We also treat endogenous housing costs using the method developed by Berry et al. (1995). Our estimation results show that college education significantly increases graduates' likelihood of working in the city where their college is located. However, a model that does not consider the self‐selection effect overestimates this impact. The impact of college location on a graduate's migration decision varies considerably across cities. There is significant heterogeneity between students from universities of different tiers and rural versus urban areas. Meanwhile, the graduates show a marked home preference when choosing their job locations, and they tend to avoid working in cities with high housing costs. These findings shed light on debates on place‐based higher education policies and spatial distribution of human capital with a high level of education.
Foreign Demand, Competition Strategy, and Export Markups: Evidence from Chinese Multi‐Product Exporters
Authors: Xu Ming , Zhong Tenglong , Xie Qian , Liu Hongkui 
Published: May 2022

AbstractUsing Chinese microdata from 2000 to 2013, we document how demand shocks in export markets lead multi‐product exporters to adjust markups across products. We find that, in response to positive demand shocks, quality‐based competitive multi‐product firms increase product markups significantly, particularly for core products, whereas cost‐based competitive multi‐product firms respond by reducing product markups. The reason for this is that positive foreign demand affects markups through two opposite channels: pro‐innovative effects and pro‐competitive effects. Pro‐innovative effects are predominant among quality‐based competitive multi‐product firms, and these firms respond to positive foreign demand shocks by increasing product quality, prices, and markups. Pro‐competitive effects are predominant among cost‐based competitive multi‐product firms, and these firms respond to positive foreign demand shocks by lowering product cost, prices, and markups. We demonstrate the presence of these mechanisms empirically. The results imply that firms with different competition strategies should adopt different measures in response to foreign demand shocks.
Prenatal diagnosis and intervention improve developmental outcomes and epilepsy prognosis in children with tuberous sclerosis complex
Authors: Wang Xia , Ding Yifeng , Zhou Yuanfeng , Yu Lifei , Zhou Shuizhen , Wang Yi , Wang Ji 
Published: May 2022

AbstractAimTo assess whether prenatal diagnosis and early intervention are beneficial for developmental outcomes and epilepsy prognosis in individuals with tuberous sclerosis complex (TSC).MethodThis retrospective study originated from a single‐centre TSC‐specific cohort. We enrolled 273 individuals (138 males, 145 females; 2 years–7 years 6 months, mean 4 years 5 months, SD 1 year 6 months) with definitive TSC who completed TSC1/TSC2 genetic testing and were followed up to 2 years of age. The benefits of early attention and intervention were assessed by comparing epilepsy and developmental outcomes between groups with or without a prenatal diagnosis and with or without presymptomatic preventive intervention.ResultsThe epilepsy occurrence rate was significantly lower in individuals diagnosed prenatally than in individuals diagnosed postnatally (p = 0.027). In individuals diagnosed prenatally, the epilepsy rate in the preventive intervention subgroup was significantly lower than that in the subgroup without preventive intervention (p = 0.008). Significant improvements in cognitive, language, and motor development were observed in individuals diagnosed prenatally compared to individuals diagnosed postnatally and in the preventive intervention subgroup compared to the subgroup without preventive intervention (p < 0.05).InterpretationBased on this study, we cautiously speculate that early postpartum intervention may reduce the incidence of epilepsy and intractable epilepsy and improve developmental outcomes. Prophylactic intervention with sirolimus and vigabatrin may reduce the incidence of epilepsy. Larger prospective randomized controlled studies are required to support these findings.What this paper adds

Prenatal diagnosis and early intervention may improve developmental outcomes in children with tuberous sclerosis complex (TSC).
Prophylactic intervention with sirolimus and vigabatrin may reduce the incidence of epilepsy.
Cardiac and/or intracranial lesions combined with genetic testing can be used to diagnose TSC prenatally.
The structure–function analysis of Obg‐like GTPase proteins along the evolutionary tree from bacteria to humans
Authors: Chakraborty Asmita , Halder Sheta , Kishore Purvi , Saha Disha , Saha Sujata , Sikder Kunal , Basu Arnab 
Published: May 2022

AbstractObg proteins belong to P‐loop guanine triphosphatase (GTPase) that are conserved from bacteria to humans. Like other GTPases, Obg cycles between guanine triphosphate (GTP) bound “on” state and guanine diphosphate (GDP)‐bound “off” state, thereby controlling various cellular processes. Different members of this group have unique structural characteristics; a conserved glycine‐rich N‐terminal domain known as obg fold, a central conserved nucleotide binding domain, and a less conserved C‐terminal domain of other functions. Obg is a ribosome dependent GTPase helps in ribosome maturation by interacting with several proteins of the 50S subunit of the ribosome. Obg proteins have been widely considered as a regulator of cellular functions, helping in DNA replication, cell division. Apart from that, this protein also takes part in various stress adaptation pathways like a stringent response, sporulation, and general stress response. In this particular review, the structural features of ObgE have been highlighted and how the structure plays important role in interacting with regulators like GTP, ppGpp that are crucial for executing biological function has been orchestrated. In particular, we believe that Obg‐like proteins can provide a link between different global pathways that are necessary for fine‐tuning cellular processes to maintain the cellular energy status.
“It's part of me”: Brazilian immigrant teachers' work in a global pandemic
Authors: Oliveira Gabrielle , Kentor Corinne 
Published: May 2022

AbstractEven before COVID‐19, immigrant teachers who teach immigrant children in dual language classrooms were under a tremendous amount of pressure in their schools and districts. “I know what they are going through”, Elise, a veteran teacher from Brazil, disclosed during an interview when asked about her knowledge on children's lives. She was referencing her shared identity with her students. However, in a school where immigrant teachers were a minority and so were their students, the effects of a global pandemic further exacerbated the inequalities related to quality education for children. Scholars have pointed out that culturally knowledgeable and responsive teachers are especially important in education and care settings that serve children from immigrant families. These expectations grew exponentially since COVID‐19 hit in March of 2020. Participants in this research, Brazilian immigrant women who were teachers, toggled between their identities as they empathized, supported, and cared for their students. Elise, a Brazilian immigrant teacher with over a decade of experience and the mother of three young children of her own explained, “If before I felt I could barely help and care for my students under the pressure of performing and holding up the so called effectiveness of dual language programs, now I really feel like they (immigrant children) are out of reach. And it is on me. I feel like it is my responsibility”. With the purpose of shedding light on the ways in which immigrant Brazilian teachers understand their work as educators amid a global pandemic, this article addresses the following research questions: (i) How are Brazilian immigrant women who are teachers re‐signifying their work in light of a pandemic? (ii) How do their intersectional identities contribute to their understandings of their work?
Effects of ionic liquids and pulsed electric fields on the extraction of antioxidants from green asparagus roots
Authors: Symes Abbey , Shavandi Amin , Bekhit Alaa El‐Din Ahmed 
Published: May 2022

SummaryAsparagus officinalis root (AR) contains valuable bioactive compounds that have beneficial health properties. The aim of this study was to optimize the extraction of polyphenols and flavonoids in green AR using two novel technologies; pulsed electric field (PEF) and ionic liquids (IL). Further, the antioxidant activity of the obtained extracts was determined. The total polyphenol content, total flavonoid content (TFC), and antioxidant activity (2,2‐diphenyl‐1‐picrylhydrazyl, oxygen radical absorbance capacity and Ferric reducing/antioxidant power assays) were determined. The PEF conditions (PEF strength of 1.6 kV/cm, frequency of 200 Hz and pulse width of 20 µs) resulted in a higher extraction yield as compared to conventional solvent extraction, but had lower antioxidant activities. The optimal conditions for IL extraction were by using 0.5% 1‐butyl‐3‐methylimidazolium chloride at a solid: liquid (S:L) ratio of 1:10 for four min. The IL extraction resulted in a total of 122 mg RE/ mL TFC which was 70 to 80 folds more than the TFC obtained by PEF. The IL extracts had higher TFC and antioxidant activity than PEF, but the safety of the ILs need further research.
Evolution of lipid damage and volatile amine content in Patagonian squid (Doryteuthis gahi) by‐products during frozen storage
Authors: Aubourg Santiago P. , Trigo Marcos , González Mª Jesús , Lois Salomé , Medina Isabel 
Published: May 2022

SummaryBy‐products (viscera, tails, skin, etc.) resulting from Patagonian squid (Doryteuthis gahi) commercialisation were pooled together and stored at −10 and –18 °C for 12 months. During this storage time, 81.1–83.7 and 1.7–2.4 (g 100 g−1) ranges were detected for moisture and lipid values, respectively. An increased storage time and temperature led to free fatty acid formation and phospholipid content decrease (P < 0.05). Meantime, peroxide levels were low and included in 2.1–3.6 meq. active oxygen kg−1 lipids range. Contrary, substantial formation (P < 0.05) of thiobarbituric acid reactive substances and fluorescent compounds was proved, values being higher by increasing the time and temperature of storage of squid by‐products. Related to amine formation, trimethylamine values increased notably (P < 0.05) with storage, higher values being obtained by increasing the storage time and temperature. For total volatile amines, increased levels with storage time were detected in samples stored at −10 °C; contrary, by‐products stored at the lowest temperature tested did not provide differences (P > 0.05), resulting from the storage time. This study shows the need of appropriate storage conditions to offer the current by‐products as a source of valuable marine constituents. Present results meet the present global interests in the search for new and undervalued marine substrates to be employed commercially.
Is Eusebius of Caesarea a ‘Nicene’? A Contribution to the Notion of Conciliar Theology
Authors: Renberg Adam R. 
Published: May 2022

AbstractAmidst recent explorations in conciliar theology by Timothy Pawl and others, pressing questions about our theological readings of the councils have arisen – are we to treat the theology of the councils as unique to their historical context? Or as a unified body of ‘conciliar’ theology? This paper addresses these questions, using Eusebius of Caesarea as a unique example of Nicene theology. It defines the metrics for evaluating different definitions of the term ‘Nicene’ by distinguishing between judgements and concepts. Then, it ‘measures’ Eusebius’ theology according to the two proposed definitions. Finally, it offers constructive comments for conciliar theology, claiming that conceptual language is clarified through the councils, even if its interpretation is not immediately fixed.
Cancer‐specific and net overall survival in older patients with de novo metastatic prostate cancer initially treated with androgen deprivation therapy
Authors: Narita Shintaro , Terada Naoki , Nomura Kyoko , Sakamoto Shinichi , Hatakeyama Shingo , Kato Takuma , Matsui Yoshiyuki , Inokuchi Junichi , Yokomizo Akira , Tabata Ken‐ichi , Shiota Masaki , Kimura Takahiro , Kojima Takahiro , Inoue Takahiro , Mizowaki Takashi , Sugimoto Mikio , Kitamura Hiroshi , Kamoto Toshiyuki , Nishiyama Hiroyuki , Habuchi Tomonori ,   the Japanese Urological Oncology Group
Published: May 2022

ObjectiveThis study aimed to assess survival outcomes in older patients with de novo metastatic prostate cancer who initially received androgen deprivation therapy.MethodsThe retrospective multicenter study included 2784 men with metastatic prostate cancer who were treated with androgen deprivation therapy between 2008 and 2017. Patients were classified into <75, 75–79, and ≥80 age groups. Propensity score matching was conducted to assess the cancer‐specific survival of the groups. The 5‐year net overall survival of each group was derived to evaluate relative survival compared with the general population using the Pohar–Perme estimator and the 2019 Japan Life Table.ResultsDuring the follow‐up (median, 34 months), 1014 patients died, of which 807 died from metastatic prostate cancer progression. Compared with the <75 group, the cancer‐specific survival of the 75–79 group was similar (hazard ratio 1.07; 95% confidence interval 0.84–1.37; P = 0.580), whereas that of the ≥80 group was significantly worse (hazard ratio 1.41; 95% confidence interval 1.10–1.80; P = 0.006). The 5‐year net overall survival of the <75, 75–79, and ≥80 age groups were 0.678, 0761, and 0.718, respectively. The 5‐year net overall survival of patients aged ≥80 years with low‐ and high‐volume disease were 0.893 and 0.586, respectively, which was comparable with those in patients aged <75 years (0.872 and 0.586, respectively).ConclusionsOlder metastatic prostate cancer patients aged ≥80 years had poorer cancer‐specific survival compared with younger patients. Conversely, 5‐year net overall survival in older patients aged ≥80 years was comparable with that in younger patients aged <75 years.
In vitro colistin susceptibility of pandrug-resistant Ac. baumannii is restored in the presence of selenium nanoparticles
Authors: Ušjak Dušan , Novović Katarina , Filipić Brankica , Kojić Milan , Filipović Nenad , Stevanović Magdalena M. , Milenković Marina T. 
Published: May 2022

Abstract

Aims
To investigate the synergistic activity of colistin and selenium nanoparticles (SeNPs) against pandrug-resistant (PDR) Ac. baumannii.

Methods and Results
Chequerboard and time-kill assays were employed to explore the potential synergistic interactions between colistin and SeNPs against Ac. baumannii isolates (8), previously determined as colistin-resistant (MIC range 16–256 μg ml−1). Also, whole-genome sequencing (WGS) and gene expression analyses were used to elucidate the mechanisms of colistin resistance. Exceptionally strong synergistic activity (FICI range 0.004–0.035) of colistin and SeNPs against colistin-resistant isolates was revealed. Colistin (0.5 or 1 μg ml−1) used in combination with SeNPs (0.5 μg ml−1) was able to reduce initial inoculum during the first 4 h of incubation, in contrast to colistin (0.5, 1 or 2 μg ml−1) alone.

Conclusions
These findings propose colistin/SeNPs combination as a new option to fight PDR Ac. baumannii, the therapeutic possibilities of which should be proved in future in vivo studies.

Significance and Impact of Study
Here we present the first evidence of synergy between colistin and selenium compounds against bacteria in general. Also, WGS and gene expression analyses provide some new insights into Ac. baumannii colistin resistance mechanisms.
Case report: Epicardial ligation of the left atrial appendage in a patient with an inaccessible left atrial cavity
Authors: Nentwich Karin , Ene Elena , Müller Julian , Berkowitz Arthur , Kerber Sebastian , Deneke Thomas 
Published: May 2022

AbstractIt has been shown that endocardial occlusion of the left atrial appendage (LAA) is equally effective in preventing embolic events compared to oral anticoagulation in patients with nonvalvular atrial fibrillation.An 82‐year‐old female patient was admitted for LAA occlusion for repetitive GI bleeding. She had high CHADSVASC Score and HASBLED with long persistent atrial fibrillation with many comorbities. The preprocedural transesophageal echo revealed a great mass in the left atrium (Picture 1).Cardiac surgery was denied, we performed an epicardial only ligation for closing the LAA. For this approach we performed an epicardial puncture and contrast injection within the pericardial space to delineate the LAA. An epicardial wire with a suction mechanism at its distal end was attached to the anterior lobe of the LAA. Using this epicardial wire the snare could be advanced over the appendage and closed down. Complete exclusion of the LAA was achieved. There were no procedural complications and the patient is doing well after 3 months.
Expression of PD‐L1 on regulatory B cells in patients with acute myeloid leukaemia and its effect on prognosis
Authors: Shi Yingqing , Liu Zhuogang , Wang Hongtao 
Published: May 2022

AbstractProgrammed death‐ligand 1 (PD‐L1) is involved in immunosuppression in variety of tumours. Regulatory B cells (Bregs) are critical immune regulatory cells, and it has been demonstrated that the number of regulatory B cells in patients with acute myeloid leukaemia (AML) is much higher than that in healthy donors (HDs), which is linked to a poor prognosis. This study aimed to determine whether increased expression of PD‐L1, including in Bregs, is associated with a worse prognosis in individuals with AML. The proportion of Bregs, PD‐L1 expression in Bregs and PD‐1 expression in T cells were determined using flow cytometry using patient samples from 21 newly diagnosed AML patients at different stages of treatment and 25 HDs. We confirmed PD‐L1 expression in Bregs, and PD‐1 expression in CD3+CD4+T cells in bone marrow and peripheral blood samples from AML patients was higher than that in samples from HDs. The complete remission (CR) and progression‐free survival (PFS) of Bregs with high PD‐L1 expression were significantly decreased following induction chemotherapy. PD‐L1 expression is indeed increased in Bregs from individuals with AML, and high PD‐L1 expression is related to a poor prognosis.