bluuebunny/crossref_metadata_2025 huggingface dataset:
Dispute Settlement in the WTO
Authors: Herdegen Matthias
Published: June 2024

This chapter discusses the dispute settlements in the World Trade Organization (WTO). It enumerates the three stages of the WTO dispute settlement process after detailing the establishment of the Dispute Settlement Body (DSB) by the Understanding on Rules and Procedures Governing the Settlement of Disputes (DSU). Essentially, the DSU sped up the entire dispute settlement process. Moreover, the DSU facilitates the adoption of findings and recommendations given by expert committees dealing with a dispute before introducing an appeal mechanism. Despite the sometimes ambiguous language of the DSU, the member found in breach of WTO law has an obligation of full compliance in terms of withdrawing the wrongful measure.
WTO Law in Broader Perspective
Authors: Herdegen Matthias
Published: June 2024

This chapter presents a broader perspective on the World Trade Organization (WTO) law. It explains that WTO agreements often explicitly refer to obligations or standards established in context with other regimes. Thus, problems arise when treaties lay down objectives which collide with free trade, however, it could be reconciled by exceptions in the multilateral WTO Agreements. Moreover, customary law may affect the understanding and interpretation of WTO rules, especially when universal human rights and environmental standards are involved. The chapter mentions the possibility of controversy in line with the interplay between the WTO dispute settlement regime and specific mechanisms of dispute resolution under free trade agreements.
International Sales and Contract Law
Authors: Herdegen Matthias
Published: June 2024

This chapter covers the interplay between international sales and contract law. It introduces the application of the Rome Convention, the Rome I Regulation, and the Common European Law on Sales. The United Nations Commission on International Trade Law (UNCITRAL) mainly serves to prepare and promote the use and adoption of legislative and non-legislative instruments in several key areas of commercial law. The UNCITRAL drafted and adopted the UN Convention on Contracts for the International Sale of Goods of 1980 (CISG) to integrate and balance the principles of different legal and economic systems around the world. The chapter then explains how modern free trade agreements address legal issues of e-commerce in special sections.
International Building and Construction Contracts
Authors: Herdegen Matthias
Published: June 2024

This chapter discusses the correlation between international building and construction contracts. International construction contracts belong to the category of long-term contracts which are particularly sensitive to unforeseen developments. The chapter then explains the work of the FIDIC (Fédération Internationale des Ingénieurs Conseils) which adopted various sets of standard terms which international usage incorporates into contracts. It then provides an outline of long-term contracts, such as the classical form of BOT (build, operate, transfer). A special form of building contract provides that contractors shall also operate the building or installation (most of which are infrastructures and power plants) for a given time.
International Tax Law
Authors: Herdegen Matthias
Published: June 2024

This chapter discusses the extent of the international tax law. It primarily revolves around the rules on taxation in cross-border contexts. National tax law reaches out to bases of taxation located abroad, while a State’s tax jurisdiction extends to foreign individuals who earn income or hold property within the State. The chapter elaborates on the key concepts of the world income principle that signifies an unrestricted tax liability covering all income or taxable assets, and double taxation that remains to be a central issue of international tax law. It also cites another contentious issue of extraterritorial enforcement of tax law, which relates to government measures to coerce foreign banks to disclose accounts held by nationals abroad.
Foreign Investment in Practice
Authors: Herdegen Matthias
Published: June 2024

This chapter details the notion and practice of foreign investment. It acknowledges that foreign investment is a crucial factor for economic and social development, sustained economic growth, poverty reduction, improved infrastructure, and financial stability. Thus, the adequate protection of foreign investments relates to economic growth and often contributes to the improvement of infrastructure and education. The chapter looks into the types of investors after discussing that foreign investment is divided into direct investment and portfolio (indirect) investment. It then cites the control of foreign investment, mentioning how regulations may exclude strategic sectors from foreign investments or limit foreign direct investments.
The Interplay of Investment Protection and Other Areas of International Law
Authors: Herdegen Matthias
Published: June 2024

This chapter covers the interplay of investment protection and other areas of international law. For some time, investment protection has drawn popular criticism for being insensitive to environmental issues or environmental protection. Thus, the international rules on investment must be read in context with human rights, labour standards, and international environmental law. Codes of conduct for investors, self-commitments, and mechanisms of surveillance by the home State of investors are instruments to establish and to control corporate social responsibility. The chapter cites the numerous treaties that dedicate specific clauses to legitimate measures to protect the environment, health, and life of living beings.
International Monetary Law and International Financial Relations
Authors: Herdegen Matthias
Published: June 2024

This chapter discusses the correlation between international monetary law and international financial relations. It starts with the impact of monetary relations on international trade and business, which highlights the international monetary law involved with cross-border payments and capital movements. Financial aid to countries with balance of payment problems provided by governments and international organizations, such as the International Monetary Fund (IMF), became an important mechanism to stabilize currencies. The chapter then presents the Bretton Woods system in line with the development of currency exchange arrangements. It considers the development and role of cryptocurrencies and digital central bank money in payment transactions.
Debt Crises and State Insolvency
Authors: Herdegen Matthias
Published: June 2024

This chapter explores the issue of debt crises and state insolvency. The power of taxation and State property nourish the far-spread concept of the State as a reliable debtor, so State insolvency is often triggered by an unsustainable burden of foreign debt. Several mechanisms were developed to alleviate the debt burden of poor countries vis-à-vis private creditors. The chapter then details how the Paris Club and London Club (Bank Advisory Committee) helped with rescheduling and restructuring sovereign debt. It details the process of debt-equity swaps that reduce debt and stimulate investment, citing that its success primarily depends on the investment climate prevailing in the debtor country.
Introduction
Authors: Clooney Amal
Published: June 2024

This introductory chapter provides an overview of the right to freedom of expression in international law. The chapter surveys the drafting history of the treaty provisions that enshrine this right and the development of jurisprudence interpreting them. It analyses the impact on the right to free speech of states’ reservations, declarations and derogations to article 19 of the ICCPR and regional instruments. It also canvasses whether these treaty provisions have reached customary international law status and therefore apply to states—such as China, Myanmar and Cuba—that have not ratified these agreements. Finally, this chapter charts points of convergence and divergence among the jurisprudence of international and regional human rights bodies as they interpret and apply international and regional treaties.
Hate Speech
Authors: Clooney Amal , Gardoll Alice
Published: June 2024

This chapter examines the regulation of hateful speech: an urgent issue as social media allows hate speech to spread faster and wider than ever before. However, this must be balanced with the right to speak freely. International law sets out the standards for penalizing hateful speech and unlike other types of speech, states can be required rather than simply permitted to penalize hate speech. International and regional treaties therefore create a web of mandatory and discretionary penalties that add to the complexity of states’ compliance with these standards. This chapter explores the minimum international standards that apply to states when it comes to drafting, interpreting and applying both mandatory and discretionary restrictions to speech. It explores key points of divergence between human rights bodies’ interpretation of these restrictions, such as in relation to blasphemy and denialism laws. It also provides insight into the recent role of technology and social media companies in responding to online hate speech. And it makes recommendations based on international standards applicable to hate speech, or suggests a best practice approach where international bodies have taken divergent views.
False Speech
Authors: Milanovic Marko , Webb Philippa
Published: June 2024

sAlthough prohibitions on false speech have existed for at least 140 years, many laws criminalizing misinformation have been introduced in recent times. States have responded to the rise of social media and its role in spreading false information by introducing laws limiting free speech. And while there are certain circumstances under which false speech can be penalized, lies, alone, should not be the basis for legal sanction. Under international law, state regulation of false speech must comply with individuals’ freedom of expression, and this chapter explores where these lines are drawn in international treaties and human rights jurisprudence. The chapter outlines international standards relating to when false speech can be penalized and makes recommendations as to how the law should be applied or reformed to meet the challenges of ‘truth decay’.
Evidence for rapid variability at high energies in GRBs
Authors: Aldrich E Casey , Nemiroff Robert J
Published: June 2024

Intrinsic variability was searched for in arrival times of six gamma-ray bursts (GRBs) at high energies – between 30 MeV and 2 GeV – detected by the Fermi satellite’s Large Area Telescope (LAT). The GRBs were selected from the Fermi LAT catalogue with preference for events with numerous photons, a strong initial pulse, and measured redshifts. Three long GRBs and three short GRBs were selected and tested. Two different variability-detection algorithms were deployed, one counting photons in pairs, and the other multiplying time gaps between photons. In both tests, a real GRB was compared to 1000 Monte Carlo versions of itself smoothed over a wide range of different time-scales. The minimum detected variability time-scales for long bursts (GRB 080916C, GRB 090926A, GRB 131108A) was found to be (0.005, 10.0, 10.0) s for the photon pair test and (2.0, 20.0, 10.0) s for the time-gap multiplication test. Additionally, the minimum detected variability time-scales for the short bursts (GRB 090510, GRB 140619B, GRB 160709A) was found to be (0.05, 0.01, 20.0) s for the photon pair test and (0.05, 0.01, 20.0) s for the gap multiplication test. Statistical uncertainties in these times are about a factor of 2. The durations of these variability time-scales may be used to constrain the geometry, dynamics, speed, cosmological dispersion, Lorentz-invariance violations, weak equivalence principle violations, and GRB models.
Selfing Promotes Spread and Introgression of Segregation Distorters in Hermaphroditic Plants
Authors: Wang Hongru , Planche Léo , Shchur Vladimir , Nielsen Rasmus
Published: June 2024

Segregation distorters (SDs) are genetic elements that distort the Mendelian segregation ratio to favor their own transmission and are able to spread even when they incur fitness costs on organisms carrying them. Depending on the biology of the host organisms and the genetic architecture of the SDs, the population dynamics of SDs can be highly variable. Inbreeding is considered an effective mechanism for inhibiting the spread of SDs in populations, and can evolve as a defense mechanism against SDs in some systems. However, we show that inbreeding in the form of selfing in fact promotes the spread of SDs acting as pollen killers in a toxin–antidote system in hermaphroditic plants by two mechanisms: (i) By reducing the effective recombination rate between killer and antidote loci in the two-locus system and (ii) by increasing the proportion of SD alleles in individual flowers, rather than in the general gene-pool. We also show that in rice (Oryza sativa L.), a typical hermaphroditic plant, all molecularly characterized SDs associated with pollen killing were involved in population hybridization and have introgressed across different species. Paradoxically, these loci, which are associated with hybrid incompatibility and can be thought of as Bateson–Dobzhansky–Muller incompatibility loci are expected to reduce gene-flow between species, in fact cross species boundaries more frequently than random loci, and may act as important drivers of introgression.
CLEMENT: genomic decomposition and reconstruction of non-tumor subclones
Authors: Chung Young-soo , Kang Seungseok , Kim Jisu , Lee Sangbo , Kim Sangwoo
Published: June 2024

Genome-level clonal decomposition of a single specimen has been widely studied; however, it is mostly limited to cancer research. In this study, we developed a new algorithm CLEMENT, which conducts accurate decomposition and reconstruction of multiple subclones in genome sequencing of non-tumor (normal) samples. CLEMENT employs the Expectation-Maximization (EM) algorithm with optimization strategies specific to non-tumor subclones, including false variant call identification, non-disparate clone fuzzy clustering, and clonal allele fraction confinement. In the simulation and in vitro cell line mixture data, CLEMENT outperformed current cancer decomposition algorithms in estimating the number of clones (root-mean-square-error = 0.58–0.78 versus 1.43–3.34) and in the variant-clone membership agreement (∼85.5% versus 70.1–76.7%). Additional testing on human multi-clonal normal tissue sequencing confirmed the accurate identification of subclones that originated from different cell types. Clone-level analysis, including mutational burden and signatures, provided a new understanding of normal-tissue composition. We expect that CLEMENT will serve as a crucial tool in the currently emerging field of non-tumor genome analysis.
Multiplexed sequential imaging in living cells with orthogonal fluorogenic RNA aptamer/dye pairs
Authors: Zheng Ru , Wu Rigumula , Liu Yuanchang , Sun Zhining , Xue Zhaolin , Bagheri Yousef , Khajouei Sima , Mi Lan , Tian Qian , Pho Raymond , Liu Qinge , Siddiqui Sidrat , Ren Kewei , You Mingxu
Published: June 2024

Detecting multiple targets in living cells is important in cell biology. However, multiplexed fluorescence imaging beyond two-to-three targets remains a technical challenge. Herein, we introduce a multiplexed imaging strategy, ‘sequential Fluorogenic RNA Imaging-Enabled Sensor’ (seqFRIES), which enables live-cell target detection via sequential rounds of imaging-and-stripping. In seqFRIES, multiple orthogonal fluorogenic RNA aptamers are genetically encoded inside cells, and then the corresponding cell membrane permeable dye molecules are added, imaged, and rapidly removed in consecutive detection cycles. As a proof-of-concept, we have identified in this study four fluorogenic RNA aptamer/dye pairs that can be used for highly orthogonal and multiplexed imaging in living bacterial and mammalian cells. After further optimizing the cellular fluorescence activation and deactivation kinetics of these RNA/dye pairs, the whole four-color semi-quantitative seqFRIES process can be completed in ∼20 min. Meanwhile, seqFRIES-mediated simultaneous detection of critical signalling molecules and mRNA targets was also achieved within individual living cells. We expect our validation of this new seqFRIES concept here will facilitate the further development and potential broad usage of these orthogonal fluorogenic RNA/dye pairs for multiplexed and dynamic live-cell imaging and cell biology studies.
protoSpaceJAM: an open-source, customizable and web-accessible design platform for CRISPR/Cas insertional knock-in
Authors: Peng Duo , Vangipuram Madhuri , Wong Joan , Leonetti Manuel D
Published: June 2024

CRISPR/Cas-mediated knock-in of DNA sequences enables precise genome engineering for research and therapeutic applications. However, designing effective guide RNAs (gRNAs) and homology-directed repair (HDR) donors remains a bottleneck. Here, we present protoSpaceJAM, an open-source algorithm to automate and optimize gRNA and HDR donor design for CRISPR/Cas insertional knock-in experiments, currently supporting SpCas9, SpCas9-VQR and enAsCas12a Cas enzymes. protoSpaceJAM utilizes biological rules to rank gRNAs based on specificity, distance to insertion site, and position relative to regulatory regions. protoSpaceJAM can introduce ‘recoding’ mutations (silent mutations and mutations in non-coding sequences) in HDR donors to prevent re-cutting and increase knock-in efficiency. Users can customize parameters and design double-stranded or single-stranded donors. We validated protoSpaceJAM’s design rules by demonstrating increased knock-in efficiency with recoding mutations and optimal strand selection for single-stranded donors. An additional module enables the design of genotyping primers for deep sequencing of edited alleles. Overall, protoSpaceJAM streamlines and optimizes CRISPR knock-in experimental design in a flexible and modular manner to benefit diverse research and therapeutic applications. protoSpaceJAM is available open-source as an interactive web tool at protospacejam.czbiohub.org or as a standalone Python package at github.com/czbiohub-sf/protoSpaceJAM.
A novel cathode interphase formation methodology by preferential adsorption of a borate-based electrolyte additive
Authors: Zhang Danfeng , Ma Jiabin , Zhang Chen , Liu Ming , Yang Ke , Li Yuhang , Cheng Xing , Wang Ziqiang , Wang Huiqi , Lv Wei , He Yan-Bing , Kang Feiyu
Published: June 2024

The coupling of high-capacity cathodes and lithium metal anodes promises to be the next generation of high-energy-density batteries. However, the fast-structural degradations of the cathode and anode challenge their practical application. Herein, we synthesize an electrolyte additive, tris(2,2,3,3,3-pentafluoropropyl) borane (TPFPB), for ultra-stable lithium (Li) metal||Ni-rich layered oxide batteries. It can be preferentially adsorbed on the cathode surface to form a stable (B and F)-rich cathode electrolyte interface film, which greatly suppresses the electrolyte-cathode side reactions and improves the stability of the cathode. In addition, the electrophilicity of B atoms in TPFPB enhances the solubility of LiNO3 by 30 times in ester electrolyte to significantly improve the stability of the Li metal anode. Thus, the Li||Ni-rich layered oxide full batteries using TPFPB show high stability and an ultralong cycle life (up to 1500 cycles), which also present excellent performance even under high voltage (4.8 V), high areal mass loading (30 mg cm−2) and wide temperature range (−30∼60°C). The Li||LiNi0.9Co0.05Mn0.05O2 (NCM90) pouch cell using TPFPB with a capacity of 3.1 Ah reaches a high energy density of 420 Wh kg−1 at 0.1 C and presents outstanding cycling performance.
Three-dimensional quantum Griffiths singularity in bulk iron-pnictide superconductors
Authors: Liu Shao-Bo , Tian Congkuan , Cai Yongqing , Cui Hang , Wei Xinjian , Chen Mantang , Zhao Yang , Sui Yuan , Guan Shuyue , Jia Shuang , Zhang Yu , Feng Ya , Li Jiankun , Cui Jian , Song Yuanjun , Hao Tingting , Chen Chaoyu , Chen Jian-Hao
Published: June 2024

The quantum Griffiths singularity (QGS) is a phenomenon driven by quenched disorders that break conventional scaling invariance and result in a divergent dynamic critical exponent during quantum phase transitions (QPT). While this phenomenon has been well-documented in low-dimensional conventional superconductors and in three-dimensional (3D) magnetic metal systems, its presence in 3D superconducting systems and in unconventional high-temperature superconductors (high-Tc SCs) remains unclear. In this study, we report the observation of robust QGS in the superconductor-metal transition (SMT) of both quasi-2D and 3D anisotropic unconventional high-Tc superconductor CaFe1-xNixAsF (x <5%) bulk single crystals, where the QGS states persist to up to 5.3 K. A comprehensive quantum phase diagram is established that delineates the 3D anisotropic QGS of SMT induced by perpendicular and parallel magnetic fields. Our findings reveal the universality of QGS in 3D superconducting systems and unconventional high-Tc SCs, thereby substantially expanding the range of applicability of QGS.
Serologic Testing of US Blood Donations to Identify Severe Acute Respiratory Syndrome Coronavirus 2 and Other Coronaviruses, December 2019 to July 2020
Authors: Grimm Kacie , Saá Paula , Cheedarla Narayanaiah , Gerty Michael S , Groves Jamel A , Dodd Roger Y , Roback John , Stramer Susan L
Published: June 2024

Background

The first coronavirus disease 2019 (COVID-19) case in the United States was recognized on 19 January 2020, but the time of introduction of the virus into the United States is unknown. An existing sample cohort was examined for serologic evidence of early severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections.

Methods

A repository of 46 120 samples from healthy routine blood donors, representing 46 states and the District of Columbia, was tested for total antibodies to SARS-CoV-2 nucleocapsid (anti-N) using a commercial test. All reactive samples were further tested using an experimental receptor-binding domain (RBD)–specific immunoglobulin G (IgG) enzyme-linked immunosorbent assay. Further testing was also conducted for anti-spike (anti-S) antibodies by commercial tests, experimental anti-S immunologic blocking, and for antibodies to the 4 human cold coronaviruses.

Results

Anti-N reactivity was observed in 92 tested samples (0.2%), 91 of which had adequate volume for further testing; of these, 55 were confirmed positive by anti-RBD. None of these reactive findings were attributable to the other human coronaviruses tested. The confirmed-positive frequency increased over time paralleling patterns observed for COVID-19 cases reported in the United States (in contrast to stable patterns over time for the cold coronaviruses). Nine confirmed positive samples (0.07%) were identified among the 13 364 donations collected between 13 December 2019 and 22 January 2020. None of these early confirmed-positive samples were reactive by commercial anti-S tests suggesting very recent infection.

Conclusions

The samples tested in this study were broadly representative of the United States, and all were from individuals who had successfully donated blood. The antibody-reactive results of this study suggest that SARS-CoV-2 was likely present in the United States before 19 January 2020.
Association Between Diagnostic Delays and Spinal Involvement in Human Brucellosis: A Retrospective Case-Control Study
Authors: Pu Zhongshu , Liu Yiwen , Bai Manling , Ling Tong , Pan Jing , Xu Dengrong , Dai Peijun , Yan Yongping
Published: June 2024

Background

Spinal involvement is a common but serious complication of human brucellosis. However, information on the risk factors associated with spinal involvement in individuals with brucellosis is limited.

Methods

This retrospective case-control study aimed to determine the potential risk factors associated with spinal complications in inpatients with brucellosis.

Results

During the study period, brucellosis was diagnosed in 377 patients, of whom 108 (28.64%) showed spinal involvement. Those with spinal involvement were significantly older than patients in the control group (mean age [standard deviation], 53.25 [10.48] vs 43.12 [13.84] years, respectively; P < .001). The diagnostic delays were significantly longer in patients with spinal involvement than in the control group (mean delay [standard deviation], 11.17 [13.55] vs 6.03 [8.02] weeks; P = .001). Age >40 years (odds ratio, 5.42 [95% confidence interval, 2.65–11.05]; P < .001) and diagnostic delay >4 weeks (2.94 [1.62–5.35]; P < .001) were independently associated with spinal involvement in brucellosis. The lumbar spine at the L3–5 level was the most affected (152 of 249 [61.04%]). Back pain (92 of 108 in case patients vs 21 of 108 in controls; P < .001) and splenomegaly (23 vs 42 of 108, respectively; P = .005) differed significantly between the 2 groups.

Conclusions

Age >40 years and diagnostic delay >4 weeks increased the risk of spinal involvement in brucellosis. Therefore, the time from symptom onset to diagnosis should be shortened, using effective measures to reduce spinal involvement risk.
Evaluation of administration-related reactions with subcutaneous daratumumab with and without premedication
Authors: Padmaraju Kashyap , Kelly Kaitlin , Jakubowiak Andrzej J , Derman Benjamin A
Published: June 2024

Background

Daratumumab-hyaluronidase-fihj (Dara-SQ) is frequently used in the treatment of plasma cell disorders and is associated with improved outcomes. Dara-SQ was shown to be non-inferior to intravenous daratumumab (Dara-IV) in efficacy, safety, and associated with fewer administration-related reactions (ARRs). Despite the lower ARR risk with Dara-SQ, package labeling still recommends indefinite premedication. In this study, we investigated the safety of premedication discontinuation after one cycle of Dara-SQ.

Materials and Methods

This pre-post interventional quality improvement study included all patients aged 18 years and older diagnosed with multiple myeloma or light chain (AL) amyloidosis who received at least one dose of Dara-SQ. Patients in Arm 1 received Dara-SQ per package labeling, while patients in Arm 2 had premedication omitted (excluding dexamethasone) after cycle 1. The primary endpoint was the incidence of ARR after cycle 1. Overall ARR rate and therapy time saved were also evaluated.

Results

A total of 102 patients (63 in Arm 1 and 39 in Arm 2) were included. There were zero reactions in either arm after cycle 1 across 1479 Dara-SQ doses administered over a 30-month period with or without premedication omission. The overall ARR rate was 2.9% (3/102), which all occurred prior to premedication omission. Therapy timed saved from premedication omission was 194 hours in a 6-month period, equating to approximately $140 000 USD.

Conclusion

ARRs to Dara-SQ were rare, mild, and occurred during cycle 1 prior to premedication omission. Omission of noncorticosteroid premedication is safe, feasible, and carries substantial time and cost savings for patients and infusion centers.
Molecular mechanisms underlying gene regulatory variation of maize metabolic traits
Authors: Chu Yi-Hsuan , Lee Yun Sun , Gomez-Cano Fabio , Gomez-Cano Lina , Zhou Peng , Doseff Andrea I , Springer Nathan , Grotewold Erich
Published: June 2024

Variation in gene expression levels is pervasive among individuals and races or varieties, and has substantial agronomic consequences, for example, by contributing to hybrid vigor. Gene expression level variation results from mutations in regulatory sequences (cis) and/or transcription factor (TF) activity (trans), but the mechanisms underlying cis- and/or trans-regulatory variation of complex phenotypes remain largely unknown. Here, we investigated gene expression variation mechanisms underlying the differential accumulation of the insecticidal compounds maysin and chlorogenic acid in silks of widely used maize (Zea mays) inbreds, B73 and A632. By combining transcriptomics and cistromics, we identified 1,338 silk direct targets of the maize R2R3-MYB TF Pericarp color1 (P1), consistent with it being a regulator of maysin and chlorogenic acid biosynthesis. Among these P1 targets, 464 showed allele-specific expression (ASE) between B73 and A632 silks. Allelic DNA-affinity purification sequencing identified 34 examples in which P1 allelic specific binding (ASB) correlated with cis-expression variation. From previous yeast one-hybrid studies, we identified 9 TFs potentially implicated in the control of P1 targets, with ASB to 83 out of 464 ASE genes (cis) and differential expression of 4 out of 9 TFs between B73 and A632 silks (trans). These results provide a molecular framework for understanding universal mechanisms underlying natural variation of gene expression levels, and how the regulation of metabolic diversity is established.
The U-box E3 ubiquitin ligase PUB35 negatively regulates ABA signaling through AFP1-mediated degradation of ABI5
Authors: Du Chang , Liu Meng , Yan Yujie , Guo Xiaoyu , Cao Xiuping , Jiao Yuzhe , Zheng Jiexuan , Ma Yanchun , Xie Yuting , Li Hongbo , Yang Chengwei , Gao Caiji , Zhao Qingzhen , Zhang Zhonghui
Published: June 2024

Abscisic acid (ABA) signaling is crucial for plant responses to various abiotic stresses. The Arabidopsis (Arabidopsis thaliana) transcription factor ABA INSENSITIVE 5 (ABI5) is a central regulator of ABA signaling. ABI5 BINDING PROTEIN 1 (AFP1) interacts with ABI5 and facilitates its 26S-proteasome-mediated degradation, although the detailed mechanism has remained unclear. Here, we report that an ABA-responsive U-box E3 ubiquitin ligase, PLANT U-BOX 35 (PUB35), physically interacts with AFP1 and ABI5. PUB35 directly ubiquitinated ABI5 in a bacterially reconstituted ubiquitination system and promoted ABI5 protein degradation in vivo. ABI5 degradation was enhanced by AFP1 in response to ABA treatment. Phosphorylation of the T201 and T206 residues in ABI5 disrupted the ABI5–AFP1 interaction and affected the ABI5–PUB35 interaction and PUB35-mediated degradation of ABI5 in vivo. Genetic analysis of seed germination and seedling growth showed that pub35 mutants were hypersensitive to ABA as well as to salinity and osmotic stresses, whereas PUB35 overexpression lines were hyposensitive. Moreover, abi5 was epistatic to pub35, whereas the pub35-2 afp1-1 double mutant showed a similar ABA response to the two single mutants. Together, our results reveal a PUB35–AFP1 module involved in fine-tuning ABA signaling through ubiquitination and 26S-proteasome-mediated degradation of ABI5 during seed germination and seedling growth.
Photoreceptor-induced sinapate synthesis contributes to photoprotection in Arabidopsis
Authors: Leonardelli Manuela , Tissot Nicolas , Podolec Roman , Ares-Orpel Florence , Glauser Gaétan , Ulm Roman , Demarsy Emilie
Published: June 2024

Plants must balance light capture for photosynthesis with protection from potentially harmful ultraviolet (UV) radiation. Photoprotection is mediated by concerted action of photoreceptors, but the underlying molecular mechanisms are not fully understood. In this study, we provide evidence that UV RESISTANCE LOCUS 8 (UVR8) UV-B, phytochrome red, and cryptochrome blue-light photoreceptors converge on the induction of FERULIC ACID 5-HYDROXYLASE 1 (FAH1) that encodes a key enzyme in the phenylpropanoid biosynthesis pathway, leading to the accumulation of UV-absorbing sinapate esters in Arabidopsis (Arabidopsis thaliana). FAH1 induction depends on the basic leucine zipper transcription factors ELONGATED HYPOCOTYL 5 (HY5) and HY5 HOMOLOG that function downstream of all 3 photoreceptors. Noticeably, mutants with hyperactive UVR8 signaling rescue fah1 UV sensitivity. Targeted metabolite profiling suggests that this phenotypic rescue is due to the accumulation of UV-absorbing metabolites derived from precursors of sinapate synthesis, namely, coumaroyl glucose and feruloyl glucose. Our genetic dissection of the phenylpropanoid pathway combined with metabolomic and physiological analyses show that both sinapate esters and flavonoids contribute to photoprotection with sinapates playing a major role for UV screening. Our findings indicate that photoreceptor-mediated regulation of FAH1 and subsequent accumulation of sinapate “sunscreen” compounds are key protective mechanisms to mitigate damage, preserve photosynthetic performance, and ensure plant survival under UV.
Epistemic infringement and the wrong of propagandizing
Authors: Leydon-Hardy Lauren
Published: June 2024

The first part of this paper presents a dilemma for arationalism about propaganda. Arationalists hold that propaganda is constitutively reliant on bypassing audience-side rationality. According to the twin pillars of arationalism, then, propaganda is distinguished by the arationalism of audience-side uptake, and criticizable for its circumvention of audience-side rationality. Here, I argue that if the twin pillars of arationalism hold, then arationalists must either deny that bald-faced propaganda is propaganda or deny that bald-faced propaganda is objectionable qua propaganda. Against arationalism, I argue that propagandizing is apt to epistemically infringe on an audience. Propagandizing constitutively involves the systematic contravention of the norms typifying the relationship between communicator and audience, with the characteristic effect of eroding the audience's epistemic agency. The epistemic harm of propaganda is that it has the power to alienate its audience from itself both epistemically and politically by illegitimately constraining what is epistemically possible for its audience.
Perceptions About Monetary Policy
Authors: Bauer Michael D , Pflueger Carolin E , Sunderam Adi
Published: June 2024

We estimate perceptions about the Federal Reserve’s monetary policy rule from panel data on professional forecasts of interest rates and macroeconomic conditions. The perceived dependence of the federal funds rate on economic conditions varies substantially over time, in particular over the monetary policy cycle. Forecasters update their perceptions about the Fed’s policy rule in response to monetary policy actions, measured by high-frequency interest rate surprises, suggesting that they have imperfect information about the rule. Monetary policy perceptions matter for monetary transmission, as they affect the sensitivity of interest rates to macroeconomic news, term premia in long-term bonds, and the response of the stock market to monetary policy surprises. A simple learning model with forecaster heterogeneity and incomplete information about the policy rule motivates and explains our empirical findings.
A circadian-informed lighting intervention accelerates circadian adjustment to a night work schedule in a submarine lighting environment
Authors: Guyett Alisha , Lovato Nicole , Manners Jack , Stuart Nicole , Toson Barbara , Lechat Bastien , Lack Leon , Micic Gorica , Banks Siobhan , Dorrian Jillian , Kemps Eva , Vakulin Andrew , Adams Robert , Eckert Danny J , Scott Hannah , Catcheside Peter
Published: June 2024

Study Objective

Night work has detrimental impacts on sleep and performance, primarily due to misalignment between sleep–wake schedules and underlying circadian rhythms. This study tested whether circadian-informed lighting accelerated circadian phase delay, and thus adjustment to night work, compared to blue-depleted standard lighting under simulated submariner work conditions.

Methods

Nineteen healthy sleepers (12 males; mean ± SD aged 29 ± 10 years) participated in two separate 8-day visits approximately 1 month apart to receive, in random order, circadian-informed lighting (blue-enriched and dim, blue-depleted lighting at specific times) and standard lighting (dim, blue-depleted lighting). After an adaptation night (day 1), salivary dim-light melatonin onset (DLMO) assessment was undertaken from 18:00 to 02:00 on days 2–3. During days 3–7, participants completed simulated night work from 00:00 to 08:00 and a sleep period from 10:00 to 19:00. Post-condition DLMO assessment occurred from 21:00 to 13:00 on days 7–8. Ingestible capsules continuously sampled temperature to estimate daily core body temperature minimum (Tmin) time. Tmin and DLMO circadian delays were compared between conditions using mixed effects models.

Results

There were significant condition-by-day interactions in Tmin and DLMO delays (both p < .001). After four simulated night shifts, circadian-informed lighting produced a mean [95% CI] 5.6 [3.0 to 8.2] hours greater delay in Tmin timing and a 4.2 [3.0 to 5.5] hours greater delay in DLMO timing compared to standard lighting.

Conclusions

Circadian-informed lighting accelerates adjustment to shiftwork in a simulated submariner work environment. Circadian lighting interventions warrant consideration in any dimly lit and blue-depleted work environments where circadian adjustment is relevant to help enhance human performance, safety, and health.
Current cell therapies for systemic lupus erythematosus
Authors: Dao Lan T M , Vu Thu Thuy , Nguyen Quyen Thi , Hoang Van T , Nguyen Thanh Liem
Published: June 2024

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease in which multiple organs are damaged by the immune system. Although standard treatment options such as hydroxychloroquine (HCQ), glucocorticoids (GCs), and other immunosuppressive or immune-modulating agents can help to manage symptoms, they do not offer a cure. Hence, there is an urgent need for the development of novel drugs and therapies. In recent decades, cell therapies have been used for the treatment of SLE with encouraging results. Hematopoietic stem cell transplantation, mesenchymal stem cells, regulatory T (Treg) cell, natural killer cells, and chimeric antigen receptor T (CAR T) cells are advanced cell therapies which have been developed and evaluated in clinical trials in humans. In clinical application, each of these approaches has shown advantages and disadvantages. In addition, further studies are necessary to conclusively establish the safety and efficacy of these therapies. This review provides a summary of recent clinical trials investigating cell therapies for SLE treatment, along with a discussion on the potential of other cell-based therapies. The factors influencing the selection of common cell therapies for individual patients are also highlighted.
XIIIThe Victorian Period
Authors: Garza Ana Alicia , Snailham Fiona , Blackburn-Daniels Sally , Baker William
Published: June 2024

The coverage for 2022 has four sections: 1. General and Prose Including Dickens; 2. The Novel; 3. Poetry; 4. Miscellaneous. Section 1 is by Ana Alicia Garza; section 2 is by Fiona Snailham; section 3 is by Sally Blackburn-Daniels; section 4, which is mixed genre, is by William Baker, who thanks for their assistance Dominic Edwards, Brent E. Kinser, Marcus Neacey, and Jean Saunders, The coverage is shorter than usual owing to contributor unreliability; it is hoped that coverage for 2023 publications will include those for 2022 publications not covered here especially in the areas of periodicals and publishing history.
Urea transporter UT‐A1 as a novel drug target for hyponatremia
Authors: Li Nannan , Zhang Hang , Wang Shuyuan , Xu Yue , Ying Yi , Li Jing , Li Xiaowei , Li Min , Yang Baoxue
Published: June 2024

Hyponatremia is the most common disorder of electrolyte imbalances. It is necessary to develop new type of diuretics to treat hyponatremia without losing electrolytes. Urea transporters (UT) play an important role in the urine concentrating process and have been proved as a novel diuretic target. In this study, rat and mouse syndromes of inappropriate antidiuretic hormone secretion (SIADH) models were constructed and analyzed to determine if UTs are a promising drug target for treating hyponatremia. Experimental results showed that 100 mg/kg UT inhibitor 25a significantly increased serum osmolality (from 249.83 ± 5.95 to 294.33 ± 3.90 mOsm/kg) and serum sodium (from 114 ± 2.07 to 136.67 ± 3.82 mmol/L) respectively in hyponatremia rats by diuresis. Serum chemical examination showed that 25a neither caused another electrolyte imbalance nor influenced the lipid metabolism. Using UT‐A1 and UT‐B knockout mouse SIADH model, it was found that serum osmolality and serum sodium were lowered much less in UT‐A1 knockout mice than in UT‐B knockout mice, which suggest UT‐A1 is a better therapeutic target than UT‐B to treat hyponatremia. This study provides a proof of concept that UT‐A1 is a diuretic target for SIADH‐induced hyponatremia and UT‐A1 inhibitors might be developed into new diuretics to treat hyponatremia.
The Role of Faculty Development in Advancing Change at the Organizational Level
Authors: Steinert Yvonne , O’Sullivan Patricia S. , Irby David M.
Published: June 2024

Although the traditional goal of faculty development (FD) has been to enhance individual growth and development, this goal may no longer suffice to address the compelling challenges faculty members are facing, such as increasing workloads, emotional well-being, and institutional support for education. Addressing these challenges will require change at the organizational level. The purpose of this perspective is to articulate a vision for FD programming that describes ways in which FD leaders, together with other educational leaders, can bring about change at the organizational level to support excellence and innovation in health professions education. To impact the organization at large, the authors propose a model that includes 4 major goals: (1) promoting individual and group development, through educational and leadership development programs, coaching and mentoring, and advanced degrees; (2) advocating for infrastructure and resources, including academies of medical educators, educational scholarship units, educational awards, and intramural funding for educational innovation and scholarship; (3) influencing policies and procedures, by engaging educators on key committees, reviewing appointment and promotion criteria, defining educator roles and portfolios, and valuing diversity, equity, and inclusion; and (4) contributing to organization-wide initiatives, such as addressing “hot button” issues, identifying value factors that support investments in FD and medical education, and enhancing the visibility of educators. In this model, the 4 goals are dynamically interconnected and can impact the culture of the organization. For each goal, the authors offer evidence-informed actions that FD leaders, along with other educational leaders, can adopt to improve the organizational culture and inspire institutionally relevant actions. Because each institution is unique, the options are illustrative and not prescriptive. The intent is to provide examples of how FD leaders and programs can enhance the educational mission through broader engagement with their institutions.
Long-Term Follow-Up of Patients with Advanced Colorectal Liver Metastasis: A Survival Analysis from the Randomized Controlled Multicenter Trial LIGRO
Authors: Björk Dennis , Hasselgren Kristina , Røsok Bård I. , Larsen Peter N. , Sparrelid Ernesto , Lindell Gert , Schultz Nicolai A. , Bjørnbeth Bjorn A. , Isaksson Bengt , Lindhoff Larsson Anna , Rizell Magnus , Björnsson Bergthor , Sandström Per
Published: June 2024

Objective:

The objective of this study was to evaluate the long-term oncological outcomes of patients with colorectal liver metastasis (CRLM) randomized for associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) or 2-stage hepatectomy (TSH).

Introduction:

For advanced CRLM, TSH or ALPPS may be needed for tumor freedom. The randomized, controlled, multicenter trial LIGRO showed an increased resection rate in patients who underwent ALPPS but no difference in morbidity or mortality. The 2-year survival analysis revealed better overall survival in the ALPPS group. Here, the long-term survival analysis from the LIGRO trial is reported.

Methods:

In the LIGRO trial, 100 patients were randomized to TSH or ALPPS, with the option of rescue ALPPS if insufficient growth was found after the initial step of TSH. Patients were enrolled between June 2014 and August 2016. Follow-up data for this study were collected between November 2022 and February 2023.

Results:

In total, 16 patients were alive at the end of the follow-up period. The estimated median follow-up time was 93 months. Estimated median overall survival times were 45 months in the ALPPS group and 27 months in the TSH group (P = 0.057), with 5-year survival rates of 31% and 20%, respectively. Positive prognostic factors were liver tumor-free status at the first follow-up and rectal primary tumor. Negative prognostic factors were extrahepatic disease and increasing CLRM size.

Conclusion:

Liver tumor-free status is a predictor of long-term survival, along with extrahepatic disease, large CRLM size, and rectal primary tumor. Survival did not significantly differ between patients treated with ALPPS or TSH.
An Enigmatic Fluid Accumulation Following Descemet Membrane Endothelial Keratoplasty After Prior Laser In Situ Keratomileusis
Authors: Özen Aydin , Linke Stephan J. , Spitzer Martin S.
Published: June 2024

Purpose:

To report a case of interface fluid syndrome (IFS) following Descemet membrane endothelial keratoplasty (DMEK) 13 years after laser in situ keratomileusis (LASIK).

Methods:

A 79-year-old patient with bullous keratopathy underwent uneventful DMEK. Thirteen years prior, he had undergone LASIK. After DMEK, he developed an IFS, which was confirmed by a fluid accumulation in the flap interface, visible in the anterior segment optical coherence tomography (AS-OCT). In this case, IFS is presumed to have been triggered by the corticosteroid eye drops administered postoperatively. Measurements of the intraocular pressure (IOP) via applanation tonometry yielded erroneously low results.

Results:

The discontinuation of the corticosteroid eye drops, along with the initiation of IOP-lowering therapy, led to an improvement in fluid accumulation and a decrease in IOP. Regular ophthalmic examinations with a palpatory assessment of IOP and monitoring of fluid via AS-OCT are recommended. In this case, no more fluid could be detected in the flap interface after 14 months, and IOP was normal.

Conclusions:

IFS can occur many years after LASIK treatment. Corticosteroids should be discontinued, and IOP-lowering therapy should be initiated to prevent irreversible damage to the optic nerve. Applanation tonometry leads to inaccurately low IOP measurements; therefore, a palpatory assessment of IOP is recommended. AS-OCT is a crucial imaging modality that should be employed for monitoring.