bluuebunny/crossref_metadata_2025 huggingface dataset:
Multidimensional Poverty
Authors: Kakwani Nanak , Son Hyun H.
Published: September 2022

There is now a widespread consensus that poverty is multifaceted, reflecting deprivation people suffer in many aspects of life. The literature on measuring multidimensional poverty has expanded rapidly in recent times. This chapter carefully reviews the development of multidimensional poverty. Although the literature on multidimensional poverty has made considerable progress in identifying the poor and developing multifaceted poverty indices, too many unresolved issues remain to be considered. The chapter has provided a comprehensive discussion of many unresolved problems. The literature has developed many multidimensional measures, making many arbitrary assumptions that lead to an arbitrary degree of poverty. The chapter proposes an alternative analysis of multifaceted poverty requiring a lesser degree of arbitrariness. The inequity index developed in this chapter would be an indispensable tool in formulating public policies to reduce multidimensional poverty. The chapter presents the illustration of multidimensional poverty in Brazilian municipalities for 2010. The empirical estimates suggest the analysis of ill-being (not well-being) indicators divided into four broad dimensions: health, education, living conditions, and labor market activities. The ill-being indicators fall into a mixture of both output and outcome indicators. The chapter concludes that it would be meaningless to aggregate them into a composite poverty index. From the policy perspective, it is also more insightful to analyze poverty in various dimensions instead of constructing a composite index.
Tax Progressivity and Redistribution Effect of Taxes
Authors: Kakwani Nanak , Son Hyun H.
Published: September 2022

Efficiency and equity are the fundamental principles of taxation. This chapter concerns equity in taxation, focusing on the distribution of the tax burden. The measures of tax progressivity and the redistributive effect of taxation are metrics widely used to assess the fairness of taxes. This chapter has utilized the three equity axioms, also called equity principles, to derive the tax progressivity and redistributive effect measures. The violation of any equity principles exerts negative influences on the redistributive impact of the tax. These negative influences on the redistributive effect on the tax provide the means to characterize the type of inequity present in a tax system and assess its significance. The chapter has analyzed the degree of inequities in the Australian tax system. Inequity in taxation can arise when systematic discrimination against a social group in tax payment exists. Tax discrimination happens when different social groups face different tax schedules. This chapter demonstrates that tax discrimination against any social group results in necessary social welfare loss. The dollar loss of social welfare quantifies the magnitude of discrimination. The chapter has extended the idea of tax discrimination to designing government relief packages in response to the COVID-19 pandemic. Using Brazilian data, the chapter has illustrated the calculation of social welfare loss caused by excluding some social groups from the relief package. This illustration demonstrates that discrimination can cause significant welfare loss to society.
Targeting Tools to Evaluate Social Programs
Authors: Kakwani Nanak , Son Hyun H.
Published: September 2022

This chapter presents several new methods for evaluating the targeting efficiency and the social rate of return for social programs. The chapter applies these tools to assess the Chinese rural Dibao using CHIP 2013 data, the most extensive safety net program globally covering more than 40 million beneficiaries. It shows the poor targeting efficiency of the program, yielding a significantly negative social rate of return. The chapter has identified the causes of such a high degree of inefficiency in the program. Given the limitations of accurately obtaining people’s income or consumption, the chapter recommends a proxy means test as a targeting framework. The basic idea of a proxy means test is identifying beneficiaries by easily identifiable variables that predict a household in poverty. A nationally representative household survey makes it possible to design such a proxy means test. Such a system will be an objective way of selecting program beneficiaries. It should significantly improve targeting and reduce the cost of running the program. That should help China achieve its goal of alleviating extreme poverty by 2030.
Alignment and alignment change in the Indo-European family and beyond
Authors: Dahl Eystein
Published: September 2022

This chapter provides a general introduction to the volume, with a brief discussion of the analytical terms A, S, and P/O, and the ways in which they are employed in the literature. Moreover, notions such as split alignment and mixed alignment are defined, and examples of different types of synchronic alignment patterns are given. The chapter gives an overview of the most frequent mechanisms of alignment change, reanalysis, and extension, noting that extension can have scope over both split- and mixed-alignment patterns, sometimes resulting in a tension between the two levels. The final part of the chapter outlines the main points of the other chapters of the volume.
Alignment in Proto-Indo-European
Authors: Dahl Eystein
Published: September 2022

This chapter presents a reconstruction of the basic alignment system of Proto-Indo-European (PIE) and discusses the most central hypotheses concerning its prehistory. The reconstruction of the PIE alignment system is based on a comparison between languages belonging to the most archaic branches of the Indo-European family, including data from Hittite (Anatolian), Vedic Sanskrit (Indo-Iranian), Ancient Greek (Greek), and Latin (Italic). This reconstruction yields an alignment system with a consistent split between neuter and non-neuter nouns, where neuter nouns are defective on three levels of analysis. Nouns of this type lack morphological distinctions between nominative and accusative case, they fail to trigger verb agreement, and only appear in S/P function. Furthermore, the chapter discusses some important recent works dealing with the prehistory of the PIE alignment system, looking at the various merits and shortcomings of the most influential hypotheses in this field, that the PIE alignment system originates from an accusative system, an ergative system or a semantic/stative-active system.
Split alignment, mixed alignment, and the spread of accusative morphosyntax in some archaic Indo-European languages
Authors: Cotticelli Paola , Dahl Eystein
Published: September 2022

This chapter explores the interaction between nominative–accusative alignment and other alignment patterns in Latin, Classical Greek, Vedic Sanskrit, Hittite, Classical Armenian, and Lithuanian. Although these languages have similar typological properties, they display several important differences at a micro level. We argue that these languages mirror different stages of a general development towards consistently accusative alignment, which above all affects the inherited finite verbal system. On the other hand, some of the languages under consideration also show development patterns that run counter to this general tendency, a fact showing that different types of alignment change may overlap or occur simultaneously, affecting different parts of the verbal system.
Fortunate Returns
Authors: Degenhardt Jane Hwang
Published: September 2022

Chapter 2 considers how Shakespeare’s Merchant of Venice (c.1596) and Thomas Heywood’s The Four Prentices of London (c.1594) generate theatrical wonder by embracing the aesthetic and affective potential of a hidden providence, while the same time demonstrating how the inaccessibility of providential knowledge creates opportunities to empower human interventions. By analogizing the risks associated with sea travel, overseas investment, the transmission of news, the operations of a lottery, and theatrical performance, these plays endorse the concept of adventure as a productive means to engaging fortune and responding to unknown outcomes. Playwrights drew upon the structural and temporal relationship between fortune and providence to experiment with new forms of representation, utilizing both on-stage and off-stage space to simulate tests of fortune that presumed to yield wondrous results. At the same time, they demonstrate how theatrical simulations of fortune provide opportunities to indulge the power of performative deception.
Navigating Fortune’s Global Compass
Authors: Degenhardt Jane Hwang
Published: September 2022

Chapter 3 considers how the stage modeled the ethical pursuit of fortune by endorsing prudent decision-making, affective labor, and sexual restraint to morally navigate the opportunities and fluctuations of fortune within a global economy. Pairing Thomas Dekker’s Old Fortunatus (c.1600) and Thomas Heywood’s Fair Maid of the West, Part I (c.1600), the discussion focuses on the stage’s investment in linking the attainment of financial fortune, materialized in the form of gold, with a moral economy based on desert. It argues further that the moral navigation of fortune was premised upon a new human orientation toward the world as a global entity, and explains how the stage forged new understandings of worldly opportunity by re-animating such concepts as “circumference,” “compass,” and “horizon,” which in turn required new ethical orientations. This chapter employs an inter-imperial analysis to examine the global spheres of mobility that operate in these plays.
Metasemantics, Moral Realism, and Moral Doctrines
Authors: Tiefensee Christine
Published: September 2022

This essay considers the relationship between Matthew Kramer’s moral realism as a moral doctrine and expressivism, understood as a distinctly non-representationalist metasemantic theory of moral vocabulary. More precisely, it argues that Kramer is right in stating that moral realism as a moral doctrine does not stand in conflict with expressivism. But it also goes further, by submitting that advocates of moral realism as a moral doctrine must adopt a position such as expressivism in some shape or form. Accordingly, if you do not want to accept theories such as expressivism, you cannot defend moral realism as a moral doctrine. Similarly, if you want moral realism to compete with expressivism, you cannot accept Kramer’s take on moral realism either. Hence, moral realism as a moral doctrine stands and falls with theories such as expressivism, or so this chapter will argue.
What Politicians (Don’t) Tell You about Welfare State Change
Authors: Kumlin Staffan , Goerres Achim
Published: September 2022

This chapter analyses primary data comprising party congress speeches in election years in Germany, Norway, and Sweden. Are reform pressures put on the agenda by leading politicians? Moreover, do politicians dare to connect pressures to reforms, and in particular to more unpopular ones? Further, the empirics register whether politicians discuss pressures mainly in terms of economic sustainability (known in the ideational leadership model as ‘cognitive arguments’), or whether they also appeal to various ‘normative’ arguments. A second set of questions concern actor-, context-, and country-related explanations of variation in party messages. For example, we examine differences between government and opposition, and over time (particularly before and after the financial crisis of 2008). Other analyses look for party differences between left and right—what ‘choice’ are citizens presented with? Are there differences in which pressures are stressed, in which policy solutions are emphasized, or in which normative concepts are invoked?
Do People Adjust Policy Preferences to Reform Pressures?
Authors: Kumlin Staffan , Goerres Achim
Published: September 2022

This chapter uses primary panel data from Germany and Norway to analyse if perceptions of reform pressures change policy preferences over time. Panel data, of course, are often called for in research on welfare attitudes but hard to come by. Such data are valuable here as they give a handle on the direction of causation: are welfare state preferences affected by information and perceptions about reform pressures or do people adjust sustainability perceptions to preferences already held? Panel data are also attractive as they provide insights into the longevity of opinion formation processes involving sustainability perceptions. Panel waves were collected roughly one year apart and thus indicate if sustainability worries matter over longer timespans than can typically be gauged in experimental research. Most importantly, however, Chapter 8 addresses a key knowledge gap in research on the political consequences of welfare state sustainability perceptions. What we know from past research is that such perceptions can be politically important in tempering electoral punishment of governments for unpopular reforms. Less clear, however, is whether perceptions also affect underlying policy demands in a more fundamental sense.
Law Beyond Israel
Authors: Zellentin Holger M.
Published: September 2022

The Hebrew Bible formulates two sets of law: one for the Israelites and one for the gentile “residents” living in the Holy Land. Law Beyond Israel: From the Bible to the Qur’an argues that these biblical laws for non-Israelites form the historical basis of qur’anic law. The study corroborates its central claim by assessing laws for gentiles in late antique Jewish and especially in Christian legal discourse, pointing to previously underappreciated legal continuity from the Hebrew Bible to the New Testament and from late antique Christianity to nascent Islam. This volume first sketches the legal obligations that the Hebrew Bible imposes on humanity more broadly and, more specifically, on the non-Israelite residents of the Holy Land. It then traces these laws through Second Temple Judaism to the early Jesus movement, illustrating how the biblical laws for residents inform those formulated in the Acts of the Apostles. Building on this legal continuity, the study employs detailed historical and literary analyses of legal narratives in order to make three propositions. First, rabbinic laws for gentiles, the so-called Noahide Laws, while offering a more lenient interpretation than the one we find in Acts, are equally based on the biblical laws for gentile residents of the Holy Land. Second, Christians generally appreciated and even expanded the gentile laws of Acts. Third, the Qur’an remakes traditional Arabian religious practice by formulating its own distinctive approach to the biblical laws for gentiles, in close continuity with—and at times in critical distance from—late antique Jewish and especially Christian gentile law.
The Poetics of Incest Law
Authors: Zellentin Holger M.
Published: September 2022

This chapter will focus on literary form at the same time as examining the continuity of biblical, late antique, and qur’anic incest laws. The legal continuities from the Bible to the Qur’an described in Chapters 1 and 2 largely point to a continuity of practice, coupled with the type of broader lexical and conceptual continuity, amidst partial change, one can expect if laws develop over centuries and pass several cultural and linguistic boundaries in the process. Yet in the case of the Qur’an’s legislation on prohibited marriages (in Q 4 Sūrat al-Nisāʾ 22–23), law as formulated in the Hebrew Bible seems to have been accorded a more palpable presence. This chapter will argue that the nature and order of the qur’anic prohibitions suggests that the Scripture of Islam integrates and updates a catalogue very similar to the one preserved in the Hebrew Bible (in Lev 18:6–18), which, once again, is addressed to Israelites and gerim alike. The Qur’an, in this case, can be argued to stand closer to the Bible than Latin, Greek, and West Syrian law, which evidently reflect their Roman legal context. In focusing on the Bible, the Qur’an could even be said to share an attitude with the East Syrian tradition on this matter, yet even here we can find manifest echoes of Byzantine legal reforms. The Qur’an’s general leniency for certain types of first-time offenders, along with its dispensations for marriages contracted prior to a couple’s joining the qur’anic community, is argued to stand in conversation with both West and East Syrian as well as with Byzantine marriage law. We will see that the qur’anic incest laws equally maintain a demonstrable pagan Arabian heritage.
Mechanisms of Legal Evolution
Authors: Verhagen Hendrik L. E.
Published: September 2022

This chapter gives an outline of the specific institutional mechanisms for the evolution of Roman private law in the Principate. Transactional ‘legal variants’ provided input to the legal system and had the potential of triggering legal change when they became the subject of litigation in the formula procedure. By interpreting existing conditions of the conditional programmes encapsulated in the forms of action (formulae), or by incidentally changing or adding conditions, Roman law could respond to new transactional practices. For a substantial part of the classical period the praetor’s edict provided an effective mechanism of stabilizing legal innovations. After the codification of the praetor’s edict (Edictum perpetuum) under emperor Hadrian, the imperial chancery became the most important institutional agency for legal change and stability. The intellectual framework for all these mechanisms of legal evolution was formed by Roman jurisprudence. The Roman jurists were the effective ‘determiners’ of Roman law.
From Forfeiture to Sale
Authors: Verhagen Hendrik L. E.
Published: September 2022

This chapter focuses on secured lending practices in the first century ad, in particular as documented in the Sulpicii archive. Originally, the Roman pledge was a forfeiture: if the debtor failed to pay the secured debt, the creditor became owner of the collateral. In the Sulpicii archive there is a document evidencing a more ‘modern’ arrangement: the creditor sells the collateral and takes recourse against the proceeds (TPSulp 79). This document also provides that any surplus will be paid back to the debtor, in the second century ad of pignus and hypotheca evolved to true security interests. What had started as a transactional practice—the licence to sell coupled with the surplus/deficit-clause—evolved in the second century ad into a rule of law. The transactional practice can be regarded as the ancestor of the modern pledge enforceable by sale.
From Single to Multiple Pledge
Authors: Verhagen Hendrik L. E.
Published: September 2022

This chapter describes the evolution of the multiple pledge as a slow process. For a considerable time the granting of a pledge would deprive the debtor of the legal power to grant other rights of pledge over the pledged property. One way of getting around this was the pledge of the superfluum of the execution of the original pledge. The other way was that it was recognized that subsequent rights of pledge could be granted subject to the condition that the first pledge had terminated. Only in the second half of the second century ad did it come to be accepted that multiple unconditional pledges could coexist over the same property. As a corollary of the multiple pledge the right of lower-ranking creditors to take over the preferential position of higher-ranking creditors (ius offerendi et succedendi) originated and evolved. This right was applied analogously in order to avoid adverse consequences of novation.
Fiscal Privileges and Title Registries
Authors: Verhagen Hendrik L. E.
Published: September 2022

This chapter discusses instances in which all of someone’s assets would be subject to a right of pledge arising in favour of the imperial treasury. It will give an outline of the origins, scope, and legal nature of these fiscal general pledges. In most respects the scope and legal consequences of these fiscal general pledges were the same as those of conventional general pledges. This chapter suggests that fiscal general pledges may not have undermined the effectiveness of the Roman law of real security at all. Like conventional pledges they were subject to the prior tempore principle and only in the late classical period this may have changed. Not only fiscal general pledges but also their lack of publicity significantly contributes to the negative judgment by modern Romanists on the Roman law of real security. Here also the adverse consequences may have been less devastating than they are often perceived to be in modern literature
Late Classical Execution Practices
Authors: Verhagen Hendrik L. E.
Published: September 2022

The evolution from forfeiture to sale entailed that in high and late classical law forfeiture was no longer the general rule. The secured creditor would normally take recourse by selling the charged property to third parties. This chapter will examine how certain forfeiture arrangements can be reconciled with the evolution of pignus into a security interest, which was enforceable by sale and pursuant to which the creditor could only take recourse for the amount of the secured debt. The conclusion for classical law is that during the entire classical period forfeiture arrangements were deemed legally valid, probably at first as express forfeiture clauses and over time as constructive forfeiture arrangements (conditional sale, transfer in lieu of payment). It seems that at the end of the classical period forfeiture arrangements, under which the surplus value accrued to the creditor, became invalid. Under Constantine, leges commissoriae were expressly declared void.
Roads and Jobs in Ethiopia
Authors: Fiorini Matteo , Sanfilippo Marco
Published: September 2022

Does improving roads affect jobs and structural transformation? A novel geocoded data set covering the universe of Ethiopian roads matched with individual data allows the relationship between improvements in road infrastructure and labor-market outcomes over the 1994–2013 period to be identified. At the district level, greater market access due to better roads correlates with the process of structural transformation in Ethiopia. Improvements in market access are related to reductions in the share of agricultural workers and increases in that of workers in the services sector, but not in manufacturing. Heterogeneity in this relationship exists across industries, gender, education level, and age cohorts. Patterns of internal migration and changes in economic opportunities can help rationalize these findings.
Evaluation of a Model for Predicting Onset of Septoria nodorum Blotch in Winter Wheat
Authors: Adhikari Urmila , Cowger Christina , Ojiambo Peter S.
Published: September 2022

Prediction models that aid growers in making decisions on timing of fungicide application are important components of integrated management programs for several foliar diseases of wheat. The risk of Septoria nodorum blotch (caused by Parastagonospora nodorum) onset in winter wheat has been reported to be influenced by location, amount of wheat residue in the field, and cumulative daily infection values 2 weeks prior to day of year (DOY) 102. A model previously developed based on these predictor variables was evaluated for its ability to predict disease onset under field conditions. An experiment was conducted at three locations in North Carolina in 2018, 2019, and 2020, where plots were either treated with >20% wheat residue or received no residue treatment. Plots were monitored for disease symptoms, and disease onset was defined to have occurred when mean disease incidence in a plot was 50%. Of the 298 disease cases recorded, disease onset occurred early (i.e., prior to DOY 102) in 257 cases, while onset was late (i.e., on or after DOY 102) in 41 cases. Model accuracy based on correct classification ranged from 0.67 to 0.95, with a mean of 0.87 across the study period. Similarly, sensitivity rates of the model ranged from 0.88 to 1.0 with a mean of 0.98 across all years. However, the model had low specificity, with a mean rate of 0.15 across the study period. Overall, there was no significant difference in the frequency of observed and predicted cases in the study (χ2 = 0.50, P = 0.7788, df = 2). Time to disease onset was significantly correlated with grain yield and explained 26% of variation in yield (P < 0.0001). Results indicated that the disease onset model performs well in predicting early disease onset but requires further evaluation and improvement, particularly in the Piedmont, where it over-predicted early onset in 2 successive years.
The Aim of the Editor
Authors: Kirton Carl A.
Published: September 2022

AJN's new editor recommits to the journal's original mission.
Historical Feature: A Long History of Abortion
Authors: McSpedon Corinne
Published: September 2022

The history of abortion in this country is more complex than suggested by the recent Supreme Court decision overturning Roe v. Wade. This article takes a closer look at the lengthy and nuanced history of the meanings and contexts of abortion in American history and AJN's archives, revealing the various roles played and challenges encountered by nurses then and now. A version of this article was first published July 11 on ajnoffthecharts.com.
Risk Factors for Postoperative Delirium Identified
Authors: Rosenberg Karen
Published: September 2022

According to this study:

A meta-analysis identified 11 significant risk factors for delirium after gastrointestinal surgery that could help clinicians implement preventive measures.
Solitary Intratarsal Blue Nevus
Authors: Charles Norman C. , Kim Eleanore T.
Published: September 2022

A 42-year-old woman presented with a small pigmented lesion of the palpebral conjunctiva that had been present for a few months. Because of the possibility of melanoma, the lesion was resected. Microscopic examination displayed an intratarsal blue nevus at the level of the meibomian glands comprised of bland nonpigmented and pigmented cells that enveloped a sebaceous gland and its ducts. The cells were of admixed spindle and epithelioid configuration and were immunoreactive for Melan-A. The Ki67 proliferative marker was negative in these cells, contrasting with the epithelium of the overlying conjunctiva and the sebaceous ducts, and thereby militating against the diagnosis of melanoma. Clusters of melanophages were also present. Although an intratarsal blue nevus has been described as a component of a combined nevus, the current lesion demonstrates the occurrence of a sole tarsal blue nevus. Palpebral pigmented lesions should be customarily excised because many are melanomas.
Within-host virus evolution during the extended treatment of RSV infection with mutagenic drugs
Authors: Illingworth Christopher J. R. , Kreins Alexandra Y. , Margarit-Soler Adriana , Best Tim , Dyal Patricia , Lucchini Giovanna , Rao Kanchan , Williams Rachel , Worth Austen , Breuer Judith
Published: September 2022

Antiviral drugs causing viral mutagenesis have shown value against a broad range of RNA viruses causing respiratory illnesses. While drug-induced accumulation of mutations generally decreases viral fitness, the potential for mutagenesis to generate escape variants is unknown and concerns have been raised about adaptive evolution promoting drug-resistance. We report prolonged treatment of a life-threatening RSV infection with a combination of two viral RNA-dependent RNA polymerase (RdRp) inhibitors, ribavirin and favipiravir, in a child with severe combined immunodeficiency undergoing haematopoietic stem cell transplantation. Viral deep sequencing of longitudinally collected RSV samples determined that ribavirin caused a 3-fold increase in the viral mutation rate. There was no synergistic effect upon addition of favipiravir. Viral load remained unchanged throughout antiviral treatment, but genomic modelling predicted loss of viral fitness secondary to drug-induced mutagenesis. The viral changes coincided with stabilisation of the patient’s clinical condition. In the absence of viral clearance, adaptive evolution occurred on a complex fitness landscape, leading to increased population diversity at the haplotype level. The evolutionary consequences of using mutagenic antiviral drugs are likely to be hard to predict, but in this example within-host virus evolution under extended treatment with mutagenic drugs resulted in an overall loss of viral fitness due to deleterious mutations accumulating faster than could be outweighed by positive selection. These genomic findings occurred in tandem with evidence of clinical improvement and are potentially associated.
Exome re-analysis driven by deep phenotyping increases diagnostic yield
Authors: Dutta Atanu Kumar , Bhunia Niladri Sekhar , Bhowmik Rohit , Mishra Nihar Ranjan , Sonowal Rimjhim , Goswami Kalyan , C Anbu Kayalvizhi
Published: September 2022

Objective

To explore if clinician driven systematic reanalysis of “negative” exome sequencing data of patients with a strong suspicion of a Mendelian disease by a Clinical Geneticist using deep phenotyping can increase the diagnostic yield.

Methods

Ten patients were deep phenotyped using Gestalt matching (Face2Gene) and OMIM database searching (Phenomizer) to build a list of candidate genes of interest. The Variant Call Format (vcf) files for individual patients were obtained from the sequencing laboratory and reanalyzed in the wANNOVAR server. The annotated list of variants was queried for the genes of interest. Copy number variant analysis was performed using ExomeDepth (v1.1.10) R package.

Results

A homozygous pathogenic mutation in the NPHP3 gene (c.2805C>T) was identified in one child with Renal-Hepatic-Pancreatic Dysplasia and a multiexon deletion in the CUL7 gene was identified in another child with 3M syndrome.

Conclusions

Systematic re-analysis of exome sequencing data by a Clinical Geneticist can increase the diagnostic yield with minimal additional cost.
Reserpine maintains photoreceptor survival in retinal ciliopathy by resolving proteostasis imbalance and ciliogenesis defects
Authors: Chen Holly Y. , Swaroop Manju , Papal Samantha , Mondal Anupam K. , Tawa Gregory J. , Regent Florian , Shimada Hiroko , Nagashima Kunio , de Val Natalia , Jacobson Samuel G. , Zheng Wei , Swaroop Anand
Published: September 2022

Ciliopathies manifest from sensory abnormalities to syndromic disorders with multiorgan pathologies, with retinal degeneration a highly penetrant phenotype. Photoreceptor cell death is a major cause of incurable blindness in retinal ciliopathies. To identify drug candidates to maintain photoreceptor survival, we performed an unbiased, high-throughput screening of over 6,000 bioactive small molecules using retinal organoids differentiated from induced pluripotent stem cells (iPSC) of rd16 mouse, which is a model of Leber congenital amaurosis (LCA)10 caused by mutations in the cilia-centrosomal gene CEP290. We identified five non-toxic positive hits, including the lead molecule reserpine, which improved photoreceptor survival in rd16 organoids. Reserpine also maintained photoreceptors in retinal organoids derived from induced pluripotent stem cells of LCA10 patients and in rd16 mouse retina in vivo. Reserpine-treated patient organoids revealed modulation of signaling pathways related to cell survival/death, metabolism, and proteostasis. Further investigation uncovered misregulation of autophagy associated with compromised primary cilium biogenesis in patient organoids and rd16 mouse retina. Reserpine partially restored the balance between autophagy and the ubiquitin-proteasome system, at least in part by increasing the cargo adaptor p62 and improving primary cilium assembly. Our study identifies effective drug candidates in preclinical studies of CEP290 retinal ciliopathies through cross-species drug discovery using iPSC-derived organoids, highlights the impact of proteostasis in the pathogenesis of ciliopathies, and provides new insights for treatments of retinal neurodegeneration.
Intraoperative phrenic stimulation offsets diaphragm fiber weakness during cardiothoracic surgery
Authors: Bresciani Guilherme , Beaver Thomas , Martin A. Daniel , van der Pijl Robbert , Mankowski Robert , Leeuwenburgh Christiaan , Ottenheijm Coen A.C. , Martin Tomas , Arnaoutakis George , Ahmed Shakeel , Mariani Vinicius , Xue Wei , Smith Barbara K. , Ferreira Leonardo F.
Published: September 2022

Rationale

Mechanical ventilation rapidly induces slow and fast fiber contractile dysfunction in the human diaphragm, which could be attenuated by phrenic nerve stimulation. Here, we present data from a controlled trial of intraoperative phrenic stimulation to offset slow and fast fiber contractile dysfunction and myofilament protein derangements.

Objectives

In this study, we tested the hypothesis that intraoperative hemidiaphragm stimulation would mitigate slow and fast fiber loss of contractile function in the human diaphragm.

Methods

Nineteen adults (9 females, age 59 ±12 years) consented to participate. Unilateral phrenic twitch stimulation was applied for one minute, every 30 minutes during cardiothoracic surgery. Thirty minutes following the last stimulation bout, biopsies were obtained from the hemidiaphragms for single fiber force mechanics and quantitation of thin filament protein abundance. Effects of stimulation and fiber type on force mechanics were evaluated with linear mixed models with the subject treated as a random intercept effect.

Measurements and Main Results

Subjects underwent 6 ±2 hemidiaphragm stimulations at 17 ±6 mA, during 278 ±68 minutes of mechanical ventilation. In slow-twitch fibers, cross-sectional area (p<0.0001) and specific force (p<0.0005) were significantly greater on the stimulated side. Longer-duration surgeries were associated with lower slow-twitch specific force (p<0.001). Stimulation did not alter contractile function of fast-twitch fibers or calcium-sensitivity in either fiber type. There were no differences in abundance or phosphorylation of myofilament proteins.

Conclusion

Unilateral phrenic stimulation during open chest surgery preserved contractile function of slow-twitch diaphragm fibers, but had no effect on relative abundance of sarcomeric proteins.
Schistosoma mansonicercarial invadolysin cleaves complement C3 and suppresses proinflammatory cytokine production
Authors: Hambrook Jacob R. , Hanington Patrick C.
Published: September 2022

Schistosoma mansoniemploys immune evasion and immunosuppression to overcome immune responses mounted by its snail and human hosts. Myriad immunomodulating factors underlie this process, some of which are proteases. Here, we demonstrate that one protease, an invadolysin we have termed SmCI-1, is released from the acetabular glands ofS. mansonicercaria and is involved in creating an immunological milieu favorable for survival of the parasite. We confirm the presence of SmCI-1 in the cercarial stage ofS. mansoniand demonstrate that it is released during transformation into the schistosomula. We confirm SmCI-1 functions as a metalloprotease with the capacity to cleave collagen type IV, gelatin and fibrinogen. We also show that complement component C3b is cleaved by this protease, resulting in inhibition of the classical and alternative complement pathways. Finally, we assess the effect of SmCI-1 on cytokine release from human peripheral blood mononuclear cells, providing compelling evidence that SmCI-1 promotes an anti-inflammatory microenvironment by enhancing production of IL-10 and suppressing the production of inflammatory cytokines like IL-1B and IL-12p70 and those involved in eosinophil recruitment and activation, like eotaxin-1 and IL-5.
ZnO nanoparticles and SWCNT induced general stress response pathway in HepG2 cells at non-cytotoxic doses revealed by RNA sequencing
Authors: Mittal Deepti , Ali Syed Azmal , Kaul Gautam
Published: September 2022

Nanoparticles (NPs) are important in a variety of sectors, including disease diagnostics, medicine, nutrition, and many other industries. The risk of human exposure demands an early evaluation of both the basic dynamics of NPs’ interaction with biological systems and their potential consequences. Deciphering these occurrences will provide critical information regarding the health hazards and safety advantages associated with next-generation nanoformulations in clinical practice. We examined the HepG2 cell line in a systematic manner to determine the cellular response to single-walled carbon nanotubes (SWCNTs) and zinc oxide (ZnO) NPs. With the use of high-throughput transcriptomic methods, we found that both NPs induce comparable dysregulation of the endocytic and proteasomal complex genes in liver hepatocellular carcinoma cells, at levels (> 80 percent cell viability) that do not cause over-toxicity at early incubation period (6 h). SWCNT and ZnO NPs were shown to enter cells through clathrin-mediated pathways, affecting cytoskeleton gene expression, DNA damage and repair, protein ubiquitination, and cell transcriptional machinery. Our findings indicate that early response strategies activate stress-related mechanisms. Finally, this method for studying nanomaterial–cell interactions demonstrates how changes in the transcriptome profile may predict downstream consequences even at doses that do not cause acute toxicity.
A second generation capture panel for cost-effective sequencing of genome regulatory regions in wheat and relatives
Authors: Zhang Junli , Debernardi Juan M. , Burguener German , Choulet Frédéric , Paux Etienne , O’Connor Lauren , Enk Jacob , Dubcovsky Jorge
Published: September 2022

As genome resources for wheat expand at a rapid pace, it is important to update targeted sequencing tools to incorporate improved sequence assemblies and regions of previously unknown significance. Here, we developed an updated regulatory region enrichment capture for wheat (TriticumL.) and otherTriticeaespecies. The core target space includes sequences from two Kbp upstream of each gene predicted in the Chinese Spring wheat genome (IWGSC RefSeq Annotation v1.1) and regions of open chromatin identified with ATAC-seq from wheat leaf and root samples. To improve specificity, we aggressively filtered candidate repetitive sequences using a combination of BLASTN searches to the Triticeae Repetitive Sequence Database (TREP), identification of regions with read over-coverage from previous target enrichment experiments, and k-mer frequency analyses. The final design comprises 216 Mbp of predicted hybridization space in hexaploid wheat and showed increased specificity and coverage of targeted sequences relative to previous protocols. Test captures on hexaploid and tetraploid wheat and other diploid cereals show that the assay has broad potential utility for cost-effective promoter and open chromatin resequencing and general-purpose genotyping of variousTriticeaespecies.
Metagenomic analysis of concrete bridge reveals a microbial community dominated by halophilic Bacteria and Archaea
Authors: Kiledal E. Anders , Shaw Mark , Polson Shawn W. , Maresca Julia A.
Published: September 2022

Concrete hosts a small but diverse microbiome that changes over time. Shotgun metagenomic sequencing would enable assessment of both diversity and function of the microbial community in concrete, but because the biomass in concrete is so low, this analysis is highly affected by laboratory contamination. Here, we demonstrate improved DNA extraction from concrete, and show that this method provides DNA of sufficient quality and quantity to do shotgun metagenomic sequencing. DNA was extracted from a sample of concrete obtained from a road bridge and sequenced with Illumina MiSeq. This microbial community was dominated by halophilic Bacteria and Archaea, with enriched functional pathways related to osmotic stress responses. Prior work found that halophilic bacteria were relatively rare in younger concrete samples, which had abundant oligotrophic taxa. These results suggest that as concrete ages and weathers, salt and osmotic stresses become more important selective pressures, and suggest that long-term persistence and performance of microbes for biorepair or biosensing applications might improve if halophilic strains were used.
Splicing-dependent transcriptional activation
Authors: Uriostegui-Arcos Maritere , Mick Steven T. , Shi Zhuo , Rahman Rufuto , Fiszbein Ana
Published: September 2022

Transcription and splicing are intrinsically coupled. Transcription dynamics regulate splicing, and splicing feeds back to transcription initiation to jointly determine gene expression profiles. A recently described phenomenon called exon-mediated activation of transcription starts (EMATS) shows that splicing of internal exons can regulate transcription initiation and activate cryptic promoters. Here, we present the first complete catalog of human EMATS genes that have a weak alternative promoter located upstream and proximate to an efficiently spliced internal skipped exon. We found that EMATS genes are associated with Mendelian genetic diseases —specifically intellectual development disorders, cardiomyopathy, and immunodeficiency— and provide a list of EMATS genes with pathological variants. EMATS was originally described as a natural mechanism used during evolution to fine-tune gene expression through punctual genomic mutations that affect splicing. Here, we show that EMATS can be used to manipulate gene expression with therapeutic purposes. We constructed stable cell lines expressing a splicing reporter based on the alternative splicing of exon 7 of SMN2 gene under the regulation of different promoters. Using a small molecule (Risdiplam) and an antisense oligonucleotide (ASO) modeled after Spinraza, we promoted the inclusion of SMN2 exon 7 which triggered an increase in gene expression up to 40-folds by activating transcription initiation. We observed the strongest effects in reporters under the regulation of weak human promoters, where the highest drug doses dramatically increased exon inclusion. Overall, our findings present evidence to develop the first therapeutic strategy to use EMATS to activate gene expression using small molecules and ASOs that affect splicing.
Supervised Machine Learning Enables Geospatial Microbial Provenance
Authors: Bhattacharya Chandrima , Tierney Braden T. , Ryon Krista A. , Bhattacharyya Malay , Hastings Jaden J. A. , Basu Srijani , Bhattacharya Bodhisatwa , Bagchi Debneel , Mukherjee Somsubhro , Wang Lu , Henaff Elizabeth M. , Mason Christopher E.
Published: September 2022

The recent increase in publicly available metagenomic datasets with geospatial metadata has made it possible to determine location-specific, microbial fingerprints from around the world. Such fingerprints can be useful for comparing microbial niches for environmental research, as well as for applications within forensic science and public health. To determine the regional specificity for environmental metagenomes, we examined 4305 shotgun-sequenced samples from the MetaSUB Consortium dataset – the most extensive public collection of urban microbiomes, spanning 60 different cities, 30 countries, and 6 continents. We were able to identify city-specific microbial fingerprints using supervised machine learning (SML) on the taxonomic classifications, and we also compared the performance of ten SML classifiers. We then further evaluated the five algorithms with the highest accuracy, with the city and continental accuracy ranging from 85-89% to 90-94%, respectively. We then used these results to develop Cassandra, a random-forest-based classifier that identifies indicator species to aid in fingerprinting and can infer higher-order microbial interactions at each site. We further tested the Cassandra algorithm on the Tara Oceans dataset, the largest collection of marine-based microbial genomes, where it classified the oceanic sample locations with 83% accuracy. These results and code show the utility of SML methods and Cassandra to identify bioindicator species across both oceanic and urban environments, which can help guide ongoing efforts in biotracing, environmental monitoring, and microbial forensics (MF).
In-vitro activity of Cefiderocol against clinical isolates of meropenem-resistant Klebsiella pneumoniae from India
Authors: Borde Kalyani , Kareem M A , Sharma Ratna Mani , Dass S Manick , Ravi Vedantham , Mathai Dilip
Published: September 2022

Background

Cefiderocol (FDC), a novel siderophore drug, is active against gram negative bacteria producing carbapenemases, including metallo-beta-lactamases.

Objective

To compare the in-vitro activity of FDC with ceftazidime-avibactam (CZA), CZA/ aztreonam (AT) combination and colistin (CST), in clinical isolates of meropenem-resistant (MER-R) Klebsiella pneumoniae.

Methods

From 2052 clinical specimens submitted for culture testing, 245 K. pneumoniae isolates were recovered within a six month period in 2021. 103 non-duplicate, non-outbreak, MER-R (MIC >4 μg/ml) strains were included in the study. Identification and susceptibility was performed using VITEK-2 (bioMérieux). 10 meropenem-susceptible isolates served as controls. For FDC, BMD was performed after in-house standardisation. Disc diffusion (Liofilchem, Italy) and broth microdilution (BMD; ComASP, STC, Liofilchem, Italy) were used for susceptibility testing of CZA and CST respectively. Synergy testing for CZA and aztreonam (AT) was performed using disk approximation method. CLSI breakpoints were used for interpretation of results.

Results

For FDC, MIC50 and MIC90 was 2 μg/ml and 8 μg/ml, respectively. 80% isolates were susceptible to FDC. 26.2% isolates were susceptible to CZA, synergy testing with CZA/ AT was positive for 74 (72%) of the isolates. 89.3% had intermediate susceptibility to CST. Nine (8.7%) were susceptible only to FDC.

Conclusion

FDC is active in-vitro against MER-R K. pneumoniae > CZA/AT> CZA > CST, as observed in this study, applying CLSI criteria. Clinico-microbiological studies should be performed for assessing clinical efficacy of this novel drug in this region with high prevalence of carbapenem resistance among gram-negative organisms.
STAT1 is required to establish but not maintain IFNγ-induced transcriptional memory
Authors: Tehrani Sahar S.H. , Mikulski Pawel , Abdul-Zani Izma , Mata João F. , Siwek Wojciech , Jansen Lars E.T.
Published: September 2022

Exposure of human cells to interferon-γ (IFNγ) results in a mitotically heritable yet reversible state called long-term transcriptional memory. We previously identified the clustered GBP genes as strongly primed by IFNγ. Here we discovered that in primed cells, both interferon-responsive transcription factors STAT1 and IRF1 target chromatin with accelerated kinetics upon re-exposure to IFNγ, specifically at promotors of primed genes. Priming does not alter the degree of IFNγ-induced STAT1 activation or nuclear import, indicating that memory does not alter upstream JAK-STAT signalling. We found STAT1 to be critical to establish transcriptional memory but in a manner that is independent of mere transcription activation. Interestingly, while Serine 727 phosphorylation of STAT1 was maintained during the primed state, STAT1 is not required for the heritability of GBP gene memory. Our results suggest that memory of interferon exposure constitutes a STAT1-mediated, heritable state that is established during priming. This renders GBP genes poised for subsequent STAT1 and IRF1 binding and accelerated gene activation upon a secondary interferon exposure.