bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of parental age and polymer composition on short tandem repeatde novomutation rates
Authors: Goldberg Michael E. , Noyes Michelle D. , Eichler Evan E. , Quinlan Aaron R. , Harris Kelley
Published: December 2023

Short tandem repeats (STRs) are hotspots of genomic variability in the human germline because of their high mutation rates, which have long been attributed largely to polymerase slippage during DNA replication. This model suggests that STR mutation rates should scale linearly with a father’s age, as progenitor cells continually divide after puberty. In contrast, it suggests that STR mutation rates should not scale with a mother’s age at her child’s conception, since oocytes spend a mother’s reproductive years arrested in meiosis II and undergo a fixed number of cell divisions that are independent of the age at ovulation. Yet, mirroring recent findings, we find that STR mutation rates covary with paternal and maternal age, implying that some STR mutations are caused by DNA damage in quiescent cells rather than the classical mechanism of polymerase slippage in replicating progenitor cells. These results also echo the recent finding that DNA damage in quiescent oocytes is a significant source ofde novoSNVs and corroborate evidence of STR expansion in postmitotic cells. However, we find that the maternal age effect is not confined to previously discovered hotspots of oocyte mutagenesis, nor are post-zygotic mutations likely to contribute significantly. STR nucleotide composition demonstrates divergent effects on DNM rates between sexes. Unlike the paternal lineage, maternally derived DNMs at A/T STRs display a significantly greater association with maternal age than DNMs at GC-containing STRs. These observations may suggest the mechanism and developmental timing of certain STR mutations and are especially surprising considering the prior belief in replication slippage as the dominant mechanism of STR mutagenesis.

Author Summary

We have long known that tandem repeats are hypermutable and attributed that hypermutability to slippage during DNA replication. Contradicting this long-held theory, we show that tandem repeats accumulate mutations in maternal germ cells during periods when these cells do not replicate. This bolsters a new consensus that DNA replication is not the only driver of mutagenesis, even at loci where replicative slippage is possible. Patterns shared by certain loci enriched for mutations from older mothers may hint at mechanisms.
RNA polymerases reshape chromatin and coordinate transcription on individual fibers
Authors: Tullius Thomas W. , Isaac R. Stefan , Ranchalis Jane , Dubocanin Danilo , Churchman L. Stirling , Stergachis Andrew B.
Published: December 2023

During eukaryotic transcription, RNA polymerases must initiate and pause within a crowded, complex environment, surrounded by nucleosomes and other transcriptional activity. This environment creates a spatial arrangement along individual chromatin fibers ripe for both competition and coordination, yet these relationships remain largely unknown owing to the inherent limitations of traditional structural and sequencing methodologies. To address these limitations, we employed long-read chromatin fiber sequencing (Fiber-seq) to visualize RNA polymerases within their native chromatin context at single-molecule and near single-nucleotide resolution along up to 30 kb fibers. We demonstrate that Fiber-seq enables the identification of single-molecule RNA Polymerase (Pol) II and III transcription associated foot-prints, which, in aggregate, mirror bulk short-read sequencing-based measurements of transcription. We show that Pol II pausing destabilizes downstream nucleosomes, with frequently paused genes maintaining a short-term memory of these destabilized nucleosomes. Furthermore, we demonstrate pervasive direct coordination and anti-coordination between nearby Pol II genes, Pol III genes, transcribed enhancers, and insulator elements. This coordination is largely limited to spatially organized elements within 5 kb of each other, implicating short-range chromatin environments as a predominant determinant of coordinated polymerase initiation. Overall, transcription initiation reshapes surrounding nucleosome architecture and coordinates nearby transcriptional machinery along individual chromatin fibers.
Multiple performance peaks for scale-biting in an adaptive radiation of pupfishes
Authors: Tan Anson , St. John Michelle , Chau Dylan , Clair Chloe , Chan HoWan , Holzman Roi , Martin Christopher H.
Published: December 2023

The physical interactions between organisms and their environment ultimately shape their rate of speciation and adaptive radiation, but the contributions of biomechanics to evolutionary divergence are frequently overlooked. Here we investigated an adaptive radiation ofCyprinodonpupfishes to measure the relationship between feeding kinematics and performance during adaptation to a novel trophic niche, lepidophagy, in which a predator removes only the scales, mucus, and sometimes tissue from their prey using scraping and biting attacks. We used high-speed video to film scale-biting strikes on gelatin cubes by scale-eater, molluscivore, generalist, and hybrid pupfishes and subsequently measured the dimensions of each bite. We then trained the SLEAP machine-learning animal tracking model to measure kinematic landmarks and automatically scored over 100,000 frames from 227 recorded strikes. Scale-eaters exhibited increased peak gape and greater bite length; however, substantial within-individual kinematic variation resulted in poor discrimination of strikes by species or strike type. Nonetheless, a complex performance landscape with two distinct peaks best predicted gel-biting performance, corresponding to a significant nonlinear interaction between peak gape and peak jaw protrusion in which scale-eaters and their hybrids occupied a second performance peak requiring larger peak gape and greater jaw protrusion. A bite performance valley separating scale-eaters from other species may have contributed to their rapid evolution and is consistent with multiple estimates of a multi-peak fitness landscape in the wild. We thus present an efficient deep-learning automated pipeline for kinematic analyses of feeding strikes and a new biomechanical model for understanding the performance and rapid evolution of a rare trophic niche.
Unexplored regions of the protein sequence-structure map revealed at scale by a library of foldtuned language models
Authors: Subramanian Arjuna M. , Martinez Zachary A. , Lourenço Alec L. , Liu Shichen , Thomson Matt
Published: December 2023

The combinatorial scale of amino-acid sequence-space has traditionally precluded substantive study of the full protein sequence-structure map. It remains unknown, for instance, how much of the vast uncharted landscape of far-from-natural sequences encodes the familiar ensemble of natural folds in a fashion consistent with the laws of biophysics but seemingly untouched by evolution on Earth. The scale of sequence perturbations required to access these spaces exceeds the reach of even gold-standard experimental approaches such as directed evolution. We surpass this limitation guided by the innate capacity of protein language models (pLMs) to explore sequences outside their natural training data through generation and self-feedback. We recast pLMs as probes that explore into regions of protein “deep space” that possess little-to-no detectable homology to natural examples, while enforcing core structural constraints, in a novel sequence design approach that we term “foldtuning.” We build a library of foldtuned pLMs for >700 natural folds in the SCOP database, covering numerous high-priority targets for synthetic biology, including GPCRs and small GTPases, composable cell-surface-receptor and DNA-binding domains, and small signaling/regulatory domains. Candidate proteins generated by foldtuned pLMs reflect distinctive new “rules of language” for sequence innovation beyond detectable homology to any known protein and sample subtle structural alterations in a manner reminiscent of natural structural evolution and diversification. Experimental validation of two markedly different fold targets; the tyrosine-kinase- and small-GTPase-regulating SH3 domain and the bacterial RNase inhibitor barstar demonstrates that fold-tuning proposes protein variants that express and fold stablyin vitroand functionin vivo. Foldtuning reveals protein sequence-structure information at scale out-side of the context of evolution and promises to push forward the redesign and reconstitution of novel-to-nature synthetic biological systems for applications in health and catalysis.
DrugHIVE: Target-specific spatial drug design and optimization with a hierarchical generative model
Authors: Weller Jesse A. , Rohs Remo
Published: December 2023

Rapid advancement in the computational methods of structure-based drug design has led to their widespread adoption as key tools in the early drug development process. Recently, the remarkable growth of available crystal structure data and libraries of commercially available or readily synthesizable molecules have unlocked previously inaccessible regions of chemical space for drug development. Paired with improvements in virtual ligand screening methods, these expanded libraries are having a significant impact on the success of early drug design efforts. However, screening-based methods are limited in their scalability due to computational limits and the sheer scale of drug-like space. An approach within the quickly evolving field of artificial intelligence (AI), deep generative modeling, is extending the reach of molecular design beyond classical methods by learning the fundamental intra- and inter-molecular relationships in drug-target systems from existing data. In this work we introduce DrugHIVE, a deep hierarchical structure-based generative model that enables fine-grained control over molecular generation. Our model outperforms state of the art autoregressive and diffusion-based methods on common benchmarks and in speed of generation. Here, we demonstrate DrugHIVE’s capacity to accelerate a wide range of common drug design tasks such as de novo generation, molecular optimization, scaffold hopping, linker design, and high throughput pattern replacement. Our method is highly scalable and can be applied to high confidence AlphaFold predicted receptors, extending our ability to generate high quality drug-like molecules to a majority of the unsolved human proteome.
The PROVIDE Study: Primary care assessment of the ROche IPDM tools for Validation and Implementation in Diabetes management and Evaluation
Authors: Roshan Simran , Hunter Elena , Marriott Claire , Carruthers Ross , Poulton Barnaby , Gibson Linda , Cummin Jeremy , Rizvi Fahad , Jaspal Rusi , Wilson Philippe B.
Published: December 2023

Introduction

The adoption of digital tools in diabetes care has transformed the way people with diabetes (PwD) and healthcare professionals (HCPs) manage the condition. Digital tools allow for remote management, improved accuracy in blood glucose readings, and enhanced education for patients. This paper presents the results of a 12-month service evaluation of the Roche Diabetes Care Platform, a diabetes data management platform that was implemented into a primary care network (PCN). The aim of the implementation of the RocheDiabetes Care Platform was to address the current challenges faced by clinicians and PwD in diabetes care, such as reducing complications, improving diabetes education, and the delivery of health care to PwD. Semi-structured interviews were conducted virtually to capture the views of HCPs on their experiences with these digital tools.

Methodology

Interviews were conducted with individuals in a range of roles, intrinsic to the diabetes service management in the Leicester PCN, at each stage of implementation. This included pre-implementation, implementation, and post-implementation phases. The data was analysed using thematic analysis.

Results

The use of the RocheDiabetes Care Platform in the Leicester PCN has advanced HCPs’ management of PwD, demonstrably improving patient outcomes and enhancing interactions. There were two themes identified in the pre-implementation stage, including pre-appointment activities and challenges, and appointment activities and challenges. A further six themes were identified in the post-implementation results, including the optimisation of appointments, time and cost savings, enhanced engagement with PwD, the centralisation of resources, challenges in the PCN’s pathway of care that the RocheDiabetes Care Platform addressed and the future vision of the PCN with the RocheDiabetes Care Platform. Overall, available and accessible data helped to reduce the number of appointments efficiency. Additionally, where PwD were onboarded onto the RocheDiabetes Care Platform, and there was no specific need for the PwD to attend the practice, the number of face-to-face appointments was reduced, improving overall clinic efficiency. Over the period of the evaluation there were no (0) Did Not Attend (DNAs).
PTPRZ1-targeting RNA CAR-T cells exert antigen-specific and bystander antitumor activity in glioblastoma
Authors: Martinez Bedoya Darel , Marinari Eliana , Davanture Suzel , Cantero Castillo Luis , Erraiss Sarah , Dockerill Millicent , Barluenga Badiola Sofia , Winssinger Nicolas , Schaller Karl , Bijlenga Philippe , Momjian Shahan , Hammel Philippe , Cosson Pierre , Walker Paul R. , Dutoit Valérie , Migliorini Denis
Published: December 2023

The great success of chimeric antigen receptor (CAR)-T cell therapy in B-cell malignancies has prompted its translation to solid tumors. In the case of glioblastoma (GBM), clinical trials have shown modest efficacy, but anti-GBM CAR-T cells are being intensely developed. In this study, we selected PTPRZ1 as an attractive new target for GBM treatment. We isolated six anti-human PTPRZ1 scFv from a human phage display library and produced 2ndgeneration CAR-T cells in an RNA format. Patient-derived GBM PTPRZ1-knock-in cell lines were used to select the CAR construct (471_28z), which showed high cytotoxicity while consistently displaying high CAR expression. CAR-T cells incorporating 471_28z were able to release IFN-γ, IL-2, TNF-α, Granzyme B, IL-17A, IL-6, and soluble FasL, and displayed low tonic signaling. Additionally, they maintained an effector memory phenotype afterin vitrokilling. Importantly, 471_28z CAR-T cells displayed strong bystander killing against PTPRZ1-negative cell lines after pre-activation by PTPRZ1-positive tumor cells, but did not kill antigen-negative non-tumor cells. In an orthotopic xenograft tumor model using NSG mice, a single dose of anti-PTPRZ1 CAR-T cells significantly delayed tumor growth. Taken together, these results validate the use of PTPRZ1 as a new GBM target and prompt the use of anti-PTPRZ1 CAR-T cells for clinical translation.
Expanding RNA editing toolkit using an IDR-based strategy
Authors: Di Minghui , Lv Junjun , Jing Zhengyu , Dickinson Bryan , Chi Tian
Published: December 2023

RNA base editors should ideally be free of immunogenicity, compact, efficient and specific, which has not been achieved for C>U editing. Here we first describe a compact C>U editor entirely of human origin, created by fusing the human C>U editing enzyme RESCUE-S to CIRTS, a tiny, human-originated programmable RNA binding domain. This editor, CIRTS-RESCUEv1 (V1), was inefficient. Remarkably, a short Histidine-Rich Domain (HRD), which is derived from the Internal Disordered Region (IDR) in the human CYCT1, a protein capable of liquid-liquid phase separation (LLPS), enhanced V1 editing at on-targets as well as off-targets, the latter effect being minor. The V1-HRD fusion protein formed puncta characteristic of LLPS, and various other IDRs (but not an LLPS-impaired mutant) could replace HRD to effectively induce puncta and potentiate V1, suggesting that the diverse domains acted via a common, LLPS-based mechanism. Importantly, the HRD fusion strategy was applicable to various other types of C>U RNA editors. Our study expands the RNA editing toolbox and showcases a general method for stimulating C>U RNA base editors.
Netrin4 is a new target specific factor, ensuring adult sympathetic neuron survival via promoting protein synthesis
Authors: Zhu Zhu , Zhou Lili , Wang Yuanjiao , Zhang Xiaoxuan , Zhang Dongdong , Li Xuzhao , Zhao Bingrui , Jia Jie-Min
Published: December 2023

How mature neurons survive under homeostasis is a question of utmost importance and is known to be different from developing neurons. However, the understanding of this regard remains largely unknown. Here, based on the relationship between the sympathetic cervical ganglia (SCG) and the arterial networks of projecting and targeting organs, we report that the secretome of cerebral, but not peripheral, arterial smooth muscles (SMC) was required for the survival of sympathetic neurons. Among the secretome, we further identified that netrin-4, encoded by the ntn-4 gene, only entered neurons and not glia and played a crucial role both in vitro and in vivo. This was demonstrated with three independent lines of tamoxifen-inducible SMC-specific conditional knockout mice (cKO). Notably, in cKO mice, the local supply of exogenous netrin-4 confined to SCG selectively rescued neuronal necroptosis, which otherwise consistently occurred in a specific subgroup of SCG neurons that innervate cerebral SMCs. Mechanistically, we demonstrated that cerebral netrin-4 was endocytosed at the neurovascular interface and retrogradely long transported to peripheral soma in SCG, where it differentially regulated mRNA translations. This regulation suppressed vacuolization and neuronal necrosis, both of which took place spontaneously in cKO mice. The former is immediately followed by the latter when we injured axons using two-photon laser ablation. The findings revealed a new principle of neurovascular interactions vital for mature neuron survival, implying that under circumstances of cerebral SMC insufficient secretion, such as natural aging, may initiate mature neuronal loss due to uncontrolled vacuolization.
The expression of congenital Shoc2 variants induces AKT-dependent feedback activation of the ERK1/2 pathway
Authors: Wilson Patricia , Abdelmoti Lina , Gao Tianyan , Galperin Emilia
Published: December 2023

The Shoc2 scaffold protein is crucial in transmitting signals within the Epidermal Growth Factor Receptor (EGFR)-mediated Extracellular signal-regulated Kinase (ERK1/2) pathway. While the significance of Shoc2 in this pathway is well-established, the precise mechanisms through which Shoc2 governs signal transmission remain to be fully elucidated. Hereditary mutations in Shoc2 are responsible for Noonan Syndrome with Loose anagen Hair (NSLH). However, due to the absence of known enzymatic activity in Shoc2, directly assessing how these mutations affect its function is challenging. ERK1/2 phosphorylation is used as a primary parameter of Shoc2 function, but the impact of Shoc2 mutants on the pathway activation is unclear. This study investigates how the NSLH-associated Shoc2 variants influence EGFR signals in the context of the ERK1/2 and AKT downstream signaling pathways. We show that when the ERK1/2 pathway is a primary signaling pathway activated downstream of EGFR, Shoc2 variants cannot upregulate ERK1/2 phosphorylation to the level of the WT Shoc2. Yet, when the AKT and ERK1/2 pathways were activated, in cells expressing Shoc2 variants, ERK1/2 phosphorylation was higher than in cells expressing WT Shoc2. We found that, in cells expressing the Shoc2 NSLH mutants, the AKT signaling pathway triggers the PAK activation, followed by phosphorylation and Raf-1/MEK1/2 /ERK1/2 signaling axis activation. Hence, our studies reveal a previously unrecognized feedback regulation downstream of the EGFR and provide evidence for the Shoc2 role as a “gatekeeper” in controlling the selection of downstream effectors within the EGFR signaling network.
A thalamic hub-and-spoke circuit enables visual perception during action by coordinating visuomotor dynamics
Authors: Vega-Zuniga T. , Sumser A. , Symonova O. , Koppensteiner P. , Schmidt F. H. , Joesch M.
Published: December 2023

Distinguishing between sensory experiences elicited by external stimuli and an animal’s own actions is critical for accurate perception and motor control. However, the diversity of behaviors and their complex influences on the senses make this distinction challenging. Here, we uncover an action cue hub that coordinates both visual processing in the brain’s first visual relay and motor commands. We show that the ventral lateral geniculate nucleus (vLGN) acts as a corollary discharge (CD) center, integrating visual translational optic flow signals and motor copies from saccades, locomotion, and pupil dynamics. The vLGN relays these signals to correct action-specific visual distortions and refine perception, as shown for the superior colliculus and a depth estimation task. Simultaneously, brain-wide vLGN projections drive corrective actions necessary for accurate visuomotor control. Our results reveal an extended CD architecture that refines early visual transformations and coordinates actions via a distributed hub-and-spoke network enabling visual perception during action.
Hiding in Plain Sight: Thymic CD8+FOXP3+Tregs sequester CD25 and are enriched in human tissues
Authors: Jarvis Lorna B. , Howlett Sarah K. , Coppard Valerie , Rainbow Daniel B. , Alkwai Sarah , Ellis Lou , Georgieva Zoya , Suchanek Ondrej , Mousa Hani , Mahbubani Krishnaa , Saeb-Parsy Kourosh , Wicker Linda S. , Jones Joanne L.
Published: December 2023

For decades regulatory T cell (Treg) research has focussed on CD4+FOXP3+ Tregs, whilst characterisation of CD8+FOXP3+ Tregs has been limited by their paucity in blood. Here, by studying 95 tissues from 26 deceased transplant organ donors we demonstrate that despite representing less than 5% of circulating Tregs, fully functional, thymically derived CD8+FOXP3+ Tregs are highly enriched in human tissues particularly in non-lymphoid tissues and bone marrow, where they reside as CD25lo/-CD8+CD69+CD103+TLR9+HELIOS+FOXP3+ Tregs. Despite lacking surface CD25 expression, CD8+ Tregs in tissue are demethylated at the FOXP3 TSDR and express CD25 intracellularly. Surface CD25 expression is quickly regainedin vitro, allowing cell sorting for therapeutic expansion and confirmation of their suppressive function. We suggest that these elusive cells likely play an essential but previously unappreciated role in maintaining peripheral tolerance within human tissues.

One Sentence Summary

FOXP3+CD8+Tregs, expressing tissue residency markers and CD25 intracellularly, are enriched in human non-lymphoid tissues.
The FHA domain is essential for the autoinhibition of KIF1A/UNC-104
Authors: Niwa Shinsuke , Watanabe Taisei , Chiba Kyoko
Published: December 2023

KIF1A/UNC-104, a member of the kinesin super family motor proteins, plays a pivotal role in the axonal transport of synaptic vesicles and their precursors.Drosophila melanogasterUNC-104 (DmUNC-104) is a relatively recently discoveredDrosophilakinesin. Although some point mutations that disrupt synapse formation have been identified, the biochemical properties of DmUNC-104 protein have not been investigated. Here, we prepared recombinant full-length DmUNC-104 protein and determined the biochemical features. We analyzed the effect of a previously identified missense mutation in the FHA domain, calledbristly(bris), and found that wild-type DmUNC-104 is a mixture of monomer and dimer and thebrismutation strongly promote the dimerization. Furthermore, we found that disease-associated mutations also promote the dimerization of DmUNC-104. These findings suggest that the FHA domain is essential for the autoinhibition of KIF1A/UNC-104, and that abnormal dimerization of KIF1A is linked to human diseases.
Sex and age independent predictive call sequence alterations of pups in an autism spectrum disorder mouse model
Authors: Agarwalla Swapna , Yuvarani M S , Bandyopadhyay Sharba
Published: December 2023

Social communication deficit is a hallmark of autism spectrum disorders (ASDs). Mouse ultrasonic-vocalizations (USVs), with communicative significance, are extensively used to probe vocalization-based social communication impairment. However, most studies on ASDs mouse-models show inconsistent alterations in USVs based phenotypes over age and sex. Despite the predictable nature of mouse USVs, very few studies have taken advantage of the same. The current work explores USV pup-isolation-call (PIC) features and alterations in structural content of predictive PIC sequences of the well-establishedin-uterovalproic-acid (VPA) exposure-based ASDs model. Our study shows the importance of higher-order USV structures, with speech-like sequential dependencies that have consistent alterations in the ASDs model at all developmental ages and sex. In addition to confirming prior observations of reduced call rates and durations, as well as heightened peak frequencies in ASD model pups, our data underscores inconsistent trends in the call features across sex and age. The varying nature of call features in ASD models poses a substantial challenge in assessing intervention outcomes. The above inconsistency complicates the differentiation between the effects of aging and therapeutic impacts. Establishing consistent alteration in USVs could help uncover age- and sex-independent changes in ASD models, shedding light on associated therapeutics and developmental mechanisms.

Lay Summary

Social communication deficits are key characteristics of autism spectrum disorders (ASDs). Mouse ultrasonic vocalizations (USVs), used to study communication impairments, show inconsistent changes in ASD mouse models across age and sex. Our study investigates USV pup isolation call (PIC) features and structural content alterations in a well-established ASD model. The presence of inconsistent USV features complicates the differentiation between aging effects and therapeutic impacts. We find consistent changes in higher-order USV structures across all developmental stages and sexes which can facilitate improved intervention outcomes. Establishing consistent USV alterations could reveal age- and sex-independent changes in ASD models, aiding in understanding therapeutic strategies and developmental mechanisms
Metabolite profiling of human renal cell carcinoma reveals tissue-origin dominance in nutrient availability
Authors: Abbott Keene L. , Ali Ahmed , Reinfeld Bradley I. , Deik Amy , Subudhi Sonu , Landis Madelyn D. , Hongo Rachel A. , Young Kirsten L. , Kunchok Tenzin , Nabel Christopher S. , Crowder Kayla D. , Kent Johnathan R. , Madariaga Maria Lucia L. , Jain Rakesh K. , Beckermann Kathryn E. , Lewis Caroline A. , Clish Clary B. , Muir Alexander , Rathmell W. Kimryn , Rathmell Jeffrey C. , Vander Heiden Matthew G.
Published: December 2023

The tumor microenvironment is a determinant of cancer progression and therapeutic efficacy, with nutrient availability playing an important role. Although it is established that the local abundance of specific nutrients defines the metabolic parameters for tumor growth, the factors guiding nutrient availability in tumor compared to normal tissue and blood remain poorly understood. To define these factors in renal cell carcinoma (RCC), we performed quantitative metabolomic and comprehensive lipidomic analyses of tumor interstitial fluid (TIF), adjacent normal kidney interstitial fluid (KIF), and plasma samples collected from patients. TIF nutrient composition closely resembles KIF, suggesting that tissue-specific factors unrelated to the presence of cancer exert a stronger influence on nutrient levels than tumor-driven alterations. Notably, select metabolite changes consistent with known features of RCC metabolism are found in RCC TIF, while glucose levels in TIF are not depleted to levels that are lower than those found in KIF. These findings inform tissue nutrient dynamics in RCC, highlighting a dominant role of non-cancer driven tissue factors in shaping nutrient availability in these tumors.
Disinflation costs and macroprudential policies: real and welfare effects
Authors: Busato Francesco , Ferrara Maria , Varlese Monica
Published: December 2023

Purpose

This paper analyzes real and welfare effects of a permanent change in inflation rate, focusing on macroprudential policy’ role and its interaction with monetary policy.

Design/methodology/approach

While investigating disinflation costs, the authors simulate a medium-scale dynamic general equilibrium model with borrowing constraints, credit frictions and macroprudential authority.

Findings

Providing discussions on different policy scenarios in a context where still it is expected high inflation, there are three key contributions. First, when macroprudential authority actively operates to improve financial stability, losses caused by disinflation are limited. Second, a Taylor rule directly responding to financial variables might entail a trade-off between price and financial stability objectives, by increasing disinflation costs. Third, disinflation is welfare improving for savers, while costly for borrowers and banks. Indeed, while savers benefit from policies reducing price stickiness distortion, borrowers are worried about credit frictions, coming from collateral constraint.

Practical implications

The paper suggests threefold policy implications: the macroprudential authority should actively intervene during a disinflation process to minimize costs and financial instability deriving from it; policymakers should implement a disinflationary policy stabilizing also output; the central bank and the macroprudential regulator should pursue financial and price stability goals, separately.

Originality/value

This paper is the first attempt to study effects of a permanent inflation target reduction in focusing on the macroprudential policy’ role.
Work–life balance and employee commitment in the new normal: evidence from Indian railway using mixed-method approach
Authors: Manna Atanu , Pahari Subhajit , Biswas Debasish , Banerjee Dipa , Das Debasis
Published: December 2023

Purpose

The study principally aims to investigate the relationship among work–life balance (WLB), job satisfaction (JS) and employee commitment (EC) among the railway staff by integrating the social exchange theory (SET). The study also explores JS as a mediator in the context of the new normal.

Design/methodology/approach

A mixed-method sequential explanatory design was utilized for this study. The research instrument was administered to 533 railway employees, using purposive sampling to ensure reliability and validity. Structural equation modeling (SEM) was employed to analyze the quantitative data and measure mediation effects. Additionally, 15 interviews were conducted with employees from three job positioning groups (A, B and C) to gain further insights into commitment-related concerns.

Findings

The study found that WLB and JS positively influenced EC, with JS acting as a mediator between WLB and EC. Furthermore, factors such as fostering friendships among colleagues, effectively managing work–life integration and recognizing the importance of job roles were identified as crucial in enhancing the relationship between WLB and EC.

Originality/value

The study includes SET to examine the social exchange process while considering WLB benefits as a reward from the employer and EC as the outcome of this reward. This study contributes by examining the effects of COVID-19 on the railway industry and EC. The mixed-methods sequential explanatory design gave a comprehensive understanding of the relationships between WLB, JS and EC. The study’s implications highlight the importance of implementing supportive policies, such as flexible work schedules and a supportive organizational culture, to enhance employee commitment and reduce attrition rates. The study emphasizes the significance of prioritizing employee well-being to achieve organizational goals and enhance organizational commitment.
Numerical investigation of thermal fatigue crack growth behavior in SAC305 BGA solder joints
Authors: Apalowo Rilwan Kayode , Abas Mohamad Aizat , Muhamed Mukhtar Muhamed Abdul Fatah , Che Ani Fakhrozi , Ramli Mohamad Riduwan
Published: December 2023

Purpose

This study aims to investigate the reliability issues of microvoid cracks in solder joint packages exposed to thermal cycling fatigue.

Design/methodology/approach

The specimens are subjected to JEDEC preconditioning level 1 (85 °C/85%RH/168 h) with five times reflow at 270°C. This is followed by thermal cycling from 0°C to 100°C, per IPC-7351B standards. The specimens' cross-sections are inspected for crack growth and propagation under backscattered scanning electronic microscopy. The decoupled thermomechanical simulation technique is applied to investigate the thermal fatigue behavior. The impacts of crack length on the stress and fatigue behavior of the package are investigated.

Findings

Cracks are initiated from the ball grid array corner of the solder joint, propagating through the transverse section of the solder ball. The crack growth increases continuously up to 0.25-mm crack length, then slows down afterward. The J-integral and stress intensity factor (SIF) values at the crack tip decrease with increased crack length. Before 0.15-mm crack length, J-integral and SIF reduce slightly with crack length and are comparatively higher, resulting in a rapid increase in crack mouth opening displacement (CMOD). Beyond 0.25-mm crack length, the values significantly decline, that there is not much possibility of crack growth, resulting in a negligible change in CMOD value. This explains the crack growth arrest obtained after 0.25-mm crack length.

Practical implications

This work's contribution is expected to reduce the additional manufacturing cost and lead time incurred in investigating reliability issues in solder joints.

Originality/value

The work investigates crack propagation mechanisms of microvoid cracks in solder joints exposed to moisture and thermal fatigue, which is still limited in the literature. The parametric variation of the crack length on stress and fatigue characteristics of solder joints, which has never been conducted, is also studied.
Letter: antibiotics prescription and new‐onset irritable bowel syndrome
Authors: Chang Hui‐Chin , Gau Shuo‐Yan
Published: December 2023

LINKED CONTENT

This article is linked to Staller et al papers. To view these articles, visit https://doi.org/10.1111/apt.17736 and https://doi.org/10.1111/apt.17827
The Efficiency of Question‐Asking Strategies in a Real‐World Visual Search Task
Authors: Testoni Alberto , Bernardi Raffaella , Ruggeri Azzurra
Published: December 2023

In recent years, a multitude of datasets of human–human conversations has been released for the main purpose of training conversational agents based on data‐hungry artificial neural networks. In this paper, we argue that datasets of this sort represent a useful and underexplored source to validate, complement, and enhance cognitive studies on human behavior and language use. We present a method that leverages the recent development of powerful computational models to obtain the fine‐grained annotation required to apply metrics and techniques from Cognitive Science to large datasets. Previous work in Cognitive Science has investigated the question‐asking strategies of human participants by employing different variants of the so‐called 20‐question‐game setting and proposing several evaluation methods. In our work, we focus on GuessWhat, a task proposed within the Computer Vision and Natural Language Processing communities that is similar in structure to the 20‐question‐game setting. Crucially, the GuessWhat dataset contains tens of thousands of dialogues based on real‐world images, making it a suitable setting to investigate the question‐asking strategies of human players on a large scale and in a natural setting. Our results demonstrate the effectiveness of computational tools to automatically code how the hypothesis space changes throughout the dialogue in complex visual scenes. On the one hand, we confirm findings from previous work on smaller and more controlled settings. On the other hand, our analyses allow us to highlight the presence of “uninformative” questions (in terms of Expected Information Gain) at specific rounds of the dialogue. We hypothesize that these questions fulfill pragmatic constraints that are exploited by human players to solve visual tasks in complex scenes successfully. Our work illustrates a method that brings together efforts and findings from different disciplines to gain a better understanding of human question‐asking strategies on large‐scale datasets, while at the same time posing new questions about the development of conversational systems.
Patient and public involvement in international research: Perspectives of a team of researchers from six countries on collaborating with people with lived experiences of dementia and end‐of‐life
Authors: Vellani Shirin , Yous Marie‐Lee , Rivas Vanessa Maradiaga , Lucchese Stephanie , Kruizinga Julia , Sussman Tamara , Abelson Julia , Akhtar‐Danesh Noori , Bravo Gina , Brazil Kevin , Ganann Rebecca , Kaasalainen Sharon
Published: December 2023

Background

Patient and public involvement (PPI) is a critical priority in research, policy, academia and advocacy organizations. PPI in dementia research is gaining momentum. However, these efforts are missing in international projects aimed at those living with advanced dementia in long‐term care (LTC) homes. Additional complexities can arise in enacting PPI within the context of integration of a palliative approach to care and experiences around end‐of‐life in (EOL) dementia. The mySupport study involved implementing the Family Carer Decision Support (FCDS) intervention for care partners of those living with advanced dementia in LTC in six countries.

Research Design and Objective

An interpretive description study was conducted to explore the perspectives of international researchers from six countries on engaging people with lived experiences of dementia and EOL care in research processes. The findings from this study informed the development of a PPI strategy and a subsequent toolkit for the FCDS intervention.

Findings

Thirty‐eight interviews were completed with project researchers: 12 from the United Kingdom, 8 from Canada, 7 from Ireland, 4 each from Italy and The Netherlands and 3 from the Czech Republic. Four broad themes describe international researchers' perspectives on advancing methods of engagement for people with lived experiences of dementia and EOL in international PPI activities: (1) Groundwork to engage in research; (2) planning for research activities is key; (3) focus on meaningful engagement and (4) having foresight for practical issues shaping PPI.

Discussion and Implications

International projects that involve PPI can present many sources of challenges. The findings in this study highlight important considerations for foundational work for incorporating PPI in international projects. Learning from world leaders and those with lived experiences in various regions can be insightful and help share tools and resources.

Patient or Public Contribution

PPI was envisioned as a critical part of conducting the mySupport study. The findings from this study informed the development of a PPI strategy and an international Strategic Guiding Council that included family carers of those living with advanced dementia in LTC homes in six countries. This manuscript focused on the perspectives of researchers on their engagement with people with lived experiences of dementia and EOL. The perspectives of persons with lived experiences on engaging in the mySupport research study will be reported in a forthcoming manuscript.
Cultural acceptability of STI screening guidelines and sexual positioning assessments among black sexual minority men
Authors: Dangerfield Derek T. , Anderson Janeane N. , Tinnell Theodore
Published: December 2023

Aim

To identify attitudes towards HIV/STI screening guidelines and explore the acceptability of assessing sexual positioning practices among Black sexual minority men (SMM).

Background

Risks for HIV/STIs vary by sexual positioning practices. However, clinicians and Black SMM do not always discuss sexuality with each other. Therefore, HIV/STI screening and testing remain suboptimal.

Design

Qualitative study using focus groups.

Methods

Data were obtained from 12 focus groups and one in‐depth interview conducted in Baltimore, MD among HIV‐negative Black SMM between October 2019 and May 2020 (N = 39). Groups were stratified into three age categories: 18–24, 25–34 and 35+. Participants were given the “5 P's” from the CDC's 2015 Sexual History Screening Guidelines and asked to discuss attitudes towards existing questions regarding sexual positioning practices. Themes were identified using an electronic pile sorting approach.

Results

Most identified as homosexual/gay/same gender‐loving (68%), were employed (69%) and single (66%). Additionally, 34% had ever been diagnosed with an STI, of whom 38% had a history of repeated STI acquisition in their lifetime. Participants across age groups said clinicians should use the words “top” and “bottom” to demonstrate cultural familiarity and build trust. Some said that screening for sexual positioning was unnecessary and intrusive; others said that questions should be justified. Younger men wanted clinicians to ask questions in ways that make them feel cared for.

Discussion

Guidelines should include language for clinicians to use culturally specific language and better ways to prepare Black SMM patients for screening.

Impact to Nursing Practice

Some Black SMM will not discuss sexual positioning practices without clinicians' demonstration of cultural understanding and respect. Screening should incorporate culturally responsive language, justification and convey care.

Reporting Method

Consolidated criteria for reporting qualitative research (COREQ).

No Patient or Public Contribution

There was no patient or public involvement in the design or drafting of this discursive paper.
Explicit improvements for Lp$\mathrm{L}^p$‐estimates related to elliptic systems
Authors: Böhnlein Tim , Egert Moritz
Published: December 2023

We give a simple argument to obtain ‐boundedness for heat semigroups associated to uniformly strongly elliptic systems on by using Stein interpolation between Gaussian estimates and hypercontractivity. Our results give explicitly in terms of ellipticity. It is optimal at the endpoint . We also obtain ‐estimates for the gradient of the semigroup, where depends on ellipticity but not on dimension.
Congenital segmental dilatation of the intestine in a neonate
Authors: Nebashi Hikari , Inoue Momoko , Ashizuka Syuuichi , Samura Osamu
Published: December 2023

A woman in her 30s at 29 weeks of gestation was diagnosed with a fetal abdominal cyst and polyhydramnios. As the cyst gradually increased in size, an elective caesarean section was performed at 38 weeks of gestation. The neonate experienced respiratory distress due to tense abdominal distension shortly after birth. An emergency laparotomy was performed. The intestinal tract was markedly dilated and contiguous with the cyst. The small bowel distal to the dilated intestine had herniated through the defect. The dilated segment was resected, and an ileostomy was created. The operative and histopathological findings suggested segmental dilatation of the intestine (SDI). SDI is a rare gastrointestinal disorder presenting during the neonatal period. It can cause respiratory failure in newborns by compression owing to its large size. SDI should be considered in the differential diagnosis of relatively large abdominal cysts, and collaboration with paediatric surgeons and neonatologists is necessary for successful outcomes.
Country adoption of WHO 2019 guidance on HIV testing strategies and algorithms: a policy review across the WHO African region
Authors: Fajardo Emmanuel , Lastrucci Céline , Bah Nayé , Mingiedi Casimir Manzengo , Ba Ndoungou Salla , Mosha Fausta , Lule Frank John , Paul Margaret Alia Samson , Hughes Lago , Barr-DiChiara Magdalena , Jamil Muhammad S , Sands Anita , Baggaley Rachel , Johnson Cheryl
Published: December 2023

Objectives

In 2019, the WHO released guidelines on HIV testing service (HTS). We aim to assess the adoption of six of these recommendations on HIV testing strategies among African countries.

Design

Policy review.

Setting

47 countries within the WHO African region.

Participants

National HTS policies from the WHO African region as of December 2021.

Primary and secondary outcome measures: Uptake of WHO recommendations across national HTS policies including the standard three-test strategy; discontinuation of a tiebreaker test to rule in HIV infection; discontinuation of western blotting (WB) for HIV diagnosis; retesting prior to antiretroviral treatment (ART) initiation and the use of dual HIV/syphilis rapid diagnostic tests (RDTs) in antenatal care. Country policy adoption was assessed on a continuum, based on varying levels of complete adoption.

Results

National policies were reviewed for 96% (n=45/47) of countries in the WHO African region, 38% (n=18) were published before 2019 and 60% (n=28) adopted WHO guidance. Among countries that had not fully adopted WHO guidance, not yet adopting a three-test strategy was the most common reason for misalignment (45%, 21/47); of which 31% and 22% were in low-prevalence (<5%) and high-prevalence (≥5%) countries, respectively. Ten policies (21%) recommended the use of WB and 49% (n=23) recommended retesting before ART initiation. Dual HIV/syphilis RDTs were recommended in 45% (n=21/47) of policies.

Conclusions

Many countries in the African region have adopted WHO-recommended HIV testing strategies; however, efforts are still needed to fully adopt WHO guidance. Countries should accelerate their efforts to adopt and implement a three-test strategy, retesting prior to ART initiation and the use of dual HIV/syphilis RDTs.