bluuebunny/crossref_metadata_2025 huggingface dataset:
Tensions in Knowledge Accumulation Using Coordinated Intervention Experiments to Improve Public Policy
Authors: Bowers Jake , Greenberg Natasha , Holmes Morgan , Posner Daniel N.
Published: June 2024

This chapter has two main goals. It introduces and explains the value of coordinated randomized experiments for informing public policymaking with a special focus on international development, and then articulates tensions inherent in these coordinated experiments. It explains why coordination can help build the evidence base for policy innovation by helping funders and policymakers test existing theories of change in ways that facilitate the cumulation of knowledge across studies. It then articulates tensions or trade-offs that reasonable decision-makers might face given choices between coordinated and uncoordinated experiments, and provides some rough guides to help decision-makers navigate those tensions. We write from the perspective of encouraging coordinated experiments and offer practical alternatives that might be easier to implement than extant models for policy-oriented decision-makers.
SANT proteins modulate gene expression by coordinating histone H3KAc and Khib levels and regulate plant heat tolerance
Authors: Zhou Xishi , Fan Yujin , Zhu Xiying , Zhao Ruihua , He Junna , Li Pengfeng , Shang Shengping , Goodrich Justin , Zhu Jian-Kang , Zhang Cui-Jun
Published: June 2024

Histone post-translational modifications (PTMs), such as acetylation and recently identified lysine 2-hydroxyisobutyrylation (Khib), act as active epigenomic marks in plants. SANT domain-containing proteins SANT1, SANT2, SANT3, and SANT4 (SANT1/2/3/4), derived from PIF/Harbinger transposases, form a complex with HISTONE DEACETYLASE 6 (HDA6) to regulate gene expression via histone deacetylation. However, whether SANT1/2/3/4 coordinates different types of PTMs to regulate transcription and mediate responses to specific stresses in plants remains unclear. Here, in addition to modulating histone deacetylation, we found that SANT1/2/3/4 proteins acted like HDA6 or HDA9 in regulating the removal of histone Khib in Arabidopsis (Arabidopsis thaliana). Histone H3 lysine acetylation (H3KAc) and histone Khib were coordinated by SANT1/2/3/4 to regulate gene expression, with H3KAc playing a predominant role and Khib acting complementarily to H3KAc. SANT1/2/3/4 mutation significantly increased the expression of heat-inducible genes with concurrent change of H3KAc levels under normal and heat stress conditions, resulting in enhanced thermotolerance. This study revealed the critical roles of Harbinger transposon-derived SANT domain-containing proteins in transcriptional regulation by coordinating different types of histone PTMs and in the regulation of plant thermotolerance by mediating histone acetylation modification.
Trophoblast-specific overexpression of the LAT1 increases transplacental transport of essential amino acids and fetal growth in mice
Authors: Rosario Fredrick J , Barentsen Kenneth , Powell Theresa L , Urschitz Johann , Brown Thomas L , Kanai Yoshikatsu , Jansson Thomas
Published: June 2024

Placental System L amino acid transporter activity is decreased in pregnancies complicated by intrauterine growth restriction (IUGR) and increased in fetal overgrowth. However, it is unknown if changes in the expression/activity of placental Large Neutral Amino Acid Transporter Small Subunit 1 (Slc7a5/LAT1) are mechanistically linked to placental function and fetal growth. We hypothesized that trophoblast-specific Slc7a5 overexpression increases placental transport of essential amino acids, activates the placental mechanistic target of rapamycin (mTOR) signaling, and promotes fetal growth in mice. Using lentiviral transduction of blastocysts with a Slc7a5 transgene, we achieved trophoblast-specific overexpression of Slc7a5 (Slc7a5 OX) with increased fetal (+27%) and placental weights (+10%). Trophoblast-specific Slc7a5 overexpression increased trophoblast plasma membrane (TPM) LAT1 protein abundance and TPM System L transporter (+53%) and System A transporter activity (+ 21%). Slc7a5 overexpression also increased transplacental transport of leucine (+ 85%) but not of the System A tracer, 14C-methylamino isobutyric acid, in vivo. Trophoblast-specific overexpression of Slc7a5 activated placental mTORC1, as assessed by increased (+44%) phosphorylation of S6 ribosomal protein (Ser 235/236), and mTORC2 as indicated by phosphorylation of PKCα-Tyr-657 (+47%) and Akt-Ser 473 (+96%). This is the first demonstration that placental transport of essential amino acids is mechanistically linked to fetal growth. The decreased placental System L activity in human IUGR and the increased placental activity of this transporter in some cases of fetal overgrowth may directly contribute to the development of these pregnancy complications.
Comparison of anti-IL-6 receptor and JAK inhibitors in patients with rheumatoid arthritis from the real-world practice FIRST registry
Authors: Miyazaki Yusuke , Nakayamada Shingo , Tanaka Hiroaki , Hanami Kentaro , Fukuyo Shunsuke , Kubo Satoshi , Miyagawa Ippei , Yamaguchi Ayako , Todoroki Yasuyuki , Inoue Yoshino , Ueno Masanobu , Tanaka Yoshiya
Published: June 2024

Objectives

A molecular-targeted drug that is suitable as the second choice for patients with rheumatoid arthritis (RA) who show an inadequate response to the first biological disease-modifying antirheumatic drug (bDMARD) is unknown. This study aimed to analyse the efficacy and safety of interleukin-6 receptor (IL-6Ri) and Janus kinase inhibitors (JAKis), often selected as molecular-targeted drugs for second or subsequent treatments.

Methods

The efficacy and safety of JAKis and IL-6Ri were compared using propensity score-based inverse probability of treatment weighting (PS-IPTW) using propensity scores after 26 weeks of therapy in patients with RA.

Results

The remission rate at week 26, determined by the clinical disease activity index (CDAI), and the incidence of infection were higher in the JAKis than in the IL-6Ri group. The CDAI trajectories were divided into four according to the growth mixture modeling. IL-6Ri demonstrated greater efficacy in RA patients with ineffective to single bDMARD therapy compared with those with multiple ineffective bDMARDs. In patients who failed to respond to one bDMARD, there was no significant difference in the CDAI remission rate at week 26 between the JAKis (29.1%) and IL-6Ri (21.8%) groups (P = 0.21). However, for patients who did not respond to at least two bDMARDs, the CDAI remission rate at week 26 was higher in the JAKis than in the IL-6Ri group.

Conclusions

IL-6Ri offers a superior balance of efficacy and safety compared with JAKis for RA patients unresponsive to one bDMARD. However, JAKis may suit patients who do not respond to multiple bDMARDs.
Do increases in work uncertainty help older workers maintain higher levels of occupational future time perspective?
Authors: Rudolph Cort W , Zacher Hannes
Published: June 2024

In this study, we consider how changes in work uncertainty (i.e., systematic, linear trajectories that reflect over-time changes in resource, task, and input/output uncertainty) moderate the generally negative relation between employee age and occupational future time perspective (OFTP) (i.e., employeesâ€™ perceptions of their remaining time, opportunities, and limitations at work). Based on the theoretical model of uncertainty regulation and propositions from socioemotional selectivity theory, we argue that increases (vs. decreases) in work uncertainty present the potential for new opportunities, particularly among older (vs. younger) workers, who can draw on their age-related strengths for dealing with uncertainty. Specifically, we argue that increases in work uncertainty allow older workers to make use of their accumulated knowledge and experience, which, in turn, helps them to maintain higher levels of OFTP. We consider longitudinal data collected among a sample of nâ€…=â€…720 employees in Germany. Considering substantive variables, variously measured across 18 months, we find evidence in partial support of the general proposition that increases in work uncertainty across three months (i.e., June through September of 2022) buffer the relation between age and OFTP collected at four subsequent timepoints (November of 2022, and June, November, and December of 2023). We discuss the implications of these findings for the future development of the model of uncertainty regulation.
Optimize and Thrive
Authors: Hathaway Sarah , Earle Melinda
Published: June 2024

Although electronic health record optimization programs are common in healthcare organizations, a dearth of published evaluations of these programs exists. Little is known about the ability of optimization programs to handle flooding requests for change and achieve their objectives of cost savings, value, quality of care, and efficiency. This program evaluation reviewed one organization's electronic health record clinical optimization program. The evaluation examines the implementation of the insulin dosing calculator project at five hospitals within a large nonprofit healthcare organization using interviews, project documents, reported insulin dosing errors, and workflow observation to determine if the program provides sufficient structure and processes to successfully implement large optimization projects and achieve the project's desired outcomes. This evaluation finds that the optimization program processes support the implementation of large projects. The program can improve the planning of human resources to increase productivity and reduce waste. A clearer definition of meaningful project outcomes at the onset would allow the program to measure and communicate its accomplishments across the organization.
Risk Assessment for Nuclear Terrorism Probability and Its Application on a Hypothetical Nuclear Facility
Authors: Kot Joeun L. , Harris Jason T.
Published: June 2024

Radiation protection contains the key elements of nuclear safety and security. Despite the overlap between nuclear safety and security, their objectives differ fundamentally, focusing on unintentional accidents and intentional malicious events, respectively. As such, the Potential Facility Risk Index (PFRI), originally created for security purposes, has evolved into an approach that combines conventional probabilistic risk assessment (PRA), which is a widely employed method to evaluate the safety risks of nuclear facilities. This research has developed a risk assessment model within the PFRI framework to calculate the probability of nuclear terrorism. Three essential components of the model are integrated: an analysis of historical nuclear terrorism data to determine an initial threat frequency; the target-specific factor using analytical hierarchy process (AHP) target attractiveness analysis; and the adversary motivation factor based on site-specific social influences from the Profiles of Individual Radicalization in the United States (PIRUS) dataset. Applied to a hypothetical nuclear facility, the model produces a nuclear terrorism probability of 8.97 × 10−3 y − 1. The systematic methodology proposed in the study enables the derivation of nuclear terrorism probability with results in the same risk unit as safety risk assessment. This method allows decision makers to seamlessly incorporate nuclear safety and security risk assessments, offering a comprehensive perspective. Consequently, it enriches comprehension of nuclear facility risks and establishes the groundwork for future advancements.
A randomised controlled trial of the effect of intra-articular lidocaine on pain scores in inflammatory arthritis
Authors: Rutter-Locher Zoe , Norton Sam , Denk Franziska , McMahon Stephen , Taams Leonie S. , Kirkham Bruce W. , Bannister Kirsty
Published: June 2024

Chronic pain in inflammatory arthritis (IA) reflects a complex interplay between active disease in a peripheral joint and central pronociceptive mechanisms. Because intra-articular lidocaine may be used to abolish joint-specific peripheral input to the central nervous system, we aimed to validate its use as a clinical tool to identify those patients with IA whose pain likely incorporates centrally mediated mechanisms. We began by investigating whether there was a placebo response of intra-articular injection in patients with IA 1:1 randomised to receive intra-articular lidocaine or control (0.9% saline). After, in a larger patient cohort not randomized to placebo vs lidocaine groups, we tested whether patients with IA could be stratified into 2 cohorts based on their response to intra-articular lidocaine according to markers of centrally mediated pain. To this end, we evaluated postlidocaine pain numerical rating scale (NRS) scores alongside baseline painDETECT, fibromyalgia criteria fulfillment, and quantitative sensory testing outcomes. Numerical rating scale scores were collected at baseline and 3-, 5-, and 10-minutes postinjection. Firstly, the placebo effect of intra-articular injection was low: compared to baseline, the mean pain NRS score 5-minutes postinjection was reduced by 3.5 points in the lidocaine group vs 1.2 points in the control group. Secondly, postlidocaine NRS scores were significantly higher in those with a high (>18) baseline painDETECT score, fibromyalgia, and low-pressure pain threshold at the trapezius (P = 0.002, P = 0.001, P = 0.005, respectively). Persistent high pain after intra-articular lidocaine injection could be used as an indicator of pronociceptive mechanisms that are centrally mediated, informing centrally targeted analgesic strategies.
Brugada syndrome following febrile episode caused by malarial infection: a case report
Authors: Aryal Egesh , Mainali Agya , Aryal Saurav
Published: June 2024

Background:

Brugada syndrome (BrS) is a rare genetic disorder with specific electrocardiographic (ECG) patterns carrying an increased risk of sudden cardiac death.

Case presentation:

The authors present a 36-year-old gentleman who had a travel history to the Central African Republic and came to the hospital with a fever and chest pain. The lab investigation revealed Falciparum Malaria infection and the ECG pattern revealed the type 1 Brugada pattern, which was normalized with anti-malarial medication and symptomatic treatment of fever.

Discussion:

BrS is a disorder with high prevalence in males and people of the Asian continent. Patients can present with symptoms like syncope, seizure, and nocturnal agonal respiration or may be asymptomatic. The ECG pattern of BrS could be seen in the febrile phase and normalized when non-febrile, like in our patient. Prompt treatment of fever and follow-up with cardiologists would be an effective treatment of asymptomatic patients, whereas ICD is a management of choice for symptomatic patients.

Conclusion:

For a patient with chest pain, fever, and an ECG pattern of ST elevation, a clinician should think BrS one of the differential diagnoses.
Reimagining the role of community health workers in SAARC countries
Authors: Riaz Mehr Muhammad Adeel , Jindal Rahul M.
Published: June 2024

Following the Alma Ata declaration, SAARC countries have established their workforce of community health workers (CHWs) to address primary healthcare needs. Initially focused on maternal and child health, the countries now confront a changing healthcare landscape characterized by noncommunicable diseases (NCDs), mental health issues, and surgical conditions. These developments have led to the emergence of specialized CHWs tasked with managing NCDs and mental health concerns, prompting a reevaluation of the balance between specialization and maintaining a generalist approach. The effectiveness of CHWs during crises hinges on critical factors such as standardized training, opportunities for career advancement, and equitable compensation. This viewpoint makes a call to introduce a specialist category of CHW to align with evolving healthcare requirements in SAARC countries.
Exploring Research on Competitive Para-cyclists and Its Related Factors
Authors: Villa del Bosque Gerardo , González-Devesa Daniel , Villa-Vicente José Gerardo , García-Fresneda Adrián , Suárez-Iglesias David , Ayán-Pérez Carlos
Published: June 2024

This scoping review aimed to explore the characteristics and performance factors of competitive para-cyclists. A systematic search for studies on competitive para-cycling on WOS, PubMed, SPORTDiscus, and Scopus was performed until December 2023. The following five methodological phases were followed: (i) identifying the research question, (ii) identifying relevant studies, (iii) study selection, (iv) charting the data, and (v) collating, summarizing, and reporting the results. A systematic search across multiple databases was performed until March 2024. Five methodological phases were employed: identifying the research question, relevant studies, study selection, charting data, and summarizing results. A total of 36 relevant studies were selected. Three main research themes emerged: sport performance (n = 15), biomechanics (n = 12), and physical and mental health (n = 9). Despite progress, gaps were identified, particularly in physiological response to exercise, fitness, and training. Biomechanics studies focused on prosthetic use and aerodynamics, mostly involving lower-limb amputees and simulated tandem competition. Injury risk in para-cycling appeared comparable to able-bodied cycling, but comprehensive studies considering confounding variables are needed. Overall, while research on para-cycling is growing, more studies with larger and diverse samples across all sport classes are essential to advance scientific understanding in this field.
Indication for spinal sensitization in chronic low back pain: mechanical hyperalgesia adjacent to but not within the most painful body area
Authors: Sirucek Laura , De Schoenmacker Iara , Scheuren Paulina Simonne , Lütolf Robin , Gorrell Lindsay Mary , Langenfeld Anke , Baechler Mirjam , Rosner Jan , Wirth Brigitte , Hubli Michèle , Schweinhardt Petra
Published: June 2024

Introduction:

In 85% of patients with chronic low back pain (CLBP), no specific pathoanatomical cause can be identified. Besides primary peripheral drivers within the lower back, spinal or supraspinal sensitization processes might contribute to the patients' pain.

Objectives:

The present study conceptualized the most painful area (MP) of patients with nonspecific CLBP as primarily affected area and assessed signs of peripheral, spinal, and supraspinal sensitization using quantitative sensory testing (QST) in MP, a pain-free area adjacent to MP (AD), and a remote, pain-free control area (CON).

Methods:

Fifty-nine patients with CLBP (51 years, SD = 16.6, 22 female patients) and 35 pain-free control participants individually matched for age, sex, and testing areas (49 years, SD = 17.5, 19 female participants) underwent a full QST protocol in MP and a reduced QST protocol assessing sensory gain in AD and CON. Quantitative sensory testing measures, except paradoxical heat sensations and dynamic mechanical allodynia (DMA), were Z-transformed to the matched control participants and tested for significance using Z-tests (α = 0.001). Paradoxical heat sensations and DMA occurrence were compared between cohorts using Fisher's exact tests (α = 0.05). The same analyses were performed with a high-pain and a low-pain CLBP subsample (50% quantile).

Results:

Patients showed cold and vibration hypoesthesia in MP (all Ps < 0.001) and mechanical hyperalgesia (P < 0.001) and more frequent DMA (P = 0.044) in AD. The results were mainly driven by the high-pain CLBP subsample. In CON, no sensory alterations were observed.

Conclusion:

Mechanical hyperalgesia and DMA adjacent to but not within MP, the supposedly primarily affected area, might reflect secondary hyperalgesia originating from spinal sensitization in patients with CLBP.
Brief Report: Low-Dose Methotrexate Does Not Affect Measures of HIV-1 Persistence in Individuals With Chronically Treated HIV-1 Infection
Authors: Cyktor Joshua C. , Yeh Eunice , Ribaudo Heather , Hoeth Dianna , Naqvi Asma , Bell Tanvir , Ridker Paul M. , Fichtenbaum Carl , Daar Eric S. , Havlir Diane , Tawakol Ahmed , Lederman Michael M. , Stein James H. , Deeks Steven G. , Currier Judith S. , Hsue Priscilla Y. , Mellors John W. ,   for the A5314 Team
Published: June 2024

Background:

People with HIV-1 often have chronic inflammation leading to severe non-AIDS morbidity and mortality. The AIDS Clinical Trials Group Study A5314 sought to lower inflammation with low-dose methotrexate (LDMTX). The primary study outcomes were reported previously but here we present the impact of LDMTX on multiple measures of HIV-1 persistence.

Methods:

A5314 was a phase 2 randomized, double-blind, multicenter trial in 176 adult people with HIV-1 on virally suppressive antiretroviral therapy. LDMTX (5–15 mg/wk) was administered for 24 weeks with an additional 12 weeks of participant follow-up. The current analyses of HIV-1 persistence were restricted to 60 participants (30 LDMTX and 30 placebo) randomly selected from the total population. Plasma HIV-1 RNA, total HIV-1 DNA, and cell-associated HIV-1 RNA (CA HIV-1 RNA) were measured by sensitive quantitative PCR assays.

Results:

LDMTX treatment had no significant effect on sensitive measures of plasma HIV-1 RNA, HIV-1 DNA, CA HIV-1 RNA, or CA HIV-1 RNA/DNA ratio at any time point or from baseline to week 24. As observed in the main study, absolute peripheral CD4+ and CD8+ T-cell numbers decreased from baseline to week 24 among the 30 participants receiving LDMTX compared with placebo (median decrease of −31.5 CD4+ T cells/µL, −83.5 CD8+ T cells/µL).

Conclusions:

LDMTX had no significant effect on any measure of HIV-1 persistence in plasma or peripheral blood mononuclear cells. Further studies are needed to determine whether other immunosuppressive and/or immunoreductive interventions are safe and capable of affecting HIV-1 persistence.
Right Ex-situ split grafts for adult liver transplantation - A Multicenter Benchmarking Analysis
Authors: Boulanger Natacha , Muller Xavier , Dondero Federica , Golse Nicolas , Goumard Claire , Breton Antoine , Sepulveda Ailton , Allard Marc-Antoine , Savier Eric , Dokmak Safi , Pittau Gabriella , Ciacio Oriana , Salloum Chady , Perdigão Fabiano , Rousseau Géraldine , Lim Chetana , Rossignol Guillaume , Vibert Eric , Sa Cunha Antonio , Mohkam Kayvan , Azoulay Daniel , Adam René , Scatton Olivier , Lesurtel Mickael , Cherqui Daniel , Soubrane Olivier , Mabrut Jean Yves
Published: June 2024

Objective:

To analyse outcomes after adult right ex-situ split graft liver transplantations (RSLT) and compare with available outcome benchmarks from whole liver transplantation (WLT).

Summary Background Data:

Ex-situ SLT may be a valuable strategy to tackle the increasing graft shortage. Recently established outcome benchmarks in WLT offer a novel reference to perform a comprehensive analysis of results after ex-situ RSLT.

Methods:

This retrospective multicenter cohort study analyzes all consecutive adult SLT performed using right ex-situ split grafts from 01.01.2014 to 01.06.2022. Study endpoints included 1 year graft and recipient survival, overall morbidity expressed by the comprehensive complication index (CCI©) and specific post-LT complications. Results were compared to the published benchmark outcomes in low-risk adult WLT scenarii.

Results:

In 224 adult right ex-situ SLT, 1y recipient and graft survival rates were 96% and 91.5%, within the WLT benchmarks. The 1y overall morbidity was also within the WLT benchmark (41.8 CCI points vs. <42.1). Detailed analysis, revealed cut surface bile leaks (17%, 65.8% Grade IIIa) as a specific complication without a negative impact on graft survival. There was a higher rate of early hepatic artery thrombosis (HAT) after SLT, above the WLT benchmark (4.9% vs. ≤4.1%), with a significant impact on early graft but not patient survival.

Conclusion:

In this multicentric study of right ex-situ split graft LT, we report 1-year overall morbidity and mortality rates within the published benchmarks for low-risk WLT. Cut surface bile leaks and early HAT are specific complications of SLT and should be acknowledged when expanding the use of ex-situ SLT.
Tumor-intrinsic and Cancer-associated Fibroblast Subtypes Independently Predict Outcomes in Pancreatic Cancer
Authors: Lee Jaewon J. , Kearney Joseph F. , Trembath Hannah E. , Hariharan Arthi , LaBella Michelle E. , Kharitonova Elena V. , Chan Priscilla S. , Morrison Ashley B. , Cliff Ashley , Meyers Michael O. , Kim Hong Jin , Rashid Naim U. , Peng Xianlu L. , Yeh Jen Jen
Published: June 2024

Objective:

To assess the utility of tumor-intrinsic and cancer-associated fibroblast (CAF) subtypes of pancreatic ductal adenocarcinoma (PDAC) in predicting response to neoadjuvant therapy (NAT) and overall survival (OS).

Background:

PDAC remains a deadly disease with limited treatment options, and both the tumor as well as the microenvironment play an important role in pathogenesis. Gene expression–based tumor-intrinsic subtypes (classical and basal-like) have been shown to predict outcomes, but tumor microenvironment subtypes are still evolving.

Methods:

RNA-sequencing was performed on 114 deidentified resected PDAC tumors. Clinical data were collected by retrospective chart review. Single sample classifiers were used to determine classical and basal-like subtypes as well as tumor-permissive permCAF and tumor-restraining restCAF subtypes. Survival was analyzed using the log-rank test.

Results:

Patients who received NAT had an increase in OS, with a median survival of 27.9 months compared with 20.1 months for those who did not receive NAT, but the difference did not reach statistical significance (hazard ratio: 0.64, P=0.076). Either tumor-intrinsic or CAF subtypes alone were associated with OS regardless of NAT or no NAT, and patients with classical or restCAF subtypes had the best outcomes. When evaluated together, patients with the classical-restCAF subtype had the best OS and basal-permCAF the worst OS (P<0.0001). Patients undergoing NAT with the classical-restCAF subtype demonstrated the longest OS compared with the other groups (P=0.00041).

Conclusions:

CAF subtypes have an additive effect over tumor-intrinsic subtypes in predicting survival with or without neoadjuvant FOLFIRINOX in PDAC. Molecular subtyping of both tumor and CAF compartments of PDAC may be important steps in selecting first-line systemic therapy.
Banff 2022 Kidney Commentary: Reflections and Future Directions
Authors: Rabant Marion , Adam Benjamin A. , Aubert Olivier , Böhmig Georg A. , Clahsen Van-Groningen Marian , Cornell Lynn D. , de Vries Aiko P.J. , Huang Edmund , Kozakowski Nicolas , Perkowska-Ptasinska Agnieszka , Riella Leonardo V. , Rosales Ivy A. , Schinstock Carrie , Simmonds Naomi , Thaunat Olivier , Willicombe Michelle
Published: June 2024

In September 2022, in Banff, Alberta, Canada, the XVIth Banff meeting, corresponding to the 30th anniversary of the Banff classification, was held, leading to 2 recent publications. Discussions at the Banff meeting focused on proposing improvements to the Banff process as a whole. In line with this, a unique opportunity was offered to a selected group of 16 representatives from the pathology and transplant nephrology community, experts in the field of kidney transplantation, to review these 2 Banff manuscripts. The aim was to provide an insightful commentary, to gauge any prospective influence the proposed changes may have, and to identify any potential areas for future enhancement within the Banff classification. The group expressed its satisfaction with the incorporation of 2 new entities, namely “microvascular inflammation/injury donor-specific antibodies–negative and C4d negative” and “probable antibody-mediated rejection,” into category 2. These changes expand the classification, facilitating the capture of more biopsies and providing an opportunity to explore the clinical implications of these lesions further. However, we found that the Banff classification remains complex, potentially hindering its widespread utilization, even if a degree of complexity may be unavoidable given the intricate pathophysiology of kidney allograft pathology. Addressing the histomorphologic diagnosis of chronic active T cell–mediated rejection (CA TCMR), potentially reconsidering a diagnostic-agnostic approach, as for category 2, to inflammation in interstitial fibrosis and tubular atrophy and chronic active T cell–mediated rejection was also an important objective. Furthermore, we felt a need for more evidence before molecular diagnostics could be routinely integrated and emphasized the need for clinical and histologic context determination and the substantiation of its clinical impact through rigorous clinical trials. Finally, our discussions stressed the ongoing necessity for multidisciplinary decision-making regarding patient care.
Efficient carbon recycling between calcification and photosynthesis in red coralline algae
Authors: Mao J. , Burdett H. L. , Kamenos N. A.
Published: June 2024

Red coralline algae create abundant, spatially vast, reef ecosystems throughout our coastal oceans with significant ecosystem service provision, but our understanding of their basic physiology is lacking. In particular, the balance and linkages between carbon-producing and carbon-sequestering processes remain poorly constrained, with significant implications for understanding their role in carbon sequestration and storage. Using dual radioisotope tracing, we provide evidence for coupling between photosynthesis (which requires CO
2
) and calcification (which releases CO
2
) in the red coralline alga
Boreolithothamnion soriferum
(previously
Lithothamnion soriferum
)—a marine ecosystem engineer widely distributed across Atlantic mid-high latitudes. Of the sequestered HCO
3
−
, 38 ± 22% was deposited as carbonate skeleton while 39 ± 14% was incorporated into organic matter via photosynthesis. Only 38 ± 2% of the sequestered HCO
3
−
was transformed into CO
2
, and almost 40% of that was internally recycled as photosynthetic substrate, reducing the net release of carbon to 23 ± 3% of the total uptake. The calcification rate was strongly dependent on photosynthetic substrate production, supporting the presence of photosynthetically enhanced calcification. The efficient carbon-recycling physiology reported here suggests that calcifying algae may not contribute as much to marine CO
2
release as is currently assumed, supporting a reassessment of their role in blue carbon accounting.
Test of the negative feedback hypothesis of colony size sensing in social insects
Authors: Kikuchi T. , Hayashi Y. , Fujito Y. , Fujiwara-Tsujii N. , Kawabata S. , Sugawara K. , Yamaoka R. , Tsuji Kazuki
Published: June 2024

Social insects can sense colony size—even without visual information in a dark environment. How they achieve this is yet largely unknown. We empirically tested a hypothesis on the proximate mechanism using ant colonies. In
Diacamma
colonies, the monogynous queen is known to increase the effort devoted to queen pheromone transmission behaviour (patrolling) as the colony grows, as if she perceives colony size. The negative feedback hypothesis assumes that, through repeated physical contact with workers, the queen monitors the physiological state (fertility) of workers and increases her patrolling effort when she encounters more fertile workers. Supporting this hypothesis, we found that the queen increased her patrolling effort in response to a higher ratio of fertile workers under the experimental condition of constant colony size. Furthermore, chemical analyses and bioassays suggested that cuticular hydrocarbons have queen pheromone activity and can mediate the observed queen–worker communication of fertility state. Such a self-organizing mechanism of sensing colony size may also operate in other social insects living in small colonies.
A pan-respiratory antiviral chemotype targeting a transient host multi-protein complex
Authors: Michon Maya , Müller-Schiffmann Andreas , Lingappa Anuradha F. , Yu Shao Feng , Du Li , Deiter Fred , Broce Sean , Mallesh Suguna , Crabtree Jackelyn , Lingappa Usha F. , Macieik Amanda , Müller Lisa , Ostermann Philipp Niklas , Andrée Marcel , Adams Ortwin , Schaal Heiner , Hogan Robert J. , Tripp Ralph A. , Appaiah Umesh , Anand Sanjeev K. , Campi Thomas W. , Ford Michael J. , Reed Jonathan C. , Lin Jim , Akintunde Olayemi , Copeland Kiel , Nichols Christine , Petrouski Emma , Moreira Ana R. , Jiang I-ting , DeYarman Nicholas , Brown Ian , Lau Sharon , Segal Ilana , Goldsmith Danielle , Hong Shi , Asundi Vinod , Briggs Erica M. , Phyo Ngwe Sin , Froehlich Markus , Onisko Bruce , Matlack Kent , Dey Debendranath , Lingappa Jaisri R. , Prasad Dharma M. , Kitaygorodskyy Anatoliy , Solas Dennis , Boushey Homer , Greenland John , Pillai Satish , Lo Michael K. , Montgomery Joel M. , Spiropoulou Christina F. , Korth Carsten , Selvarajah Suganya , Paulvannan Kumar , Lingappa Vishwanath R.
Published: June 2024

We present a novel small molecule antiviral chemotype that was identified by an unconventional cell-free protein synthesis and assembly-based phenotypic screen for modulation of viral capsid assembly. Activity of PAV-431, a representative compound from the series, has been validated against infectious viruses in multiple cell culture models for all six families of viruses causing most respiratory diseases in humans. In animals, this chemotype has been demonstrated efficacious for porcine epidemic diarrhoea virus (a coronavirus) and respiratory syncytial virus (a paramyxovirus). PAV-431 is shown to bind to the protein 14-3-3, a known allosteric modulator. However, it only appears to target the small subset of 14-3-3 which is present in a dynamic multi-protein complex whose components include proteins implicated in viral life cycles and in innate immunity. The composition of this target multi-protein complex appears to be modified upon viral infection and largely restored by PAV-431 treatment. An advanced analog, PAV-104, is shown to be selective for the virally modified target, thereby avoiding host toxicity. Our findings suggest a new paradigm for understanding, and drugging, the host–virus interface, which leads to a new clinical therapeutic strategy for treatment of respiratory viral disease.
Advances in the synthesis and applications of macrocyclic polyamines
Authors: Gao Yongguang , Guo Lina , Liu Xinhua , Chen Na , Yang Xiaochun , Zhang Qing
Published: June 2024

Macrocyclic polyamines constitute a significant class of macrocyclic compounds that play a pivotal role in the realm of supramolecular chemistry. They find extensive applications across diverse domains including industrial and agricultural production, clinical diagnostics, environmental protection and other multidisciplinary fields. Macrocyclic polyamines possess a distinctive cavity structure with varying sizes, depths, electron-richness degrees and flexibilities. This unique feature enables them to form specific supramolecular structures through complexation with diverse objects, thereby attracting considerable attention from chemists, biologists and materials scientists alike. However, there is currently a lack of comprehensive summaries on the synthesis methods for macrocyclic polyamines. In this review article, we provide an in-depth introduction to the synthesis of macrocyclic polyamines while analysing their respective advantages and disadvantages. Furthermore, we also present an overview of the recent 5-year advancements in using macrocyclic polyamines as non-viral gene vectors, fluorescent probes, diagnostic and therapeutic reagents as well as catalysts. Looking ahead to future research directions on the synthesis and application of macrocyclic polyamines across various fields will hopefully inspire new ideas for their synthesis and use.
Mechanisms of enhanced cardiorespiratory performance under hyperoxia differ with exposure duration in yellowtail kingfish
Authors: Morgenroth Daniel , McArley Tristan , Khan Javed , Sandblom Erik
Published: June 2024

Hyperoxia has been shown to expand the aerobic capacity of some fishes, although there have been very few studies examining the underlying mechanisms and how they vary across different exposure durations. Here, we investigated the cardiorespiratory function of yellowtail kingfish (
Seriola lalandi
) acutely (~20 h) and chronically (3–5 weeks) acclimated to hyperoxia (~200% air saturation). Our results show that the aerobic performance of kingfish is limited in normoxia and increases with environmental hyperoxia. The aerobic scope was elevated in both hyperoxia treatments driven by a ~33% increase in maximum O
2
uptake (MO
2max
), although the mechanisms differed across treatments. Fish acutely transferred to hyperoxia primarily elevated tissue O
2
extraction, while increased stroke volume-mediated maximum cardiac output was the main driving factor in chronically acclimated fish. Still, an improved O
2
delivery to the heart in chronic hyperoxia was not the only explanatory factor as such. Here, maximum cardiac output only increased in chronic hyperoxia compared with normoxia when plastic ventricular growth occurred, as increased stroke volume was partly enabled by an ~8%–12% larger relative ventricular mass. Our findings suggest that hyperoxia may be used long term to boost cardiorespiratory function potentially rendering fish more resilient to metabolically challenging events and stages in their life cycle.
Cardiometabolic health, cortical thickness, and neurotransmitter systems: a large-scale multivariate study
Authors: Nicolaisen-Sobesky Eliana , Maleki Balajoo Somayeh , Mahdipour Mostafa , Mihalik Agoston , Hoffstaedter Felix , Mourao-Miranda Janaina , Tahmasian Masoud , Eickhoff Simon B. , Genon Sarah
Published: June 2024

There is a recognized link between risk factors for non-communicable diseases and brain health. However, the specific effects that they have on brain health are still poorly understood, preventing its implementation in clinical practice. For instance, the association between such risk factors and cortical thickness (CT) has been primarily explored using univariate/bivariate methods and global/lobar measures of CT and has yielded inconsistent results. In this work, we aim to study the relationship between risk factors for non-communicable diseases and CT. In addition, we adopt a systems-level perspective to understand such relationship, by integrating several brain features including brain structure and function as well as neurotransmitter systems.

Here, we analyzed latent dimensions linking a broad set of risk factors for non-communicable diseases to parcel-wise CT across the whole cortex (including raw, proportional, and brain size- corrected measures). We used a multivariate approach (regularized canonical correlation analysis (RCCA)) embedded in a machine learning framework that allows to capture inter- individual variability and to assess the generalizability of the model. The brain patterns (captured in association with risk factors) were characterized from a multi-level perspective, by comparing them with patterns of brain structure, function, and neurotransmitter systems. Analyses were performed separately in women (n=3685, 46-81 years) and in age-matched men (n=3685, 46-81 years) to avoid sex-bias on the results.

We found one significant latent dimension (women: rrange=0.25-0.30, p=0.005-0.005; men: rrange=0.31-0.34, p=0.005-0.005), capturing variability in cardiometabolic health, including physical activity, body morphology/composition, basal metabolic rate, and blood pressure. This cardiometabolic health dimension was linked to a CT axis of inter-individual variability from the insula and cingulate cortex to occipital and parietal areas. Interestingly, this brain pattern was associated with the binding potentials of several neurotransmitter systems, including serotoninergic, dopaminergic, cholinergic, and GABAergic systems. Of note, this latent dimension was similar across sexes and across CT measures (raw, proportional, and brain-size corrected).

We observed a robust, multi-level and multivariate link between cardiometabolic health, CT, and neurotransmitter systems. These findings support the urgency of further investigation into the interaction between brain health and physical health and contributes to the challenge to the classical conceptualization of neuropsychiatric and physical illnesses as categorical entities. Therefore, regular monitoring of cardiometabolic risk factors may reduce their adverse effects on brain health and prevent the development of brain diseases.
Isolating Poroelastic and Viscoelastic Mechanisms of Soft Tissues and Hydrogels Through Sequential Microscale Indentation Testing: New Applications of Indentation Theory for Microscale Characterization
Authors: Zahin Muhtadi Munawar , Al Barghouthi Abeer , Dickerson Darryl A.
Published: June 2024

Soft hydrated materials, including biological tissues and hydrogels, exhibit complex time-dependent mechanical behaviors due to their poroelastic and viscoelastic properties. These properties often manifest on overlapping time scales, making it challenging to isolate the individual contributions of poroelasticity and viscoelasticity to the overall mechanical response. This study presents a novel semi-analytical model for characterizing these properties through sequential microscale load relaxation indentation testing. By extending existing theories, we developed a poroviscoelastic framework that enables the deconvolution of poroelastic and viscoelastic effects. Using this model to fit sequential microscale indentation data, we characterized porcine heart and liver tissues, as well as collagen and GelMA hydrogels, revealing distinct differences in their poroelastic and viscoelastic parameters. Our findings demonstrate that this approach not only provides rapid and detailed insights into the mechanical properties at the microscale but also offers significant advantages over traditional methods in terms of speed, computational efficiency, and practicality. This methodology has broad implications for advancing the understanding of tissue mechanics and the design of biomimetic materials for tissue engineering applications.

Statement of Significance

This study introduces a novel approach to understanding the mechanical behavior of soft hydrated materials, like tissues and hydrogels. This study introduces a semi-analytical model to describe the time dependent behavior and a practical approach to distinguish between poroelasticity and viscoelasticity at the microscale. By providing this model along with a rapid and efficient characterization method, our approach enhances understanding of time-dependent mechanical behaviors critical for soft tissue mechanics and biomaterials design.
4G cloning: rapid gene assembly for expression of multisubunit protein complexes in diverse hosts
Authors: Taschner Michael , Dickinson Joe Bradley , Roisné-Hamelin Florian , Gruber Stephan
Published: June 2024

Multi-subunit protein complexes are at the heart of many cellular processes, and studying their biochemical activities and structuresin vitrorequires their reconstitution by recombinant expression and purification. Obtaining targets at sufficient purity and scale typically requires the screening of several protein variants and expression hosts. Existing cloning strategies allow to produce constructs for co-expression of proteins, but are often time-consuming, labour-intensive, host-specific, or involving error-prone assembly steps. Here we present a unique set of vectors together with a novel assembly strategy designed to overcome these limitations. It allows for the generation of expression constructs for multi-subunit protein complexes for various hosts in a single cloning step. Its modular nature allows the system to be easily extended to target additional expression hosts or to include new tags or regulatory sequences. As a proof of principle, we present the parallel construction of expression vectors for several Structural Maintenance of Chromosomes (SMC) complexes, allowing us to devise strategies for the recombinant production of these targets in bacteria, insect cells, and human cells, respectively. This work will help laboratories working on protein complexes to streamline their workflow, increase their productivity and improve the quality of the purified material.
Co-Contraction Embodies Uncertainty: An Optimal Feedforward Strategy for Robust Motor Control
Authors: Berret Bastien , Verdel Dorian , Burdet Etienne , Jean Frédéric
Published: June 2024

Despite our environment is often uncertain, we generally manage to generate stable motor behaviors. While reactive control plays a major role in this achievement, proactive control is critical to cope with the substantial noise and delays that affect neuromusculoskeletal systems. In particular, muscle co-contraction is exploited to robustify feedforward motor commands against internal sensorimotor noise as was revealed by stochastic optimal open-loop control modeling. Here, we extend this framework to neuromusculoskeletal systems subjected to random disturbances originating from the environment. The analytical derivation and numerical simulations predict a singular relationship between the degree of uncertainty in the task at hand and the optimal level of anticipatory co-contraction. This prediction is confirmed through a single-joint pointing task experiment where an external torque is applied to the wrist near the end of the reaching movement with varying probabilities across blocks of trials. We conclude that uncertainty calls for impedance control via proactive muscle co-contraction to stabilize behaviors when reactive control is insufficient for task success.

Author summary

This work presents a computational framework for predicting how humans modulate muscle co-contraction to cope with uncertainties of different origins. In our neuromusculoskeletal system, uncertainties have both internal (sensorimotor noise) and external (environmental randomness) origins. The present study focuses on the latter type of uncertainty, which had not been dealt with systematically previously despite its importance in everyday life. Therefore, we thoroughly investigated how random disturbances occurring with some probability in a motor task shape the feedforward control of mechanical impedance through muscle co-contraction. Here we provide theoretical, numerical and experimental evidence that the optimal level of co-contraction steeply increases with the uncertainty of our environment. These findings show that muscle co-contraction embodies uncertainty and optimally mitigates its consequences on task execution when feedback control is insufficient due to sensory noise and delays.