bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and safety of adhesion barrier in living-donor liver transplantation with right liver graft to prevent delayed gastric emptying
Authors: Kim Sang-Hoon , Lee Sung-Gyu , Hwang Shin , Ahn Chul-Soo , Kim Ki-Hun , Moon Deok-Bog , Ha Tea-Yong , Song Gi-Won , Park Gil-Chun , Yoon Young-In , Kang Woo-Hyoung , Cho Hwui-Dong , Ha Su-Min , Na Byeong-Gon , Kim Minjae , Kim Sung-Min , Yang Geunhyeok , Oh Rak-Kyun , Jung Dong-Hwan
Published: February 2023

Delayed gastric emptying (DGE) is a common complication of liver transplantation. This study aimed to clarify the efficacy and safety of the application of an adhesion barrier for preventing DGE in living-donor liver transplantation. This retrospective study included 453 patients who underwent living-donor liver transplantation using a right lobe graft between January 2018 and August 2019, and the incidence of postoperative DGE and complications was compared between patients in whom adhesion barrier was used (n=179 patients) and those in whom adhesion barrier was not used (n=274 patients). We performed 1:1 propensity score matching between the 2 groups, and 179 patients were included in each group. DGE was defined according to the International Study Group for Pancreatic Surgery classification. The use of adhesion barrier was significantly associated with a lower overall incidence of postoperative DGE in liver transplantation (30.7 vs. 17.9%; p=0.002), including grades A (16.8 vs. 9.5%; p=0.03), B (7.3 vs. 3.4%; p=0.08), and C (6.6 vs. 5.5%; p=0.50). After propensity score matching, similar results were observed for the overall incidence of DGE (29.6 vs. 17.9%; p=0.009), including grades A (16.8 vs. 9.5%; p=0.04), B (6.7 vs. 3.4%; p=0.15), and C (6.1 vs. 5.0%; p=0.65). Univariate and multivariate analyses showed a significant correlation between the use of adhesion barrier and a low incidence of DGE. There were no statistically significant differences in postoperative complications between the 2 groups. The application of an adhesion barrier could be a safe and feasible method to reduce the incidence of postoperative DGE in living-donor liver transplantation.
Use, Durability, and Risks for Discontinuation of Initial and Subsequent Biologics in a Large Pediatric-Onset IBD Cohort
Authors: Kaplan Jess L. , Liu Chunyan , King Eileen C. , Bass Julie A. , Patel Ashish S. , Tung Jeanne , Chen Shiran , Lissoos Trevor , Candela Ninfa , Saeed Shehzad , Colletti Richard B. ,   for the ImproveCareNow Network
Published: February 2023

Background:

Biologic medications are recommended for treatment of moderately-to-severely active Crohn disease (CD) or ulcerative colitis (UC) in children. However, many patients require sequential biologic treatment because of nonresponse or loss of response to the initial biologic.

Methods:

We analyzed pediatric inflammatory bowel disease (IBD) data from the ImproveCareNow Network registry between May 2006 and September 2016, including time to biologic initiation, choice of first subsequent biologics, biologic durability, and reasons for discontinuation.

Results:

Of 17,649 patients with IBD [CD: 12,410 (70%); UC: 5239 (30%)], 7585 (43%) were treated with a biologic agent before age 18 (CD: 50%; UC: 25%). Biologic treatment was more likely for CD than UC (odds ratio, 3.0; 95% CI: 2.8–3.2; P < 0.0001). First biologic agents for all patients were anti-tumor necrosis factor agents (88% infliximab, 12% adalimumab). Probability of remaining on the first biologic was significantly higher in CD than UC (P < 0.0001). First biologics were discontinued because of loss of response (39%), intolerance (23%), and nonresponse (19%). In univariate analysis, factors associated with discontinuation of first and/or second biologics in CD include colonic-only disease, corticosteroid use, upper gastrointestinal tract involvement, and clinical and biochemical markers of severe disease. Biologic durability improved with later induction date.

Conclusions:

Treatment with biologic medications is common in pediatric IBD. Patients with CD are more likely to receive biologics, receive biologics earlier in disease course, and remain on the first biologic longer than patients with UC. Multiple factors may predict biologic durability in children with IBD.
Costs, Health Benefits, and Cost-Effectiveness of Chlamydia Screening and Partner Notification in the United States, 2000–2019: A Mathematical Modeling Analysis
Authors: Rönn Minttu M. , Li Yunfei , Gift Thomas L. , Chesson Harrell W. , Menzies Nicolas A. , Hsu Katherine , Salomon Joshua A.
Published: February 2023

Background

Chlamydia remains a significant public health problem that contributes to adverse reproductive health outcomes. In the United States, sexually active women 24 years and younger are recommended to receive annual screening for chlamydia. In this study, we evaluated the impact of estimated current levels of screening and partner notification (PN), and the impact of screening based on guidelines on chlamydia associated sequelae, quality adjusted life years (QALYs) lost and costs.

Methods

We conducted a cost-effectiveness analysis of chlamydia screening, using a published calibrated pair formation transmission model that estimated trends in chlamydia screening coverage in the United States from 2000 to 2015 consistent with epidemiological data. We used probability trees to translate chlamydial infection outcomes into estimated numbers of chlamydia-associated sequelae, QALYs lost, and health care services costs (in 2020 US dollars). We evaluated the costs and population health benefits of screening and PN in the United States for 2000 to 2015, as compared with no screening and no PN. We also estimated the additional benefits that could be achieved by increasing screening coverage to the levels indicated by the policy recommendations for 2016 to 2019, compared with screening coverage achieved by 2015.

Results

Screening and PN from 2000 to 2015 were estimated to have averted 1.3 million (95% uncertainty interval [UI] 490,000–2.3 million) cases of pelvic inflammatory disease, 430,000 (95% UI, 160,000–760,000) cases of chronic pelvic pain, 300,000 (95% UI, 104,000–570,000) cases of tubal factor infertility, and 140,000 (95% UI, 47,000–260,000) cases of ectopic pregnancy in women. We estimated that chlamydia screening and PN cost $9700 per QALY gained compared with no screening and no PN. We estimated the full realization of chlamydia screening guidelines for 2016 to 2019 to cost $30,000 per QALY gained, compared with a scenario in which chlamydia screening coverage was maintained at 2015 levels.

Discussion

Chlamydia screening and PN as implemented in the United States from 2000 through 2015 has substantially improved population health and provided good value for money when considering associated health care services costs. Further population health gains are attainable by increasing screening further, at reasonable cost per QALY gained.
Book Chapter (Kluwer) - Preprint Version.pdf
Authors: Aliu Armando , Aliu Dorian
Published: February 2023

  

The research aims to analyze the impact of the World Trade Organization on enhancing the legitimacy of global economic governance within the scope of the WTO law. The world economic outlook and macro-data indicators demonstrate that the convergence of interests amongst state actors and nonstate actors reinforces the efficiency of Bretton Woods institutions, such as the World Bank and the International Monetary Fund. The objective of this study is to highlight the fact that the WTO has vital efforts to strengthen the legitimacy of the global economic governance mechanism and liberalize economic activity in the world economic system. In a more liberalized transnational relations environment, the activities, operations, and efforts of nonstate actors provide a ground to stabilize economic cooperation and sustainable development. From a macro perspective, the study aims to monitor the first five-year period of the global financial crisis (2008-2013) and present the descriptive statistics and intercorrelations for 36 OECD countries. The research results indicate that 36 states’ governments should develop sustainable solutions to issues related to GDP, social security, and public / private expenditure in global economic governance platforms. In collaboration with governments, the WTO’s role is vital to cooperate with ILO and enhance its legitimacy and efficiency in labor relations, industrial relations, and employment protection. The research results illustrate that global economic governance has been reshaped by a ‘duality of global governance approach’ (i.e., a de facto G2: US-China relations), and the principles of global economic development have been reconstructed during the transition period from the Washington consensus to the Beijing consensus (G2 hegemony), competitively.
Modeling Methods in Craniofacial Virtual Surgical Planning
Authors: Riordan Edward , Yung Amanda , Cheng Kai , Lim Lydia , Clark Jonathan , Rtshiladze Michael , Ch’ng Sydney
Published: February 2023

Despite the widespread use of virtual surgical planning (VSP), few papers describe the modeling methods used to generate the digital simulations that underpin VSP. This paper aims to review the modeling methods that are currently available for use in VSP and the implications of their use in clinical practice. A literature review was undertaken of the two broad categories of modeling techniques; contour-based planning—namely mirroring from the contralateral side, templating from a normative database, and extrapolation from surrounding landmarks—and occlusal-based planning (OBP). The indications for each modeling method were discussed, including mandibular/maxillary reconstruction, pediatric craniofacial surgery, and orthognathic, as well as the limitations to the accuracy of modeling types. Unilateral defects of the upper/midface, wherein contour accuracy is paramount, are best reconstructed using mirroring methods, whereas bilateral defects—or cases with asymmetry due to craniofacial dysmorphology—are most suited to normative-data-based methods. Cases involving resection of the alveolar margin, in which functional occlusion is the primary outcome are best managed with OBP. Similarly, orthognathic surgery typically uses OBP, although complex cases involving asymmetry, such as clefts, may benefit from a combination of OBP and normative data methods. The choice of modeling methods is, therefore, largely driven by the defect type and the goals of reconstruction.
Feasibility and Safety of a “Shared Care” Model in Complex Hepatopancreatobiliary Surgery
Authors: Lee Alex , Al-Arnawoot Ahmed , Rajendran Luckshi , Lamb Tyler , Turner Anastasia , Reid Morgann , Rekman Janelle , Mimeault Richard , Abou Khalil Jad , Martel Guillaume , Bertens Kimberly A. , Balaa Fady
Published: February 2023

Objective:

To determine the safety of a fully functioning shared care model (SCM) in hepatopancreatobiliary surgery through evaluating outcomes in pancreaticoduodenectomy.

Background:

SCMs, where a team of surgeons share in care delivery and resource utilization, represent a surgeon-level opportunity to improve system efficiency and peer support, but concerns around clinical safety remain, especially in complex elective surgery.

Methods:

Patients who underwent pancreaticoduodenectomy between 2016 and 2020 were included. Adoption of shared care was demonstrated by analyzing shared care measures, including the number of surgeons encountered by patients during their care cycle, the proportion of patients with different consenting versus primary operating surgeon (POS), and the proportion of patients who met their POS on the day of surgery. Outcomes, including 30-day mortality, readmission, unplanned reoperation, sepsis, and length of stay, were collected from the institution’s National Surgical Quality Improvement Program (NSQIP) database and compared with peer hospitals contributing to the pancreatectomy-specific NSQIP collaborative.

Results:

Of the 174 patients included, a median of 3 surgeons was involved throughout the patients’ care cycle, 69.0% of patients had different consenting versus POS and 57.5% met their POS on the day of surgery. Major outcomes, including mortality (1.1%), sepsis (5.2%), and reoperation (7.5%), were comparable between the study group and NSQIP peer hospitals. Length of stay (10 day) was higher in place of lower readmission (13.2%) in the study group compared with peer hospitals.

Conclusions:

SCMs are feasible in complex elective surgery without compromising patient outcomes, and wider adoption may be encouraged.
Uncinate Duct Dilatation Predicts Additional Risk for High-Grade Dysplasia or Invasive Carcinoma Among Fukuoka-Positive Intraductal Papillary Mucinous Neoplasms
Authors: Yang Alan Z. , Kongboonvijit Sasiprang , Fernandez-del Castillo Carlos F. , Fong Zhi Ven , Zelga Piotr J. , Ferrone Cristina R. , Lillemoe Keith D. , Kambadakone Avinash , Qadan Motaz
Published: February 2023

Objective:

To determine whether uncinate duct dilatation (UDD) increases the risk of high-grade dysplasia or invasive carcinoma (HGD/IC) in Fukuoka-positive intraductal papillary mucinous neoplasms (IPMNs).

Background:

Though classified as a branch duct, the uncinate duct is the primary duct of the pancreatic ventral anlage. We hypothesized that UDD, like main duct dilatation, confers additional risk for HGD/IC.

Methods:

A total of 467 patients met inclusion criteria in a retrospective cohort study of surgically resected IPMNs at the Massachusetts General Hospital. We used multivariable logistic regression to analyze the association between UDD (defined as ≥4 mm) and HGD/IC, controlling for Fukuoka risk criteria. In a secondary analysis, the modeling was repeated in the 194 patients with dorsal branch duct IPMNs (BD-IPMNs) in the pancreatic neck, body, or tail.

Results:

Mean age at surgery was 70, and 229 (49%) patients were female. In total, 267 (57%) patients had only worrisome features and 200 (43%) had at least 1 high-risk feature. UDD was present in 164 (35%) patients, of whom 118 (73%) had HGD/IC. On multivariable analysis, UDD increased the odds of HGD/IC by 2.8-fold, even while controlling for Fukuoka risk factors (95% CI: 1.8–4.4, P<0.001). Prevalence of HGD/IC in all patients with UDD was 73%, compared with 74% in patients with high-risk stigmata and 73% in patients with main duct IPMNs. In the secondary analysis, UDD increased the odds of HGD/IC by 3.2-fold in patients with dorsal BD-IPMNs (95% CI: 1.3–7.7, P=0.010).

Conclusions:

UDD confers additional risk for HGD/IC unaccounted for by current Fukuoka criteria. Further research can extend this study to Fukuoka-negative patients, including unresected patients.
Normothermic Regional Perfusion Can Improve Both Utilization and Outcomes in DCD Liver, Kidney, and Pancreas Transplantation
Authors: Bekki Yuki , Croome Kristopher P. , Myers Bryan , Sasaki Kazunari , Tomiyama Koji
Published: February 2023

Background.

Normothermic regional perfusion (NRP) has gained widespread adoption in multiple European countries. The aim of this study was to examine the influence of thoracoabdominal-NRP (TA-NRP) on the utilization and outcomes of liver, kidney, and pancreas transplantation in the United States.

Methods.

Using the US national registry data between 2020 and 2021, donation after circulatory death (DCD) donors were separated into 2 groups: DCD with TA-NRP and without TA-NRP. There were 5234 DCD donors; among them 34 donors were with TA-NRP. After 1:4 propensity score matching, the utilization rates were compared between DCD with and without TA-NRP.

Results.

Although the utilization rates of kidney and pancreas were comparable (P = 0.71 and P = 0.06, 94.1% versus 95.6% and 8.8% versus 2.2%, respectively), that of liver in DCD with TA-NRP was significantly higher (P < 0.001; 70.6% versus 39.0%). Among 24 liver transplantations, 62 kidney transplantations, and 3 pancreas transplantations from DCD with TA-NRP, there were 2 liver grafts and 1 kidney graft that failed within 1 y after transplantation.

Conclusions.

TA-NRP in the United States significantly increased the utilization rate of abdominal organs from DCD donors with comparable outcomes after transplantation. Increasing use of NRP may expand the donor pool without compromising transplant outcomes.
Mechanisms of collective learning: how can animal groups improve collective performance when repeating a task?
Authors: Collet Julien , Morford Joe , Lewin Patrick , Bonnet-Lebrun Anne-Sophie , Sasaki Takao , Biro Dora
Published: February 2023

Learning is ubiquitous in animals: individuals can use their experience to fine-tune behaviour and thus to better adapt to the environment during their lifetime. Observations have accumulated that, at the collective level, groups can also use their experience to improve collective performance. Yet, despite apparent simplicity, the links between individual learning capacities and a collective's performance can be extremely complex. Here we propose a centralized and broadly applicable framework to begin classifying this complexity. Focusing principally on groups with stable composition, we first identify three distinct ways through which groups can improve their collective performance when repeating a task: each member learning to better solve the task on its own, members learning about each other to better respond to one another and members learning to improve their complementarity. We show through selected empirical examples, simulations and theoretical treatments that these three categories identify distinct mechanisms with distinct consequences and predictions. These mechanisms extend well beyond current social learning and collective decision-making theories in explaining collective learning. Finally, our approach, definitions and categories help generate new empirical and theoretical research avenues, including charting the expected distribution of collective learning capacities across taxa and its links to social stability and evolution.

This article is part of a discussion meeting issue ‘Collective behaviour through time’.
Ageing in a collective: the impact of ageing individuals on social network structure
Authors: Siracusa Erin R. , Pereira André S. , Brask Josefine Bohr , Negron-Del Valle Josué E. , Phillips Daniel ,   Cayo Biobank Research Unit, Platt Michael L. , Higham James P. , Snyder-Mackler Noah , Brent Lauren J. N.
Published: February 2023

Ageing affects many phenotypic traits, but its consequences for social behaviour have only recently become apparent. Social networks emerge from associations between individuals. The changes in sociality that occur as individuals get older are thus likely to impact network structure, yet this remains unstudied. Here we use empirical data from free-ranging rhesus macaques and an agent-based model to test how age-based changes in social behaviour feed up to influence: (i) an individual's level of indirect connectedness in their network and (ii) overall patterns of network structure. Our empirical analyses revealed that female macaques became less indirectly connected as they aged for some, but not for all network measures examined. This suggests that indirect connectivity is affected by ageing, and that ageing animals can remain well integrated in some social contexts. Surprisingly, we did not find evidence for a relationship between age distribution and the structure of female macaque networks. We used an agent-based model to gain further understanding of the link between age-based differences in sociality and global network structure, and under which circumstances global effects may be detectable. Overall, our results suggest a potentially important and underappreciated role of age in the structure and function of animal collectives, which warrants further investigation.

This article is part of a discussion meeting issue ‘Collective behaviour through time’.
Behavioural changes in slime moulds over time
Authors: Rolland Angèle , Pasquier Emilie , Malvezin Paul , Cassandra Craig , Dumas Mathilde , Dussutour A.
Published: February 2023

Changes in behaviour over the lifetime of single-cell organisms have primarily been investigated in response to environmental stressors. However, growing evidence suggests that unicellular organisms undergo behavioural changes throughout their lifetime independently of the external environment. Here we studied how behavioural performances across different tasks vary with age in the acellular slime mould
Physarum polycephalum
. We tested slime moulds aged from 1 week to 100 weeks. First, we showed that migration speed decreases with age in favourable and adverse environments. Second, we showed that decision making and learning abilities do not deteriorate with age. Third, we revealed that old slime moulds can recover temporarily their behavioural performances if they go throughout a dormant stage or if they fuse with a young congener. Last, we observed the response of slime mould facing a choice between cues released by clone mates of different age. We found that both old and young slime moulds are attracted preferentially toward cues left by young slime moulds. Although many studies have studied behaviour in unicellular organisms, few have taken the step of looking for changes in behaviour over the lifetime of individuals. This study extends our knowledge of the behavioural plasticity of single-celled organisms and establishes slime moulds as a promising model to investigate the effect of ageing on behaviour at the cellular level.

This article is part of a discussion meeting issue ‘Collective behaviour through time’.
Dynamics of collective motion across time and species
Authors: Papadopoulou Marina , Fürtbauer Ines , O'Bryan Lisa R. , Garnier Simon , Georgopoulou Dimitra G. , Bracken Anna M. , Christensen Charlotte , King Andrew J.
Published: February 2023

Most studies of collective animal behaviour rely on short-term observations, and comparisons of collective behaviour across different species and contexts are rare. We therefore have a limited understanding of intra- and interspecific variation in collective behaviour over time, which is crucial if we are to understand the ecological and evolutionary processes that shape collective behaviour. Here, we study the collective motion of four species: shoals of stickleback fish (
Gasterosteus aculeatus
), flocks of homing pigeons (
Columba livia
), a herd of goats (
Capra aegagrus hircus
) and a troop of chacma baboons (
Papio ursinus
). First, we describe how local patterns (inter-neighbour distances and positions), and group patterns (group shape, speed and polarization) during collective motion differ across each system. Based on these, we place data from each species within a ‘swarm space’, affording comparisons and generating predictions about the collective motion across species and contexts. We encourage researchers to add their own data to update the ‘swarm space’ for future comparative work. Second, we investigate intraspecific variation in collective motion over time and provide guidance for researchers on when observations made over different time scales can result in confident inferences regarding species collective motion.

This article is part of a discussion meeting issue ‘Collective behaviour through time’.
The evolution of intergroup cooperation
Authors: Rodrigues António M. M. , Barker Jessica L. , Robinson Elva J. H.
Published: February 2023

Sociality is widespread among animals, and involves complex relationships within and between social groups. While intragroup interactions are often cooperative, intergroup interactions typically involve conflict, or at best tolerance. Active cooperation between members of distinct, separate groups occurs very rarely, predominantly in some primate and ant species. Here, we ask why intergroup cooperation is so rare, and what conditions favour its evolution. We present a model incorporating intra- and intergroup relationships and local and long-distance dispersal. We show that dispersal modes play a pivotal role in the evolution of intergroup interactions. Both long-distance and local dispersal processes drive population social structure, and the costs and benefits of intergroup conflict, tolerance and cooperation. Overall, the evolution of multi-group interaction patterns, including both intergroup aggression and intergroup tolerance, or even altruism, is more likely with mostly localized dispersal. However, the evolution of these intergroup relationships may have significant ecological impacts, and this feedback may alter the ecological conditions that favour its own evolution. These results show that the evolution of intergroup cooperation is favoured by a specific set of conditions, and may not be evolutionarily stable. We discuss how our results relate to empirical evidence of intergroup cooperation in ants and primates.

This article is part of a discussion meeting issue ‘Collective behaviour through time’.
Molecular patterns and processes in evolving sociality: lessons from insects
Authors: Sumner Seirian , Favreau Emeline , Geist Katherine , Toth Amy L. , Rehan Sandra M.
Published: February 2023

Social insects have provided some of the clearest insights into the origins and evolution of collective behaviour. Over 20 years ago, Maynard Smith and Szathmáry defined the most complex form of insect social behaviour—superorganismality—among the eight major transitions in evolution that explain the emergence of biological complexity. However, the mechanistic processes underlying the transition from solitary life to superorganismal living in insects remain rather elusive. An overlooked question is whether this major transition arose via incremental or step-wise modes of evolution. We suggest that examination of the molecular processes underpinning different levels of social complexity represented across the major transition from solitary to complex sociality can help address this question. We present a framework for using molecular data to assess to what extent the mechanistic processes that take place in the major transition to complex sociality and superorganismality involve nonlinear (implying step-wise evolution) or linear (implying incremental evolution) changes in the underlying molecular mechanisms. We assess the evidence for these two modes using data from social insects and discuss how this framework can be used to test the generality of molecular patterns and processes across other major transitions.

This article is part of a discussion meeting issue ‘Collective behaviour through time’.
Intrinsic and effective severity of COVID-19 cases infected with the ancestral strain and Omicron BA.2 variant in Hong Kong
Authors: Wong Jessica Y. , Cheung Justin K. , Lin Yun , Bond Helen S. , Lau Eric H. Y. , Ip Dennis K. M. , Cowling Benjamin J. , Wu Peng
Published: February 2023

Background

Understanding severity of infections with SARS-CoV-2 and its variants is crucial to inform public health measures. Here we used COVID-19 patient data from Hong Kong to characterise the severity profile of COVID-19 and to examine factors associated with fatality of infection.

Methods

Time-varying and age-specific effective severity measured by case-hospitalization risk and hospitalization risk was estimated with all individual COVID-19 case data collected in Hong Kong from 23 January 2020 through to 26 October 2022 over six epidemic waves, in comparison with estimates of influenza A(H1N1)pdm09 during the 2009 pandemic. The intrinsic severity of Omicron BA.2 was compared with the estimate for the ancestral strain with the data from unvaccinated patients without previous infections. Factors potentially associated with the fatality risk of hospitalized Omicron patients were also examined.

Results

With 32,222 COVID-19 hospitalizations and 9,669 deaths confirmed over 6 epidemic waves in Hong Kong, the time-varying hospitalization fatality risk dramatically increased from below 10% before the largest fifth wave of Omicron BA.2, to 41% during the peak of the fifth wave when hospital resources were severely constrained. The age-specific fatality risk in unvaccinated hospitalized Omicron cases was comparable to the estimates for unvaccinated cases with the ancestral strain. During epidemics predominated by Omicron BA.2, the highest fatality risk was amongst unvaccinated patients aged ≥80 years and the risk was inversely associated with the number of vaccination doses received.

Conclusions

Omicron has comparable intrinsic severity to the ancestral Wuhan strain although the effective severity is substantially lower in Omicron cases due to vaccination. With a moderate-to-high coverage of vaccination, hospitalized COVID-19 patients caused by Omicron subvariants appeared to have similar age-specific risks of fatality to patients hospitalized with influenza A(H1N1)pdm09.
Impacts of Virtual Reality Experiences: Enhanced Undergraduate Student Performance and Engagement with use of 360-degree video
Authors: Vola Erica , Stoltz Rebecca , Schumpert Charles A.
Published: February 2023

Virtual reality has been used for a variety of training and gaming purposes. Recent studies have demonstrated their use in higher education enhances student engagement and positively impacts student performance. In this study, we implemented 360-degree video in an introductory biology lab and assessed student attitudes, engagement, and performance on various assessments as well as the overall course performance. Students were extremely positive about virtual reality, had minimal issues handling the technology, and indicated that engagement with the topic was better with virtual reality. Student performance increased on 2 of the 3 formative assessments analyzed, 1 of 1 summative assessment analyzed, and overall course grades in semesters with virtual reality were higher than in semesters without virtual reality. These results suggest virtual reality in higher education may enhance not only student engagement and performance, but also enhance student attitude about the topic.
Extensive profiling of histidine-containing dipeptides reveals species- and tissue-specific distribution and metabolism in mice, rats and humans
Authors: Van der Stede Thibaux , Spaas Jan , de Jager Sarah , De Brandt Jana , Hansen Camilla , Stautemas Jan , Vercammen Bjarne , De Baere Siegrid , Croubels Siska , Van Assche Charles-Henri , Pastor Berta Cillero , Vandenbosch Michiel , Van Thienen Ruud , Verboven Kenneth , Hansen Dominique , Bové Thierry , Lapauw Bruno , Van Praet Charles , Decaestecker Karel , Vanaudenaerde Bart , Eijnde Bert O , Gliemann Lasse , Hellsten Ylva , Derave Wim
Published: February 2023

Histidine-containing dipeptides (HCDs) are pleiotropic homeostatic molecules linked to inflammatory, metabolic and neurological diseases, as well as exercise performance. Using a sensitive UHPLC-MS/MS approach and an optimized quantification method, we performed a systematic and extensive profiling of HCDs in the mouse, rat, and human body (in n=26, n=25, n=19 tissues, respectively). Our data show that tissue HCD levels are uniquely regulated by carnosine synthase (CARNS1), an enzyme that was preferentially expressed by fast-twitch skeletal muscle fibers and brain oligodendrocytes. Cardiac HCD levels are remarkably low compared to other excitable tissues. Carnosine is unstable in human plasma, but is preferentially transported within red blood cells in humans but not rodents. The low abundant carnosine analog N-acetylcarnosine is the most stable plasma HCD, and is enriched in human skeletal muscles. Here, N-acetylcarnosine is continuously secreted into the circulation, which is further induced by acute exercise in a myokine-like fashion. Collectively, we provide a novel basis to unravel tissue-specific, paracrine, and endocrine roles of HCDs in human health and disease.

Significance statement

By extensively profiling the pluripotent histidine-containing dipeptides across three species, we generated many new insights into species- and tissue-specific histidine-containing dipeptide metabolism. For instance, the only stable analog that is specific for the human circulation (N-acetylcarnosine) is continuously released from muscle tissue and is positively regulated by physical exercise. The great number of analyses and experiments involving humans establishes great translational value of the findings. These new data open exciting opportunities to study histidine-containing dipeptide metabolism, including paracrine and/or endocrine signaling of these dipeptides, possibly contributing to the potent health-promoting exercise effects.
Comprehensive characterization of tumor microenvironment in colorectal cancer via histopathology-molecular analysis
Authors: Wu Xiangkun , Yan Hong , Qiu Mingxing , Qu Xiaoping , Wang Jing , Xu Shaowan , Zheng Yiran , Ge Minghui , Yan Linlin , Liang Li
Published: February 2023

Purpose

To explain how the tumor microenvironment (TME) contributes to biological and clinical heterogeneity of colorectal cancer (CRC).

Methods

Using multi-omics analysis, single cell transcriptomic sequencing analysis and artificial intelligence-enabled spatial analysis of whole-slide images, we performed a comprehensive characterization of TME in colorectal cancer (CCCRC).

Results

CRC samples were classified into four CCCRC subtypes with distinct TME features, namely, C1 as the proliferative subtype with low immunogenicity; C2 as the immunosuppressed subtype with the terminally exhausted immune characteristics; C3 as the immune-excluded subtype with the distinct upregulation of stromal components and a lack of T cell infiltration in tumor core; and C4 as the immunomodulatory subtype with the remarkable upregulation of anti-tumor immune components. The four CCCRC subtypes had distinct histopathological and molecular characteristics, therapeutic efficacy, and prognosis. The C1 subtype was more sensitive to chemotherapy, the C2 and C3 subtypes were more sensitive to WNT pathway inhibitor SB216763 and Hedgehog pathway inhibitor vismodegib, and the C4 subtype was suitable for ICB treatment. Finally, we established a single-sample gene classifier for identifying the CCCRC subtypes.

Conclusions

Our integrative analyses ultimately established a holistic framework to thoroughly dissect the TME of CRC, and the CCCRC classification system with high biological interpretability might facilitate biomarker discoveries and clinical treatment decisions in the future.
Accurate label-free quantification by directLFQ to compare unlimited numbers of proteomes
Authors: Ammar Constantin , Schessner Julia Patricia , Willems Sander , Michaelis André C. , Mann Matthias
Published: February 2023

Recent advances in mass spectrometry (MS)-based proteomics enable the acquisition of increasingly large datasets within relatively short times, which exposes bottlenecks in the bioinformatics pipeline. Whereas peptide identification is already scalable, most label-free quantification (LFQ) algorithms scale quadratic or cubic with the sample numbers, which may even preclude the analysis of large-scale data. Here we introduce directLFQ, a ratiobased approach for sample normalization and the calculation of protein intensities. It estimates quantities via aligning samples and ion traces by shifting them on top of each other in logarithmic space. Importantly, directLFQ scales linearly with the number of samples, allowing analyses of large studies to finish in minutes instead of days or months. We quantify 10,000 proteomes in 10 minutes and 100,000 proteomes in less than two hours - thousand-fold faster than some implementations of the popular LFQ algorithm MaxLFQ. In-depth characterization of directLFQ reveals excellent normalization properties and benchmark results, comparing favorably to MaxLFQ for both data-dependent acquisition (DDA) and data-independent acquisition (DIA). Additionally, directLFQ provides normalized peptide intensity estimates for peptide-level comparisons. It is available as an open-source Python package and as a GUI with a one-click installer and can be used in the AlphaPept ecosystem as well as downstream of most common computational proteomics pipelines.
Rapid Molecular Mechanotyping with Microfluidic Force Spectroscopy
Authors: van Galen Martijn , Bok Annemarie , Peshkovsky Taieesa , van der Gucht Jasper , Albada Bauke , Sprakel Joris
Published: February 2023

Molecular mechanotyping, the quantification of changes in the stability of supramolecular interactions and chemical bonds under the action of mechanical forces, is an essential tool in the field of mechanochemistry. This is conventionally done in single-molecule force-spectroscopy (smFS) assays, for example with optical tweezers or Atomic Force Microscopy. While these techniques provide detailed mechanochemical insights, they are time-consuming, technically demanding and expensive; as a result, high-throughput screening of the mechanochemical properties of molecules of interest is challenging. To resolve this, we present a rapid, simple and low-cost mechanotyping assay: microfluidic force spectroscopy (µFFS), which probes force-dependent bond stability by measuring the detachment of microparticles, bound to microfluidic channels by the interaction of interest, under hydrodynamic forcing. As this allows the simultaneous observation of hundreds of microparticles, we obtain a quantitative mechanotype in a single measurement, using readily available equipment. We validate our method by studying the stability of DNA duplexes, previously characterized through smFS. We further show that we can quantitatively describe the experimental data with simulations, which allows us to link theµFFS data to single-bond mechanochemical properties. This opens the way to use (µFFS) as a rapid molecular mechanotyping tool.
Land-cover change in Cuba may favor biodiversity: An example usingOmphalea(Angiosperma: Euphorbiaceae) andUrania boisduvalii(Lepidoptera: Uraniidae)
Authors: Nuñez-Penichet Claudia , Maita-Chamba Juan , Soberón Jorge
Published: February 2023

Changes in land cover directly affect biodiversity. Here we assessed land-cover change in Cuba in the past 35 years and analyzed how this change may affect the distribution ofOmphaleaplants andUrania boisduvaliimoths. We analyzed the vegetation cover of the Cuban archipelago between 1985 and 2020. We used Google Earth Engine to classify two satellite image compositions into seven cover types: forest and shrubs, mangrove, soil without vegetation cover, wetlands, pine forest, agriculture, and water bodies. We considered three different areas for quantifications of land-cover change: (1) protected areas, (2) areas of potential distribution ofOmphalea, and (3) areas of potential distribution of the plant within the protected areas. We found that the category of “forest and shrubs” have increased significantly in Cuba in the past 35 years and that most of the gained forest and shrub areas were agricultural land in the past. This same pattern was observed in the areas of potential distribution ofOmphalea; whereas almost all cover types were mostly stables inside the protected areas. The transformation of agricultural areas into forest and shrubs could represent an interesting opportunity for biodiversity conservation in Cuba. Other detailed studies about biodiversity composition in areas of forest and shrubs gain would greatly benefit our understanding on the value of such areas for conservation.
Genome-wide screen reveals Rab12 GTPase as a critical activator of pathogenic LRRK2 kinase
Authors: Dhekne Herschel S. , Tonelli Francesca , Yeshaw Wondwossen M. , Chiang Claire Y. , Limouse Charles , Jaimon Ebsy , Purlyte Elena , Alessi Dario R. , Pfeffer Suzanne R.
Published: February 2023

Activating mutations in the Leucine Rich Repeat Kinase 2 (LRRK2) cause Parkinson’s disease. LRRK2 phosphorylates a subset of Rab GTPases, particularly Rab10 and Rab8A, and we showed previously that phosphoRabs play an important role in LRRK2 membrane recruitment and activation (Vides et al., 2022). To learn more about LRRK2 pathway regulation, we carried out an unbiased, CRISPR-based genome-wide screen to identify modifiers of cellular phosphoRab10 levels. A flow cytometry assay was developed to detect changes in phosphoRab10 levels in pools of mouse NIH-3T3 cells harboring unique CRISPR guide sequences. Multiple negative and positive regulators were identified; surprisingly, knockout of the Rab12 gene was especially effective in decreasing phosphoRab10 levels in multiple cell types and knockout mouse tissues. Rab-driven increases in phosphoRab10 were specific for Rab12, LRRK2 dependent and PPM1H phosphatase reversible; they were seen with wild type and pathogenic G2019S and R1441C LRRK2. AlphaFold modeling revealed a novel Rab12 binding site in the LRRK2 Armadillo domain and we show that residues predicted to be essential for Rab12 interaction at this site influence overall phosphoRab levels in a manner distinct from Rab29 activation of LRRK2. Our data support a model in which Rab12 binding to a new site in the LRRK2 Armadillo domain activates LRRK2 kinase for Rab phosphorylation and could serve as a new therapeutic target for a novel class of LRRK2 inhibitors that do not target the kinase domain.
Maturation and Refinement of the Maculae and Foveae in the Anolis sagrei lizard
Authors: Wahle M. Austin , Kim Hannah Q. , Menke Douglas B. , Lauderdale James D. , Rasys Ashley M.
Published: February 2023

In primates, the fovea is a pit in the center of the macula, which is a region of the retina with a high concentration of cone photoreceptor cells that accounts for a large degree of visual acuity in primates. The maturation of this primate visual acuity area is characterized by the shallowing and widening of the foveal pit, a decrease in the diameter of the rod-free zone, and packing of photoreceptor cells more densely into this area of the retina, which occurs sometime after birth. Maturation occurs concurrently with progressing age and development, which further correlates with increasing eye size, retinal length, and retinal area. These observations have led to the hypothesis that the maturation of the fovea might be a function of mechanical variables that remodel the retina. However, this has never been explored outside of primates. Here, we take advantage of the Anolis sagrei lizard, which has a bifoveated retina, to study maturation of the fovea and macula. Eyes were collected from male and female lizards from five different age groups - hatchling, 2-month, 4-month, 6-month, and adult. We found that Anolis maculae undergo a maturation process somewhat different than what has been observed in primates. Anole macular diameters actually increase in size and undergo minimal photoreceptor cell packing, possessing a near complete complement of these cells at the time of hatching. As the anole eye expands, foveal centers experience little change in overall retina cell density with most cell redistribution occurring at the macular borders and peripheral retina areas.
Marginal specificity in protein interactions constrains evolution
Authors: Ghose Dia A. , Przydzial Kaitlyn E. , Mahoney Emily M. , Keating Amy E. , Laub Michael T.
Published: February 2023

The evolution of novel functions in biology relies heavily on gene duplication and divergence, creating large paralogous protein families. Selective pressure to avoid detrimental cross-talk often results in paralogs that exhibit exquisite specificity for their interaction partners. But how robust or sensitive is this specificity to mutation? Here, using deep mutational scanning, we demonstrate that a paralogous family of bacterial signaling proteins exhibits marginal specificity, such that many individual substitutions give rise to substantial cross-talk between normally insulated pathways. Our results indicate that sequence space is locally crowded despite overall sparseness, and we provide evidence that this crowding has constrained the evolution of bacterial signaling proteins. These findings underscore how evolution selects for ‘good enough’ rather than optimized phenotypes, leading to restrictions on the subsequent evolvability of paralogs.

Significance Statement

Large paralogous protein families are found throughout biology, the product of extensive gene duplication. To execute different functions inside cells, paralogs typically acquire different specificities, interacting with only desired, cognate partners and avoiding cross-talk with non-cognate proteins. But how robust is this interaction specificity to mutation? Can individual mutations lead to cross-talk or do paralogs diverge enough such that multiple mutations would be required, providing a mutational ‘buffer’ against cross-talk? To address these questions, we built mutant libraries that produce all possible single substitutions of a bacterial kinase and then screened for cross-talk to non-cognate proteins. Strikingly, we find that many single substitutions can produce cross-talk, meaning that these pathways typically exhibit only ‘marginal specificity’, and demonstrate that this restricts their evolvability.
Ongoing HIV replication in lymph node sanctuary sites in treated patients contributes to the total latent HIV at a very slow rate
Authors: Paryad-zanjani Sasan , Jagarapu Aditya , Piovoso Michael J. , Zurakowski Ryan
Published: February 2023

Lymph nodes (LNs) serve as a sanctuary site for HIV viruses due to the heterogeneous distribution of the antiretrovirals (ARVs) inside the LNs. There is an ongoing debate whether this represents ongoing cycles of viral replication in the LNs or merely residual virus production by latently infected cells. Previous work has claimed that the measured levels of genetic variation in proviruses sampled from the blood were inconsistent with ongoing replication. However, it is not clear what rate of variation is consistent with ongoing replication in small sanctuary sites.

In this study, we used a spherically symmetric compartmental ODE model to track the HIV viral dynamics in the LN and predict the contribution of ongoing replication within the LN to the wholebody proviral pool in an ARV-suppressed patient. This model tracks the reaction-diffusion dynamics of uninfected, actively infected, and latently infected T-cells as well as free virus within the LN parenchyma and the blood, and distinguishes between latently infected cells created before ARV therapy and during ARV therapy.

We simulated suppressive therapy beginning in year 5 post-infection. Each LN sanctuary site had a volume of 1 ml, and we considered cases of 1ml, 30ml, and 250ml total volume, which represent a single active sanctuary site, moderate systemic involvement, and involvement of the total lymphoid tissue. Viral load in the blood rapidly dropped and remained below the limit of detection in all cases but remained high in the LN sanctuary sites. Novel latent cells increased systemically over time but very slowly, taking between 25 and 50 years to reach 5% of the total latent pool, depending on the volume of lymphoid tissue involvement.

Putative sanctuary sites in LNs are limited in volume and produce novel latent cells slowly. Assays to detect genetic drift due to such sites would require very deep sequencing if sampling only from the blood. Previous studies showing a lack of genetic drift are consistent with the expected contribution of ongoing replication in lymph node sanctuary sites.