bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Calcitonin Administration on the Amount of Bone Formation After Sutural Expansion Using Micro-CT
Authors: Alatabi Hayder Saad Hanfoosh , Tobji Samir , Haouas Zohra
Published: August 2023

Objective:

Calcitonin injections were used in this investigation to see whether they influenced the quantity of bone formation after a rabbit model was subjected to micro-computed tomography expansion.

Materials and Methods:

Research was conducted on a total of 16 white male rabbits. Randomly, 4 groups of 4 rabbits each had their bone-borne expanders triggered by the Hyrax appliances as follows: In the first group (the control), the expansion was (0.5) mm per day for 12 days. In the second group, the same expansion protocol was used with 3 subcutaneous injections of calcitonin). In the third group, the expansion was (2.5) mm per day for 7 days followed by (0.5) mm per day for 7 days. In the fourth group, the same expansion protocol was used with 3 subcutaneous injections of calcitonin. As a result, all groups had their Hyrax devices expanded by 6 mm in total. Sutural separation and new bone growth were examined by micro-computed tomography after 6 weeks of retention. To end the experiment, the rabbits were given a high dosage of phenobarbitone (90 mg/kg).

Results:

In the calcitonin-receiving group, there was a significant increase in anterior and posterior sutural separation, when compared with non-calcitonin-receiving groups. In the (2.5) mm instant expansion protocol, there was a significant increase in anterior and posterior sutural separation, when compared with the (0.5) mm instant expansion protocol.

Conclusion:

Calcitonin and the instant expansion protocol enhance new bone formation in rabbits.
Comparison of Posttreatment Stability Between Mandibular Setback Surgery-Early and Conventional Surgery in Class III Patients: A 4.6-Year Follow-Up
Authors: Shin Yonsoo , Choi Tae-Hyun , Yoon Ji-Young , Kim Young-Kyun , Yun Pil-Young , Lee Nam-Ki
Published: August 2023

Objectives:

This retrospective study aims to compare long-term stability between the mandibular setback surgery-early (MSE) approach, involving minimal orthodontics, and the mandibular setback conventional surgery (MCS) approach, involving sufficient orthodontics, in Class III patients with mandibular prognathism.

Methods:

Among 210 patients who underwent orthognathic surgery, a total of 40 subjects were enrolled based on standardized inclusion criteria: only mandibular surgery, <5 mm setback difference between right and left of the mandible, orthodontics with fixed appliances, and more than 2 years of follow-up after treatment. These patients were allocated to the MSE (n = 20) and MCS groups (n = 20) according to the duration of presurgical orthodontics. Changes in cephalometric measurements were compared between the MSE and MCS groups before surgery (T0), 1 month after surgery (T1), at the end of treatment (T2), and posttreatment retention (T3).

Results:

The MSE and MCS groups had a mean presurgical orthodontic duration of 2 and 9.5 months, respectively. From T1 to T2, the MSE group showed a significantly larger forward movement of the mandible than the MCS group (2.1 versus 0.7 mm; P < 0.001). In addition, from T2 to T3 (average 4.6 years), the MSE group presented anterior relapse of 0.6 mm in the mandible, but there were no statistically significant intergroup differences.

Conclusion:

Although the MSE group showed greater postsurgical forward mandibular relapse than the MCS group, the two groups exhibited similar skeletal and dental stability during the posttreatment retention.
Racial Disparities Following Reconstructive Flap Procedures
Authors: Chwa Emily S. , Applebaum Sarah A. , Khazanchi Rushmin , Wester James R. , Gosain Arun K.
Published: August 2023

Background:

Prior reports have highlighted disparities in healthcare access, environmental conditions, and food insecurity between Black and White populations in the United States. However, limited studies have explored racial disparities in postoperative complications, particularly reconstructive flap surgeries.

Methods:

Cases of flap reconstruction based on named vascular pedicles were identified in the American College of Surgeons National Surgical Quality Improvement Program database and grouped into 3 time periods: 2005 to 2009, 2010 to 2014, and 2015 to 2019. Logistic regression was used to compare rates of postoperative complications between White and Black patients within each time period while controlling for comorbidities. Data for flap failure was only available from 2005 to 2010.

Results:

A total of 56,116 patients were included in the study, and 6293 (11.2%) were Black. Black patients were significantly younger than White patients and had increased rates of hypertension, smoking, and diabetes across all years (P<0.01). Black patients had significantly higher rates of sepsis compared to White patients in all time periods. From 2005 to 2009, Black patients had a significantly higher incidence of flap failure (aOR=2.58, P<0.01), return to the operating room (aOR=1.53, P=0.01), and having any complication (aOR=1.48, P<0.01). From 2010 to 2019, White patients had a higher incidence of superficial surgical site infection.

Conclusions:

Surgical complication rates following flap reconstruction based on a named vascular pedicle were higher for Black patients. Limited data on this topic currently exists, indicating that additional research on the drivers of racial disparities is warranted to improve plastic surgery outcomes in Black patients.
The Reactivation of Scleroderma After Autologous Fat Grafting
Authors: Wang Hayson Chenyu , Long Xiao
Published: August 2023

Background:

Patients with localized scleroderma (LS) often have to seek plastic surgery to improve facial esthetic impairment.

Aims:

The authors reported a case of the reactivation of LS after autologous fat grafting (AFG).

Patient:

A man presented with facial atrophy and skin fibrosis on the cheek with a history of LS. The disease had remained stable for 9 years and he was suggested to stop oral medication. With irreversible esthetic impairment on the face, he sought plastic surgery for improvement. He underwent twice AFG into the right cheek with about 60 mL fat graft each. The donor sites were the abdomen and both thighs.

Results:

Six months after the last AFG, the patient found new lesions occur on the lateral forehead. The patient was later diagnosed with reactivation of LS.

Conclusion:

The understanding of the surgical risk and perioperative management for patients with LS needs more research.
Predictors of fetal delivery in pregnant trauma patients: A multicenter study
Authors: Santos Jeffrey W. , Grigorian Areg , Lucas Alexa N. , Fierro Nicole , Dhillon Navpreet K. , Ley Eric J. , Smith Jennifer , Burruss Sigrid , Dahan Alden , Johnson Arianne , Ganske William , Biffl Walter L. , Bayat Dunya , Castelo Matthew , Wintz Diane , Schaffer Kathryn B. , Zheng Dennis J. , Tillou Areti , Coimbra Raul , Tuli Rahul , Santorelli Jarrett E. , Emigh Brent , Schellenberg Morgan , Inaba Kenji , Duncan Thomas K. , Diaz Graal , Tay-Lasso Erika , Zezoff Danielle C. , Nahmias Jeffry
Published: August 2023

BACKGROUND

Pregnant trauma patients (PTPs) undergo observation and fetal monitoring following trauma due to possible fetal delivery (FD) or adverse outcome. There is a paucity of data on PTP outcomes, especially related to risk factors for FD. We aimed to identify predictors of posttraumatic FD in potentially viable pregnancies.

METHODS

All PTPs (≥18 years) with ≥24-weeks gestational age were included in this multicenter retrospective study at 12 Level-I and II trauma centers between 2016 and 2021. Pregnant trauma patients who underwent FD ((+) FD) were compared to those who did not deliver ((−) FD) during the index hospitalization. Univariate analyses and multivariable logistic regression were performed to identify predictors of FD.

RESULTS

Of 591 PTPs, 63 (10.7%) underwent FD, with 4 (6.3%) maternal deaths. The (+) FD group was similar in maternal age (27 vs. 28 years, p = 0.310) but had older gestational age (37 vs. 30 weeks, p < 0.001) and higher mean injury severity score (7.0 vs. 1.5, p < 0.001) compared with the (−) FD group. The (+) FD group had higher rates of vaginal bleeding (6.3% vs. 1.1%, p = 0.002), uterine contractions (46% vs. 23.5%, p < 0.001), and abnormal fetal heart tracing (54.7% vs. 14.6%, p < 0.001). On multivariate analysis, independent predictors for (+) FD included abdominal injury (odds ratio [OR], 4.07; confidence interval [CI], 1.11–15.02; p = 0.035), gestational age (OR, 1.68 per week ≥24 weeks; CI, 1.44–1.95; p < 0.001), abnormal FHT (OR, 12.72; CI, 5.19–31.17; p < 0.001), and premature rupture of membranes (OR, 35.97; CI, 7.28–177.74; p < 0.001).

CONCLUSION

The FD rate was approximately 10% for PTPs with viable fetal gestational age. Independent risk factors for (+) FD included maternal and fetal factors, many of which are available on initial trauma bay evaluation. These risk factors may help predict FD in the trauma setting and shape future guidelines regarding the recommended observation of PTPs.

LEVEL OF EVIDENCE

Therapeutic/Care Management; Level III.
Association of High-Deductible Health Plans and Time to Surgery for Breast and Colon Cancer
Authors: Sheckter Clifford C , Rochlin Danielle H , Rubenstein Robyn , Shamsunder Meghana G , Morris Arden M , Wagner Todd H , Matros Evan
Published: August 2023

BACKGROUND:

High-deductible health plans (HDHPs) have been shown to delay timing of breast and colon cancer screening, although the relationship to the timing of cancer surgery is unknown. The objective of this study was to characterize timing of surgery for breast and colon cancer patients undergoing cancer operations following routine screening.

STUDY DESIGN:

Data from the IBM MarketScan Commercial Claims Database from 2007 to 2016 were queried to identify patients who underwent screening mammogram and/or colonoscopy. The calendar quarters of screening and surgery were analyzed with ordinal logistic regression. The time from screening to surgery (time to surgery, TTS) was evaluated using a Cox proportional hazard function.

RESULTS:

Among 32,562,751 patients who had screening mammograms, 0.7% underwent breast cancer surgery within the following year. Among 9,325,238 patients who had screening colonoscopies, 0.9% were followed by colon cancer surgery within a year. The odds of screening (OR 1.146 for mammogram, 1.272 for colonoscopy; p < 0.001) and surgery (OR 1.120 for breast surgery, 1.219 for colon surgery; p < 0.001) increased each quarter for HDHPs compared to low-deductible health plans. Enrollment in an HDHP was not associated with a difference in TTS. Screening in Q3 or Q4 was associated with shorter TTS compared to screening in Q1 (hazard ratio 1.061 and 1.046, respectively; p < 0.001).

CONCLUSIONS:

HDHPs were associated with delays in screening and surgery. However, HDHPs were not associated with delays in TTS. Interventions to improve cancer care outcomes in the HDHP population should concentrate on reducing barriers to timely screening.
Does Trauma Center Volume Account for the Association Between Trauma Center Verification Level and In-Hospital Mortality among Children Injured by Firearms in California?
Authors: Sullivan Gwyneth A , Reddy Susheel , Reiter Audra J , Zeineddin Suhail , Visenio Michael , Hu Andrew , Mackersie Robert , Kabre Rashmi , Raval Mehul V , Stey Anne M
Published: August 2023

BACKGROUND:

Heterogeneity in trauma center designation and injury volume offer possible explanations for inconsistencies in pediatric trauma center designation’s association with lower mortality among children. We hypothesized that rigorous trauma center verification, regardless of volume, would be associated with lower firearm injury-associated mortality in children.

STUDY DESIGN:

This retrospective cohort study leveraged the California Office of Statewide Health Planning and Development patient discharge data. Data from children aged 0 to 14 years in California from 2005 to 2018 directly transported with firearm injuries were analyzed. American College of Surgeons (ACS) trauma center verification level was the primary predictor of in-hospital mortality. Centers’ annual firearm injury volume data were analyzed as a mediator of the association between center verification level and in-hospital mortality. Two mixed-effects multivariable logistic regressions modeled in-hospital mortality and the estimated association with center verification while adjusting for patient demographic and clinical characteristics. One model included the center’s firearm injury volume and one did not.

RESULTS:

The cohort included 2,409 children with a mortality rate of 8.6% (n = 206). Adjusted odds of mortality were lower for children at adult level I (adjusted odds ratio [aOR] 0.38, 95% CI 0.19 to 0.80), pediatric (aOR 0.17, 95% CI 0.05 to 0.61), and dual (aOR 0.48, 95% CI 0.25 to 0.93) trauma centers compared to nontrauma/level III/IV centers. Firearm injury volume did not mediate the association between ACS trauma center verification and mortality (aOR/10 patient increase in volume 1.01, 95% CI 0.99 to 1.03).

CONCLUSIONS:

Trauma center verification level, regardless of firearm injury volume, was associated with lower firearm injury-associated mortality, suggesting that the ACS verification process is contributing to achieving optimal outcomes.
Pacific oysters do not compensate growth retardation following extreme acidification events
Authors: Lutier Mathieu , Pernet Fabrice , Di Poi Carole
Published: August 2023

Ocean acidification caused by anthropogenic carbon dioxide emissions alters the growth of marine calcifiers. Although the immediate effects of acidification from global ocean models have been well studied on calcifiers, their recovery capacity over a wide range of pH has never been evaluated. This aspect is crucial because acidification events that arise in coastal areas can far exceed global ocean predictions. However, such acidification events could occur transiently, allowing for recovery periods during which the effects on growth would be compensated, maintained or amplified. Here we evaluated the recovery capacity of a model calcifier, the Pacific oysterCrassostrea gigas. We exposed juveniles to 15 pH conditions between 6.4 and 7.8 for 14 days. Oyster growth was retarded below pH 7.1 while shells were corroded at pH 6.5. We then placed the oysters under ambient pH > 7.8 for 42 days. Growth retardation persisted at pH levels below pH 7.1 even after the stress was removed. However, despite persistent retardation, growth has resumed rapidly suggesting that the oysters can recover from extreme acidification. Yet we found that the differences in individual weight between pH conditions below 7.1 increased over time, and thus the growth retardation cannot be compensated and may affect the fitness of the bivalves.
Andrew David McLachlan. 25 January 1935—8 July 2022
Authors: Stone A. J. , Stewart M. , Eisenberg D. S. , Crowther FRS R. A.
Published: August 2023

Andrew McLachlan enjoyed a wide-ranging career, starting as a theoretical chemist and ending as a molecular biologist. After reading physics as an undergraduate at Trinity College, Cambridge, he joined the Theoretical Chemistry Section of the Chemistry Department to study for a PhD. His work on electron spin resonance then led to his election as a research fellow at Trinity. Following postdoctoral work in the United States, he returned to Cambridge as a college lecturer in physics at Trinity and was eventually appointed a university lecturer in chemistry. Despite a productive research programme in various aspects of theoretical chemistry, he decided that a move into the newly developing subject of molecular biology would provide an exciting opportunity. Accordingly, in 1967 he accepted an offer to join the Medical Research Council Laboratory of Molecular Biology. The initial plan was to work on the mechanism of oxygen uptake by haemoglobin, but he quickly became interested in wider problems of protein structure. In particular, he developed methods for aligning the sequences of different proteins and for detecting repeated sequences and motifs, leading to an interest in the evolution of protein sequences. In collaboration with others, he applied his methods to a wide range of proteins, providing important understanding of their structures and relationships.
A functional framework for interpreting phalangeal form
Authors: Dickinson Edwin , Young Melody W. , Flaim Nicholas D. , Sawiec Aleksander , Granatosky Michael C.
Published: August 2023

Across tetrapods, the proportional lengths of the manual and pedal phalanges are highly constrained, following a generalized blueprint of shortening in a proximodistal gradient. Despite this, several lineages of both mammals (e.g. sloths, bats and colugos) and birds (e.g. raptors, parrots and woodpeckers) have broken this pattern, shortening the proximal phalanx while elongating more distal elements. As yet, no unifying explanation for this convergence has been empirically evaluated. This study combines a comparative phylogenetic assessment of phalangeal morphology across mammals and birds with a novel bioinspired robotics approach to explicitly test functional hypotheses relating to these morphotypes. We demonstrate that shortening the proximal phalanx allows taxa to maximize forces produced at the proximal interphalangeal joint, while elongation of subsequent elements maintains total ray length—ensuring arboreal species can still enclose large-diameter supports. Within suspensory and vertically clinging mammals, we additionally observe a secondary adaptation towards maximizing grip strength: namely increasing the height of the trochleae to increase the moment arm of digital flexor muscles that cross the joint. Together, our analyses highlight that numerous tetrapod lineages independently converged upon this morphotype to maximize proximal gripping strength, an adaptation to support specialized hunting and locomotor behaviours.
Wind tunnel evaluation of novel drafting formations for an elite marathon runner
Authors: Marro Massimo , Leckert Jack , Rollier Ethan , Salizzoni Pietro , Bailly Christophe
Published: August 2023

Drafting is a strategy in marathon running races that reduces the drag force acting on a designated runner. Drafting involves a formation of athletes, called pacers, running in front of (and sometimes behind) the designated runner. The present experiments evaluated complex formations involving up to seven pacers with the aim of enhancing the performances of an elite marathoner. Wind tunnel measurements with 1/10 scale articulated runner manikins were carried out. First, simple formations with one or two pacers were examined and the results were compared with previous investigations. Second, the runner formations of the Nike Breaking2 and INEOS 1:59 Challenge events whose goal was to break the 2 h marathon barrier were studied. The main finding was the identification of three complex formations of six and seven pacers that allow a drag-force reduction of about 60% with respect to a solo runner and an estimated time saving of 262 s. These results point to how it may be possible to run the fastest marathon ever.
Computational modelling distinguishes diverse contributors to aneurysmal progression in the Marfan aorta
Authors: Li David S. , Cavinato Cristina , Latorre Marcos , Humphrey Jay D.
Published: August 2023

Thoracic aortic aneurysms are characterized by a progressive loss of biomechanical functionality resulting from degenerative changes in wall composition, microstructure, and mechanical properties. Among the many causes of these lesions, Marfan syndrome is the most common heritable condition, resulting from mutations to the gene that codes the elastin-associated glycoprotein fibrillin-1. Key histopathological features of the aneurysmal Marfan aorta include extensive degradation of elastic fibres, significant remodelling of fibrillar collagens and compromised smooth muscle cell function. Computational growth and remodelling models have confirmed the importance of compromised elastic fibre integrity in aneurysmal dilatation, but we show here that this contributor alone is not sufficient to describe biomechanical data collected from the two most common mouse models of Marfan syndrome. Rather, our simulations suggest that compromised mechanosensing and mechanoregulation of extracellular matrix by mural cells also play central roles in the natural history. Determination of optimal disease-contributing parameters further suggests a rapid reduction in cellular mechanosensing and mechanoregulation relative to diminished elastic fibre integrity, highlighting the importance of inter- and intra-lamellar elastin in the Marfan aorta. Aneurysmal dilatation in Marfan syndrome thus results from multiple contributors to progressive degeneration of the aortic wall, and computational mechanobiological models can help disentangle these contributions.
Haemophilus Influenzae bloodstream infection and third-generation cephalosporins susceptibility testing: a comparative case study using EUCAST and CLSI guidelines
Authors: Merlino John , Rizzo Sophia , English Suzanne , Baskar Sai Rupa , Siarakas Steven , Mckew Genevieve , Fernanado Shelanah , Gray Timothy
Published: August 2023

Introduction. In this comparative case study, we discuss clinically-relevant discrepancies of antimicrobial susceptibility testing (AST) interpretation for ceftriaxone against a non-typable, beta-lactamase negative, ampicillin-resistant (BLNAR) Haemophilus influenzaeisolated from a blood culture.
Case report: A 74 year old man presented with a 3-day illness characterised by shortness of breath and dry cough, and was noted to be febrile and hypoxic on admission. A blood culture bottle flagged positive with Gram-negative coccobacilli, later identified as Haemophilus influenzae with the patient commenced on ceftriaxone. The isolate was beta-lactamase negative and antibiotic susceptibility testing (AST) using disc diffusion revealed the isolate resistant to ceftriaxone and ampicillin by EUCAST methodology, with the patient subsequently changed to amoxicillin/clavulanate. Further AST using the CLSI methodology in parallel demonstrated discrepant results between the two susceptibility methods. The patient recovered without complications.
Conclusion. This discrepancy could lead to inconsistent reporting of susceptibilities between laboratories, and consequently antibiotic prescribing, especially for invasive isolates. As more laboratories adopt EUCAST methodologies for AST interpretation in Australia and globally, it is important for clinicians to consider the clinical implications of these methodological discrepancies.
Calcification and trophic responses of Mesophotic reefs to carbonate chemistry variability
Authors: Noyes Timothy J. , Garley Rebecca , Bates Nicholas R.
Published: August 2023

Mesophotic coral ecosystems (MCEs) are extensions of adjacent shallow water coral reefs. Accessibility to these ecosystems is challenging due to their depth limits (∼ 30 – 150 m) and as a result, scientific knowledge of these reef systems is limited. It has been posited that the depth limits of MCEs diminish anthropogenic effects experienced by shallow reef systems. A lack of empirical measurements to date has made this hypothesis impossible to determine for mesophotic reef metabolism. The alkalinity anomaly technique was utilized to determine rates of net ecosystem calcification (NEC) and net ecosystem production (NEP) from 30, 40 and 60 m mesophotic reefs during a 15-month period. Seawater chemistry was determined to be chemically conducive for calcification (average aragonite saturation Ωaragoniteof 3.58, average calcite saturation Ωcalciteof 5.44) with estimates of NEC indicating these reef systems were net accretive and within global average values for shallow coral reefs (< 30 m). The strongest periods of calcification occurred in late summer and were coupled with strong autotrophic signals. These episodes were followed by suppressed calcification and autotrophy and in the case of the 60 m reefs, a switch to heterotrophy. Whilst there was variability between the three reefs depths, the overall status of the mesophotic system was net autotrophic. This determination was the opposite of trophic status estimates previously described for adjacent shallow reefs. Whilst there were periods of net dissolution, the mesophotic reef system was net accretive (i.e., gross calcification > gross CaCO3dissolution). The measured inorganic carbon chemistry and estimates of NEC and NEP represent the first such biogeochemical measurements for MCEs. The values established by this study demonstrate just how close these understudied ecosystems are in terms of the known boundary thresholds for low saturation state reefs. Making predictions on how these ecosystems will respond to future climatic conditions, will require greater sampling effort over long times scales to decouple the environmental controls exerted on such ecosystems.
Characteristics of motor evoked potentials in patients with peripheral vascular disease
Authors: Sarai Pawandeep , Luff Charlotte , Rohani-Shukla Cyrus , Strutton Paul H
Published: August 2023

With an aging population, it is common to encounter people diagnosed with peripheral vascular disease (PVD). Some will undergo surgeries during which the spinal cord may be compromised and intraoperative neuromonitoring with motor evoked potentials (MEPs) is employed to help mitigate paralysis. No data exists on characteristics of MEPs in older, PVD patients, which would be valuable for patients undergoing spinal cord at-risk surgery or participating in neurophysiological research.

Transcranial magnetic stimulation, which can be delivered to the awake patient, was used to stimulate the motor cortex of 20 patients (mean (±SD) age 63.2yrs (±11.5) with confirmed PVD, every 10 minutes for one hour with MEPs recorded from selected upper and lower limb muscles. Data were compared to that from 20 healthy volunteers recruited for a protocol development study (28yrs (±7.6)). MEPs did not differ between patient’s symptomatic and non-symptomatic legs. MEP amplitudes were smaller in patients than in healthy participants in the upper limbs muscles, but not in lower limb muscles. Disease severity did not correlate with MEP amplitude. There were no differences over time in the coefficient of variation of MEP amplitude at each time point nor over the paradigm between groups. Latencies of MEPs were longer in patients for brachioradialis and vastus lateralis, but not in the other muscles studied.

The results obtained suggest PVD alone does not impact MEPs; there were no differences between more symptomatic and less symptomatic legs. Further, disease severity did not corelate with MEP characteristics. Differences observed in MEPs between patients and healthy participants are more likely a result of ageing.

With an aging population, more patients with PVD and cardiovascular risk factors will be participating in neurophysiological studies or undergoing surgery where spinal cord integrity is monitored. Our data show that MEPs from these patients can be easily evoked and interpreted.
LFSPROShiny: an interactive R/Shiny app for prediction and visualization of cancer risks in families with deleterious germlineTP53mutations
Authors: Nguyen Nam H , Dodd-Eaton Elissa B , Peng Gang , Corredor Jessica L. , Jiao Wenwei , Woodman-Ross Jacynda , Arun Banu K. , Wang Wenyi
Published: August 2023

Purpose

LFSPRO is an R library that implements risk prediction models for Li-Fraumeni syndrome (LFS), a genetic disorder characterized by deleterious germline mutations in theTP53gene. To facilitate the use of these models in clinics, we developed LFSPROShiny, an interactive R/Shiny interface of LFSPRO that allows genetic counselors (GCs) to perform risk predictions without any programming components, and further visualize the risk profiles of their patients to aid the decision-making process.

Methods

LFSPROShiny implements two models that have been validated on multiple LFS patient cohorts: a competing-risk model that predicts cancer-specific risks for the first primary, and a recurrent-event model that predicts the risk of a second primary tumor. Starting with a visualization template, we keep regular contact with GCs, who ran LFSPROShiny in their counseling sessions, to collect feedback and discuss potential improvement. Upon receiving the family history as input, LFSPROShiny renders the family into a pedigree, and displays the risk estimates of the family members in a tabular format. The software offers interactive overlaid side-by-side bar charts for visualization of the patients’ cancer risks relative to the general population.

Results

We walk through a detailed example to illustrate how GCs can run LFSPROShiny in clinics, from data preparation to downstream analyses and interpretation of results with an emphasis on the utilities that LFSPROShiny provides to aid decision making.

Conclusion

Since Dec 2021, we have applied LFSPROShiny to over 100 families from counseling sessions at MD Anderson Cancer Center. Our study suggests that software tools with easy-to-use interfaces are crucial for the dissemination of risk prediction models in clinical settings, hence serving as a guideline for future development of similar models.
Free energies of the Gln tautomerization and rotation mechanism of dark-state recovery in blue light-using flavin proteins
Authors: Pérez de Alba Ortíz Alberto , Rovira Carme , Ensing Bernd
Published: August 2023

Blue light-using flavin (BLUF) proteins are light-sensors that regulate responsive movement, gene expression and enzyme activity in diverse organisms. Their signaling times range from seconds to minutes, indicating a uniquely flexible dark-state recovery mechanism. Unlike other light-sensors, the flavin chromophore is non-covalently bonded to the protein. Hence, the switching occurs via a change in the protein-flavin hydrogen-bond network, involving conserved residues transferring protons, tautomerizing, rotating, and approaching or leaving the chromophore pocket; triggering secondary structure displacements. The specific deactivation steps and residue roles have remained controversial. The detailed process is difficult to probe experimentally, and although simulations can track it, the computational effort is daunting. We combine forefront techniques to simulate, for the first time, explicit dynamics of the deactivation. A hybrid quantum mechanics/molecular mechanics scheme focuses the computational resolution in the flavin’s vicinity, while our path-based methods sample the mechanism of dark-state recovery with high efficiency. Our protocol delivers free-energy profiles for the deactivation of two BLUF proteins, BlrB and AppA; corroborating a proposed mechanism based on the rotation and tautomerization of a conserved Gln. We find that the conformation of a Trp and a Met near the flavin is crucial to modulate the rate-determining barrier, which differs significantly between the BlrB and AppA proteins. Our work evidences how specific variations of the deactivation mechanism control vast differences in signaling times.
Flexible regulation of representations on a drifting manifold enables long-term stable complex neuroprosthetic control
Authors: Natraj Nikhilesh , Seko Sarah , Abiri Reza , Yan Hongyi , Graham Yasmin , Tu-Chan Adelyn , Chang Edward F. , Ganguly Karunesh
Published: August 2023

The nervous system needs to balance the stability of neural representations with plasticity. It is unclear what is the representational stability of simple actions, particularly those that are well-rehearsed in humans, and how it changes in new contexts. Using an electrocorticography brain-computer interface (BCI), we found that the mesoscale manifold and relative representational distances for a repertoire of simple imagined movements were remarkably stable. Interestingly, however, the manifold’s absolute location demonstrated day-to-day drift. Strikingly, representational statistics, especially variance, could be flexibly regulated to increase discernability during BCI control without somatotopic changes. Discernability strengthened with practice and was specific to the BCI, demonstrating remarkable contextual specificity. Accounting for drift, and leveraging the flexibility of representations, allowed neuroprosthetic control of a robotic arm and hand for over 7 months without recalibration. Our study offers insight into how electrocorticography can both track representational statistics across long periods and allow long-term complex neuroprosthetic control.
Mechanism of proton-powered c-ring rotation in a mitochondrial ATP synthase
Authors: Blanc Florian E. C. , Hummer Gerhard
Published: August 2023

Proton-powered c-ring rotation in mitochondrial ATP synthase is crucial to convert the transmembrane protonmotive force into torque to drive the synthesis of ATP. Capitalizing on recent cryo-EM structures, we aim at a structural and energetic understanding of how functional directional rotation is achieved. We performed multi-microsecond atomistic simulations to determine the free energy profiles along the c-ring rotation angle before and after the arrival of a new proton. Our results reveal that rotation proceeds by dynamic sliding of the ring over the a-subunit surface, during which interactions with conserved polar residues stabilize distinct intermediates. Ordered water chains line up for a Grotthuss-type proton transfer in one of these intermediates. After proton transfer, a high barrier prevents backward rotation and an overall drop in free energy favors forward rotation, ensuring the directionality of c-ring rotation required for the thermodynamically disfavored ATP synthesis. The essential arginine of the a-subunit stabilizes the rotated configuration through a salt-bridge with the c-ring. Overall, we describe a complete mechanism for the rotation step of the ATP synthase rotor, thereby illuminating a process critical to all life at atomic resolution.
Regional and fine-scale local adaptation in salinity tolerance inDaphniainhabiting contrasting clusters of inland saline waters
Authors: Brans Kristien I. , Vad Csaba F. , Horváth Zsófia , Santy Luca , Cuypers Kiani , Ptacnik Robert , De Meester Luc
Published: August 2023

Understanding the spatial scales at which organisms can adapt to strong natural and human-induced environmental gradients is important. Salinisation is a key threat to biodiversity, ecosystem functioning, and the provision of ecosystem services of freshwater systems. Clusters of naturally saline habitats represent ideal test cases to study the extent and scale of local adaptation to salinisation. We studied local adaptation of the water fleaDaphnia magna, a key component of pond food webs, to salinity in two contrasting landscapes - a dense cluster of sodic bomb crater ponds and a larger-scale cluster of soda pans. We show regional differentiation in salinity tolerance reflecting the higher salinity levels of soda pans versus bomb crater ponds. We found local adaptation to differences in salinity levels at the scale of tens of metres among bomb crater pond populations but not among geographically more distant soda pan populations. More saline bomb crater ponds showed an upward shift of the minimum salt tolerance observed across clones and a consequent gradual loss of less tolerant clones in a nested pattern. Our results show evolutionary adaptation to salinity gradients at different spatial scales and fine-tuned local adaptation in neighbouring habitat patches in a natural landscape.
Variable Gain DNA Nanostructure Charge Amplifiers for Biosensing
Authors: Majikes Jacob M. , Cho Seulki , Cleveland Thomas E. , Liddle J. Alexander , Balijepalli Arvind
Published: August 2023

Electronic measurements of engineered nanostructures comprised solely of DNA (DNA nanostructures) enable new signal conditioning modalities in biosensing. Here, we demonstrate how DNA nanostructures that alter their conformation upon binding a nucleic acid analyte drastically, and reversibly, amplify the measured electrochemical signal. This amplification was controlled by the applied electrical field to achieve a response ≈ 2×104times greater than that measured from DNA hybridization. Because the amplification is independent of the interaction between the analyte and the DNA nanostructure, our approach provides a platform for tuning the response of the system for high performance that is agnostic of the end application. These molecularly precise self-assembled DNA nanostructures when paired with scalable electronic readout can therefore lead the way to highly sensitive multiplexed biosensing.
Tuning of B12photochemistry in the CarH photoreceptor to avoid radical photoproduct
Authors: Camacho Ines S. , Wall Emma , Sazanovich Igor V. , Gozzard Emma , Towrie Mike , Hunt Neil T. , Hay Sam , Jones Alex R.
Published: August 2023

Time-resolved infrared spectroscopy reveals the flow of electron density through coenzyme B12in the light-activated, bacterial transcriptional regulator, CarH. The protein stabilises a series of charge transfer states that result in a photoresponse that avoids reactive, and potentially damaging, radical photoproducts.
Linking spontaneous and stimulated spine dynamics
Authors: Eggl M. F. , Chater T. E. , Petkovic J. , Goda Y. , Tchumatchenko T.
Published: August 2023

Our brains continuously acquire and store memories through synaptic plasticity. However, spontaneous synaptic changes can also occur and pose a challenge for maintaining stable memories. Despite fluctuations in synapse size, recent studies have shown that key population-level synaptic properties remain stable over time. This raises the question of how local synaptic plasticity affects the global population-level synaptic size distribution and whether individual synapses undergoing plasticity escape the stable distribution to encode specific memories. To address this question, we(i)studied spontaneously evolving spines and(ii)induced synaptic potentiation at selected sites while observing the spine distribution pre- and post-stimulation. We designed a stochastic model to describe how the current size of a synapse affects its future size under baseline and stimulation conditions and how these local effects give rise to population-level synaptic shifts. Our study offers a new understanding of how seemingly spontaneous synaptic fluctuations and local plasticity both contribute to population-level synaptic dynamics.
Increasing NPYergic transmission in the hippocampus rescues aging-related deficits of long-term potentiation in the mouse dentate gyrus
Authors: Klinger Katharina , del Ángel Miguel , Çalışkan Gürsel , Stork Oliver
Published: August 2023

Loss of neuropeptide Y (NPY)-expressing interneurons in the hippocampus and decaying cholinergic neuromodulation are thought to contribute to impaired cognitive function during aging. However, the interaction of these two neuromodulatory systems in maintaining hippocampal synaptic plasticity during healthy aging has not been explored so far. Here we report profound sex differences in the Neuropeptide-Y (NPY) levels in the dorsal dentate gyrus (DG) with higher NPY concentrations in the male mice compared to their female counterparts and a reduction of NPY levels during aging specifically in males. This change in aged males is accompanied by a deficit in theta burst-induced long-term potentiation (LTP) in the medial perforant path-to-dorsal DG (MPP-DG) synapse, which can be rescued by enhancing cholinergic activation with the acetylcholine esterase blocker, physostigmine. Importantly, NPYergic transmission is required for this rescue of LTP. Moreover, exogenous NPY application alone is sufficient to recover LTP induction in aged male mice, even in the absence of the cholinergic stimulator. Together, our results suggest that in male mice NPYergic neurotransmission is a critical factor for maintaining dorsal DG LTP during aging.
Successful regeneration of the adult zebrafish retina is dependent on inflammatory signaling
Authors: Bludau Oliver , Weber Anke , Bosak Viktoria , Kuscha Veronika , Dietrich Kristin , Hans Stefan , Brand Michael
Published: August 2023

Inflammation can lead to persistent and irreversible loss of retinal neurons and photoreceptors in mammalian vertebrates. In contrast, in the adult zebrafish brain, acute neural inflammation is both necessary and sufficient to stimulate regeneration of neurons. Here, we report on the critical, positive role of the immune system to support retina regeneration in adult zebrafish. After sterile, ablation of photoreceptors by phototoxicity, we find rapid response of tissue-resident microglia and neutrophils, which returns to homeostatic levels within 14 days post lesion. Pharmacological or genetic impairment of immune cell reactivity results in a reduced Müller glia stem cell response, seen as decreased reactive proliferation, and a strikingly reduced number of regenerated cells from them, including photoreceptors. Conversely, injection of the immune stimulators flagellin, zymosan, or M-CSF into the vitreous of the eye, in spite of the absence of a retinal lesion, leads to a robust proliferation response and the up-regulation of regeneration-associated marker genes in Müller glia. Our results suggest that neuroinflammation is a necessary and sufficient driver for retinal regeneration in the adult zebrafish retina.
Generation of Human Regulatory Dendritic Cells from Cryopreserved Healthy Donor Cells and Hematopoietic Stem Cell Transplant Recipients
Authors: Scroggins Sabrina M. , Schlueter Annette J.
Published: August 2023

Acute graft versus host disease (GVHD) remains a significant complication following hematopoietic stem cell transplant (HSCT), despite improved human leukocyte antigen (HLA) matching and advances in prophylactic treatment regimens. Previous studies have shown promising results for future regulatory dendritic cell (DCreg) therapies in the amelioration of GVHD. This study evaluates the effects of cryopreservation on DCreg generation, generation of young and older DCreg in serum-free media, and the feasibility of DCreg generated from young and older HSCT donor monocytes. DCreg were generated in X-vivo 15 serum-free media from donor monocytes. Donors included young and older individuals, either healthy donors or HSCT patients. Phenotypic differences in cell populations were assessed via flow cytometry while pro-inflammatory and anti-inflammatory cytokine production was evaluated in culture supernatants. The number of DCreg generated from cryopreserved monocytes of healthy donors was not significantly different from freshly isolated monocytes. DCreg generated from cryopreserved monocytes had similar levels of co-stimulatory molecule expression, inhibitory molecule expression, and cytokine production as freshly isolated monocytes. Young and older healthy donor monocytes generated similar numbers of DCreg with similar cytokine production and phenotype. Although monocytes from older HSCT patients produced significantly fewer DCreg, DCreg from young and older HSCT patients have a comparable phenotype and cytokine production. Monocytes from young and older myelodysplastic syndrome (MDS) patients generated reduced numbers of DCreg compared to non-MDS monocytes. Results suggest cryopreservation of monocytes from many HSCT patients allows for cost effective generation of DCreg for the prevention and treatment of GVHD on an as needed basis. Although generation of DCreg from MDS patients require further assessment, these data support the possibility ofin vitrogenerated DCreg as a therapy to reduce GVHD-associated morbidity and morbidity in young and older HSCT recipients.
Informing virtual clinical trials of hepatocellular carcinoma with spatial multi-omics analysis of a human neoadjuvant immunotherapy clinical trial
Authors: Zhang Shuming , Deshpande Atul , Verma Babita K. , Wang Hanwen , Mi Haoyang , Yuan Long , Ho Won Jin , Jaffee Elizabeth M. , Zhu Qingfeng , Anders Robert A. , Yarchoan Mark , Kagohara Luciane T. , Fertig Elana J. , Popel Aleksander S.
Published: August 2023

Human clinical trials are important tools to advance novel systemic therapies improve treatment outcomes for cancer patients. The few durable treatment options have led to a critical need to advance new therapeutics in hepatocellular carcinoma (HCC). Recent human clinical trials have shown that new combination immunotherapeutic regimens provide unprecedented clinical response in a subset of patients. Computational methods that can simulate tumors from mathematical equations describing cellular and molecular interactions are emerging as promising tools to simulate the impact of therapy entirelyin silico. To facilitate designing dosing regimen and identifying potential biomarkers, we developed a new computational model to track tumor progression at organ scale while reflecting the spatial heterogeneity in the tumor at tissue scale in HCC. This computational model is called a spatial quantitative systems pharmacology (spQSP) platform and it is also designed to simulate the effects of combination immunotherapy. We then validate the results from the spQSP system by leveraging real-world spatial multi-omics data from a neoadjuvant HCC clinical trial combining anti-PD-1 immunotherapy and a multitargeted tyrosine kinase inhibitor (TKI) cabozantinib. The model output is compared with spatial data from Imaging Mass Cytometry (IMC). Both IMC data and simulation results suggest closer proximity between CD8 T cell and macrophages among non-responders while the reverse trend was observed for responders. The analyses also imply wider dispersion of immune cells and less scattered cancer cells in responders’ samples. We also compared the model output with Visium spatial transcriptomics analyses of samples from post-treatment tumor resections in the original clinical trial. Both spatial transcriptomic data and simulation results identify the role of spatial patterns of tumor vasculature and TGFβ in tumor and immune cell interactions. To our knowledge, this is the first spatial tumor model for virtual clinical trials at a molecular scale that is grounded in high-throughput spatial multi-omics data from a human clinical trial.
Ecological predictors of organelle genome evolution: Phylogenetic correlations with taxonomically broad, sparse, unsystematized data
Authors: Giannakis Konstantinos , Richards Luke , Johnston Iain G.
Published: August 2023

Comparative analysis of variables across phylogenetically linked observations can reveal mechanisms and insights in evolutionary biology. As the taxonomic breadth of the sample of interest increases, challenges of data sparsity, poor phylogenetic resolution, and complicated evolutionary dynamics emerge. Here, we investigate a cross-eukaryotic question where all these problems exist: which organismal ecology features are correlated with gene retention in mitochondrial and chloroplast DNA (organelle DNA or oDNA). Through a wide palette of synthetic control studies, we characterize the specificity and sensitivity of a collection of parametric and non-parametric phylogenetic comparative approaches to identify relationships in the face of such sparse and awkward datasets. We combine and curate ecological data coupled to oDNA genome information across eukaryotes, including a new semi-automated approach for gathering data on organismal traits from less systematized open-access resources including encyclopedia articles on species and taxa. Combining this unique dataset with our benchmarked comparative approaches, we confirm support for several known links between organismal ecology and organelle gene retention, identify several previously unidentified relationships constituting possible ecological contributors to oDNA genome evolution, and provide support for a recently hypothesized link between environmental demand and oDNA retention. We, with caution, discuss the implications of these findings for organelle evolution and of this pipeline for broad comparative analyses in other fields.