bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmaceutical Pollution from Human Use and the Polluter Pays Principle
Authors: Malmqvist Erik , Fumagalli Davide , Munthe Christian , Larsson D G Joakim
Published: July 2023

Human consumption of pharmaceuticals often leads to environmental release of residues via urine and faeces, creating environmental and public health risks. Policy responses must consider the normative question how responsibilities for managing such risks, and costs and burdens associated with that management, should be distributed between actors. Recently, the Polluter Pays Principle (PPP) has been advanced as rationale for such distribution. While recognizing some advantages of PPP, we highlight important ethical and practical limitations with applying it in this context: PPP gives ambiguous and arbitrary guidance due to difficulties in identifying the salient polluter. Moreover, when PPP does identify responsible actors, these may be unable to avoid or mitigate their contribution to the pollution, only able to avoid/mitigate it at excessive cost to themselves or others, or excusably ignorant of contributing. These limitations motivate a hybrid framework where PPP, which emphasizes holding those causing large-scale problems accountable, is balanced by the Ability to Pay Principle (APP), which emphasizes efficiently managing such problems. In this framework, improving wastewater treatment and distributing associated financial costs across water consumers or taxpayers stand out as promising responses to pharmaceutical pollution from human use. However, sound policy depends on empirical considerations requiring further study.
Ethical Considerations for Augmenting Surveys with Auxiliary Data Sources
Authors: Struminskaya Bella , Sakshaug Joseph W
Published: July 2023

Survey researchers frequently use supplementary data sources, such as paradata, administrative data, and contextual data to augment surveys and enhance substantive and methodological research capabilities. While these data sources can be beneficial, integrating them with surveys can give rise to ethical and data privacy issues that have not been completely resolved. In this research synthesis, we review ethical considerations and empirical evidence on how privacy concerns impact participation in studies that collect these novel data sources to supplement surveys. We further discuss potential approaches for safeguarding participants’ data privacy during data collection and dissemination that may assuage their concerns. Finally, we conclude with open questions and suggested avenues for future research.
Prenatal Genetic Screening in Twin Pregnancy
Authors: Buckley Lauren , Hopkins Maeve , Kuller Jeffrey A. , Dugoff Lorraine
Published: July 2023

Twin pregnancy presents unique considerations for aneuploidy screening. Pre-test counseling regarding benefits, alternatives, and options for aneuploidy screening should be provided to all patients carrying twin pregnancy. This article aims to review the options for aneuploidy screening in twin pregnancy including the potential benefits and limitations.
Psychopharmacological Considerations for Gender-Affirming Hormone Therapy
Authors: Kim Hyun-Hee , Goetz Teddy G. , Grieve Victoria , Keuroghlian Alex S.
Published: July 2023

The field of transgender health has grown exponentially since the early 2010s. While this increased visibility has not been without controversy, there is growing acknowledgement of the needs of transgender, nonbinary, and gender expansive (TNG) patients and the health disparities they experience compared to the cisgender population. There is also increased interest among clinicians and trainees in providing gender-affirming care in all medical specialties. This is particularly relevant in psychiatry as mental health disparities in TNG patients have been well-documented. TNG patients experience significant minority stress and higher rates of psychiatric illness, self-harm, suicidality, and psychiatric hospitalization compared to their cisgender peers. In this review, we will cover potential interactions and side effects relevant to psychiatric medication management for the three most common medication classes prescribed as part of gender-affirming hormone therapy (GAHT): gonadotropin-releasing hormone receptor agonists, estradiol, and testosterone. Although no studies directly examining the efficacy of psychiatric medications or their interactions with GAHT for TNG patients have been published yet, we have synthesized the existing literature from both cisgender and TNG patients to shed light on health care disparities seen in TNG patients. Since clinicians’ lack of comfort and familiarity with gender-affirming care contributes significantly to these disparities, we hope this narrative review will help psychiatric prescribers provide TNG patients with the same quality of care that cisgender patients receive.
Perception of eHealth Programs for Cardiovascular Health
Authors: Su Jing Jing , Bayuo Jonathan , Abu-Odah Hammoda , Lin Rose S.Y. , He Qijun , Molassiotis Alex
Published: July 2023

Background

Despite emerging evidence on the effectiveness of eHealth interventions in improving cardiovascular health, little is known about the perception of use and efficacy of these interventions and real-world application.

Objective

We sought to develop an in-depth understanding of the perceptions of eHealth interventions in improving cardiovascular health.

Methods

This is a systematic review and meta-synthesis of qualitative studies. A comprehensive search of multiple databases and a manual search of the references list were conducted. Meta-synthesis of qualitative data was performed to review and interpret the findings. The study report followed the ENTREQ checklist.

Results

Four themes emerged regarding perceptions of eHealth interventions: preferred eHealth intervention design features, enabling healthcare professionals' support, eHealth engagement for health benefits, and barriers to eHealth engagement. Intervention design features should integrate motivational elements, use an eHealth literacy lens, and enhance cultural relevance. Healthcare professionals appreciated these new working methods but voiced concern about competency building. Real-world usage initiation was driven by perceived needs and usefulness, whereas persistent engagement was inspired by intrinsic motivation in participants.

Conclusions

eHealth interventions were appreciated as a valuable opportunity for providing alternative/supplementary cardiac care for health optimization. Participants commented on the need for more explicit and accurate health information presentation, and they appreciated the motivational elements in empowering them with self-determination over daily self-care behaviors. Professionals raised the need for specific guidance to enhance competency and intervention fidelity when delivering eHealth care.
Comparison of Predictive Models for Prevention of Missed Endoscopy Appointments- failure of a Predictive Model to Outperform Overbooking Model
Authors: Hookey Lawrence , Lu Thomas , Khan Sana , Reed Joshua , Day Andrew , Norman Patrick
Published: July 2023

Background:

Patient late cancelation and nonattendance for endoscopy appointments is an ongoing problem affecting the productivity and wait times of endoscopy units. Previous research evaluated a model for predictive overbooking and had promising results.

Study:

All endoscopy visits at an outpatient endoscopy unit during 4 nonconsecutive months were included in the data analysis. Patients who did not attend their appointment, or canceled with 48 hours of their appointment were considered nonattendees. Demographic, health, and prior visit behavior data was collected and the groups compared.

Results:

1780 patients attended 2331 visits in the study period. Comparing the attendee versus non-attendees, there were significant differences in mean age, prior absenteeism, prior cancelations, and total number of hospital visits. No significant differences were seen between groups in winter versus non-winter months, the day of the week, sex distribution, type of procedure booked, or whether the referral was from specialist clinic or direct to procedure. The visit cancelation proportion (calculated excluding current visit) was substantially higher in the absentee group (P<0.0001). A predictive model was developed and compared to current booking as well as a straight overbooking of 7%. Both overbooking models performed better than the current practice, but the predictive overbooking model did not outperform straight overbooking.

Conclusions:

Developing an endoscopy unit specific predictive model may not be more beneficial than straight overbooking as calculated by missed appointment percentage.
The Impact of Chronic Cannabis Use on Esophageal Motility in Patients Referred for Esophageal Manometry
Authors: Ugwuegbu Obinna , Shibli Fahmi , Kim Yeseong , Rangan Vikram , Kurin Michael , Ayoub Fares , Ganocy Stephen , Kavitt Robert , Fass Ronnie
Published: July 2023

Background:

Tetrahydrocannabinol, the main psychoactive compound in cannabis, binds with high affinity to the cannabinoid 1 receptor. Small randomized controlled studies using conventional manometry have shown that the cannabinoid 1 receptor can modulate esophageal function, namely transient lower esophageal sphincter relaxation frequency and lower esophageal sphincter tone. The effect of cannabinoids on esophageal motility in patients referred for esophageal manometry has not been fully elucidated using high-resolution esophageal manometry (HREM). We aimed to characterize the clinical effect of chronic cannabis use on esophageal motility utilizing HREM.

Methods:

Patients who underwent HREM from 2009 to 2019 were identified at 4 academic medical centers. The study group consisted of patients with a noted history of chronic cannabis use, a diagnosis of cannabis-related disorder, or a positive urine toxicology screen. Age and gender-matched patients with no history of cannabis use were selected to form the control group. Data on HREM metrics based on the Chicago classification V3, and the prevalence of esophageal motility disorders were compared. Confounding effects of BMI and medications on esophageal motility were adjusted for.

Results:

Chronic cannabis use was found to be an independent negative predictor of weak swallows (β=−8.02, P=0.0109), but not a predictor of failed swallows (P=0.6890). The prevalence of ineffective esophageal motility was significantly lower in chronic cannabis users compared with nonusers (OR=0.44, 95% CI 0.19–0.93, P=0.0384). There was no significant difference in the prevalence of other esophageal motility disorders between the 2 cohorts. In patients with dysphagia as their primary indication for HREM, chronic cannabis use was found to be independently associated with increased median integrated relaxation pressure (β=6.638, P=0.0153) and increased mean lower esophageal sphincter resting pressure (β=10.38, P=0.0084).

Conclusions:

Chronic cannabis use is associated with decreased weak swallows and reduced prevalence of ineffective esophageal motility in patients referred for esophageal manometry. In patients referred for dysphagia, chronic cannabis use is associated with increased integrated relaxation pressure and lower esophageal sphincter resting pressure, though not to levels above the normal range.
Preventing biological waste: Effective use of viable tissue in traumatized lower extremities
Authors: Lansford Jefferson L. , McCarthy Conor F. , Souza Jason M. , Saberski Ean R. , Potter Benjamin K.
Published: July 2023

Severe open lower extremity trauma requires debridement to remove contamination and devitalized tissues. Aggressive debridement should be balanced with preservation of viable tissue. These often damaged but preserved viable tissues are “spare parts” that augment the options available for reconstruction. The long-term goal of reconstruction should be functional limb restoration and optimization. Injury patterns, levels, and patient factors will determine whether this endeavor is better accomplished with limb salvage or amputation. This article reviews the rationale and strategies for preserving spare parts throughout debridement and then incorporating them as opportunistic grafts in the ultimate reconstruction to facilitate healing and maximize extremity function.

Level of Evidence:

5.
Unique Genomic Alterations and Microbial Profiles Identified in Patients With Gastric Cancer of African, European, and Asian Ancestry
Authors: Abate Miseker , Walch Henry , Arora Kanika , Vanderbilt Chad M. , Fei Teng , Drebin Harrison , Shimada Shoji , Maio Anna , Kemel Yelena , Stadler Zsofia K. , Schmeltz Joseph , Sihag Smita , Ku Geoffrey Y. , Gu Ping , Tang Laura , Vardhana Santosha , Berger Michael F. , Brennan Murray F. , Schultz Nikolaus D. , Strong Vivian E.
Published: July 2023

Objective:

Here, we characterize differences in the genetic and microbial profiles of GC in patients of African (AFR), European, and Asian ancestry.

Background:

Gastric cancer (GC) is a heterogeneous disease with clinicopathologic variations due to a complex interplay of environmental and biological factors, which may affect disparities in oncologic outcomes..

Methods:

We identified 1042 patients with GC with next-generation sequencing data from an institutional Integrated Mutation Profiling of Actionable Cancer Targets assay and the Cancer Genomic Atlas group. Genetic ancestry was inferred from markers captured by the Integrated Mutation Profiling of Actionable Cancer Targets and the Cancer Genomic Atlas whole exome sequencing panels. Tumor microbial profiles were inferred from sequencing data using a validated microbiome bioinformatics pipeline. Genomic alterations and microbial profiles were compared among patients with GC of different ancestries.

Results:

We assessed 8023 genomic alterations. The most frequently altered genes were TP53, ARID1A, KRAS, ERBB2, and CDH1. Patients of AFR ancestry had a significantly higher rate of CCNE1 alterations and a lower rate of KRAS alterations (P < 0.05), and patients of East Asian ancestry had a significantly lower rate of PI3K pathway alterations (P < 0.05) compared with other ancestries. Microbial diversity and enrichment did not differ significantly across ancestry groups (P > 0.05).

Conclusions:

Distinct patterns of genomic alterations and variations in microbial profiles were identified in patients with GC of AFR, European, and Asian ancestry. Our findings of variation in the prevalence of clinically actionable tumor alterations among ancestry groups suggest that precision medicine can mitigate oncologic disparities.
Swelling of Atrophic Optic Discs in Idiopathic Intracranial Hypertension
Authors: Xie Jim Shenchu , Donaldson Laura , Margolin Edward A.
Published: July 2023

Background:

Monitoring patients with idiopathic intracranial hypertension (IIH) and optic atrophy may be difficult as papilledema may not be appreciable on ophthalmoscopy. This retrospective chart review evaluated whether papilledema recurrence can be detected in this population using optical coherence tomography (OCT).

Methods:

Serial clinical assessments, ophthalmoscopy, and peripapillary OCT were reviewed in a cohort of patients with IIH and optic atrophy. Atrophy was defined as moderate if average peripapillary retinal nerve fiber layer (pRNFL) thickness was ≤80 μm and severe if average pRNFL thickness was ≤60 μm on at least 2 consecutive high-quality OCT scans. Based on the upper tolerance limit of test–retest variability, mean pRNFL elevation of ≥6 μm with subsequent decrease to baseline thickness was considered papilledema.

Results:

In a cohort of 165 patients with IIH, 32 eyes of 20 patients and 22 eyes of 12 patients demonstrated moderate and severe optic atrophy, respectively. Over a median follow-up of 198.5 weeks (range, 14.0–428.9), 63.3% (19 of 30) of patients had at least 1 episode of relapse, and 50.0% (15 of 30) had at least 1 episode of papilledema. There was a total of 36 relapse episodes, of which 7 occurred in patients with clinical signs and symptoms but no OCT evidence of relapse, 12 occurred in patients with OCT changes but no clinical signs and symptoms of relapse, and 17 occurred in patients with both clinical and OCT evidence to support relapse. The median percent pRNFL increase in the latter 2 groups was 13.7% (range, 7.5–111.8), and 7 eyes (13.0%) of 5 patients (16.7%) showed thickening greater than 20.0% from baseline. The rate, magnitude, and concordance of pRNFL swelling were similar between moderately vs severely atrophic eyes.

Conclusions:

Papilledema recurrence can be detected in atrophic optic discs using OCT. All patients with atrophic IIH should be longitudinally monitored with pRNFL measurement. Concurrence of other relapse-suggestive features should prompt further evaluation.
Biological–physical interactions are fundamental to understanding and managing coastal dynamics
Authors: Solan Martin , Spencer Tom , Paterson David M. , Unsworth Christopher A. , Christie Elizabeth K. , Blight Andrew J. , Brown Jenny , Brooks Helen , Lichtman I. Dougal , Wei Xiaoyan , Li Xiaorong , Thorne Pete , Leyland Julian , Godbold Jasmin A. , Thompson Charlie , Williams Megan E. , Plater Andrew , Moller Iris , Amoudry Laurent O.
Published: July 2023

There is an urgent need to address coastal dynamics as a fundamental interaction between physical and biological processes, particularly when trying to predict future biological–physical linkages under anticipated changes in environmental forcing. More integrated modelling, support for observational networks and the use of management interventions as controlled experimental exercises should now be vigorously pursued.
First case of ventilator-associated pneumonia due to Aeromonas hydrophila
Authors: Srivastava Amit , Tripathy Sarvodaya , Gutte Shreyas Hanumantrao , Sahu Chinmoy , Gurjar Mohan , Patel Sangram Singh
Published: July 2023

Introduction Aeromonas hydrophila is an opportunistic pathogen that can cause various infections, including pneumonia, in immunocompromised individuals. This case report presents a rare occurrence of nosocomial pneumonia caused by Aeromonas hydrophila in a female patient with chronic kidney disease (CKD).
Case presentation The patient exhibited sign and symptoms of nosocomial pneumonia and was successfully treated with intravenous Ciprofloxacin. The discussion highlights the characteristics of Aeromonas species, its virulence factors, risk factors for infection, and diagnostic methods.
Conclusion It emphasizes the need for awareness and suspicion of Aeromonas as a potential cause of ventilator-associated pneumonia (VAP) in ICU settings, as well as the importance of early detection and appropriate treatment for improved outcomes. To the best of the author’s knowledge, no case report has been published reporting Aeromonas attributing to VAP.
Dengue virus M and E proteins belonging to genotype II (Cosmopolitan) of serotype 2 are influenced by the nature of M residue 36
Authors: Decotter Jason , Desprès Philippe , Gadea Gilles
Published: July 2023

Mosquito-borne dengue disease is caused by the dengue virus serotype-1 to serotype-4. The contemporary dengue outbreaks in the southwestern Indian ocean coincided with the widespread of dengue virus serotype 2 genotype II (Cosmopolitan), including epidemic viral strains DES-14 and RUN-18 isolated in Dar es Salaam (Tanzania) in 2014 and La Reunion Island (France) in 2018, respectively. Heterodimeric interaction between prM (intracellular precursor of surface structural M protein) and envelope E proteins is required during the initial stage of dengue virus assembly. Amino acid 127 of DES-14 prM protein (equivalent to M36) has been identified as an infrequent valine whereas RUN-18 has a common isoleucine. In the present study, we examined the effect of M-I36V mutation on the expression of a recombinant RUN-18 E protein co-expressed with prM in human epithelial A549 cells. The M ectodomain of dengue virus serotype 2 embeds a pro-apoptotic peptide referred as D2AMP. The impact of M-I36V mutation on the death-promoting capability of D2AMP was assessed in A549 cells. We showed that valine at position M36 affects expression of recombinant RUN-18 E protein and potentiates apoptosis-inducing activity of D2AMP. We propose that the nature of M residue 36 influences the virological characteristics of dengue 2 M and E proteins belonging to genotype II that contributes to global dengue burden.
Vancomycin-sensitive Enterococcus faecium bacteraemia – hospital transmission and mortality in a Danish University Hospital
Authors: Hansen Sanne Groenvall Kjaer , Roer Louise , Karstensen Kasper Thystrup , Hoegh Silje Vermedal , Hansen Frank , Klein Kasper , Rosenvinge Flemming S. , Holm Anette , Skov Marianne N. , Hammerum Anette M. , Hasman Henrik
Published: July 2023

Introduction. The emergence of vancomycin-resistant

Enterococcus faecium

(VREfm) has left the vancomycin-sensitive

E. faecium

(VSEfm) strains almost unnoticed.

Hypothesis. Molecular characteristics, hospital transmission patterns and clinical impact of VSEfm have changed, and VSEfm is a predictor of VREfm introduction.

Aim. We wanted to do a molecular characterization of VSEfm to identify hospital transmissions and links between VSEfm and VREfm, and to investigate the demographics, treatment and impact on mortality of VSEfm bacteraemia.

Methodology. VSEfm and VREfm blood culture isolates from Odense University Hospital, Denmark, from 2015 to 2019 were characterized using whole-genome sequencing and core-genome multilocus sequence typing (cgMLST). Clonal shifts and diversity of the VREfm isolates were compared to the VSEfm isolates. Hospital records were used for clinical data and transmission investigation of VSEfm cases.

Results. Six-hundred and thirty VSEfm isolates from 599 patients belonged to 42 sequence types (STs) and 131 complex types (CTs) in several clusters. Multiple types were involved in putative transmission, occurring over the entire period. Twenty-seven VREfm bacteraemia cases were included. No correlation between the VSEfm and VREfm clones was identified. The 30 day mortality was 40 %, but only in 6.3 % of the cases, VSEfm bacteraemia was the likely cause of death.

Conclusion. The molecular types of VSEfm bacteraemia isolates are changing and diverse. No direct correlation between VSEfm and the introduction of VREfm was found, but widespread hospital transmission indicates a presence of risk factors that could facilitate transmission of other micro-organisms as well. VSEfm bacteraemia is rarely the cause of death, indicating that 30 day mortality does not reflect the cause of death.
Sweet and sour synergy: exploring the antibacterial and antibiofilm activity of acetic acid and vinegar combined with medical-grade honeys
Authors: Harrison Freya , Blower Anisa , de Wolf Christopher , Connelly Erin
Published: July 2023

Oxymel, a combination of honey and vinegar, has been used as a remedy for wounds and infections in historical and traditional medical settings. While honey is now clinically used to treat infected wounds, this use of a complex, raw natural product (NP) mixture is unusual in modern western medicine. Research into the antimicrobial activity of NPs more usually focuses on finding a single active compound. The acetic acid in vinegar is known to have antibacterial activity at low concentrations and is in clinical use to treat burn wound infections. Here, we investigated the potential for synergistic activity of different compounds present in a complex ingredient used in historical medicine (vinegar) and in an ingredient mixture (oxymel). We conducted a systematic review to investigate published evidence for antimicrobial effects of vinegars against human pathogenic bacteria and fungi. No published studies have explicitly compared the activity of vinegar with that of a comparable concentration of acetic acid. We then characterized selected vinegars by HPLC and assessed the antibacterial and antibiofilm activity of the vinegars and acetic acid, alone and in combination with medical-grade honeys, against

Pseudomonas aeruginosa

and

Staphylococcus aureus

. We found that some vinegars have antibacterial activity that exceeds that predicted by their acetic acid content alone, but that this depends on the bacterial species being investigated and the growth conditions (media type, planktonic vs. biofilm). Pomegranate vinegars may be particularly interesting candidates for further study. We also conclude that there is potential for acetic acid, and some vinegars, to show synergistic antibiofilm activity with manuka honey.
COMPARISON OF LARGE SUBCOSTAL HERNIAS TREATED WITH OPEN ANTERIOR COMPONENTS SEPARATION OR OPEN TRANSVERSUS ABDOMINIS RELEASE TECHNIQUES
Authors: Espinosa-de-los-Monteros Antonio , Fernandez-Alva Daniela , Solis-Reyna Rodrigo Alejandro , de-la-Garza-Elizondo Cesar Alberto , Vazquez-Guadalupe Joseph , Posadas-Trujillo Oscar Emmanuel , Diaz-Trueba Flavio Enrique
Published: July 2023

Background

Large subcostal incisional hernias are considered as complex defects, and a few different approaches have been described for repair. The purpose of this comparative cross-sectional study is to evaluate the outcomes of patients with large subcostal incisional hernias treated with either the open anterior components separation technique (ACS) or with the open transversus abdominis release technique (TAR).

Methods

From the database of patients with large complex incisional hernias who underwent abdominal wall reconstruction with open techniques between April 2007 and October 2022 at our institution, on May 25th, 2023 we identified those whose hernias were located in the subcostal areas and who underwent reconstruction with a components separation technique and mesh. Perioperative variables and outcomes were compared between the patients with large subcostal hernias who underwent abdominal wall reconstruction with either the ACS or the TAR techniques.

Results

Thirty-one patients with large subcostal hernias were included in the study. ACS and intra-abdominal mesh was used in 11 patients; TAR and retro-muscular mesh was performed in 20 patients. More postoperative local abdominal wall complications were seen in patients undergoing ACS as opposed to TAR (55% vs 15%, p=0.02). Hernia recurrence was more common in patients undergoing ACS as opposed to TAR (55% vs 5%, p=0.008).

Conclusions

More post-operative complications and recurrences were seen in patients undergoing ACS as opposed to TAR.
Interindividual differences in pain can be explained by fMRI, sociodemographic, and psychological factors
Authors: Gim Suhwan , Lee Dong Hee , Lee Sungwoo , Woo Choong-Wan
Published: July 2023

In a recent article, Hoeppli et al. (2022) reported that sociodemographic and psychological factors were not associated with interindividual differences in reported pain intensity. In addition, the interindividual differences in pain could not be detected by thermal pain-evoked brain activities measured by functional Magnetic Resonance Imaging (fMRI). Their comprehensive analyses provided convincing evidence for these null findings, but here we provide another look at their conclusions by analyzing their behavioral data and a large-scale fMRI dataset involving thermal pain (N= 124). Our main findings are as follows: First, a multiple regression model incorporating all available sociodemographic and psychological measures could significantly predict the interindividual differences in reported pain intensity. The key to achieving a significant prediction was including multiple individual difference measures in a single model. Second, with fMRI data from a relatively homogeneous group of 124 participants, we could identify brain regions and a multivariate pattern-based predictive model significantly correlated with the interindividual differences in reported pain intensity. Our results, along with the findings of Hoeppli et al., highlight the challenge of predicting interindividual differences in pain, but also suggest that it is not an impossible task.
Artificial Tactile Stimulation Provides Haptic Cuing in Force Field Adaptation
Authors: Avraham Chen , Avraham Guy , Nisky Ilana
Published: July 2023

When interacting with objects with unfamiliar dynamics, the sensorimotor system uses haptic information to develop internal representations of the new dynamics. These representations are subsequently used to manipulate the objects by applying predictive forces that comply with the mechanical properties of the objects. In a recent study (Farajian et al. 2020), we showed that when participants evaluated the stiffness of elastic objects, adding artificial tactile stimulation created an illusion of higher stiffness, increasing the grip force control used to interact with the object. Here, we took a step further in understanding how kinesthetic and tactile information is integrated into the control of objects. Specifically, we examined how added skin stretch influenced thelearningof novel forces. We found that the extent of force compensation that the participants exhibited depended on the direction of the artificial skin stretch applied simultaneously with the force; learning was enhanced when the skin was stretched in the opposite direction to the external force and diminished when the skin was stretched in the same direction. Strikingly, when the skin stretch stimulation was delivered during probe trials in which the force perturbation was absent, the behavior pattern was flipped, with an increase in force compensation for the same-direction skin stretch stimulation and vice versa. Modeling suggests that these results reflect a unique effect of tactile stimulation during the learning of novel forces; rather than becoming integrated with the dynamic information, it is used by the sensorimotor system as a guidance cue, possibly through explicit mechanisms, providing information on the way to compensate for the forces and optimize movements. We believe that these findings propose a novel instructive role of tactile stimulation during interaction with a dynamic object. This provides a significant potential to leverage these effects in the development of devices aiming to assist and guide users in many human-in-the-loop applications, such as rehabilitation and surgical robotics.
Discovery & Evaluation of novel fluorescence molecules for selective recognition of G-quadruplexes structure
Authors: Neha  , Ranjan Prashant , Das Parimal , Kumar Surendra , Singh Roop Shikha , Pandey Daya Shankar
Published: July 2023

Currently, G-quadruplex structure targeting strategies are considered as a promising anticancer approach. In the search of selective and potent G-quadruplex binders, Here we discuss an analysis of a few chroman derivatives ligands: (A) chroman 7-[2-pyrrolo]-pyrrole-[1,2-a]12H pyrrolino[2,3-b]chroman-4-one, and (C) 4-methyl-7-[2-pyrrolo]-pyrrole[1,2-a]12H pyrrolino[2,3-b]chroman-4-one and their respective borondifluoride complexes B and D as a quadruplex targeting compounds which found to stabilize G-quadruplex structure. To investigate the binding characteristics of these molecules with G-quadruplex vs. duplex selectivity,In vitrobiophysical studies were performed by steady-state fluorescence, UV-visible titration, fluorescent TO displacement assay, CD thermal melting, circular dichroism spectroscopy, and cellular imaging by employing both telomeric and PRCC G-quadruplex forming sequences. Our investigation shows that these chromam ligands and their complexes are able to selectively bind and stabilize parallel and mixed hybrid topology of G-quadruplex bothIn vitroand in cellular conditions. A molecular docking study also suggests the binding of these compounds with G-quadruplex conformation. Collectively our study suggests these chroman complexes as a potentially useful fluorescent chemical product for G-quadruplex specific ligands and expands an option for G-quadruplex targeting ligands.
Phase-Amplitude Coupling Detection and Analysis of Human 2-Dimensional Neural Cultures in Multi-well Microelectrode Array in Vitro
Authors: Salimpour Yousef , Anderson William S. , Dastyeb Raha , Liu Shiyu , Ming Guo-li , Song Hongjun , Maragakis Nicholas J. , Habela Christa W.
Published: July 2023

Human induced pluripotent stem cell (hiPSC)-derived neurons offer the possibility of studying human-specific neuronal behaviors in physiologic and pathologic statesin vitro. However, it is unclear whether these cultured neurons can achieve the fundamental network behaviors that are required to process information in the human brain. Investigating neuronal oscillations and their interactions, as occurs in cross-frequency coupling (CFC), is potentially a relevant approach. Microelectrode array culture plates provide a controlled framework to study populations of hiPSC-derived cortical neurons (hiPSC-CNs) and their electrical activity. Here, we examined whether networks of two-dimensional cultured hiPSC-CNs recapitulate the CFC that is present in networksin vivo. We analyzed the electrical activity recorded from hiPSC-CNs grown in culture with hiPSC-derived astrocytes. We employed the modulation index method for detecting phase-amplitude coupling (PAC) and used an offline spike sorting method to analyze the contribution of a single neuron’s spiking activities to network behavior. Our analysis demonstrates that the degree of PAC is specific to network structure and is modulated by external stimulation, such as bicuculine administration. Additionally, the shift in PAC is not driven by a single neuron’s properties but by network-level interactions. CFC analysis in the form of PAC explores communication and integration between groups of nearby neurons and dynamical changes across the entire network.In vitro, it has the potential to capture the effects of chemical agents and electrical or ultrasound stimulation on these interactions and may provide valuable information for the modulation of neural networks to treat nervous system disordersin vivo.

Significance

Phase amplitude coupling (PAC) analysis demonstrates that the complex interactions that occur between neurons and network oscillations in the human brain,in vivo, are present in 2-dimensional human cultures. This coupling is implicated in normal cognitive function as well as disease states. Its presencein vitrosuggests that PAC is a fundamental property of neural networks. These findings offer the possibility of a model to understand the mechanisms and of PAC more completely and ultimately allow us to understand how it can be modulatedin vivoto treat neurologic disease.
Associations of Blood Inflammatory Cytokines and Hair Cortisol with Depression Symptoms and Cognitive Functioning in Huntington’s Disease
Authors: Bilal Hiba , McDonald Stuart J. , Stout Julie C. , Harding Ian H.
Published: July 2023

Background

Huntington’s disease (HD) is an inherited neurodegenerative disease involving progressive motor abnormalities, cognitive decline, and psychiatric disturbances. Depression and cognitive difficulties are among the most impactful symptoms of HD, yet the pathogenesis of these symptoms is not fully understood. HD involves low-level chronic inflammation and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which are linked to depression and cognitive impairment in non-HD populations. However, previous research on the relationships of these pathologies with depression and cognition in HD is limited and inconsistent.

Methods

Fifty-three adults with the HD gene expansion (30 pre-manifest, 23 manifest) completed measures of depression and cognitive functioning. Forty-eight out of 53 participants provided hair samples for quantification of cortisol, and 34 participants provided blood samples for quantification of peripheral inflammatory cytokines. We examined the associations of four cytokines (interleukin (IL)-6, IL-10, IL-1β, and tumour necrosis factor (TNF)-α) and cortisol levels with depression and cognitive scores.

Results

In unadjusted models, higher levels of plasma IL-6, IL-10, and TNF-α correlated with higher depression scores, and higher levels of IL-10 and TNF-α correlated with poorer cognitive performance. After controlling for age, sex, and body mass index, only the correlations of IL-10 with depression and cognitive performance remained significant. No correlations were evident with hair cortisol.

Conclusions

Peripheral inflammation is associated with depression symptoms and cognitive impairment in HD. Our findings suggest that interactions between the immune and nervous systems are important in HD, and that inflammatory cytokines may be suitable as therapeutic targets for future clinical trials in HD.
Sex-specific prefrontal-hypothalamic control of behavior and stress responding
Authors: Schaeuble Derek , Wallace Tyler , Pace Sebastian A. , Hentges Shane T. , Myers Brent
Published: July 2023

Depression and cardiovascular disease are both augmented by daily life stress. Yet, the biological mechanisms that translate psychological stress into affective and physiological outcomes are unknown. Previously, we demonstrated that stimulation of the ventromedial prefrontal cortex (vmPFC) has sexually divergent outcomes on behavior and physiology. Importantly, the vmPFC does not innervate the brain regions that initiate autonomic or neuroendocrine stress responses; thus, we hypothesized that intermediate synapses integrate cortical information to regulate stress responding. The posterior hypothalamus (PH) directly innervates stress-effector regions and receives substantial innervation from the vmPFC. In the current studies, circuit-specific approaches examined whether vmPFC synapses in the PH coordinate stress responding. Here we tested the effects of optogenetic vmPFC-PH circuit stimulation in male and female rats on social and motivational behaviors as well as physiological stress responses. Additionally, an intersectional genetic approach was used to knock down synaptobrevin in PH-projecting vmPFC neurons. Our collective results indicate that male vmPFC-PH circuitry promotes positive motivational valence and is both sufficient and necessary to reduce sympathetic-mediated stress responses. In females, the vmPFC-PH circuit does not affect social or preference behaviors but is sufficient and necessary to elevate neuroendocrine stress responses. Altogether, these data suggest cortical regulation of stress reactivity and behavior is mediated, in part, by projections to the hypothalamus that function in a sex-specific manner.
Nischarin negatively impacts ShcD-mediated tumor cell migration
Authors: Hago Rayan A. , Wong Sook P. , Hachim Mahmood Y. , Hachim Ibrahim Y. , Saber-Ayad Maha , Prigent Sally A , Ahmed Samrein B.M.
Published: July 2023

ShcD was previously found to promote cell motility in melanoma cells. Screening of a yeast two hybrid mouse embryo cDNA library identified Nischarin, a negative regulator to cell motility, as an interacting partner to the ShcD-CH2 domain. Therefore, we aimed to investigate the interaction between Nischarin and ShcD in mammalian cells and to determine their functional impact on cell migration. The Nischarin/ShcD interaction was confirmed by transfection and co-immunoprecipitation assays using full-length constructs in HEK293, MCF7 and MM253 cell lines. Deletion of the first 93 amino acids of ShcD abrogated the interaction indicating the importance of these residues for Nischarin binding. Co-expression of Nischarin and ShcD demonstrated an inhibitory effect on the levels of phospho-ERK and phospho-LIMK. In support of this, Nischarin was found to block the migratory activities of ShcD. A brief in silico analysis of publicly available breast cancer patient data was performed to elucidate the effect of Nischarin/ShcD co-expression on the patients’ overall survival. Patients with high expression of both proteins had better survival than those with only ShcD overexpression. Our results reveal that the novel protein Nischarin is an interacting partner to ShcD. In addition, we report that the tumour suppressive abilities of Nischarin can overcome ShcD-mediated cell migration when both proteins are concomitantly expressed.

*This abstract was presented in the National Cancer Research Institute (NCRI)-2019
Virally induced CRISPR/Cas9-based knock-in of fluorescent albumin allows long-term visualization of cerebral circulation in infant and adult mice
Authors: Vittani Marta , Knak Philip Aleksander Gade , Fukuda Masahiro , Nagao Masaki , Wang Xiaowen , Kjaerby Celia , Konno Ayumu , Hirai Hirokazu , Nedergaard Maiken , Hirase Hajime
Published: July 2023

Albumin, a protein produced by liver hepatocytes, represents the most abundant protein in blood plasma. We have previously engineered a liver-targeting adeno-associated viral vector (AAV) that expresses fluorescent protein-tagged albumin to visualize blood plasma in mice. While this approach is versatile for imaging in adult mice, transgene expression vanishes when AAV is administered in neonates due to dilution of the episomal AAV genome in the rapidly growing liver. Here, we use CRISPR/Cas9 genome editing to insert the fluorescent protein mNeonGreen (mNG) gene into the albumin (Alb) locus of hepatocytes to produce fluorescently labeled albumin (Alb-mNG). We constructed a CRISPR AAV that includes ∼1 kb homologous arms around Alb exon 14 to express Alb-mNG. Subcutaneous injection of this AAV with AAV-CMV-Cas9 in postnatal day 3 mice resulted in two-photon visualization of the cerebral cortex vasculature within ten days. The expression levels of Alb-mNG were persistent for at least three months and were so robust that vasomotion and capillary blood flow could be assessed transcranially in early postnatal mice. This knock-in approach provides powerful means for micro- and macroscopic imaging of cerebral vascular dynamics in postnatal and adult mice.
Distinct phases of cellular signaling revealed by time-resolved protein synthesis
Authors: Lee Gihoon , Muir Tom W.
Published: July 2023

The post-translational regulation of protein function is involved in most cellular processes. As such, synthetic biology tools that operate at this level provide opportunities for manipulating cellular states. Here, we deploy a proximity-triggered protein trans-splicing technology to enable the time-resolved synthesis of target proteins from pre-made parts. The modularity of the strategy allows for the addition or removal of various control elements as a function of the splicing reaction, in the process permitting the cellular location and/or activity state of starting materials and products to be differentiated. The approach is applied to a diverse set of proteins, including the kinase oncofusions BCR/ABL and DNAJB1/PRKACA where dynamic cellular phosphorylation events are dissected, revealing distinct phases of signaling and identifying molecular players connecting the oncofusion to cancer transformation as novel therapeutic targets of cancer cells. We envision that the tools and control strategies developed herein will allow the activity of both naturally occurring and designer proteins to be harnessed for basic and applied research.
A divide and conquer approach (DACA) to predict high fidelity structure of large multidomain protein BRWD1
Authors: Mondal Rajkrishna , Mandal Malay , Lahiri Tapobrata
Published: July 2023

Therapeutic importance in inhibiting Bromodomain and WD Repeat Domain containing BRWD1 against numerous human pathophysiological processes including cancers prompts prediction of a workable structure of this large protein. Here, a novel divide and conquer strategy was adopted to utilize smaller overlapping sequence-fragments of BRWD1 to further utilize their predicted structures as derived templates for prediction of complete BRWD1 structure in absence of its desired homologues in the template database. The novelty of this methodology stemmed from the requirement of templates of high sequence similarity in any comparative model based predictors whereas, the own fragments of the same target protein, BRWD1 could successfully fulfill this criteria. Additionally, the outputs of different high performing predictors including AlphaFold and RoseTTAFold were systematically integrated under the premise of Inductive Reasoning. The resultant structures were validated using existing validation parameters. Finally, a new validation paradigm was adopted to screen the best structure from the result presenting in-silico studies of known interactions of BRWD1 with various small molecules like, BD inhibitors, modified histone tails, DNA motifs and interacting proteins. The algorithm proposed in this work also paved the way for prediction of authentic structures of large size proteins.
Quantifying visual acuity inHeliconiusbutterflies
Authors: Wright Daniel Shane , Manel Anupama Nayak , Guachamin-Rosero Michelle , Chamba-Vaca Pamela , Baquet Caroline Nicole , Merrill Richard M.
Published: July 2023

Heliconiusbutterflies are well-known for their colourful wing patterns, which advertise distastefulness to potential predators and are used during mate choice. However, the relative importance of different aspects of these signals will depend on the visual abilities ofHeliconiusand their predators. Previous studies have investigated colour sensitivity and neural anatomy, but visual acuity (the ability to perceive detail) has not been studied in these butterflies. Here, we provide the first estimate of visual acuity inHeliconius: from a behavioural optomotor assay, we found that mean visual acuity = 0.49 cycles-per-degree (cpd), with higher acuity in males than females. We also estimated visual acuity from eye morphology and reported slightly lower values (mean visual acuity = 0.38 cpd), but acuity was still higher in males. Finally, we estimated how visual acuity affectsHeliconiusvisual perception compared to a potential avian predator. Whereas the bird predator maintained high resolving power,Heliconiuslost the ability to resolve detail at greater distances, though colours may remain salient. These results will inform future studies ofHeliconiuswing pattern evolution, as well as other aspects in these highly visual butterflies, which have emerged as an important system in studies of adaptation and speciation.
A disease associated mutant reveals how Ltv1 orchestrates RP assembly and rRNA folding of the small ribosomal subunit head
Authors: Blomqvist Ebba K. , Huang Haina , Karbstein Katrin
Published: July 2023

Ribosomes are complex macromolecules assembled from 4 rRNAs and 79 ribosomal proteins (RPs). Their assembly is organized in a highly hierarchical manner, which is thought to avoid dead-end pathways, thereby enabling efficient assembly of ribosomes in the large quantities needed for healthy cellular growth. Moreover, hierarchical assembly also can help ensure that each RP is included in the mature ribosome. Nonetheless, how this hierarchy is achieved remains unknown, beyond the examples that depend on direct RP-RP interactions, which account for only a fraction of the observed dependencies. Using assembly of the small subunit head and a disease-associated mutation in the assembly factor Ltv1 as a model system, we dissect here how the hierarchy in RP binding is constructed. Our data demonstrate that the LIPHAK-disease-associated Ltv1 mutation leads to global defects in head assembly, which are explained by direct binding of Ltv1 to 5 out of 15 RPs, and indirect effects that affect 4 additional RPs. These indirect effects are mediated by conformational transitions in the nascent subunit that are regulated by Ltv1. Mechanistically, Ltv1 aids the recruitment of some RPs via direct protein-protein interactions, but surprisingly also delays the recruitment of other RPs. Delayed binding of key RPs also delays the acquisition of RNA structure that is stabilized by these proteins. Finally, our data also indicate direct roles for Ltv1 in chaperoning the folding of a key rRNA structural element, the three-helix junction j34-35-38. Thus, Ltv1 plays critical roles in organizing the order of both RP binding to rRNA and rRNA folding, thereby enabling efficient 40S subunit assembly.