bluuebunny/crossref_metadata_2025 huggingface dataset:
p16 Immunohistochemistry as a Screening Tool for Homozygous CDKN2A Deletions in CNS Tumors
Authors: Zschernack Valentina , Andreiuolo Felipe , Dörner Evelyn , Wiedey Anna , Jünger Stephanie T. , Friker Lea L. , Maruccia Riccardo , Pietsch Torsten
Published: November 2023

The 2021 World Health Organization classification of tumors of the central nervous system emphasizes the significance of molecular parameters for an integrated diagnosis. Homozygous deletion of cyclin-dependent kinase inhibitor 2a (CDKN2A) has been associated with an adverse prognosis in IDH-mutant gliomas, supratentorial ependymomas, meningiomas, and MPNST. In this study, we examined the value of p16 protein immunohistochemistry as a rapid and cost-effective screening tool for a homozygous CDKN2A deletion. Genetic analyses for CDKN2A in 30 pleomorphic xanthoastrocytomas, 32 IDH-wild-type high-grade gliomas, 40 supratentorial ependymomas with ZFTA-RELA gene fusion, 21 IDH-mutant astrocytomas, and 24 meningiomas were performed mainly by a molecular inversion probe assay, a high-resolution, quantitative technology for the assessment of chromosomal copy number alterations. Immunohistochemistry for p16 proved to have a high positive predictive value (range 90% to 100%) and an overall low negative predictive value (range 22% to 93%) for a homozygous CDKN2A deletion. In a setting where molecular testing is limited for cost and time reasons, p16 immunohistochemistry serves as a useful and rapid screening tool for identifying cases that should be subjected to further molecular testing for CDKN2A deletions.
A Cardiovascular Risk Optimization Program in People With Schizophrenia: A Pilot Randomized Controlled Clinical Trial
Authors: Riera-Molist Núria , Assens-Tauste Montse , Roura-Poch Pere , Guimerà-Gallent Marta , Santos-López Josep Manel , Serra-Millas Montserrat , Frau-Rosselló Neus , Gallego-Peña Estefania , Foguet-Boreu Quintí
Published: November 2023

Background:

Cardiovascular disease is one of the leading causes of premature death in people with schizophrenia. Some modifiable factors that have been implicated include unhealthy lifestyle, medication side effects, and physical comorbidities. The goal of this study was to assess the efficacy of a 6-month, multifactorial cardiovascular risk intervention to reduce cardiovascular risk (CVR) in people with schizophrenia.

Methods:

We conducted a 2-arm, parallel, randomized clinical trial in a regional mental health center. Participants with at least 1 poorly controlled cardiovascular risk factor (CVRF) (hypertension, diabetes mellitus, hypercholesterolemia, or tobacco smoking) were randomly assigned to the intervention group or to a control group. The subjects in the intervention group received a patient-centered approach that included promoting a healthy lifestyle, pharmacological management of CVRFs, psychotropic drug optimization, and motivational follow-up [Programa d’optimització del RISc CArdiovascular (PRISCA)]. The main outcome was change in CVR as assessed using the Framingham-REGICOR function, after 6 months compared with the baseline in both groups.

Results:

Forty-six participants were randomly assigned to the PRISCA group (n=23) or the control group (n=23). The most prevalent CVRFs at baseline were hypercholesterolemia (84.8%) and tobacco smoking (39.1%). The PRISCA group showed a significant reduction in the REGICOR score (−0.96%; 95% CI: −1.60 to −0.32, P=0.011) after 6 months (relative risk reduction of 20.9%), with no significant changes in the control group (0.21%; 95% CI: −0.47 to 0.89, P=0.706). In the PRISCA group, low-density lipoprotein cholesterol also decreased significantly (−27.14 mg/dL; 95% CI: −46.28 to −8.00, P=0.008).

Conclusion:

A patient-centered, multifactorial cardiovascular risk intervention improved CVR in people with schizophrenia after 6 months, which was achieved mainly by improving the lipid profile.
The Relationship of Self-identified Weight Status With Perceived Mental and Physical Health
Authors: Hamilton Antonia , Smith Shannon R. , Lydecker Janet A.
Published: November 2023

Objective:

This study examined whether individuals with higher weight (body mass index in the overweight or obesity range) self-identified as having overweight or obesity (Ow/Ob). The study also examined whether self-identifying as having Ow/Ob was associated with perceived mental health, perceived physical health, depression, and eating disorder psychopathology.

Methods:

Four study groups were created: those with Ow/Ob who self-identified as having Ow/Ob (Ow/Ob+), those with Ow/Ob who did not self-identify as having Ow/Ob (Ow/Ob–), those with core features of binge-eating disorder (BED) and Ow/Ob, and those with bulimia nervosa (BN) and Ow/Ob. Analyses of variance compared study groups on perceived health, depression, and eating disorder psychopathology.

Results:

The BED and BN groups were more likely to self-identify as having overweight/obesity compared with Ow/Ob groups without eating disorders. The Ow/Ob– group had the best-perceived health and the lowest levels of eating disorder psychopathology and depression compared with the other groups. The Ow/Ob+ group had better perceived mental health than the BED and BN groups but did not differ significantly from the Ow/Ob– group in perceived mental health. Perceived physical health in the Ow/Ob+ group was better than in the BED group and worse than in the Ow/Ob– group. The Ow/Ob+ group had higher levels of eating disorder psychopathology than the Ow/Ob– group.

Conclusions:

Self-identifying as having obesity is associated with eating disorder psychopathology as well as poorer perceived mental and physical health. Providers should engage patients in discussions about their weight with the understanding that self-identifying as having overweight or obesity might indicate the presence of eating disorder psychopathology. Future clinical research should investigate the directionality or possible bidirectionality of this relationship.
Extreme Risk Protection Orders: Legislative Intent and Clinician Guidance
Authors: Wortzel Hal S. , Simonetti Joseph A. , Knoepke Christopher E. , Simpson Joseph R. , Brar Leah , Westmoreland Patricia , Matarazzo Bridget B.
Published: November 2023

In this second column of a 2-part series exploring extreme risk protections orders, we utilize recent events in Colorado, including legislative efforts to expand the list of eligible petitioners to include clinicians, as an opportunity to explore questions and challenges faced by mental health and medical professionals serving in this capacity. Clinicians are in need of more clear guidance, given an emerging role that comes without clear evidence or practice standards to inform individualized clinical decision-making, and which potentially pits public safety interests against patient care needs, especially those pertaining to therapeutic relationships. In the interim, clinicians will best serve their patients by continuing to practice in a fashion that is analogous to decision-making around other interventions with serious implications for patient autonomy such as involuntary hospitalization. Ongoing collaboration with legislators is needed to arrive at laws that are informed by the limitations inherent in clinical risk assessment and that can be translated into clinical practices that simultaneously support patient needs and community safety.
Catatonia as the Presentation of Encephalopathy Associated With Autoimmune Thyroiditis: A Case Report and Literature Review
Authors: Ali Hossam Tharwat , Mohamed Farah Riyad , Al-Ghannami Ahmed Khaled , Caprara Ana Leticia Fornari , Rissardo Jamir Pitton
Published: November 2023

Encephalopathy can be associated with autoimmune disorders such as autoimmune thyroiditis, and it can present with a wide range of neuropsychiatric manifestations. However, it rarely presents with catatonia. We present the case of a middle-aged female with Hashimoto’s thyroiditis presenting with catatonia. A literature review of previous similar cases highlighting significant points is also included. A 48-year-old female presented to the emergency department with catatonic symptoms that had worsened over the previous 5 days. A similar condition was reported to have occurred and resolved spontaneously 3 months earlier. On examination, the patient appeared uncooperative and unresponsive. She showed typical symptoms of catatonia, with a score of 21 points on the Bush-Francis Catatonia Rating Scale. Routine tests were within normal ranges except for an elevated level of C-reactive protein and an elevated erythrocyte sedimentation rate. Computed tomography, magnetic resonance imaging, and cerebrospinal fluid analysis were all normal. An electroencephalogram showed diffuse delta-theta range slowing with no epileptiform discharges. Lorazepam was initiated but did not control the catatonic symptoms. Re-evaluation revealed thyroid swelling and elevated levels of thyroperoxidase antibodies. IV methylprednisolone was therefore initiated and produced complete resolution of the catatonic symptoms in 4 hours. The patient was discharged and prescribed prednisone 1 mg/kg daily. At follow-up, the patient continued to show complete resolution of the catatonic symptoms. It is noteworthy that the patient developed hypothyroidism 6 months after this catatonic episode for which levothyroxine 50 mcg/d was prescribed. Encephalopathy associated with autoimmune thyroiditis can initially present with catatonic symptoms in euthyroid cases. The mainstay of treatment is steroids which result in complete resolution of the catatonic symptoms.
Flipping the switch: dynamic modulation of membrane transporter activity in bacteria
Authors: Elston Rory , Mulligan Christopher , Thomas Gavin H.
Published: November 2023

The controlled entry and expulsion of small molecules across the bacterial cytoplasmic membrane is essential for efficient cell growth and cellular homeostasis. While much is known about the transcriptional regulation of genes encoding transporters, less is understood about how transporter activity is modulated once the protein is functional in the membrane, a potentially more rapid and dynamic level of control. In this review, we bring together literature from the bacterial transport community exemplifying the extensive and diverse mechanisms that have evolved to rapidly modulate transporter function, predominantly by switching activity off. This includes small molecule feedback, inhibition by interaction with small peptides, regulation through binding larger signal transduction proteins and, finally, the emerging area of controlled proteolysis. Many of these examples have been discovered in the context of metal transport, which has to finely balance active accumulation of elements that are essential for growth but can also quickly become toxic if intracellular homeostasis is not tightly controlled. Consistent with this, these transporters appear to be regulated at multiple levels. Finally, we find common regulatory themes, most often through the fusion of additional regulatory domains to transporters, which suggest the potential for even more widespread regulation of transporter activity in biology.
Age and anatomical region related differences in vascularization of the porcine meniscus using micro-computed tomography imaging
Authors: Karjalainen V-P. , Herrera M V. R. , Modina S. , Peretti G. M. , Pallaoro M. , Elkhouly K. , Saarakkala S. , Mobasheri A. , Di Giancamillo A. , Finnilä M.A.
Published: November 2023

Meniscal lesions in vascularized regions are known to regenerate while lack of vascular supply leads to poor healing. Here we developed and validated novel methodology for three-dimensional structural analysis of meniscal vascular structures with high-resolution micro-computed tomography (µCT).

We collected porcine medial menisci from 10 neonatal (not-developed meniscus, n-) and 10 adults (fully developed meniscus, a-). The menisci were cut into anatomical regions (anterior horn (n-AH & a-AH), central body (n-CB & a-CB), and posterior horn (n-PH & a-PH).

Specimens were cut in half, fixed, and one specimen underwent critical point drying and µCT imaging, while other specimen underwent immunohistochemistry and vascularity biomarker CD31 staining for validation of µCT. Parameters describing vascular structures were calculated from µCT.

The vascular network in neonatal spread throughout meniscus, while in adult was limited to a few vessels in outer region, mostly on femoral side. a-AH, a-CB, and a-PH had three, five, and seven times greater vascular volume than neonate, respectively. Moreover, thickness of blood vessels, in three regions, was six times higher in adult than in newborn. Finally, a-PH appeared to have thicker blood vessels than both a-AH and a-CB.

For the first time, critical point drying-based µCT imaging allowed detailed three-dimensional visualization and quantitative analysis of vascularized meniscal structures. We showed more vascularity in neonatal menisci, while adult menisci had fewer and thicker vascularity especially limited to the femoral surface which is involved in load transmission response, thus suggesting how nutritional support in this area of the outer zone is more necessary.
Degron-controlled protein degradation inEscherichia coli: New Approaches and Parameters
Authors: Cronan Glen E. , Kuzminov Andrei
Published: November 2023

Protein degron tags have proven uniquely useful for characterization of gene function. Degrons mediate quick depletion, usually within minutes, of a protein of interest – allowing researchers to characterize cellular responses to the loss of function. To develop a general purpose degron tool inE. coli,we sought to build upon a previously characterized system of SspB-dependent inducible protein degradation. For this, we created a family of expression vectors containing a destabilized allele of SspB, capable of a rapid and nearly perfect “off-to-on” induction response. Using this system, we demonstrated control over several enzymes of DNA metabolism, but also found with other substates apparent limitations of a SspB-dependent system. Several degron target proteins were degraded too slowly to affect their complete depletion during active growth, whereas others appeared completely refractory to degron-promoted degradation. We demonstrated that a model substrate, beta-galactosidase, was positively recognized as a degron substrate, but failed to be degraded by the ClpXP protease — demonstrating an apparently unknown mechanism of protease resistance. Thus, only a minority of our, admittedly biased, selection of degron substates proved amenable to rapid SspB-catalyzed degradation. We conclude that substrate-dependence of the SspB system remains a critical factor for the success of this degron system. For substrates that prove degradable, we provide a series of titratable SspB-expression vehicles.
Efficient workflow for validating homology-independent targeted integration-mediated gene insertion in rod photoreceptor cells to treat dominant-negative mutations causing retinitis pigmentosa
Authors: Onishi Akishi , Tsunekawa Yuji , Mandai Michiko , Ishimaru Aiko , Ohigashi Yoko , Sho Junki , Yasuda Kazushi , Suzuki Keiichiro , Izpisua Belmonte Juan Carlos , Matsuzaki Fumio , Takahashi Masayo
Published: November 2023

Among the genome-editing methods for repairing disease-causing mutations resulting in dominant inhibition, homology-independent targeted integration (HITI)-mediated gene insertion of the normal form of the causative gene is useful because it allows the development of mutation-agnostic therapeutic products. For the rapid optimization and validation of highly effective HITI-treatment gene constructs against dominant-negative inheritance of inherited retinal dystrophy, we improved the gene constructs available in both plasmid and adeno-associated virus (AAV) vectors, and established a workflow that uses in vivo electroporation to verify the in vivo efficacy. By targeting the mouse Rhodopsin gene, we derived a construct in which HITI-mediated gene insertion occurs in 80%-90% of transduced mouse rod photoreceptor cells. This construct suppressed degeneration and induced visual restoration in the mutant mice. The HITI-treatment constructs for the rhodopsin gene were shown to be effective in AAV vectors, and this construction is available for the mouse Peripherin 2 gene. These findings suggest that the workflow reported here may be useful for the generation of HITI-treatment constructs for various target genes and for the development of gene therapy products.
Pseudogenes in plasmid genomes reveal past transitions in plasmid mobility
Authors: Hanke Dustin M. , Wang Yiqing , Dagan Tal
Published: November 2023

Evidence for gene non-functionalization due to mutational processes is found in genomes in the form of pseudogenes. Pseudogenes are known to be rare in prokaryote chromosomes, with the exception of lineages that underwent an extreme genome reduction (e.g., obligatory symbionts). Much less is known about the frequency of pseudogenes in prokaryotic plasmids; those are genetic elements that can transfer between cells and may encode beneficial traits for their host. Non-functionalization of plasmid-encoded genes may alter the plasmid characteristics, e.g., mobility, or their effect on the host. Analyzing 10, 832 prokaryotic genomes, we find that plasmid genomes are characterized by threefold-higher pseudogene density compared to chromosomes. The majority of plasmid pseudogenes correspond to deteriorated transposable elements. A detailed analysis of enterobacterial plasmids furthermore reveals frequent gene non-functionalization events associated with the loss of plasmid self-transmissibility. Reconstructing the evolution of closely related plasmids reveals that non-functionalization of the conjugation machinery led to the emergence of non-mobilizable plasmid types. Examples are virulence plasmids inEscherichiaandSalmonella. Our study highlights non-functionalization of core plasmid mobility functions as one route for the evolution of domesticated plasmids. Pseudogenes in plasmids supply insights into past transitions in plasmid mobility that are akin to transitions in bacterial lifestyle.
Leadership and governance of mental healthcare and integration at the community level: a mixed methods study in Ghana
Authors: Yaro Peter Badimak , Asampong Emmanuel , Tabong Philip Teg-Nefaah , Thornicroft Graham , Tindana Paulina
Published: November 2023

Leadership and governance are key components of health systems, nevertheless research into leadership and governance of mental healthcare at the community level is probably the least well researched and understood part of these systems. As part of assessing the integration of mental health in Primary Health Care in Ghana, the leadership and governance organisation and structures to ensure oversight and coordination were examined. A concurrent mixed-methods design involving both quantitative and qualitative research methods approach was adopted. The quantitative data were collected through a questionnaire, which was either self-administered or interviewer administered, on 1010 respondents with 830 completed (response rate 82%). Key informant interviews and focus group discussions were used to collect the qualitative data. Thematic content analysis with the use of NVivo 12 was applied for the qualitative field data and Stata SE16 was used for quantitative data. Data triangulation strategy was used to report the qualitative and quantitative results. The study showed that leadership and governance of mental health at the PHC level were lowly developed due to the modest level of awareness of the Mental Health Law, inadequate functioning of mental health units and coordination, low level of private sector participation in mental health care services, and low levels of provision of monitoring, supervision, and evaluation. This affected the integration of mental health at the PHC level, which was also gauged as low. The study concludes that despite the presence of legislation and policy aiming to achieve decentralised and integrated mental health services at the PHC level, mental health care is still a low-level priority within the health care system in Ghana and tends to operate within a silo. The study recommends that more practical and concerted leadership of mental health at the regional and district levels is required to drive decentralisation and integration at these levels.
Neurocognitive Impairment in Ugandan Children with Sickle Cell Anemia Compared to Sibling Controls: A cross-sectional study
Authors: Bangirana Paul , Boehme Amelia K. , Birabwa Annet , Opoka Robert O. , Munube Deogratias , Mupere Ezekiel , Kasirye Phillip , Muwanguzi Grace , Musiimenta Maxencia , Ru George , Green Nancy S. , Idro Richard
Published: November 2023

Introduction

Neurocognitive function in Ugandan children aged 1-12 years with sickle cell anemia (SCA) were compared to their non-SCA siblings to identify risk factors for disease-associated impairment.

Methods

This cross-sectional neurocognitive function study of children with SCA (N=242) and non-SCA siblings (N=127) used age- and linguistically-appropriate standardized tests of cognition, executive function and attention for children ages 1-4 and 5-12 years. Test scores were converted to locally derived age-normalized z-scores. The SCA group underwent standardized stroke examination for prior stroke and transcranial doppler ultrasound (TCD) to determine stroke risk by arterial flow velocity.

Results

The SCA group was younger than siblings (mean ages 5.46±3.0 versus 7.11±3.51 years, respectively; p <.001), with lower hemoglobin concentration (7.32±1.02 vs. 12.06±1.42, p <.001). Overall cognitive SCA z-scores were lower: -0.73 ±0.98 vs. siblings -0.25 ±1.12 (p<.001), with comparable findings for executive function of -1.09±0.94 versus -0.84±1.26 (p=0.045), respectively. Attention z-scores for ages 5-12 for the SCA group and controls were similar: -0.37±1.4 vs. -0.11±0.17 (p=.09). Overall differences by SCA status were largely driven by the older age group, as z-scores in the younger sub-sample did not differ from controls. Analyses revealed the strongest predictors of poor neurocognitive outcomes among the SCA sample to be the disease, age and prior stroke (each p<.001). Impact from anemia and SCA were indistinguishable.

Discussion

Neurocognitive testing in children with SCA compared to non-SCA siblings revealed poorer SCA-associated functioning in children older than age 4. Results indicate need for trials assessing impact from disease modification for children with SCA.
Mechanistic basis of the dynamic response of TWIK1 ionic selectivity to pH
Authors: Chatelain Franck C. , Gilbert Nicolas , Bichet Delphine , Jauch Annaïse , Feliciangeli Sylvain , Lesage Florian , Bignucolo Olivier
Published: November 2023

At neutral pH, the TWIK1 channel is highly selective for K+. When exposed to acidification, it becomes permeable to Na+. This change occurs within minutes and is reversible. By combining pKa calculations, molecular dynamics (MD) simulations, mutagenesis and electrophysiology, we identified a network of residues involved in this unique property. MD simulations captured crucial features associated with channel gating and previously observed by cryogenic electron microscopy (cryo-EM) at pH7.4 and pH5, such as the pH-dependent orientation of the lateral side chain of the proton sensor His122 and the elongation of the entire pore structure upon acidification. Between the closed and open states of TWIK1 observed by cryo-EM, MD simulations show that the channel undergoes additional conformational changes between pH 7.5 to 6 that involves the His122, Glu235, Lys246 and Phe109 residues. A complex network of interactions surrounding the selectivity filter at high pH transforms into a simple set of stronger interactions at low pH. In particular, His122 protonated by acidification moves away from Lys246 and engages in a salt bridge with Glu235. In addition, stacking interactions between Phe109 and His122, which stabilize the selectivity filter in its K+-selective state at high pH, disappear upon acidification. This causes dissociation of the Phe109 aromatic side chain from this network, ultimately leading to the Na+-permeable conformation of the channel.
Genomic tailoring of autogenous poultry vaccines to reduceCampylobacterfrom farm to fork
Authors: Calland Jessica K. , Pesonen Maiju E. , Mehat Jai , Pascoe Ben , Haydon David J. , Lourenco Jose , Mourkas Evangelos , Hitchings Matthew D. , La Ragione Roberto M. , Hammond Philip , Wallis Timothy S. , Corander Jukka , Sheppard Samuel K.
Published: November 2023

Campylobacteris a leading cause of food-borne gastroenteritis worldwide, linked to the consumption of contaminated poultry meat. Targeting this pathogen at source, vaccines for poultry can provide short term caecal reductions inCampylobacternumbers in the chicken intestine. However, this approach is unlikely to reduceCampylobacterin the food chain or human incidence. This is likely as vaccines typically target only a subset of the high strain diversity circulating among chicken flocks and rapid evolution diminishes vaccine efficacy over time. To address this, we used a genomic approach to develop a whole-cell autogenous vaccine targeting isolates harbouring genes linked to survival outside of the host. We hyper-immunised a whole major UK breeder farm to passively target offspring colonisation using maternally-derived antibody. Monitoring progeny, broiler flocks revealed a near-complete shift in the post-vaccinationCampylobacterpopulation with a ∼50% reduction in isolates harbouring extra-intestinal survival genes and a significant reduction ofCampylobactercells surviving on the surface of meat. Based on these findings, we developed a logistic regression model that predicted that vaccine efficacy could be extended to target 46% of a population of clinically relevant strains. Immuno-manipulation of poultry microbiomes towards less harmful commensal isolates by competitive exclusion, has major potential for reducing pathogens in the food production chain.
StaphylococcalsRNA IsrR down-regulates methylthiotransferase MiaB under iron-deficient conditions
Authors: Barrault Maxime , Leclair Elise , Kumeko Etornam Kofi , Jacquet Eric , Bouloc Philippe
Published: November 2023

Staphylococcus aureusis a major contributor to bacterial-associated mortality, owing to its exceptional adaptability across diverse environments. Iron is vital to most organisms but can be toxic in excess. To manage its intracellular iron,S. aureus, like many pathogens, employs intricate systems. We have recently identified IsrR as a key regulatory RNA induced during iron starvation. Its role is to reduce the synthesis of non-essential iron-containing proteins under iron-depleted conditions. In this study, we unveil IsrR’s regulatory action on MiaB, an enzyme responsible for methylthio group addition to specific sites on transfer RNAs (tRNAs). We use predictive tools and reporter fusion assays to demonstrate IsrR’s binding to the Shine-Dalgarno sequence ofmiaBRNA, thereby impeding its translation. The effectiveness of IsrR hinges on the integrity of a specific C-rich region. As MiaB is non-essential and has iron-sulfur clusters, IsrR induction spares iron by downregulatingmiaB. This may improveS. aureusfitness and aid in navigating the host’s nutritional immune defenses.

IMPORTANCE

In many biotopes, including those found within an infected host, bacteria confront the challenge of iron deficiency. They employ various strategies to adapt to this scarcity of nutrients, one of which involves regulating iron-containing proteins through the action of small regulatory RNAs. Our study shows how IsrR, a small RNA fromS. aureus, prevents the production of MiaB, a tRNA-modifying enzyme containing iron-sulfur clusters. With this illustration, we propose a new substrate for an iron-sparing small RNA, which, when downregulated should reduce the need for iron and save it to essential functions.
PINK1 regulated basal mitophagy is evident in skeletal muscles
Authors: Singh Francois , Wilhelm Lea , Prescott Alan R. , Ostacolo Kevin , Zhao Jin-Feng , Ogmundsdottir Margret H. , Ganley Ian G.
Published: November 2023

PINK1, mutated in familial forms of Parkinson’s disease, initiates mitophagy following mitochondrial depolarization. However, it is difficult to monitor this pathway physiologically in mice as loss of PINK1 does not alter basal mitophagy levels in most tissues. To further characterize this pathwayin vivo, we usedmito-QC mice in which loss of PINK1 was combined with the mitochondrial-associated POLGD257Amutation. We focused on skeletal muscle as gene expression data indicates that this tissue has the highest PINK1 levels. We found that loss of PINK1 in oxidative hindlimb muscle significantly reduced mitophagy. Of interest, the presence of the POLGD257Amutation, while having a minor effect in most tissues, restored levels of muscle mitophagy caused by the loss of PINK1. Although our observations highlight that multiple mitophagy pathways operate within a single tissue, we identify skeletal muscle as a tissue of choice for the study of PINK1-dependant mitophagy under basal conditions.
NaP-TRAP, a novel massively parallel reporter assay to quantify translation control
Authors: Strayer Ethan C. , Krishna Srikar , Lee Haejeong , Vejnar Charles , Beaudoin Jean-Denis , Giraldez Antonio J.
Published: November 2023

Thecis-regulatory elements encoded in a mRNA determine its stability and translational output. While there has been a considerable effort to understand the factors driving mRNA stability, the regulatory frameworks governing translational control remain elusive. We have developed a novel massively parallel reporter assay (MPRA) to measure mRNA translation, Nascent Peptide Translating Ribosome Affinity Purification (NaP-TRAP). NaP-TRAP measures translation in a frame specific manner through the immunocapture of epitope tagged nascent peptides of reporter mRNAs. In contrast to existing MPRA methods, NaP-TRAP does not require specialized equipment and is readily adaptable to steady-state and dynamic model systems. We have employed NaP-TRAP to quantify Kozak strength and the regulatory landscapes of 5’ UTRs in the developing zebrafish embryo and in human cells, characterizing general and developmentally dynamiccis-regulatory elements. To this end, we identify U-rich motifs as general enhancers, and upstream ORFs and GC-rich motifs as global repressors of translation. We also observe a translational switch during the maternal-to-zygotic transition, where C-rich motifs shift from repressors to prominent activators of translation. Conversely, we show that microRNA sites in the 5’ UTR repress translation following the zygotic expression of miR-430. Together these results demonstrate that NaP-TRAP is a versatile, accessible, and powerful method to decode the regulatory functions of UTRs across different systems.
Dynamic Responses of Striatal Cholinergic Interneurons Control the Extinction and Updating of Goal-Directed Learning
Authors: Huang Zhenbo , Chen Ruifeng , Ho Matthew , Xie Xueyi , Wang Xuehua , Wang Jun
Published: November 2023

Striatal cholinergic interneurons (CINs) regulate behavioral flexibility, but their exact contribution to this process remains elusive. In this study, we report that extinction learning enhances acetylcholine (ACh) release. Mimicking this enhancement by optogenetically inducing CIN burst firing promotes extinction learning. CINs receive excitatory thalamic inputs, and we observed that extinction training augmented thalamic activity. Optogenetically stimulating these thalamic inputs caused CIN burst firing and enhanced ACh release, strengthening extinction learning. Notably, CIN burst firing is usually followed by a pause in firing. We found that disrupting this pause through continuous optogenetic stimulation reversibly impaired the updating of goal-directed behaviors. Furthermore, excessive alcohol consumption reduced thalamus-induced burst-pause firing in CINs and impaired the reversal of goal-directed learning. In summary, thalamic-driven CIN burst firing promotes extinction learning, while the pause is pivotal for reversing goal-directed behavior, a process impacted by excessive alcohol. These findings shed light on how CIN’s dynamic responses affect behavioral flexibility.

Highlights

H1.Burstfiring of CINs promotes extinction learning

H2. Thalamic-CINexcitationenhances extinction learning

H3.Pauseof CIN is critical for the reversal of goal-directed learning

H4. Chronic alcohol consumption reduces theburst-pauseofCINsand impairs the reversal of goal-directed learning.
Ancestral variation and its impact on wild house mouse genomes
Authors: Lawal Raman Akinyanju , Dumont Beth L.
Published: November 2023

Ancestral alleles are important contributors to adaptation and disease risk in populations. House mice emerged in and/or around the Indian subcontinent, but the genetic composition of this ancestral population and the extent to which ancestral variants contribute to contemporary global mouse diversity are poorly understood. To address these knowledge gaps, we assessed the origins and demographic patterning of global mouse diversity using a set of 169 wild mouse genome sequences from across the world. This dataset includes 37 mouse genomes from the broadly designated ancestral regions, providing crucial resources needed to evaluate the contributions and the impact of ancestral diversity on the genomic scale. We show that house mice emerged in the Indo-Pakistan region around 700 kya, withM. m. castaneusat the root of theM. musculusspecies. Migration out of the Indo-Pakistan homeland led to the subsequent emergence of theM. m. domesticusandM. m. musculussubspecies ∼360 and 260 kya, respectively. A modest fraction of ancestral alleles have persisted long-term across mouse populations through balancing selection, and we demonstrate that such regions are strongly enriched for genes with immune-related functions. Finally, we find widespread allele-sharing acrossMus musculuslineages and show that this trend is largely due to incomplete lineage sorting, an interpretation contrary to some recent claims of pervasive subspecies introgression. Together, our work underscores the contributions of ancestral variants to contemporary house mouse diversity and adaptation, and refines our understanding of the natural evolutionary history of this important model species.
A comparison of four self-controlled study designs in an analysis of COVID-19 vaccines and Myocarditis using Five European Databases
Authors: Schultze Anna , Martin Ivonne , Messina Davide , Bots Sophie , Belitser Svetlana , Carreras-Martínez Juan José , Correcher-Martinez Elisa , Urchueguía-Fornes Arantxa , Martín-Pérez Mar , García-Poza Patricia , Villalobos Felipe , Pallejà-Millán Meritxell , Bissacco Carlo Alberto , Segundo Elena , Souverein Patrick , Riefolo Fabio , Durán Carlos E. , Gini Rosa , Sturkenboom Miriam , Klungel Olaf , Douglas Ian
Published: November 2023

Introduction

The aim of this study was to assess the possible extent of bias due to violation of a core assumption (event-dependent exposures) when using self-controlled designs to analyse the association between COVID-19 vaccines and myocarditis.

Methods

We used data from five European databases (Spain: BIFAP, FISABIO VID, and SIDIAP; Italy: ARS-Tuscany; England: CPRD Aurum) converted to the ConcePTION Common Data Model. Individuals who experienced both myocarditis and were vaccinated against COVID-19 between 1 September 2020 and the end of data availability in each country were included. We compared a self-controlled risk interval study (SCRI) using a pre-vaccination control window, an SCRI using a post-vaccination control window, a standard SCCS and an extension of the SCCS designed to handle violations of the assumption of event-dependent exposures.

Results

We included 1,757 cases of myocarditis. In unadjusted analyses, agreement between study designs varied by vaccine brand. There was good agreement between all designs for AstraZeneca and Pfizer, but for Moderna we found harmful incidence rate ratios (IRR) using the standard and extended SCCS (standard SCCS: IRR = 3.12, 95%CI = 1.53 – 6.40; extended SCCS: IRR = 2.43, 95%CI = 1.11 – 5.33) compared with no association with the SCRIs (SCRI-pre: IRR = 0.60, 95%CI = 0.27 – 1.33; SCRI-post: IRR = 0.86, 95%CI = 0.34 – 2.19), although confidence intervals were wide. There was very good agreement between all designs for the unadjusted second dose analyses, confirming the known harmful association between the second dose of Moderna and Pfizer vaccines and myocarditis.

Conclusions

In the context of the known association between COVID-19 vaccines and myocarditis, we have demonstrated that two forms of SCRI and two forms of SCCS led to largely comparable results, possibly because of limited violation of the assumption of event-dependent exposures.
heyy, how are you doing? – Redefine employees’ outlook towards mental health
Authors: S. Divya , Sahi Mahima
Published: November 2023

Learning outcomes

The learning outcomes of this case study are to understand the business-to-business (B2B) consumer outlook on mental health care in emerging markets; analyse the challenges faced in creating a need for mental health care in Indian workplaces; explore the business attractiveness of the B2B model and understand the business potential of the B2B segment at heyy,; and contemplate different innovative strategies that could change consumer mindset on mental health care in emerging markets.

Case overview/synopsis

Ankit, the founder and CEO of heyy, was facing a conundrum. “heyy,” was built on normalizing mental well-being at workplaces. His mental health-care app heyy, had crossed 50,000 subscribers within a few months of launch. The mobile app was designed to spread mental health awareness and provide various levels of mental well-being interventions. Business-to-consumer and B2B customer segmentation had been targeted by this start-up. The B2B space consisted of employees working with partner organizations. The adoption rates of employees using the features of heyy, declined after the initial app download. The employees had yet to fully become acclimatized to the features of heyy,. Exploring the business potential and investigating the business attractiveness of the B2B segment were the focus of the present study. Ankit contemplated various strategies he could adopt to increase user adoption of “heyy,” services by employees in his partner organizations. The case study strives to address the question – “What are the risks faced by organizations when entering the mental health-care industry in emerging markets like India, where mental health care is still not openly discussed?”

Complexity academic level

This case study is designed to be taught as part of the “entrepreneurship development” and “strategic management” courses for undergraduates, postgraduates and students of executive programmes in management. Students need to be aware of basic strategic management concepts such as BCG matrix, SWOT analysis and business canvas before working on this case study, so they could dissect the case from multiple perspectives to get a comprehensive outlook on the case.

Supplementary materials

Teaching notes are available for educators only.

Subject code

CSS 11: Strategy.
Psychological impact of COVID-19 on university students in Oman: an examination of stress, resilience and meaning in life
Authors: Chan Moon Fai , Al-Mahrouqi Tamadhir , Al-Huseini Salim , Al-Mukhaini Maryam , Al Shehi Manar , Jahan Firdous , Al-Alawi Mohammed
Published: November 2023

Purpose

This cross-sectional online survey in Oman in April 2021 aimed to assess university students' resilience, stress levels and meaning during the COVID-19 pandemic and identify characteristic profiles.

Design/methodology/approach

A cross-sectional survey design was used to collect data from full-time students at one University in Oman. Outcomes included sociodemographic information, the brief resilience scale, the perceived stress scale-4 and the meaning in life questionnaire to explore the students' profiles.

Findings

A total of 964 students participated (response rate = 34.8%), of which 35% had low resilience scores. The average perceived stress, presence of meaning in life and search for meaning in life scores were 7.9 ± 2.3, 24.2 ± 6.9 and 24.9 ± 7.7, respectively. Cluster analysis identified three groups: low-risk and fewer impacts (cluster A, n = 503, 523%), moderate-risk and moderate impacts (cluster B, n = 160, 16.6%) and high-risk and more impacts (cluster C, n = 301, 31.2%). Cluster C students experienced more psychological problems and were at high risk during the pandemic.

Research limitations/implications

The respondents' honesty is a possible error that could influence the results. Low response rates limit its generalizability, and cause-effect relationships among mental health outcomes cannot be discerned.

Practical implications

This study identified three distinct groups of students, each with different levels of severity in their health problems. There is an increased need for education and counseling to support students during this period, and university management should focus on implementing personal precautionary measures and providing high-tech, user-friendly platforms for students to enhance their learning.

Originality/value

These findings suggest that tailored strategies should be developed to address the unique psychological needs of each group. The study provides important information for university management to understand the pandemic's psychological impact on students and develop effective interventions to support their well-being.
Family involvement and corporate financialization: evidence from China
Authors: Wang Lixia , Gu Yingqian , Liu Wanxin
Published: November 2023

Purpose

Under the background of continuous sluggishness of the real economy and expansion of asset sectors, the Chinese economy exists a trend of “from the real to the virtual.” Managing the corporate financialization is the key to prevent the real economy “from real to virtual.” The paper explores the influence of family involvement on corporate financialization since family firms are an important proportion of real sectors.

Design/methodology/approach

Based on Socioemotional Wealth Theory, this paper makes empirical study using the data of Chinese A-share listed companies from 2008 to 2022 to explore the influence of family involvement on corporate financialization, mainly from the perspectives of family engagement, family identity of CEO and family control power.

Findings

These are the findings: (1) Family engagement will inhibit corporate financialization; (2) Compared with employing external managers, family members acting as CEOs will decrease corporate financialization; (3) The proportion of family ownership is negatively correlated with the level of corporate financialization.

Originality/value

The originality of this paper include these: (1) Analyzing the differences in the financialization of real enterprises with different characteristics and attributes; (2) Expanding the research on the internal motivation of the financialization of the real enterprises, and supplementing the research literature on family firms and corporate financialization; (3) Exploring the internal influence mechanism of financialization of family firms under the background of Chinese culture.
Exploring omnichannel strategies: a path to improve customer experiences
Authors: Silva Susana C. , Silva Francisca Pinto , Dias Joana Carmo
Published: November 2023

Purpose

In today's world, retailers must embrace technological devices to provide fluid, convenient and complete customer experiences. Therefore, combining the offline and online spaces into a single strategy becomes essential, representing a significant opportunity for retailers to improve customer experience. Therefore, this study aims to explore and compare the importance of digital elements in an omnichannel experience by companies in the luxury and non-luxury segments.

Design/methodology/approach

The research offers a model to explore and compare the omnichannel strategies that brands use, considering six dimensions that cover recent technological advances, thus offering a complete experience to their customers. A multiple case study was selected based on a sample of six international companies from two different price segments (luxury and non-luxury).

Findings

The data collected allowed the authors to verify the presence of some dimensions, even though some had little evidence. Nevertheless, the dimensions connectivity, innovativeness and flexibility (only in luxury segment companies) were not present. Overall, and even though they present just little evidence, the results showed that retailers for the luxury segment invest more in delivering digital experiences within omnichannel strategies than the non-luxury ones.

Originality/value

This study improves the existing knowledge of omnichannel retailing. By analysing and comparing the omnichannel experiences, companies can identify areas for improvement and enhance the overall customer journey. Additionally, the model allows managers to compare and re-evaluate their omnichannel strategies with other competitors to gain competitiveness in an ever-evolving market.
“Open access and without fees”: Arab university professors' views on the journal access types
Authors: Altakhaineh Abdel Rahman Mitib , Mohammad Marwa Ahmed , Zibin Aseel
Published: November 2023

Purpose

Due to the high expense of obtaining and accessing scientific research, readers with diverse financial abilities are not offered equal opportunities. This study investigates the preferences for journal access types among Arab university academics and explores the implications of publishing research articles in open access vs closed access journals in low- and lower-middle income countries.

Design/methodology/approach

An online survey and an in-person focus group consisting of 74 scholars from Arab institutions throughout the Arab World were conducted.

Findings

Findings show that most professors at Arab universities favour open access publication without author fees. The results also show that this method of publishing research will help these nations advance by giving all citizens equal access to information and providing researchers with a good opportunity to be read and cited, which contributes to the overall progress of science.

Originality/value

This topic has not been investigated yet, and it is of great importance to university professors and stakeholders in higher education institutions in the Arab world.