bluuebunny/crossref_metadata_2025 huggingface dataset:
Juvenile multiple sclerosis: addressing epidemiology, diagnosis, therapeutic, and prognostic updates along with cognitive dysfunction and quality of life
Authors: Prajjwal Priyadarshi , M.D.M. Marsool , Natarajan Balaganesh , Inban Pugazhendi , Gadam Srikanth , Sowndarya Dommaraju , John Jobby , Abbas Rahim , Vaja HariOm , A.D.M. Marsool , Amir Hussin Omniat
Published: September 2023

Juvenile multiple sclerosis (JMS) is a rare but significant subtype of multiple sclerosis (MS) that affects a small percentage of patients under the age of 10 and 3–5% of all MS patients. Despite its rarity, JMS poses unique challenges in terms of diagnosis, treatment, and management, as it can significantly impact a child or adolescent’s physical, cognitive, and emotional development. JMS presents with a varying spectrum of signs and symptoms such as coordination difficulties and permanent cognitive dysfunctions and may include atypical clinical features such as seizures, acute disseminated encephalomyelitis, and optic neuritis, making diagnostic evaluations challenging. Whilst the biology of JMS shares similarities with adult-onset MS, there exist notable distinctions in disease progression, clinical manifestations, and ultimate prognoses. The International Pediatric MS Study Group (IPMSSG) was founded in 2005 to improve understanding of JMS, but there remains a lack of knowledge and guidelines on the management of this condition. This review summarizes the current knowledge on JMS, including its epidemiology, clinical presentations, diagnostic challenges, current treatment options, and outcomes. Current treatment options for JMS include disease-modifying therapies, but JMS can also result in impaired quality of life and psychiatric comorbidity, highlighting the need for comprehensive care for affected children. Through gathering and analyzing scattered studies and recent updates on JMS, the authors aim to address the gaps in current knowledge on JMS and provide an improved understanding of appropriate care for affected children. By doing so, this review hopes to contribute to improving the quality of life and outcomes for JMS patients.
Response to ifosfamide, carboplatin, etoposide (ICE) vs. dexamethasone, cytarabine cisplatin (DHAP) as salvage chemotherapy in patients with relapsed/refractory lymphoma
Authors: Devi Kanta , Soomar Salman Muhammad , Shaikh Muhammad Usman , Ali Natasha
Published: September 2023

Background:

Non-Hodgkin’s lymphomas are the eighth-most prevalent malignancy in females and the eleventh in males. No research has been conducted comparing dexamethasone, cytarabine cisplatin (DHAP) vs. ifosfamide, carboplatin, etoposide (ICE) as salvage chemotherapy regimens for relapsed or refractory lymphomas in Pakistan. This study aims to compare the response of ICE vs. DHAP as salvage chemotherapy in patients with relapsed/refractory lymphomas.

Methods:

A prospective follow-up study was conducted at the tertiary care hospital in Karachi, Pakistan, from 2019 to 2020. A total of 58 lymphoma patients after first-line chemotherapy were included in the study. The treatment response was evaluated after two cycles of salvage chemotherapy using WHO assessment criteria, and Cox regression was used to determine the hazard ratios considering the P value ≤0.05 significant.

Results:

Of 58 patients, 19 (32.8%) patients achieved complete response (CR), and 8 (13.8%) patients achieved partial response (PR), with an overall response rate of overall response rate of 46.6%. In the ICE group, the response was assessed in 19 patients. Overall response was 42.1%, CR was 31.6% and PR was 10.5%. In the DHAP group, response was evaluated in 39 patients, the overall response rate was 48.7%, CR was 33.3% and PR was 15.4%. The hazard ratio for survival in patients with relapsed/refractory lymphomas who received DHAP was 1.40 times (95% CI: 1.27–3.63, P=0.001) compared to patients who received ICE as salvage chemotherapy.

Conclusion:

DHAP seems to have a marginally better overall response rate than the ICE regimen in patients with refractory or relapsed lymphoma. However, the toxicity profile of patients in both groups was similar.
Tocilizumab in systemic sclerosis treatment: a case report
Authors: Kudsi Maysoun , Khalayli Naram , Tarcha Raghad , Al-Darwish Lama
Published: September 2023

Introduction:

In the United States, tocilizumab was approved for the treatment of scleroderma and scleroderma-related interstitial lung disease because it inhibited the decrease in forced expiratory volume, so scleroderma treatment is entering a new era.

Case presentation:

A 44-year-old female patient with systemic scleroderma, diagnosed 6 years ago, presented with breathlessness over the last week. The modified Rodnan’s score was 18. Tocilizumab 162 mg subcutaneously once every 2 weeks was prescribed. After 4 weeks, a decrease in Rodnan score was observed. Tocilizumab was stopped after 6 months without any side effects due to treatment.

Discussion:

Treatment with tocilizumab may maintain lung function nearly unchanged. Its effect on perfecting skin fibrosis seems promising. Tocilizumab may be fairly safe to use.

Conclusion:

Tocilizumab may be effective and fairly safe to use. Further exploration is anticipated to advance a new period of systemic sclerosis treatment.
Efficacy of ablation therapy on clinical outcomes in patients with atrial fibrillation: a systematic review and meta-analysis
Authors: Zahoor Mohammad Munim , Ullah Saad Ehsan , Kidiavai Harriet Mmaitsi , Eltieb Shahda A.H , Devi Anjuli , Asif Muhammad Anis , Vaswani Akshay , Hyder Ammar , Hoti Muhammad Roshan , Jawad Sayed , Arshid Sana , Shankar Abhirami , Salman Muhammad
Published: September 2023

Background:

Optimal treatment regimen for patients with atrial fibrillation (AF) remains unclear. Therefore, the authors sought to compare the outcomes of ablation therapy versus pharmacological regimens in patients with AF.

Methods:

MEDLINE, Embase, and Cochrane Central databases were searched for randomized controlled trials and observational studies comparing clinical outcomes between of ablation and pharmacological therapy in patients with AF. Stroke, all-cause mortality, cardiovascular mortality, cardiovascular hospitalization, heart failure (HF), and bleeding were among outcomes of interest. Mantel–Haenszel weighted random-effects model was used to calculate relative risks (RRs) with 95 % CIs.

Results:

The analysis included ~200 000 patients from 4 randomized controlled trials and 7 observational studies. Meta-analysis showed statistically significant reduction in stroke among patients on ablation therapy [hazard ratio (HR) 0.51, 95% CI (0.43, 0.60), P<0.00001, I2
=10%], all-cause mortality [HR 0.64, 95% CI (0.45, 0.93), P=0.02, I2
=58%], cardiovascular mortality [HR 0.35, 95% CI (0.25, 0.50), P<0.0001, I2
=0%], and HF [HR 0.40, 95% CI (0.31, 0.53), P<0.00001, I2
=30%]. However, no significant difference was revealed in the risk of cardiovascular hospitalization [HR 1.04, 95% CI (0.88, 1.23), P=0.66, I2
=89%] and bleeding [HR 1.11, 95% CI (0.97, 1.27), P=0.13, I2
=0%].

Conclusion:

Ablation significantly reduces the risk of stroke, cardiovascular mortality, all-cause mortality, and HF in AF patients, compared with medical therapy alone, supporting its use in clinical practice.
Evaluation of the endoscopic revision of dacryocystorhinostomy failure cases: a cohort study
Authors: El Bouhmadi Khadija , Loudghiri Myriam , Oukessou Youssef , Rouadi Sami , Abada Redallah , Roubal Mohamed , Mahtar Mohamed
Published: September 2023

Introduction:

The dacryocystorhinostomy (DCR) procedure is linked to a high success rate; however, cases of tearing recurrence are not rare and should be managed efficiently. Thus, evaluating cases of DCR failure allows highlighting the factors significantly impacting the results in order to realize better controlled primary surgeries.

Material and method:

Twenty-eight patients were operated in our Otolaryngology Department for endoscopic revision of DCR failure between January 2019 and June 2022. Their clinical presentation, postoperative evolution, and findings of the primary and revision surgeries were assessed until the actual follow-up.

Results:

The first surgery was based on an external approach in 17 patients and the bicanalicular silicone tube intubation was kept for a mean of 4.25 months. The recurrence delay varied from 0.5 to 9 months. Revision surgery revealed synechia in 10 patients, a completely closed DCR ostium in 22 patients (78.57%) by mucosal scarring and granulation, and lacrimal sac fibrosis in 16 patients (57.14%). A significant correlation was found between maintenance of the silicone intubation tube greater than or equal to 3 months and lacrimal sac fibrosis (P=0.016<0.05).

Conclusion:

Thus, better controlled primary surgeries with optimal exposure, wild marsupialisation of the lacrimal sac and no longer systematic bicanalicular intubation which should be dedicated to difficult anatomies and canalicular affections should guarantee better functional results.
Postoperative delirium in 47 379 individuals undergoing transcatheter aortic valve replacement: a systematic review and meta-analysis
Authors: Ochani Sidhant , Adnan Alishba , Siddiqui Amna , Kalwar Asifa , Kukreja Sandhaya , Ahmad Mushtaq , Ashraf Muhammad Hasan , Asghar Mustafa Ali
Published: September 2023

Objective:

The study aims to discuss the assessment methods used for the incidence of in-hospital postoperative delirium (IHPOD) in transcatheter aortic valve replacement (TAVR) patients and explore possible strategies for preventing and reducing postoperative complications in the geriatric population.

Methodology:

An electronic search of PubMed, Embase, BioMedCentral, Google Scholar, and the Cochrane Central Register of Controlled Trials was conducted up to August 2021, to identify studies on the IHPOD following TAVR in patients above 70 years. The primary objective of the study was to determine the incidence of delirium following TAVR and procedures like transfemoral (TF) and non-TF approaches. The secondary objectives were to determine the incidence of stroke and incidence according to the confusion assessment method (CAM) diagnostic tool. The authors only included studies published in English and excluded patients with comorbidities and studies with inaccessible full-text.

Results:

Among the selected 42 studies with 47 379 patients, the incidence of IHPOD following TAVR was 10.5% (95% CI: 9.2–11.9%, I
2=95.82%, P<0.001). Incidence based on CAM was 15.6% (95% CI: 10.5–20.7%, I
2=95.36%, P<0.001). The incidence of IHPOD after TF-TAVR was 9.3% (95% CI: 7.6–11.0%, I
2=94.52%, P<0.001), and after non-TF TAVI was 25.3% (95% CI: 15.4–35.1%, I
2=92.45%, P<0.001). The incidence of stroke was 3.7% (95% CI: 2.9–4.5%, I
2=89.76%, P<0.001). Meta-regression analyses between mean age (P=0.146), logistic EuroSCORE (P=0.099), or percentage of participants treated using the TF approach (P=0.276) were nonsignificant while stroke (P=0.010) was significant. When considering these variables, the residual heterogeneity remained high indicating that other variables influence the heterogeneity.

Conclusion:

IHPOD following TAVR was observed in 10.5% of individuals and in 15.6% using CAM. Its incidence was found to be three times higher after non-TF TAVR (25.3%) compared to TF TAVR (9.3%). Stroke showed an incidence of 3.7% after TAVR and was found to be significantly associated with the risk of developing delirium following TAVR. Further studies are needed to evaluate possible causes and risk factors responsible for delirium and to assess the role of anesthesia and cerebral embolic protection in preventing delirium after TAVR.
Delayed awakening and its associated factor following general anesthesia service, 2022: a cross-sectional study
Authors: Bayable Samuel D. , Amberbir Wubet D. , Fetene Melaku B.
Published: September 2023

Background:

The time to emerge from anesthesia is affected by patient factors, anesthetic factors, the duration of surgery, and preoperative and intraoperative pain management.

Objective:

This study aimed to determine the prevalence and contributing factors of delayed awakening following general anesthesia.

Method:

A cross-sectional study was conducted from January to June 2022. After getting ethical approval with the permission number S/C/R 37/01/2022, willing patients participate with written informed consent. Chart reviews in the preoperative and postoperative recovery rooms were used to collect data. Frequency and percentage with cross-tabulation were used to provide the descriptive statistics. To determine the predictive variables that were associated with the outcome variable, bivariable, and multivariable logistic regression models were fitted. The statistical significance was evaluated using P-values of 0.05 for multivariable regression.

Results:

In the current study, a normal emergency occurred in 91.7% of surgical patients receiving general anesthesia, while delayed awakening, emergence with hypoactive, and emergence with delirium occurred in 2.6, 3.9, and 1.8% of cases, respectively. Patients older than 64 years [adjusted odds ratio (AOR): 1.33, 95% CI: 0.83–7.191], being diploma anesthesia providers (AOR: 2.38, 95% CI: 2.05–7.15), opioids (AOR: 2.3, 95% CI: 2.20–5.76), surgery lasting longer than 2 h (AOR: 1.91, 95% CI: 1.83–6.14), estimated blood loss of more than 1500 ml (AOR: 1.20, 95% CI: 0.62–11.30), crystalloid administration of more than 3000 ml (AOR: 3.12, 95% CI: 2.19–7.32), intraoperative hypotension (AOR: 3.37, 95% CI: 2.93–9.41) and extreme body weight, were significantly linked to delayed awakening after general anesthesia.

Conclusion:

Although delayed emergence is an uncommon condition with a number of contributing causes, it is preventable, and once it has occurred, it presents a challenge for anesthetists.
Polymicrogyria: An Unusual Case of Secondary Mania
Authors: Chacón-González Jacobo , Restrepo-Martínez Miguel , Moreno-Avellán Álvaro , Ramírez-Bermúdez Jesús
Published: September 2023

Background:

Secondary mania refers to a manic episode that arises during a medical illness other than bipolar disorder or in response to a drug or medication. As the psychopathological features of secondary mania resemble those of mania due to bipolar disorder, misdiagnosis is frequent.

Purpose and Basic Procedures:

We present the case of a 20-year-old woman who developed a manic episode with psychotic symptoms, in whom polymicrogyria, a malformation of the cortical development with abnormal electroencephalographic activity, was documented. After initiating antiepileptic management, the affective symptoms completely subsided.

Main Findings:

To date, no specific recommendations are available concerning when to perform advanced studies in patients with a manic episode; however, as our case shows, these are much needed.

Principal Conclusion:

Because the treatment of secondary conditions largely depends on finding the underlying cause, patients with a new-onset mania should undergo a thorough assessment for secondary causes.
Psychedelics, With a Focus on Psilocybin: Issues for the Clinician
Authors: Garakani Amir , Alexander Jeanne L. , Sumner Calvin R. , Pine Janet H. , Gross Lawrence S. , Raison Charles L. , Aaronson Scott T. , Baron David A.
Published: September 2023

There has been a burgeoning interest in psychedelics among the public, state legislatures, psychiatrists and other clinical providers, and within the research community. Increasing numbers of studies evaluating psychedelics for depression, anxiety, posttraumatic stress disorder, and substance use disorders have been conducted or are underway. While discussing psychedelics in general, the focus of this paper is on psilocybin and its mechanism, how it exerts a psychedelic effect, dosing, and a review of the treatment studies of psilocybin, which were primarily for treatment-resistant depression and cancer-related anxiety. Future directions and potential limitations of studying and regulating psilocybin and other psychedelics are also discussed.
Commentary: Mania in Medically Ill Patients
Authors: Garakani Amir
Published: September 2023

Patients may present with manic symptoms in medical settings such as emergency rooms and on inpatient medical floors, leading to psychiatric consultation to try to determine the etiology of the symptoms. It is crucial to clarify whether the mania is secondary to a medical illness or whether the patient’s symptoms are from a primary bipolar disorder. In this issue, we publish 2 case reports of patients presenting with manic symptoms in medical settings. The first case involves polymicrogyria in the frontal lobe of the brain as a cause of secondary mania. The second case involves a patient who was previously diagnosed with bipolar disorder and subsequently developed symptoms of Behçet’s disease. In this case, it appears likely that the bipolar disorder was primary, and that the Behçet disease and the bipolar disorder may have exacerbated each other. Given the complexities involved in assessing and treating patients, especially in acute or emergency settings, it is important for primary medical and psychiatric providers to collaborate and communicate well in assuring that they obtain a thorough history of their patients’ symptoms and that patients receive a comprehensive medical evaluation before psychiatric treatment is started.
Incels: An Introduction for Mental Health Clinicians
Authors: Tastenhoye Camille A. , Dupré Juliette , Ross Nina E. , Bodnar Tanya V. , Friedman Susan Hatters
Published: September 2023

Involuntary celibates (“incels”) refers to a group consisting mostly of heterosexual men that exists predominantly in online spaces. These men are united by a belief that they are victimized by a postfeminist society, leading to an inability to engage in sexual intimacy with women. Recent acts of mass violence have been linked to self-identified incels, leading to an increased need for awareness of incel worldviews, argot, and demographics among psychiatrists. Limited research exists to describe this heterogenous group, with existing data suggesting higher rates of depression, anxiety, and suicidal ideation within the demographic. This column reviews the incel worldview, existing literature, how to identify an individual with incel beliefs based on vocabulary and internet usage, and treatment modalities.
Surgical Knee Denervation for the Treatment of Pain Caused by Primary Osteoarthritis
Authors: Hustedt Joshua W. , Reichenbach Rachel , Merrell Dallin , Watzig Ben , Robainia Joey , Silvestri Brianna
Published: September 2023

Background:

Denervation techniques have increased in popularity for treatment of primary knee osteoarthritis. However, few clinical trials have been conducted on surgical knee denervation. This study was conducted to evaluate the safety and efficacy of a surgical denervation technique for the treatment of primary knee osteoarthritis.

Methods:

Patients were included in the trial if they had failed conservative management for osteoarthritis with corticosteroid injections and were not candidates for total knee arthroplasty. Patients were treated with a surgical knee denervation. Preoperative and postoperative scores were assessed to examine the improvement in pain, function, and quality of life.

Results:

Twenty-four knee denervation procedures were performed in 21 patients. The average follow-up time was 21 months, with a minimum follow-up of 12 months. Patients experienced an improvement in pain with a decrease in visual analogue scale pain scores from 8.7 to 2.9, an improvement in function with a decrease in Western Ontario McMaster Arthritis Score scores from 69 to 32, and an improvement in quality of life with an increase in European quality of life index from 0.183 to 0.646. A clinically significant improvement in pain occurred in 92% of patients, whereas 75% of patients had an improvement in function and 83% had an improvement in quality of life.

Conclusions:

The treatment of recalcitrant knee pain in nonarthroplasty candidates is a difficult issue. This trial suggests that a surgical denervation technique provides improvement in pain, function, and quality of life. Surgical denervation may be a beneficial treatment for patients with recalcitrant pain from primary knee osteoarthritis.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, IV.
Don’t mind if I do: Arctic humpback whales respond to winter foraging opportunities before migration
Authors: Kettemer Lisa Elena , Ramm Theresia , Broms Fredrik , Biuw Martin , Blanchet Marie-Anne , Bourgeon Sophie , Dubourg Paul , Ellendersen Anna C. J. , Horaud Mathilde , Kershaw Joanna , Miller Patrick J. O. , Øien Nils , Pallin Logan J. , Rikardsen Audun H.
Published: September 2023

Migration patterns are fundamentally linked to the spatio-temporal distributions of prey. How migrating animals can respond to changes in their prey's distribution and abundance remains largely unclear. During the last decade, humpback whales (
Megaptera novaeangliae
) used specific winter foraging sites in fjords of northern Norway, outside of their main summer foraging season, to feed on herring that started overwintering in the area. We used photographic matching to show that whales sighted during summer in the Barents Sea foraged in northern Norway from late October to February, staying up to three months and showing high inter-annual return rates (up to 82%). The number of identified whales in northern Norway totalled 866 individuals by 2019. Genetic sexing and hormone profiling in both areas demonstrate a female bias in northern Norway and suggest higher proportions of pregnancy in northern Norway. This may indicate that the fjord-based winter feeding is important for pregnant females before migration. Our results suggest that humpback whales can respond to foraging opportunities along their migration pathways, in some cases by continuing their feeding season well into winter. This provides an important reminder to implement dynamic ecosystem management that can account for changes in the spatio-temporal distribution of migrating marine mammals.
Downclimbing and the evolution of ape forelimb morphologies
Authors: Fannin Luke D. , Joy Mary S. , Dominy Nathaniel J. , McGraw W. Scott , DeSilva Jeremy M.
Published: September 2023

The forelimbs of hominoid primates (apes) are decidedly more flexible than those of monkeys, especially at the shoulder, elbow and wrist joints. It is tempting to link the greater mobility of these joints to the functional demands of vertical climbing and below-branch suspension, but field-based kinematic studies have found few differences between chimpanzees and monkeys when comparing forelimb excursion angles during vertical ascent (upclimbing). There is, however, a strong theoretical argument for focusing instead on vertical descent (downclimbing), which motivated us to quantify the effects of climbing directionality on the forelimb kinematics of wild chimpanzees (Pan troglodytes) and sooty mangabeys (Cercocebus atys). We found that the shoulders and elbows of chimpanzees and sooty mangabeys subtended larger joint angles during bouts of downclimbing, and that the magnitude of this difference was greatest among chimpanzees. Our results cast new light on the functional importance of downclimbing, while also burnishing functional hypotheses that emphasize the role of vertical climbing during the evolution of apes, including the human lineage.
Variability in variability: does variation in morphological and physiological traits differ between men and women?
Authors: Halsey Lewis G. , Esteves Gabriel P. , Dolan Eimear
Published: September 2023

Many researchers presume greater variability between female participants than between males due to the menstrual cycle. This view has encouraged a sex bias in health and medical research, resulting in considerable knowledge gaps with important clinical implications. Yet in another field—evolutionary biology—the received wisdom is the reverse: that men are more variable, possibly due to male heterogamety. To test these competing hypotheses, we compared variance between the sexes for 50 morphological and physiological traits, analysing data from the NHANES database. Nearly half the traits did not exhibit sexual dimorphism in variation, while 18 exhibited greater female variation (GFV), indicating GFV does not dominate human characteristics. Only eight traits exhibited greater male variation (GMV), indicating GMV also does not dominate, and in turn offering scant support for the heterogamety hypothesis. When our analysis was filtered to include only women with regular menstrual cycles (and men of equivalent age), the number of traits with GFV and GMV were low and not statistically different, suggesting that the menstrual cycle does not typically explain GFV when it occurs. In practical terms, health and medical researchers should no longer simply assume that female participants will induce additional variation in the traits of interest.
A role for JAK2 in mediating cell surface GHR-PRLR interaction
Authors: Chen Chen , Jiang Jing , Rao Tejeshwar C. , Liu Ying , Marquez Lago Tatiana T. , Frank Stuart J. , Leier André
Published: September 2023

Growth hormone (GH) receptor (GHR) and (full-length) prolactin (PRL) receptor (PRLR) are transmembrane class I cytokine receptors that co-exist in various normal and cancerous cells. Both receptors respond to their associated ligands predominantly by activating the Janus Kinase 2 (JAK2)-signal transducer and activator of transcription (STAT) signaling pathways, and both are also known to initiate receptor-specific JAK2-independent signaling. Together with their cognate ligands, these receptors have been associated with pro-tumorigenic effects in various cancers, including breast cancer (BC). Human GH is known to bind GHR and PRLR, while PRL can only bind PRLR. A growing body of work suggests that GHR and PRLR can form heteromers in BC cells, modulating GH signal transduction. However, the dynamics of PRLR and GHR on the plasma membrane and how these could affect their respective signaling still need to be understood.

To this end, we set out to unravel the spatiotemporal dynamics of GHR and PRLR on the surface of human T47D breast cancer cells and γ2A-JAK2 cells. We applied direct stochastic optical reconstruction microscopy (dSTORM) and quantified the colocalization and availability of both receptors on the plasma membrane at the nanometer scale at different time points following treatment with GH and PRL. In cells co-expressing GHR and PRLR, we surprisingly observed that not only GH but also PRL treatment induces a significant loss of surface GHR. In cells lacking PRLR or expressing a mutant PRLR deficient in JAK2 binding, we observed that GH induces downregulation of cell surface membrane-bound GHR, but PRL no longer induces loss of surface GHR. Colocalizations of GHR and PRLR were confirmed by proximity ligation (PL) assay.

Our results suggest that PRLR-GHR interaction, direct or indirect, is indispensable for PRL- but not GH- induced loss of surface GHR and for both GH-induced and PRL-induced increase of surface PRLR, with potential consequences for downstream signaling. Furthermore, our results suggest that JAK2 binding via the receptor intracellular domain’s Box1 element is crucial for the observed regulation of one class I cytokine receptor’s cell surface availability via ligand-induced activation of another class I cytokine receptor. Our findings shed new light on the reciprocal and collective role that PRLR and GHR play in regulating cell signaling.
Tauopathy severely disrupts homeostatic set-points in emergent neural dynamics but not in the activity of individual neurons
Authors: McGregor James N. , Farris Clayton A. , Ensley Sahara , Schneider Aidan , Wang Chao , Liu Yuqi , Tu Jianhong , Elmore Halla , Ronayne Keenan D. , Wessel Ralf , Dyer Eva L. , Bhaskaran-Nair Kiran , Holtzman David M. , Hengen Keith B.
Published: September 2023

The homeostatic regulation of neuronal activity is essential for robust computation; key set-points, such as firing rate, are actively stabilized to compensate for perturbations. From this perspective, the disruption of brain function central to neurodegenerative disease should reflect impairments of computationally essential set-points. Despite connecting neurodegeneration to functional outcomes, the impact of disease on set-points in neuronal activity is unknown. Here we present a comprehensive, theory-driven investigation of the effects of tau-mediated neurodegeneration on homeostatic set-points in neuronal activity. In a mouse model of tauopathy, we examine 27,000 hours of hippocampal recordings during free behavior throughout disease progression. Contrary to our initial hypothesis that tauopathy would impact set-points in spike rate and variance, we found that cell-level set-points are resilient to even the latest stages of disease. Instead, we find that tauopathy disrupts neuronal activity at the network-level, which we quantify using both pairwise measures of neuron interactions as well as measurement of the network’s nearness tocriticality, an ideal computational regime that is known to be a homeostatic set-point. We find that shifts in network criticality 1) track with symptoms, 2) predict underlying anatomical and molecular pathology, 3) occur in a sleep/wake dependent manner, and 4) can be used to reliably classify an animal’s genotype. Our data suggest that the critical set-point is intact, but that homeostatic machinery is progressively incapable of stabilizing hippocampal networks, particularly during waking. This work illustrates how neurodegenerative processes can impact the computational capacity of neurobiological systems, and suggest an important connection between molecular pathology, circuit function, and animal behavior.
Understanding the heterogeneity of alloreactive natural killer cell function in kidney transplantation
Authors: Ruan Dan Fu , Fribourg Miguel , Yuki Yuko , Park Yeon-Hwa , Martin Maureen , Kelly Geoffrey , Lee Brian , de Real Ronaldo Miguel , Lee Rachel , Geanon Daniel , Kim-Schulze Seunghee , McCarthy Melissa , Chun Nicholas , Cravedi Paolo , Carrington Mary , Heeger Peter S. , Horowitz Amir
Published: September 2023

Human Natural Killer (NK) cells are heterogeneous lymphocytes regulated by variegated arrays of germline-encoded activating and inhibitory receptors. They acquire the ability to detect polymorphic self-antigen via NKG2A/HLA-E or KIR/HLA-I ligand interactions through an education process. Correlations among HLA/KIR genes, kidney transplantation pathology and outcomes suggest that NK cells participate in allograft injury, but mechanisms linking NK HLA/KIR education to antibody-independent pathological functions remain unclear. We used CyTOF to characterize pre- and post-transplant peripheral blood NK cell phenotypes/functions before and after stimulation with allogeneic donor cells. Unsupervised clustering identified unique NK cell subpopulations present in varying proportions across patients, each of which responded heterogeneously to donor cells based on donor ligand expression patterns. Analyses of pre-transplant blood showed that educated, NKG2A/KIR-expressing NK cells responded greater than non-educated subsets to donor stimulators, and this heightened alloreactivity persisted > 6 months post-transplant despite immunosuppression. In distinct test and validation sets of patients participating in two clinical trials, pre-transplant donor-induced release of NK cell Ksp37, a cytotoxicity mediator, correlated with 2-year and 5-year eGFR. The findings explain previously reported associations between NK cell genotypes and transplant outcomes and suggest that pre-transplant NK cell analysis could function as a risk-assessment biomarker for transplant outcomes.
Low-flux electron diffraction study on the intercellular lipid organization in the human lip stratum corneum
Authors: Kamimoto-Kuroki Junko , Nakazawa Hiromitsu , Ohnari Hiroki , Yamanoi Mutsumi , Naru Eiji , Kato Satoru
Published: September 2023

OBJECTIVE

Chapped lips, characterized by drying and cracking, remain a prevalent concern. Identifying the root causes of lip chapping is crucial for developing effective treatments. We examined the lateral packing structure of intercellular lipids (ICL) in the lip stratum corneum (SC) by low-flux electron diffraction (LFED) to obtain new insights into the causes of high transepidermal water loss (TEWL) and low water retention, which may increase the vulnerability of the lip to chapping.

METHODS

Twenty-one healthy subjects participated in this study. After water content and TEWL measurements, a layer of corneocytes was collected from each lip vermilion surface by the grid-stripping technique. The lateral packing structure of ICL on the collected corneocytes was analyzed by LFED.

RESULTS

Similar to skin SC-ICLs, we found coexistence of orthorhombic and hexagonal phases in lip SC-ICLs. We also found that electron diffraction (ED) images with no sharp peaks and a relatively small broad peak at around 2.2 nm−1appeared frequently, unlike skin SC-ICLs. This suggests that a large fraction of corneocytes in the lip SC is surrounded by thin ICL layers in the fluid phase. Such structural features of lip SC-ICLs can explain its inferior barrier function. Furthermore, we calculated the frequency of appearance of ED images with no sharp peaks,Af, and quantitatively analyzed its correlation with water content and TEWL. The analysis showed a negative correlation betweenAfand water content whenAf> 50%.

CONCLUSION

This is the first report on the detailed analysis of lipid organization in lip SC-ICLs. We showed that the LFED method in combination with quasi-noninvasive sample collection by the grid-stripping technique is useful for statistical study of the fine structures in lip SC. We also found that the proportion of ICLs in a fluid phase was much higher in lip SC than in skin SC, which may be related to lower water content and vulnerability of lip to chapping. Our findings provide a promising approach for obtaining clues to the structural factors regulating the water content and TEWL in lip SC, leading to more effective lip care products.
Impact and centrality of scientific disciplines
Authors: Aguilar-Velázquez Daniel , Herrera Rodolfo Romero , Boyer Denis , Ramos-Fernández Gabriel
Published: September 2023

The Scimago Journal Rank (SJR) is a metric that captures the centrality of a journal across an all-discipline article network, while the impact factor (IF) is the average incoming citations of a journal. We analyzed SJRs and IFs of the journals belonging to the SJR first quartile from 2013 to 2020 in 7 disciplines: mathematics, biology, physics, medicine, social sciences, chemistry, and engineering. We show that biology is the most central discipline, followed by physics and chemistry. These three disciplines also present the highest IFs. Mathematics journals display a low IF (the second-lowest among disciplines), but possesses an intermediate centrality. While the average IF has increased over the last years, the SJR average has decreased. Gini coefficients show that SJR is a slightly more egalitarian metric than IF. We discuss some possible origins of these findings.
Non-Pyrogenicity and Biocompatibility of Parylene-Coated Magnetic Bead Implants
Authors: Taylor Cameron R. , Nott Joshua K. , Ratnasena Nilmini H. , Cohen Joel M. , Herr Hugh M.
Published: September 2023

We verify the non-pyrogenicity of magnetic bead implants and submit them to a full chemical characterization and toxicological risk assessment. Further, we validate the cleaning efficacy, steam sterilization, and dry time of a magnetic bead insertion device. We believe these results to be valuable to further scientific progress in the use of magnetic bead implants for human-machine interfacing.
Mechanistic modeling of amyloid oligomer and protofibril formation
Authors: Yuzu Keisuke , Imamura Hiroshi , Nozaki Takuro , Fujii Yuki , Mohamed Badawy Shaymaa Mohamed , Morishima Ken , Okuda Aya , Inoue Rintaro , Sugiyama Masaaki , Chatani Eri
Published: September 2023

Early phase of amyloid formation, where prefibrillar aggregates such as oligomers and protofibrils are often observed, is crucial for elucidating pathogenesis. However, since oligomers and protofibrils form transiently and heterogeneously, the detailed mechanisms of their formation remain unclear. Here, we have investigated the early aggregation process of bovine and human insulin by static and dynamic light scattering in combination with thioflavin T (ThT) fluorescence and Fourier transform infrared (FTIR) spectroscopy. The time dependence of light scattering has revealed that oligomers and protofibrils form in bovine insulin, in contrast to no significant aggregation in human insulin. By focusing on bovine insulin for kinetic analysis, it has been revealed that the protofibril formation process was divided into two steps with reference to fractal dimension. When modeled the experimental data of static and dynamic light scattering based on the Smoluchowski aggregation kinetics with fractal aggregation and end-to-end association, we found the initial formation of spherical oligomers and their subsequent uniaxial docking. Furthermore, the analysis of temperature and salt concentration dependence revealed that the end-to-end association is the rate-limiting step, where structure organization occurred with dehydration. The established model for protofibril formation where oligomers are incorporated as a precursor provides insight into the molecular mechanism how protein molecules assemble during the early stage of amyloid formation.

Significance

Amyloid oligomers and protofibrils have attracted attention as critical causes of neurodegenerative diseases; however, detailed formation processes of these aggregates have been poorly understood. In this study, we established a mechanistic model of oligomer and protofibril formation of bovine insulin based on Smoluchowski aggregation kinetics in terms of static and dynamic light scattering. It has been demonstrated that early aggregation proceeds by initial fractal-like aggregation to form oligomers, and subsequent their end-to-end docking to form protofibrils. The latter step is a rate-limiting step, where structural organization occurs with dehydration. The established model is expected to broadly applicable to a variety of proteins, and thus will provides valuable insights for accelerating therapeutic development and anti-neurodegenerative drug design.
Mitochondrial-nuclear variation for metabolic plasticity with potential consequences for invasion success in New Zealand mud snails
Authors: Matoo Omera B. , Mohammed Humu , Patel Himani , Neiman Maurine , Montooth Kristi L.
Published: September 2023

Metabolic rate is an emergent organismal trait that integrates energetic costs of living and influences species distributions and response to climate change. For ectotherms, metabolic rate is likely shaped by interactions between mitochondrial and nuclear genomes and environmental temperature. Variation in reproductive mode (e.g., asexual vs. sexual reproduction) can enhance or interfere with cross-generational transmission of these interactions, with implications for evolutionary responses to selection on standing genetic variation for metabolism-related traits. We leveraged known patterns of mitochondrial-nuclear discordance in a global invader, the snailPotamopyrgus antipodarum, to measure thermal plasticity of metabolic rate in invasive vs. native asexual lineages that combined multiple mitochondrial haplotypes with nuclear genomic variation from distinct lake populations. Native lineages harbored significant mitochondrial-nuclear variation for metabolic plasticity, with some genotypes maintaining low metabolic rates at high temperature. Invasive lineages contained only a small subset of this variation, with non-plastic and lower metabolic rates relative to native lineages at high temperature. Together, these data indicate that mitochondrial-nuclear-environment interactions contribute to variation in the metabolic rate of asexual lineages. Our results also demonstrate that invasive lineages have metabolic phenotypes that could facilitate successful colonization of aquatic habitats via decreased maintenance metabolism under high temperatures.
Engineering TALE-linked deaminases to facilitate precision adenine base editing in mitochondrial DNA
Authors: Cho Sung-Ik , Lim Kayeong , Hong Seongho , Lee Jaesuk , Kim Annie , Lee Ji Min , Mok Young Geun , Chung Eugene , Han Seunghun , Cho Sang-Mi , Kim Jieun , Kim Sanghun , Kim Eun-Kyoung , Nam Ki-Hoan , Oh Yeji , Choi Minkyung , Lee Seonghyun , Lee Hyunji , Kim Jin-Soo
Published: September 2023

DddA-derived cytosine base editors (DdCBEs) and transcription activator-like effector (TALE)-linked deaminases (TALEDs) catalyze targeted base editing of mitochondrial DNA (mtDNA) in eukaryotic cells, a method useful for modeling of mitochondrial genetic disorders and developing novel therapeutic modalities. Here, we report that A-to-G editing TALEDs but not C-to-T editing DdCBEs induce tens of thousands of transcriptome-wide off-target edits in human cells. To avoid these unwanted RNA edits, we engineered the substrate-binding site in TadA8e, the deoxy-adenine deaminase in TALEDs, and created TALED variants with fine-tuned deaminase activity. Our engineered TALED variants not only reduced RNA off-target edits by > 99% but also minimized off-target mtDNA mutations and bystander edits at a target site. Unlike wild-type versions, our TALED variants were not cytotoxic and did not cause developmental arrest of mouse embryos. As a result, we obtained mice with pathogenic mtDNA mutations, associated with Leigh disease, which showed reduced heart rates.
Safety and immunogenicity of VLPCOV-02, a SARS-CoV-2 self-amplifying RNA vaccine with a modified base, 5-methylcytosine, in healthy individuals
Authors: Aboshi Masayuki , Matsuda Kenta , Kawakami Daisuke , Kono Kaoru , Kazami Yoko , Sekida Takashi , Komori Mai , Morey Amber L. , Suga Shigeru , Smith Jonathan F. , Fukuhara Takasuke , Iwatani Yasumasa , Yamamoto Takuya , Sato Nobuaki , Akahata Wataru
Published: September 2023

Continuing emergence of variants of concern resulting in reduced SARS-CoV-2 vaccine efficacy necessitates additional prevention strategies. The structure of VLPCOV-01, a lipid nanoparticle-encapsulated, self-amplifying RNA COVID-19 vaccine with a comparable immune response to BNT162b2, was revised by incorporating a modified base, 5-methylcytosine, to reduce reactogenicity, and an updated receptor-binding domain derived from Brazil (gamma) variant. Interim analyses of a phase 1 dose-escalation booster vaccination study with the resulting construct, VLPCOV-02, in healthy, previously vaccinated Japanese individuals (N=96) are reported (jRCT2051230005). A dose-related increase in solicited local and systemic adverse events was observed, which were generally rated mild or moderate. The most commonly occurring events were tenderness, pain, fatigue, and myalgia. Serum SARS-CoV-2 immunoglobulin titers increased during the 4 weeks post-immunization. VLPCOV-02 demonstrated a favorable safety profile compared with VLPCOV-01, with a lower frequency of adverse events and fewer fever events at an equivalent dose. These findings support further study of VLPCOV-02.
Comparison ofTP53Mutations in Myelodysplasia and Acute Leukemia Suggests Divergent Roles in Initiation and Progression
Authors: Jambhekar Ashwini , Ackerman Emily E. , Alpay Berk A. , Lahav Galit , Lovitch Scott B.
Published: September 2023

TP53mutation predicts adverse prognosis in many cancers, including myeloid neoplasms, but the mechanisms by which specific mutations impact disease biology, and whether they differ between disease categories, remain unknown. We analyzedTP53mutations in four myeloid neoplasm subtypes (MDS, AML, AML with myelodysplasia-related changes (AML-MRC), and therapy-related acute myeloid leukemia (tAML)), and identified differences in mutation types, spectrum, and hotspots between disease categories and compared to solid tumors. Missense mutations in the DNA-binding domain were most common across all categories, whereas inactivating mutations and mutations outside the DNA binding domain were more common in AML-MRC compared to MDS.TP53mutations in MDS were more likely to retain transcriptional activity, and co-mutation profiles were distinct between disease categories and mutation types. Our findings suggest that mutatedTP53contributes to initiation and progression of neoplasia via distinct mechanisms, and support the utility of specific identification ofTP53mutations in myeloid malignancies.

Statement of Significance

The distribution and functional consequences ofTP53mutations differ between hematologic malignancies and solid tumors, and, among myeloid neoplasms, between myelodysplastic syndrome and acute leukemia. These findings suggest distinct biological mechanisms for mutated p53 in hematologic malignancies, specifically in initiation and progression of myeloid neoplasia, that warrant further investigation.
Childhood Bullying as a Risk Factor for Late-Life Psychological Distress and Cognitive Impairment
Authors: Mejía-Guevara Iván , Periyakoil V.S.
Published: September 2023

In the United States, non-Hispanic Black (19%) older adults are more likely to develop dementia than White older adults (10%). As genetics alone cannot account for these differences, the impact of historical social factors is considered. This study examined whether childhood and late-life psychological distress associated with dementia risk could explain part of these disparities. Using longitudinal data from 379 White and 141 Black respondents from the Panel Study of Income Dynamics, we assessed the association between childhood bullying and late-life dementia risk, testing for mediation effects from late-life psychological distress. Mediation analysis was computed via negative binomial regression modeling, stratified by race (White/Black), type of bullying experience (target, bully, and bully-target), and the age range at which the experience occurred (6-12, 13-16). The results indicated that late-life psychological distress fully mediated the association between Black respondents who were bullies and dementia risk. However, no significant association was observed among White respondents. These results suggest that interventions aimed at preventing and treating psychological distress throughout the lifespan could be crucial in mitigating the development and progression of dementia risk.
Genomic and metabolic instability during long-term fermentation of an industrial Saccharomyces cerevisiae strain engineered for C5 sugar utilization.
Authors: Duperray Maelle , Delvenne Mattheo , Francois Jean Marie , Frank Delvigne , Capp Jean-Pascal
Published: September 2023

The performance of a microbial fermentation for the production of a bio-based product requires long-term robustness and stability of the producer strain. Here, we explored the genetic and metabolic stability of an industrial ethanol-producer Saccharomyces cerevisiae strain that was engineered by chromosomal integration of several copies of transgenes allowing co-fermentation of D-xylose and L-arabinose with glucose. Through sequential batch cultures in controlled bioreactor, it was found that this strain exhibited significant fluctuation of xylose and arabinose consumption starting at 50th generation and onward. Also, clones that have partly or completely lost the ability to assimilate arabinose or xylose were isolated, and this alteration was due to reduced copy number of the transgenes encoding the enzymes of the C5 sugar assimilation. However, subpopulation enriched with low or high RAD52 expression, whose expression level was reported to be proportional to homologous recombination rate did not exhibit defect in C5-sugar assimilation, arguing that other mechanisms may be responsible for copy number variation of transgenes. Overall, this work underscored genetic and metabolic instabilities, which although modest under our conditions, could in the longer term and under more stringent industrial conditions lead to a reduction of production performance.