bluuebunny/crossref_metadata_2025 huggingface dataset:
Otolithiasis in the Animal Kingdom: A Retrospective Analysis
Authors: Pender Daniel J.
Published: October 2024

Hypothesis

If otolithiasis can be demonstrated to affect multiple species, it may be possible to identify an experimental animal for prospective study of this entity.

Background

Otolithiasis refers to dislodged otolithic matter within the confines of the membranous labyrinth that has the potential to cause clinical symptoms. The mechanism involves separation of free-floating otoconia that can affect the hearing and balance functions of the ear. While this process is known to occur in humans, it is uncertain if other species are affected.

Methods

The published images of 37 whole-mount specimens of mammalian labyrinths were identified for retrospective examination. These were evaluated stereographically for the presence of calcareous material in abnormal locations within the membranous labyrinth.

Results

Thirty normal labyrinth specimens were found, exemplified by that of the Cape sea lion. Seven pathologic specimens were found, including a human, a black ape, a yellow-faced baboon, a hocheur monkey, a collie dog, a common sheep, and a common hare. Abnormal accumulations of calcareous material were found at one or more sites, more frequently in the utricle and canal system and less frequently in the endolymphatic and cochlea ducts.

Conclusions

Otolithiasis appears to occur in other animal species besides the human. Abnormal calcareous material was found in various locations within the membranous labyrinth of affected animals. One or more of these might serve as an animal model to prospectively study the phenomenon of otolithiasis.
Deep Phenotyping of a Mouse Model for Hearing Instability Disorders
Authors: Johns J. Dixon , Adadey Samuel Mawuli , Strepay Dillon , Olszewski Rafal , Hoa Michael
Published: October 2024

Hypothesis

Hearing instability in Slc26a4-insufficiency mice may be due to differential expression of genes related to ion homeostasis and activated macrophages.

Background

Hearing instability (HI) disorders, defined by either hearing fluctuation or sudden loss, remain incompletely understood. Recent studies have described a Slc26a4 (pendrin)-insufficiency mouse model (DE17.5) that offers a genetically driven model for HI, although deep audiometric and immunohistologic phenotyping of this model remains poorly characterized.

Methods

Homozygous DE17.5 mice with (F) and without (NF) HI were delineated by serial auditory brainstem responses (ABR) between postnatal days 30 and 60 and compared with adult phenotypically wild-type Slc26a4-heterozygous controls without evidence of HI (Het). HI was defined as a change in threshold of at least 15 dB in at least two frequencies or at least 20 dB in at least one frequency from the previous week. Stria vascularis (SV) cell type–specific gene expression, endolymphatic hydrops (EH), endocochlear potential (EP), and macrophage activation were analyzed and compared between the cohorts.

Results

F mice demonstrated significant reductions in the expression of cell type–specific genes related to ion homeostasis and increased macrophage activation within the SV compared with NF and Het cohorts. Both F and NF DE17.5 homozygous mice demonstrated reductions in EP and increased EH compared with the Het cohort.

Conclusions

Deep phenotyping of DE17.5 mice demonstrates changes in EP and EH compared with control; however, the HI phenotype was associated with differential ion homeostasis gene expression and increased macrophage activation in the SV. This provides potential further insights into the underlying pathogenesis and possible immunologic contributions of HI in humans.
Long-Term Outcomes of Sigmoid Sinus Wall Reconstruction for Pulsatile Tinnitus Due to Sigmoid Sinus Wall Anomalies
Authors: Ahanotu Adaobi Eleanor , Oslin Kimberly , Rasooly Marjohn , Eisenman David J.
Published: October 2024

Objective

To assess the long-term outcomes of sigmoid sinus wall reconstruction (SSWR) in patients with pulsatile tinnitus (PT) with sigmoid sinus wall anomalies (SSWAs).

Study Design

Single-center retrospective review.

Setting

Tertiary referral center.

Patients

Patients who underwent SSWR for PT with SSWAs more than 5 years prior to study initiation.

Intervention(s)

Therapeutic—all patients underwent sinus wall reconstruction for pulsatile tinnitus with sigmoid sinus anomalies.

Main Outcome Measure(s)

The primary outcomes were complete or partial resolution of PT lasting at least 5 years postoperatively and short-term relief from PT after surgery with long-term recurrence as determined by a self-assessment questionnaire and corroborated by the medical record.

Results

Thirty-five patients (37 ears) out of 58 eligible patients 5 years postoperatively from SSWR completed the survey. Short-term and long-term success rates of SSWR are 97.3% (36/37 ears) and 83.8% (31/37 ears), respectively. Of the patients, 13.5% (5/37 ears) experienced recurrence of PT on the same side following initial resolution. Of our patients, 8.6% had a confirmed diagnosis of idiopathic intracranial hypertension (IIH) after a follow-up period of more than 5 years.

Conclusions

Sinus wall reconstruction is an effective procedure for long-term control of PT in patients with SSWAs, with an acceptable safety profile and very low additional risk of exacerbating or provoking complications associated with IIH.
Incidental Findings on MRIs for Asymmetric Sensorineural Hearing Loss: A Clinical and Economic Analysis
Authors: Lee Lawrance , Islam Albina S. , Sterlin Lauren , Coelho Daniel H.
Published: October 2024

Background

The gold-standard assessment of asymmetric sensorineural hearing loss (ASNHL) is contrast-enhanced MRI. Although rates of identifying a vestibular schwannoma are low (<5%), it is generally accepted as cost-effective. Yet, the impact of incidentalomas is rarely considered. This study aims to characterize the incidence of incidentalomas in the workup of ASNHL and quantify the associated socioeconomic burden.

Study Design

Retrospective cohort study.

Setting

Single academic institution in a midsized city in the United States.

Methods

Radiology records were queried for MRI's ordered for ASNHL between January 2012 and November 2022. Results were characterized as “group 1: normal,” “group 2: abnormal read/normal variant,” “group 3: abnormal—likely cause of ASNHL,” or “group 4: abnormal—follow-up needed.” Subsequent costs of workup for group 4 were estimated using Medicare Physician Fee Schedule for Medicare costs, US Congressional Budgeting Office data for private insurer costs, and USC-Brookings Schaeffer Initiative for Health Policy estimates for uninsured individuals.

Results

Six hundred patients met the inclusion criteria. Eighteen (3.0%) were categorized in group 3, whereas 40 (6.7%) were categorized in group 4. Of these patients, 7.5% (n = 3) had interventions to manage their incidental findings. Estimated per patient cost for further workup of incidental findings amounted to approximately $744, $1,534, and $2,260 for Medicare, private insurance, and uninsured costs, respectively.

Conclusion

Incidentalomas occur over twice as often as retrocochlear pathologies responsible for ASNHL. Although the number of patients requiring treatment for incidentaloma is low, the economic impact is not insubstantial and should be considered for both individual patients and health system payers.
The diagnostic challenge of differentiating tumefactive multiple sclerosis (TMS) from other brain lesions: a case report and literature review on a rare subtype of MS
Authors: Gill Anosh , Eltawansy Sherif , Karamat Riyan Imtiaz , Nadeem Zain Ali , Esposito Sarah , Karamat Shayan Imtiaz , Aamir Minahil , Anwaar Adeel , Akilimali Aymar
Published: October 2024

Introduction and importance:

This case report is a clinical diagnosis walk through of a rare subtype of multiple sclerosis (MS). It gives an overview of how tumefactive multiple sclerosis (TMS) is systematically narrowed down as the definitive diagnosis.

Case presentation:

This 29-year-old male patient presented to the emergency department. He collapsed after experiencing pain over his right frontotemporal region followed by a seizure witnessed by his family. Magnetic Resonance Imaging of the brain displayed diffuse enlargement and abnormal T2 weighted and FLAIR hyperintense signals in the diagnostic impressions described by the radiologist of the right temporoparietal region.

Clinical discussion:

Liquefactive multiple sclerosis, also known as tumefactive multiple sclerosis or Marburg-type multiple sclerosis, is a rare subtype of the neurological disorder that can be difficult to diagnose. Unlike the traditional form of MS, TMS can present as a brain tumor and must be diagnosed with a biopsy rather than via MRI and clinical findings alone. Patients can typically present with headache, cognitive abnormalities, mental confusion, aphasia, apraxia, seizures, and weakness. Here, the authors discuss the presentation, disease diagnosis process and patient management.

Conclusion:

The patient was stabilized and discharged with a referral to the neurosurgery and neurology departments for outpatient consultation for future clinical management and treatment of their condition.
Spinal hydatid disease: a case report – an uncommon differential diagnosis in LMICs
Authors: Avetis A Kirakosyan , Emma S Maghakyan , Chavda Vishal , Chaurasia Bipin
Published: October 2024

Background and Importance:

With a 0.2–1% incidence, spinal hydatid disease is a very uncommon diagnosis. While it is uncommon in affluent nations, it should be taken into account when making a differential diagnosis for spinal cord compression syndrome, particularly in regions where it is prevalent.

Case Presentation:

The authors report a case of hydatid illness of the spine. A 52-year-old man presented with lower extremity discomfort and spastic paraparesis, trouble urinating, and back pain and edema. He had at the level of the 12th thoracic to third lumbar vertebrae (Th12-L3) with paraspinal extension. The patient was treated with 4 months of antiparasitic therapy and two surgical resections performed by general surgeons. Histological analysis showed pieces of fibrous tissue exhibiting granulomatous inflammation; however, no evidence of acid-resistant bacteria or PAS-positive chitin membrane was found. The existence of bacteria following therapy has not been confirmed by the parasitological investigation of the lesions.

Clinical Discussion:

Primary spinal hydrodatidosis is a rare condition that affects about 0.2–1% of the population.

Conclusion:

Due to the rarity of this disease, early discovery and timely treatment are critical, and this diagnosis should be considered when generating a differential diagnosis for spinal cord compression syndrome.
The risk and distribution of second primary cancers according to subsite of primary stomach cancer: a retrospective cohort population-based study
Authors: Hemade Ali , Hallit Souheil
Published: October 2024

Background:

The development of second primary cancers (SPCs) following a diagnosis of stomach cancer presents a significant clinical challenge, with varying risks depending on the anatomic subsite of the primary tumor, patient demographics, and treatment modalities. This study aims to assess the risk of SPCs in stomach cancer survivors, focusing on differences across anatomic subsites, sex, age, and treatment periods.

Methods:

The authors conducted a retrospective cohort study using data from stomach cancer patients, analyzing the incidence of SPCs based on the anatomic location of the primary tumor, with stratifications by sex, age, latency period, and year of diagnosis. Standardized incidence ratios (SIRs) were calculated to compare the observed SPC rates with those expected in the general population.

Results:

Elevated stomach SPC risk was observed across most anatomic subsites, particularly in the body (SIR 8.84) and fundus (SIR 7.34). Females exhibited higher SIRs compared to males, especially in the fundus (SIR 13.33 for females vs. 4.55 for males). Younger patients (<50 years) had significantly higher SPC risks, particularly for cancers originating in the fundus (SIR 49.56). Notably, patients diagnosed after 2010 showed the highest SIRs, indicating a potential impact of advances in diagnostic and therapeutic modalities. Nonstomach SPCs, including colorectal, lung, and thyroid cancers, were significantly elevated, with distinct patterns based on the primary tumor site.

Conclusions:

The study highlights the critical role of primary tumor location, sex, age, and treatment era in determining SPC risk in stomach cancer survivors. These findings underscore the need for tailored surveillance strategies to manage long-term cancer risks in this population.
Gather “Round”
Authors: Feld April , Carollo Matt , Freeman-Reyes Jere , McCarthy Susan , Lind Mary Ann , Weinstein Robert , O’Dea Caitlin , Joy Maria , Morley Eric J. , Aitken Paul , Schwaner Robert , Giarraputo Dominic , Heslin Samita M.
Published: October 2024

Purpose:

Emergency departments (EDs) are a vital component of the United States healthcare system and care for over 130 million patient visits annually. Nonurgent ED visits can contribute to crowding, delays in care, and adverse effects. Many high-utilizing ED patients may present with complex medical, behavioral, and social needs that are not necessarily emergent or urgent in nature. The authors created an Integrated Care Model, called the Multi-Visit Patient (MVP) program, for patients with 5 or more visits to the ED in a rolling 12-month period. The MVP program incorporated an interdisciplinary group of ED leadership and case management (CM) to identify, engage, and intervene with ED MVPs, aiming to improve their ED utilization. Patients received comprehensive screenings for depression, falls, alcohol use disorder, caregiver support, social determinants of health, and more. Based on these screenings, the CM team implemented interventions such as connecting patients with outpatient specialists and linking patients to community-based organizations to optimize stability, wellness, and reduce ED utilization.

Primary Practice Setting:

The collaboratively developed MVP program was implemented in the ED of a large, suburban, tertiary care academic hospital.

Findings/Conclusions:

The MVP program identified 221 MVP patients over a 20-month period and successfully connected with 89% of them. Of these 221 patients, 78% (172 patients) chose to engage in the MVP program, with 160 completing their engagement with an outcome. Among the patients who completed their engagement and for whom the study could match separate utilization data (151 patients), the study observed a 57% reduction in ED visits.

Implications for Case Management Practice:

Case managers play a crucial role in the effectiveness of the MVP program by coordinating comprehensive care for high-utilizing ED patients. The MVP program includes transition of care initiatives designed to improve patient outcomes. Through screenings and targeted interventions, case managers identify and address the complex medical, behavioral, and social needs of MVP patients. This collaborative, interdisciplinary approach underscores the importance of timely and coordinated care, benefiting both patients and the health system. The MVP program exemplifies the critical role of case managers in reducing unnecessary ED visits and enhancing overall patient care.
Prognostic Value and Clinical Implication of Lymph Node-to-Primary Tumor SUV Ratio in Node-Positive Hypopharyngeal Squamous Cell Carcinoma Treated With Radiotherapy With or Without Chemotherapy
Authors: Yap Wing-Keen , Lin Chia-Hsin , Hsu Ken-Hao , Lin Shin-Nan , Lin Huan-Chun , Chang Kai-Ping , Kang Chung-Jan , Hu Yu-Feng , Shih Ming-Chieh , Tsai Tsung-You
Published: October 2024

Purpose

The aim of this was to evaluate the prognostic significance of the nodal-to-primary tumor SUVmax ratio (NTR) in patients with node-positive hypopharyngeal squamous cell carcinoma (HPSCC) treated with radiotherapy with or without concurrent chemotherapy. The study aims to enhance prognostic accuracy by incorporating NTR into the American Joint Committee on Cancer (AJCC) staging system.

Patients and Methods

This retrospective study included 191 patients with biopsy-proven node-positive HPSCC treated from 2005 to 2013. NTR was calculated as the ratio of SUVmax of metastatic lymph nodes to the primary tumor’s SUVmax. Survival analyses were conducted using Cox regression models and Kaplan-Meier analysis. Receiver operating characteristic analysis compared the prognostic performance of the modified and AJCC staging systems.

Results

The median follow-up was 8.27 years, with 135 deaths (70.7%). High NTR (≥0.63) was significantly associated with worse overall survival (OS) and was an independent prognostic factor in multivariable analysis (adjusted hazards ratio [HR] = 1.63, P = 0.007). Median OS for high NTR was 17.4 months, compared with 75.2 months for low NTR. High NTR significantly predicted worse OS within AJCC stage IVA patients (HR = 6.09, P = 0.014). Patients in modified stage IVA (AJCC stage IVA with low NTR) had significantly longer OS than those in modified stage IVB (AJCC stage IVA with high NTR and AJCC stage IVB) (HR = 8.62, P = 0.003). The modified staging system incorporating NTR showed superior prognostic performance compared with the AJCC staging system.

Conclusions

NTR is a significant independent prognostic factor for OS in node-positive HPSCC patients. Integrating NTR into the AJCC staging system improves prognostic accuracy.
Functional and Aesthetic Lower Lip Reconstruction With Depressor Anguli Oris Muscle Flap and Reverse Superior Labial Artery Flap
Authors: Turan Aydın
Published: October 2024

Background

The lower lip is an important anatomical structure involved in daily activities such as eating, drinking, and speaking, as well as in facial expressions. Lower lip defects should be repaired to preserve lip function without disrupting the aesthetic harmony of the lips within the face. This goal is difficult for plastic surgeons because, for functional and aesthetic repair, it is necessary to replace the mucosa, muscle (especially contractile), and skin tissues present in the lip.

Methods

Subtotal lower lip repair was performed using an innervated depressor anguli oris muscle flap and a desepithelialized reverse superior labial artery flap in seven male patients with a mean age of 63 years. A depressor anguli oris muscle flap was used to repair the orbicularis oris muscle defect. The desepithelialized part of the reverse superior labial artery flap was used for mucosal defect repair, whereas the remaining part was used for skin defect repair. Patients were followed up for an average of 15 months. Patient lips, epithelialization, sensation, and sphincter function were clinically evaluated. Electromyography (EMG) was performed at 6 and 12 months to evaluate the function of the depressor anguli oris muscle flap.

Results

All the reverse superior labial artery flaps survived without any loss. Trapdoor deformity developed in the flaps of two patients. The desepithelialized parts of the flaps were completely epithelialized (covered with mucosa) by approximately 6th week. In the EMG controls of the patients at 6 months, the depressor anguli oris muscle was contractible. Sensation regained in the operated lip during the follow-up period.

Conclusions

The combination of an innervated depressor anguli oris muscle flap and a desepithelialized reverse superior labial artery flap is an important surgical option for the functional and aesthetic repair of subtotal lower lip defects.
Preoperative Factors Affecting Graft Survival After ABO-incompatible Adult Liver Transplantation
Authors: Nam Hyun-Jun , Kim Deok-Gie , Min Eun-Ki , Lee Jae Geun , Han Dai Hoon , Kim Sinyoung , Lee Kyung-A , Choi Gi Hong , Joo Dong Jin , Kim Hyun Ok , Kwon Soon Sung , Kim Myoung Soo
Published: October 2024

Background.

Although ABO-incompatible liver transplantation (ABOi LT) has undergone remarkable progress, the prognostic factors are poorly understood. This study aimed to elucidate the preoperative factors affecting graft survival after ABOi LT.

Methods.

Patients who underwent ABOi LT between January 2012 and December 2020 at a single institution in South Korea were retrospectively reviewed. A total of 146 recipients, including 34 patients with graft loss, were analyzed.

Results.

In the multivariate Cox proportional hazard model, recipient age (≥55 y; hazard ratio, 2.47; 95% confidence interval, 1.18-5.19; P = 0.017) and donor ABO type (donor A, hazard ratio, 3.12; 95% confidence interval, 1.33-7.33; P = 0.009) were significantly associated with an increased risk of graft loss. The most common cause of graft loss was recipient death due to bacterial infection (15/34, 44.1%). Both recipient age and donor ABO type were associated with an increased risk of recipient death due to bacterial infections. The incidence of complications after ABOi LT, including antibody-mediated rejection and diffuse intrahepatic biliary stricture, did not differ according to recipient age or donor ABO type.

Conclusions.

These findings suggest that recipient age and donor ABO type should be considered when preparing for ABOi LT. Careful monitoring and care after transplantation are required for recipients with preoperative risk factors.
Optimally warm roost temperatures during lactation do not improve body condition in a long-lived bat
Authors: Wolf Janis M. , Kerth Gerald
Published: October 2024

Lactation is the most energetically demanding time in the life of female mammals. To maximize lifetime reproductive success, females of long-lived species, such as bats, face a trade-off between investing in current and future reproduction. However, it is unclear whether global warming could influence this trade-off through shifts in the energy budget: warmer temperatures may reduce thermoregulatory costs, leaving mothers with more energy available for maternal care or for improving their own body condition (BC), which may increase survival and ensure future reproduction. Here, we investigated whether lactating Bechstein’s bats (
Myotis bechsteinii
) allocate the energy saved in optimally warm roosts into their own BC. We analysed a 14-year dataset on the individual BC of 237 females marked with radio-frequency identification tags from four wild maternity colonies. In two of the colonies, the temperature in the roosts, in which the females raised their offspring, was artificially kept in the bats’ thermoneutral zone to reduce their thermoregulation costs. We found that BC shortly after the lactation period did not differ between mothers from heated and non-heated colonies. Our results suggest that mothers do not invest the energy saved in warmer roosts in their own BC, consistent with an increased investment in maternal care.
Ultradian rhythms of activity in a wild subterranean rodent
Authors: Finn Kyle T. , Brede Otto , Bennett Nigel C. , Zöttl Markus
Published: October 2024

Many animals adapt their activity patterns to the best environmental conditions using daily rhythms. African mole-rats are among the mammals that have become models for studying how these rhythms can be entrained by light or temperature in experimental laboratory studies. However, it is unclear whether they exhibit similar circadian rhythms in their natural lightless, subterranean environment. In this study, we used biologging to investigate the activity rhythms of wild, highveld mole-rats. We show that their activity cycle exhibited an ultradian rhythm with a length between 4 and 8 h. On an individual level, mole-rats displayed about five activity bouts per day, occurring at various times during the day and night. On a population level, activity peaked in the afternoon, coinciding with the peak in ambient temperature. Our research suggests that wild subterranean mammals, which experience reduced environmental variation, are unlikely to show clear circadian rhythmicity in activity patterns. Instead, activity periods are distributed over several bouts throughout the day and night, and activity coincides with the peak in daily temperature. We propose that ultradian rhythms in activity may be more common than previously thought and discuss how physiological processes may generate differences in periodicity between laboratory and wild populations.
Being thin-skinned can still reduce damage from dynamic puncture
Authors: Zhang Bingyang , Baskota Bishal , Anderson Philip S. L.
Published: October 2024

The integumentary system in animals serves as an important line of defence against physiological and mechanical external forces. Over time, integuments have evolved layered structures (scales, cuticle and skin) with high toughness and strength to resist damage and prevent wound expansion. While previous studies have examined their defensive performance under low-rate conditions, the failure response and damage resistance of these thin layers under dynamic biological puncture remain underexplored. Here, we utilize a novel experimental framework to investigate the mechanics of dynamic puncture in both bilayer structures of synthetic tissue-mimicking composite materials and natural skin tissues. Our findings reveal the remarkable efficiency of a thin outer skin layer in reducing the overall extent of dynamic puncture damage. This enhanced damage resistance is governed by interlayer properties through puncture energetics and diminishes in strength at higher puncture rates due to rate-dependent effects in silicone tissue simulants. In addition, natural skin tissues exhibit unique material properties and failure behaviours, leading to superior damage reduction capability compared with synthetic counterparts. These findings contribute to a deeper understanding of the inherent biomechanical complexity of biological puncture systems with layered composite material structures. They lay the groundwork for future comparative studies and bio-inspired applications.
Inter-laboratory harmonization of microsphere immunoassays for SARS-CoV-2 antibody detection in dried blood spots and oral fluids
Authors: DeRosa Kate L. , Pisanic Nora , Kruczynski Kate , Heaney Christopher D. , Styer Linda M. , Mantis Nicholas J.
Published: October 2024

Dried blood spots (DBS) and oral fluids (OF) are easily attainable biospecimen types that have enabled population scale antibody monitoring for SARS-CoV-2 exposure and vaccination. However, the degree to which the two different biospecimen types can be used interchangeably remains unclear. To begin to address this question, we generated contrived DBS (cDBS) and OF (cOF) from serum panels from SARS-CoV-2 infected, vaccinated, and uninfected individuals. The contrived samples were evaluated using SARS-CoV-2 multiplexed microsphere immunoassays (MIAs) at two different institutions. Intra-laboratory tests revealed near perfect agreement between cDBS and cOF for N and S antigens, as evidenced by κ = 0.97-1 and 98%-100% agreement. Inter-laboratory comparisons were equally robust for both N (κ = 0.94-0.96; 97.5%-98 % agreement) and S (κ = 0.98 -1.0; 99.0%-100%). Furthermore, assays were transferred between labs, including methods and reagents, and a subset of cDBS and cOF samples (n = 52) were tested. Qualitative concordance remained high (κ = 0.94-1.0; 97.5%-100% agreement), confirming that integrity of the assays is retained upon transfer. In summary, our results provide evidence that DBS and OF can be used interchangeably across laboratories and institutions for the qualitative assessment of SARS-CoV-2 antibody determinations.
Shc1 cooperates with Frs2 and Shp2 to recruit Grb2 in FGF-induced lens development
Authors: Wang Qian , Li Hongge , Mao Yingyu , Garg Ankur , Park Eun Sil , Wu Yihua , Chow Alyssa , Peregrin John , Zhang Xin
Published: October 2024

Fibroblast growth factor (FGF) signaling elicits multiple downstream pathways, most notably the Ras/MAPK cascade facilitated by the adaptor protein Grb2. However, the mechanism by which Grb2 is recruited to the FGF signaling complex remains unresolved. Here we showed that genetic ablation of FGF signaling prevented lens induction by disrupting transcriptional regulation and actin cytoskeletal arrangements, which could be reproduced by deleting the juxtamembrane region of the FGF receptor and rescued by Kras activation. Conversely, mutations affecting the Frs2-binding site on the FGF receptor or the deletion of Frs2 and Shp2 primarily impact later stages of lens vesicle development involving lens fiber cell differentiation. Our study further revealed that the loss of Grb2 abolished MAPK signaling, resulting in a profound arrest of lens development. However, removing Grb2’s putative Shp2 dephosphorylation site (Y209) neither produced a detectable phenotype nor impaired MAPK signaling during lens development. Furthermore, the catalytically inactive Shp2 mutation (C459S) only modestly impaired FGF signaling, whereas replacing Shp2’s C-terminal phosphorylation sites (Y542/Y580) previously implicated in Grb2 binding only caused placental defects, perinatal lethality, and reduced lacrimal gland branching without impacting lens development, suggesting that Shp2 only partially mediates Grb2 recruitment. In contrast, we observed that FGF signaling is required for the phosphorylation of the Grb2-binding sites on Shc1 and the deletion of Shc1 exacerbates the lens vesicle defect caused by Frs2 and Shp2 deletion. These findings establish Shc1 as a critical collaborator with Frs2 and Shp2 in targeting Grb2 during FGF signaling.
Enhanced human sensorimotor integration via self-modulation of the somatosensory activity
Authors: Iwama Seitaro , Ueno Takamasa , Fujimaki Tatsuro , Ushiba Junichi
Published: October 2024

Kinesthetic motor imagery, the mental rehearsal of movement and its associated sensations1,2, activates somatosensory and motor cortices3,4. Motor imagery improves performance in neurorehabilitation5, sports6, and instrument play7. However, the mechanism that enhances performance through repetitive motor imagery remains unclear. Here, we combined individually tailored motor imagery training combined with closed-loop neurofeedback training, neurophysiology, and behavioral assessment to characterize how the training can modulate the somatosensory system and improve performance. The closed-loop training using real-time feedback of human electroencephalogram (EEG) signals enhanced participants’ self-modulation ability of intrinsic neural oscillations in the primary somatosensory cortex (S1) within 30 minutes. Further, the short-term reorganization in S1 was corroborated by the post-training reactivity enhancement revealed by changes in somatosensory evoked potential (SEP) amplitude of early component originating from S18. Meanwhile those derived from peripheral sensory fibers were maintained, suggesting that the closed-loop training manipulated cortical activities. Behavioral evaluation demonstrated improved performance during keyboard touch-typing indexed by resolved the speed-accuracy trade-off9. Collectively, our results provide evidence that mentally rehearsed movement during kinesthetic motor imagery induces functional reorganization of S1 activities that can contribute to performance improvement.
Relative stability of different conformations and pathways of ligand escape in LIV-binding protein: A molecular dynamics simulation study
Authors: Das Jayita
Published: October 2024

Periplasmic binding proteins (PBPs) are a large family of receptors and transporters, present in gram-negative bacteria, which play a pivotal role in transport, chemotaxis and quorum sensing. These class of proteins have a distinct two domain architecture that undergo large conformational transitions through a hinge motion. In particular, Leucine-Isoleucine-Valine (LIV) binding protein can sense these specific side chains and undergoes a transition from a open to a closed conformation which is traditionally viewed as ligand induced conformational change. Here, atomistic molecular dynamics simulations and well-tempered metadynamics simulations are used to understand the role of ligand (namely, Isoleucine) in the conformational transition/selection of the LIV-binding protein. Furthermore, the pathway, energetics, and sequence of events during ligand escape/unbinding are unveiled from a microscopic perspective. Two distinct ligand binding pathways are identified: (i) domain separation followed by ligand escape, and (ii) ligand escape either followed by or synchronous with domain separation. The former is found to be energetically more favorable. Water is found to play an important role in the ligand unbinding process as well as providing stability to the closed conformation in the absence of the ligand, by forming bridging hydrogen bonds between two domains.
5-HT2Creceptors in the nucleus accumbens constrain the rewarding effects of MDMA
Authors: Pomrenze Matthew B. , Vaillancourt Sam , Salgado Juliana S. , Raymond Kendall B. , Llorach Pierre , Touponse Gavin C. , Pinto Daniel F. Cardozo , Rastegar Zahra , Casey Austen B. , Eshel Neir , Malenka Robert C. , Heifets Boris D.
Published: October 2024

MDMA is a promising adjunct to psychotherapy and has well-known abuse liability, although less than other amphetamine analogs. While the reinforcing dopamine (DA)-releasing properties of MDMA are on par with methamphetamine (METH), MDMA is a far more potent serotonin (5-HT) releaser, via the 5-HT transporter (SERT). MDMA-mediated 5-HT release in a major reward center, the nucleus accumbens (NAc), drives prosocial behaviors via 5-HT1BR activation. We hypothesized that this prosocial mechanism contributes to the reduced reinforcing properties of MDMA compared to METH and used a platform of assays to predict the balance of prosocial and abuse-linked effects of (R)-MDMA, a novel entactogen in clinical development. NAc DA release, measured by GRAB-DA photometry in vivo, increased in proportion to MDMA (7.5 and 15 mg/kg, i.p.) and METH (2 mg/kg i.p.)-conditioned place preference (CPP). Using conditional knockouts (cKOs) for DAT and SERT, microdialysis, and photometry, we found that MDMA-released 5-HT limited MDMA-released DA through actions in the NAc, rather than at ventral tegmental area DAergic cell bodies. SERT cKO reduced the MDMA dose required for CPP three-fold. This enhanced MDMA-CPP and increased DA release were replicated by intra-NAc infusion of either a 5-HT reuptake inhibitor (escitalopram) to prevent MDMA interaction with SERT, or a 5-HT2CR antagonist (SB242084), but not by the 5-HT1BR antagonist NAS-181. These data support separate mechanisms for the low abuse potential versus prosocial effect of MDMA. Using this platform of assays, (R)-MDMA is predicted to have prosocial effects and low abuse potential.
A Framework for Accurate Prediction of Plastic-Degrading Enzymes using Convolutional Neural Networks
Authors: Hasnat Soharth , Shifa Fariah Anjum , Murshed Shabab , Rumee Tanveer Ahmed , Mahbub MST Murshida
Published: October 2024

The growing accumulation of plastic waste presents a significant environmental challenge, necessitating innovative approaches to mitigate its impact. Enzymatic degradation has emerged as a promising solution for addressing plastic pollution. However, the isolation and characterization of plastic-degrading enzymes (PDEs) through laboratory experiments are costly, time-consuming, and often complicated by nonculturable microorganisms. Consequently, accurate in silico identification of PDEs is desirable to explore the diversity of natural enzymes and harness their potential for combating plastic pollution. This study introduces a novel feature extraction strategy for identifying plastic-degrading enzymes, incorporating Autocorrelation (AAutoCor), Composition of k-spaced Amino Acid Pairs (KSAP), Dipeptide Deviation from Expected Mean (DDE), Composition/Transition/Distribution (C/T/D), Conjoint Triad, and Secondary Structure. A combination of ANOVA and XGBoost, feature selection methods, was applied to optimize the feature dimensions for improved performance. Seven supervised machine learning models were employed to evaluate the dataset: Convolutional Neural Network, Random Forest Classifier, Feedforward Neural Network, Logistic Regression, Naive Bayes Classifier, K-nearest Neighbor, and XGBoost Classifier. Among these models, the CNN model demonstrated the best performance, achieving an accuracy of 0.96, an F1 score of 0.80, and an ROC-AUC score of 0.96. These findings underscore the potential of the proposed system as an accurate predictor of plastic-degrading enzymes from environmental sequences. This approach significantly enhances efforts to develop sustainable solutions to plastic waste by accelerating the discovery of novel PDEs.
Dissecting Breast Cancer Heterogeneity Through Transcriptomics Insights of Diverse Etiological Factors for Common Biomarker Discovery
Authors: Hossain Mohammad Uzzal , Mehak Mariam Ahmed , Hasan SM Sajid , Sakib Mohammad Nazmus , Rahman A.B.Z. Naimur , Bhattacharjee Arittra , Chowdhury Zeshan Mahmud , Ahammad Ishtiaque , Sohag Md. Mehadi Hasan , Das Keshob Chandra , Salimullah Md.
Published: October 2024

Breast cancer has many different causes, and the key to finding effective treatments is understanding the disease’s heterogeneity. The present study used three gene expression datasets from 110 female samples related to stress, drug and hormonal imbalance, diet and nutrition, and physical activity and light exposure at night to predict differential gene expression. Interestingly, all gene expression datasets shared 22 upregulated and 4 downregulated genes, regardless of etiology. This suggests these genes share the core molecular mechanism and the biological pathway that causes breast cancer. Notably, these genes were significantly enriched in some important pathways, including cycle regulation, endoplasmic reticulum stress, and transcriptional regulation, demonstrating their potential as therapeutic targets. Further, we found UBE2J2 from upregulated genes and ZCCHC7 from downregulated genes as the top hub and bottleneck genes, which may help network connectivity and functional gene interactions. Computational study further asserted the strong binding affinity of drug-target complexes. Later, molecular dynamics simulations confirmed the predicted drug-target complexes’ stability and dynamic behavior, demonstrating these two genes as potential therapeutic targets. The findings from this analysis provide the molecular basis into the complex interplay between diverse etiologic factors and breast cancer pathogenesis, paving the way for innovative biomarker-targeted therapies.
Peptide-Based Complex Coacervates Stabilized by Cation-π Interactions for Cell Engineering
Authors: Sun Yue , Wu Xi , Li Jianguo , Verma Chandra Shekhar , Yu Jing , Miserez Ali
Published: October 2024

Complex coacervation is a form of liquid-liquid phase separation (LLPS), whereby two types of macromolecules, usually bearing opposite net charges, self-assemble into dense microdroplets driven by weak molecular interactions. Peptide-based coacervates have recently emerged as promising carriers to deliver large macromolecules (nucleic acids, proteins and complex thereof) inside cells. Thus, it is essential to understand their assembly/disassembly mechanisms at the molecular level in order to tune the thermodynamics of coacervates formation and the kinetics of cargo release upon entering the cell. In this study, we design histidine-rich peptides consisting of modular sequences in which we systematically incorporate cationic, anionic, or aromatic residues at specific positions along the sequence in order to modulate intermolecular interactions and the resulting coacervation stability. We show that cation-π interactions between arginine and aromatic side chains are particularly efficient in stabilizing complex coacervates, and these interactions can be disrupted in the protein-rich intracellular environment, triggering the disassembly of complex coacervates followed by cargo release. With the additional grafting of a disulfide-based self-immolative sidechain, these complex coacervates exhibit enhanced stability and can deliver proteins, mRNA, and CRISPR/Cas9 genome editing tools with tunable release kinetics into cells. This capability extends to challenging cell types, such as macrophages. Our study highlights the critical role of cation-π interactions in the design of peptide-based coacervates, expanding the biomedical and biotechnology potential of this emerging innovative intracellular delivery platform.

Table of Content

Tandem peptides designed from histidine-rich beak proteins are modified with either negative, positive, or aromatic residues that can undergo complex coacervation through cation-πrather than electrostatic interactions. These complex coacervates can effectively recruit various macromolecular cargos and deliver them intracellularly with controlled release kinetics, including in hard-to-transfect macrophages.
Remote force modulation of the T-cell receptor reveals an NFAT-threshold for CD4+T cell activation
Authors: Clarke Joseph , Pike Jeremy , Bending David , Owen Dylan , Wraith David C. , El Haj Alicia J
Published: October 2024

Abstract/Summary

Mechano-modulation of cell surface proteins to influence cell activation has been shown as a promising new advanced therapy for regenerative medicine applications. These strategies rely on the manipulation of mechanosensitive cell surface receptors to initiate intracellular signal transduction. The cell surface receptor of T lymphocytes (TCR), which recognises peptide-MHC molecules central to driving the adaptive immune response, has recently been suggested to be mechano-responsive. Despite this advance, little is known as to whether the TCR can be mechanically modulated to achieve TCR signalling and subsequent T cell activation, and whether these characteristics can be exploited for immunotherapies. Here, we describe a magnetic particle-based platform for mechanical modulation of the TCR and outline how this platform can be utilised to achieve CD4+T cell activation. We demonstrate that mechanical manipulation of the TCR induces cell surface clustering of the TCR and downstream TCR signalling, leading to eventual TCR downregulation and T cell activation. We investigate the temporal relationship between mechanical modulation of the TCR and subsequent T cell activation, hereby identifying that accumulation of signalling events within the NFAT-pathway is required to reach the threshold required for CD4+T cell activation, outlining an axis which controls the CD4+T cell response to external mechanical cues. These findings identify how CD4+T cells can modulate their function in response to such cues, whilst also outlining a remote-magnetic particle-based platform that may be used for the control of T cell responses.
A 128-channel receive array with enhanced SNR performance for 10.5 tesla brain imaging
Authors: Lagore Russell L , Sadeghi-Tarakameh Alireza , Grant Andrea , Waks Matt , Auerbach Edward , Jungst Steve , DelaBarre Lance , Moeller Steen , Eryaman Yigitcan , Lattanzi Riccardo , Giannakopoulos Ilias , Vizioli Luca , Yacoub Essa , Schmidt Simon , Metzger Gregory J. , Wu Xiaoping , Adriany Gregor , Ugurbil Kamil
Published: October 2024

Purpose

To develop and characterize the performance of a 128-channel head array for brain imaging at 10.5 tesla and evaluate the potential of brain imaging at this unique, >10 tesla magnetic field.

Methods

The coil is composed of a 16-channel self-decoupled loop transmit/receive array with a 112-loop receive-only (Rx) insert. Interactions between the outer transmitter and the inner 112Rx insert were mitigated using coaxial cable traps placed every 1/16 of a wavelength on each feed cable, locating most preamplifier boards outside the transmitter field and miniaturizing those placed directly on individual coils.

Results

The 128-channel array described herein achieved 77% of ultimate intrinsic SNR in the center of the brain. Transmit field maps obtained experimentally on a phantom with and without the receive array were similar and matched EM simulations, leading to FDA approval for human imaging. Anatomical and functional data, including with power demanding sequences, were acquired successfully on human volunteers.

Conclusions

Counterintuitive to expectations based on magnetic fields ≤7T, the higher channel counts provided SNR gains centrally, capturing ∼80% uiSNR. Fraction of uiSNR achieved centrally in 64Rx, 80Rx, and 128Rx arrays suggested that a plateau was being reached at 80%. At this plateau, linear to approximately quadratic B0dependent SNR gains for the periphery and the center, respectively, were observed for 10.5T relative 7T.
Avifauna composition in Rice plantations: effects of Harvesting Stage and Surrounding Vegetation. Insights from Weppa Farm, Agenebode
Authors: Ibrahim Ilyas , Antonio Benhilda , Tongken Damen , Clement Bethel , Bello Barnabas Sani , Ugomeh Othniel , Samuel Jemima Amos , Patrik Hassanatu , Dike Chukuma
Published: October 2024

Rice plantations provide important habitats for diverse avian communities which support both resident and migratory species. These ecosystems serve as breeding grounds, provide foraging resources and temporary habitats for various bird species, including waterbirds, shorebirds, and passerines. This study was conducted in Weppa Farm (total farm size ∼13000 hector), Agenebode, Etsako East local government area in Edo State, Nigeria to investigate the avifauna compositions in pre-harvested and post-harvested rice plantations and the influence of surrounding vegetation on avian abundance. Four line transects were surveyed around the rice plantation. The transects were 400m long and split into 4, 100m sections. Surveys were done on the rice field before harvest (Unharvested), during harvest (partially harvested) and post-harvest (harvested). Surveys were done in the morning (7:00-9:00 GMT) and repeated in the evening (16:00-18:00 GMT). Vegetation parameters were measured at the beginning of each section of the transect. A total of 48 different bird species from 6 feeding guilds were recorded. Granivorous birds were the most abundant feeding guild (n=599). The Unharvested rice plantation had the highest abundance (n=1453), highest richness (r=37) but not diversity (H=5.18), partially harvested farm had the least abundance (n=592) and least diversity (H=4.95). The surrounding vegetations had a significant effect on bird abundance. Granivores mainly weavers were the most abundant species. The were mainly observed foraging and using weeds as nesting material. Insectivorous birds were the second must abundant species and could serve as biocontrol for arthropod invasions on the farm. Surrounding vegetation influences the abundance of birds in a rice plantation. There was high bird abundance in areas that had trees and shrubs nearby.
Viral vectors with cluster of differentiation gene promoters to target specific cell types in the brain
Authors: Uesaka Naofumi , Sekiguchi Mariko , Takeuchi Atsuya , Masumura Ryo
Published: October 2024

Understanding brain function and developing targeted therapies for neurological disorders require precise access to specific cell types, but current methods are limited. Here, we report the development of cell-type specific adeno-associated virus (AAV) vectors utilizing promoters of cluster of differentiation genes (CD promoters) for targeted gene delivery in the brain. We newly identified CD promoters that induce gene expression selectively in specific cell types in the mouse brain. These AAVs enable in vivo calcium imaging and chemogenetic applications in specific cerebellar cells, revealing distinct and shared roles of two types of cerebellar interneurons. Notably, chemogenetic modulation of cerebellar molecular layer interneurons using a CD promoter rescued social behavior and motor deficits in a mouse model of autism spectrum disorder. Our findings demonstrate the utility of these AAVs in elucidating the functions of individual cell types in brain function and in developing novel, cell-type specific therapies for brain diseases.