bluuebunny/crossref_metadata_2025 huggingface dataset:
Neurological manifestations of lysosomal storage diseases
Authors: Elendu Chukwuka , Babawale Emmanuel A. , Babarinde Festus O. , Babatunde Olusola D. , Chukwu Christopher , Chiegboka Sobechukwu F. , Shode Omotola P. , Ngozi-ibeh Jide K. , Njoku Anthonia , Ikokwu Mary N. , Kaka Grace U. , Hassan Jemilah I. , Fatungase Oluwasunmisola O. , Osifodunrin Tolulope , Udoeze Chidi A. , Ikeji Victor I.
Published: September 2024

Lysosomal storage diseases (LSDs) encompass a group of rare inherited metabolic disorders characterized by the accumulation of undegraded substrates within lysosomes, leading to multisystemic manifestations, including profound neurological involvement. This article provides a concise overview of the neurological manifestations of LSDs, with a focus on central nervous system (CNS) involvement and treatment strategies. While the paper intricacies of each LSD subtype and its associated CNS manifestations, it aims to provide a summary of the essential findings and implications. The neurological manifestations of LSDs encompass a spectrum of symptoms, including cognitive impairment, motor dysfunction, seizures, and sensory deficits, which significantly impact patients’ quality of life and pose therapeutic challenges. Current treatment strategies primarily aim to alleviate symptoms and slow disease progression, with limited success in reversing established neurological damage. Enzyme replacement therapy, substrate reduction therapy, and emerging gene therapies hold promise for addressing CNS involvement in LSDs. However, challenges such as blood-brain barrier penetration and long-term efficacy remain. In addition to discussing treatment modalities, this article highlights the importance of early diagnosis, multidisciplinary care, and patient advocacy in optimizing outcomes for individuals affected by LSDs. Ethical considerations are also addressed, including equitable access to emerging treatments and integrating personalized medicine approaches. Overall, this article underscores the complex interplay between genetics, neuroscience, and clinical care in understanding and managing the neurological manifestations of LSDs while emphasizing the need for continued research and collaboration to advance therapeutic interventions and improve patient outcomes.
Case report: Lemmel syndrome-aggravated by consumption of fatty food
Authors: Pokharel Selene , Gurung Ram B. , Khadka Saurav , Shrestha Sneha , Upadhyaya Prashant
Published: September 2024

Introduction and importance:

One of the very rare causes of obstructive jaundice, Lemmel’s syndrome, is caused due to biliary mechanical compression by a juxtapapillary diverticulum. It is defined as obstructive jaundice due to juxtapapillary diverticulum in the absence of cholelithiasis, periampullary tumours, or other detectable obstacles. It is an extremely rare syndrome; therefore, studies need to be done for proper diagnosis and management.

Case presentation:

Our patient, a 73-year-old woman, gave a history of recent acute right hypochondriac pain that had subsided the day before. Lab investigations were performed and liver enzymes were found to be significantly raised. An endoscopy followed by an endoscopic ultrasound was performed for further diagnosis, which showed the diverticulum outpouching from the duodenum. MRCP was then performed, which revealed a dilated common bile duct and common hepatic duct, with tapering at the distal end, most likely to be a stricture. Lemmel syndrome was identified based on the clinical presentation and imaging results. A dilated common bile duct, and two large duodenal diverticula with interdiverticular papilla was discovered during the patient’s endoscopic ultrasound, which was performed by the gastrointestinal team.

Clinical discussion:

Duodenal diverticula are the second most common site of diverticula after the colon with an incidence of 1–5% in radiological series. Lemmel’s syndrome is a rare cause of obstructive jaundice associated with juxtapapillary diverticulum. With a low incidence rate, only a few cases of Lemmel’s syndrome are reported with the first case reported in 1934 by Lemmel. Imaging techniques such as barium meal, EUS, ERCP, or magnetic resonance cholangiopancreatography are used to confirm the diagnosis. Our observations demonstrate that the diverticulum, which is often found on the medial wall of the second half of the duodenum and contains bezoar, compresses the distal common bile duct laterally. Nowadays, ERCP and EUS are used to confirm the diagnosis. Only symptomatic periampullary duodenal diverticulum (PDD) requires conservative or surgical therapy. The first line of treatment for biliopancreatic PDD problems is endoscopic sphincterotomy, which is 95% effective.

Conclusion:

Lemmel syndrome occurs due to the compression of the common bile duct by a duodenal diverticulum. Imaging, including CT scans, and MRCP are important for the diagnosis of this syndrome. Treatment modalities are not the same for each patient, however.
The interplay of immunity and growth: a case of combined variable immunodeficiency and growth hormone deficiency
Authors: Majety Sameer K. , Modh Sagar , Mishra Devrakshita , Alam Nafisa , Suvvari Tarun K. , Pagadala Chandra G.M. , Muppana Gopichand
Published: September 2024

Introduction:

Common variable immunodeficiency (CVID) is one of the more common immunodeficiencies seen in clinical practice with a complex disease pathology; while growth hormone deficiency (GHD) is a disorder characterized by complete or relative absence of the human growth hormone.

Case presentation:

This case report presents a 13-year-old female patient with a long history of recurrent respiratory tract and ear infections, along with a notable failure to hit her developmental milestones early in the second decade of her life. The diagnosis was based on a thorough investigation of serum immunoglobulins for CVID and a GH stimulation test for GHD. For these, the patient was placed on a tailored regimen of IVIGs, somatropin therapy, and antibiotics for the recurrent infections.

Case discussion:

CVID patients characteristically present with recurrent respiratory and ear infections, showing a marked decrease in immunity. Often diagnosed in childhood, GHD typically presents as growth failure along with developmental delays in dentition. There has been a notable rise in the coexistence of immunodeficiency syndromes and endocrinopathies studied in the past few decades. The case highlights and discusses the complex underlying pathology at play that links the two conditions to each other, while also excluding the various differentials.

Conclusion:

The report highlights the various challenges faced by both clinicians and patients when dealing with dual health conditions that may have a relatively nonspecific presentation. Some of which include the diagnostic difficulties, financial strains on the patient leading to poor follow-up, and in the long-term, the development of various complications. This emphasizes the importance of early disease diagnosis and strict management protocols for the said disease, for the overall betterment of the patient’s quality of life.
A young female’s battle with toxic epidermal necrolysis induced by NSAIDs: a case report
Authors: Adhikari Pratik , Singh Uday , Yadav Pramodman S. , Shah Leeza , Dev Abinash , Mandal Subhash C.
Published: September 2024

Introduction:

Stevens-Johnson Syndrome (SJS) is a rare but severe mucocutaneous reaction often triggered by medications or infections, characterized by extensive epidermal detachment and mucosal involvement. This condition poses a high risk of morbidity and mortality, requiring prompt recognition and treatment.

Case presentation:

An 18-year-old Asian female from eastern Nepal presented with nonitchy red spots, high fever, and significant discomfort following the administration of ibuprofen for minor sores. She developed extensive skin involvement covering 25% of her body surface area and severe mucosal lesions. Laboratory investigations revealed anemia, leukocytosis, and coagulopathy. She was admitted to the ICU, where she received broad-spectrum antibiotics, corticosteroids, and supportive care. The patient also developed acute kidney injury during treatment but eventually recovered and was discharged after a week.

Clinical discussion:

The rapid onset of SJS in this patient reveals the unpredictable nature of drug-induced reactions. Early intervention with a multidisciplinary approach involving dermatology, intensive care, and infectious disease specialists was crucial in managing her condition. Despite the controversy surrounding corticosteroid use in SJS, their administration likely contributed to the rapid improvement in inflammation and skin healing. The case highlights the importance of early recognition, prompt management, and careful monitoring for adverse drug reactions, especially when prescribing medications known to cause SJS.

Conclusion:

The successful outcome achieved through a multidisciplinary approach provides valuable insights into the effective strategies for handling severe drug reactions, emphasizing that early diagnosis and comprehensive management in patients with SJS is critical.
Acute primary gastric volvulus with open suture gastropexy: a case report
Authors: Behboudi Behnam , Hassanpour Saeed , Fazeli Mohammad Sadegh , Tadbir-Vajargah Kiana
Published: September 2024

Introduction and importance:

Gastric volvulus is rare and may result in a closed-loop obstruction. Even with appropriate management, mortality may occur in up to 50% of patients. The conventional treatment for acute gastric volvulus has been immediate operation with reduction and detorsion of the volvulus.

Case presentation:

Here, the authors present a case of acute gastric volvulus following fasting. The patient underwent definitive surgical treatment with detorsion and gastropexy, and was discharged with no postoperative complications.

Clinical discussion:

Acute gastric volvulus is a rare yet serious medical condition that requires immediate diagnosis and intervention to prevent complications. The case presented highlights the importance of recognizing both common and subtle signs of gastric volvulus, though nonspecific symptoms may delay diagnosis. In this patient, the acute onset of symptoms following a large meal and failure to pass a nasogastric tube were early indicators that prompted imaging and led to the diagnosis of mesenteroaxial gastric volvulus. CT imaging played a crucial role in confirming the diagnosis, demonstrating its value in acute abdominal presentations where symptoms overlap with other causes of gastrointestinal obstruction. This case also emphasizes the importance of early intervention to avoid ischemic complications and improve survival rates.

Conclusion:

Acute gastric volvulus is a rare, potentially life-threatening condition that can easily be missed due to nonspecific symptoms. Early recognition, prompt imaging, and immediate surgical intervention are critical to preventing serious complications such as strangulation and necrosis.
Hyperchloremia and Prolonged Acidosis During Treatment for Pediatric Diabetic Ketoacidosis
Authors: Yıldırımçakar Didem , Öcal Murat , Altıncık Selda Ayça , Özhan Bayram
Published: September 2024

Objectives

Diabetic ketoacidosis (DKA) is characterized by metabolic acidosis with a high anion gap secondary to ketonemia. Intravenous hydration fluids used in treatment can cause chloride overload, leading to hyperchloremic metabolic acidosis (HMA). The development of HMA can lead to the persistence of acidosis despite the resolution of ketonemia.

Methods

A total of 178 DKA episodes in 153 patients treated between January 2013 and October 2023 were included in the study. Creatine-based glomerular filtration rate and HbA1c value at admission and venous blood gas parameters (pH, actual bicarbonate, base deficit), anion gap, chloride-corrected bicarbonate, nonchloride base deficit, and sodium and chloride measured at 0, 2, 4, 6, 9, 12, 18 and 24 hours were evaluated.

Results

Hyperchloremia was detected in 69.3% of participants and developed at a mean of 6.3 (±4.3) hours of treatment. The incidence of hyperchloremia increased with the duration of treatment; the rates were 8.4%, 51.3%, 65%, 76.2%, 75.5%, and 80% at 0, 6, 9, 12, 18, and 24 hours of treatment, respectively. The group with hyperchloremia had more severe acidosis, a higher HbA1c value, and a longer resolution time. At the 12th hour of treatment, acidosis continued based on pH and HCO3 levels, whereas the hyperchloremia group exhibited a low anion gap (mean 12.8). At the 6th hour of treatment, the resolution rates were significantly lower in the hyperchloremia group based on the pH and HCO3 levels but increased when assessed by chloride-corrected HCO3 and anion gap.

Conclusions

During treatment of DKA, monitoring anion gap, blood ketones, and Cl−/Na+ ratio or using regression equations in addition to routine acid-base parameters may help differentiate DKA from HMA and prevent prolonged intravenous treatment.
Trapezius Island Myocutaneous Flap for Head, Neck, and Facial Reconstruction in Neurofibromatosis Type 1-Associated Plexiform Neurofibromas
Authors: Chen Wei-liang , Zhou Bin , Huang Zi-xian , Lin Dao-wei , Zhang Jie-ming
Published: September 2024

Background:

Reconstruction of significant soft tissue defects in the head and neck region after resection of extensive plexiform neurofibromas, as well as preservation and restoration of cosmetic and functional aspects, presents a considerable challenge.

Aims:

The purpose is to evaluate the feasibility of eTMF in repairing substantial defects after the complete resection of NF1 PN.

Patients and Methods:

Patients diagnosed with substantial neurofibromatosis (NP) type 1 (NF1), according to the revised criteria, underwent complete resection and remodeling of the facial aesthetic unit. An extended vertical lower trapezius island myocutaneous flap (eTIMF) was used for the defect reconstruction. Perioperative complications were evaluated using the Clavien-Dindo classification. ECOG PS was assessed. Postoperative follow-up at 6 months and completion of UW-QOL. The questionnaire included swallowing, chewing, speech, and quality of life scores. Two patients had pathogenic missense variants: c.5609G>A (p.Arg1870Gln) in exon 38 of NF1 in the first case, and c.4600C>T (p.Arg1534*) in exon 35 in the second case.

Results:

Two eTMFs were harvested successfully. Five facial esthetic units were remodeled, and 4 units were remodeled. Two extensive tumors were nearly entirely removed. No severe complications were noted. The ECOG PS improved from grade 3 in the first week postsurgery to grade 0 by the eighth week. The UW-QOL results indicated that swallowing, chewing, and speaking functions returned to their preoperative levels, with a 40% improvement in quality of life, reaching 60% and 80%, respectively.

Conclusions:

eTMF to repair substantial defects following total resection of NF1 PN and facial esthetic unit remodeling enhances appearance, function, and psychosocial outcomes. This technique is safe, efficient, resource-conserving, and simple to implement.
The Mitochondrial Transplantation: A New Frontier in Plastic Surgery
Authors: Li Haoran , Mu Dali
Published: September 2024

Challenges such as difficult wound healing, ischemic necrosis of skin flaps, and skin aging are prevalent in plastic surgery. Previous research has indeed suggested that these challenges in plastic surgery are often linked to cellular energy barriers. As the powerhouses of the cell, mitochondria play a critical role in sustaining cellular vitality and health. Fundamentally, issues like ischemic and hypoxic damage to organs and tissues, as well as aging, stem from mitochondrial dysfunction, which leads to a depletion of cellular energy. Hence, having an adequate number of high-quality, healthy mitochondria is vital for maintaining tissue stability and cell survival. In recent years, there has been preliminary exploration into the protective effects of mitochondrial transplantation against cellular damage in systems such as the nervous, cardiovascular, and respiratory systems. For plastic surgery, mitochondrial transplantation is an extremely advanced research topic. This review focuses on the novel applications and future prospects of mitochondrial transplantation in plastic surgery, providing insights for clinicians and researchers, and offering guidance to patients seeking innovative and effective treatment options.
Early and Late Microvascular Inflammation Have Differing Etiological Causes and Clinical Expression
Authors: Nankivell Brian J. , Viswanathan Seethalakshmi
Published: September 2024

Background.

Microvascular inflammation (MVI) is an important pathological feature of antibody-mediated rejection (AMR). How posttransplant time affects its clinicopathological expression is little understood.

Methods.

This retrospective, single-center study screened 3398 kidney transplant biopsies and dichotomized 202 MVI ≥ 2 (Banff glomerulitis + peritubular capillaritis ≥ 2) samples by 9-mo median incidence time for comparison.

Results.

The prevalence of MVI ≥ 2 was 12.4% in transplant kidneys, which failed more frequently than propensity-matched normal controls (n = 202; P < 0.001). Epidemiological risk factors for early MVI ≥ 2 were delayed graft function, prior AMR, and circulating donor-specific antibodies (DSAs+). Prior recipient sensitization occurred in 72.3%. Early MVI ≥ 2 was classified AMR in 65.3% and cellular rejection in 34.7%, and demonstrated excellent functional recovery and graft survival comparable to normal control kidneys. Late MVI ≥ 2 was predicted by younger (18 = 29 y) age, female recipient, living-donation, prior methylprednisolone, cyclosporine (versus tacrolimus, levels <5 ng/mL), absent antiproliferative therapy, and DSA+ using multivariable epidemiological modeling. Nonadherence caused 49.5%, with iatrogenic minimization responsible for 47.5%, usually for recipient infection. Late MVI ≥ 2 was because of AMR in 93.1%, and characterized by greater interstitial fibrosis, tubular atrophy, complement degradation split-product 4d (C4d) staining of peritubular capillaries+, endothelial C4d staining of glomerular capillaries+, transplant glomerulopathy and vasculopathy scores, DSA strength, and graft failure than early MVI ≥ 2 or normal transplant kidneys. Death-censored graft survival in 149 unique MVI ≥ 2 kidneys was independently determined by nonadherence, serum creatinine, proteinuria, DSA+, Banff C4d staining of peritubular capillaries+, and chronic interstitial fibrosis scores. MVI score and time lost significance using multivariable Cox regression.

Conclusions.

The changing expression of MVI ≥ 2 over time is best explained by differences in underimmunosuppression and microvascular injury from AMR impacting allograft function and survival.
Corynebacterium amycolatum peritonitis in a patient undergoing peritoneal dialysis: case report and literature review
Authors: ADIL Fatima Zahra , ARAGON Imane , BENAISSA Elmostafa , BENLAHLOU Yassine , BSSAIBIS Fatna , MALEB Adil , CHADLI Mariama , ELOUENNASS Mostafa
Published: September 2024

Peritoneal dialysis is a blood purification technique used in cases of end-stage chronic kidney failure, based on the filtering capabilities of the peritoneum. Infections, often caused by poor asepsis during catheter manipulation, are generally attributed to Staphylococcus epidermidis and Staphylococcus aureus. Corynebacterium, usually considered non-pathogenic, is rarely involved in these infections. We present a case of peritonitis due to Corynebacterium amycolatum in a patient undergoing peritoneal dialysis. The diagnosis was made based on cytobacteriological examination of the dialysate fluid, which on two occasions showed high levels of white blood cells with a predominance of neutrophilic polymorphonuclear and a monomorphic appearance of colonies on agar medium, whose identification by biochemical tests and antibiotic sensitivity study confirmed the presence of Corynebacterium amycolatum. The patient was successfully treated with vancomycin, resulting in symptom resolution and sterilization of the dialysate fluid. Although rare, the involvement of Corynebacterium species underscores the importance of confirming its pathogenicity. Further studies are needed to better understand the epidemiology of these infections and guide future treatments. This case also highlights the need for a rigorous approach to confirming the pathogenicity of Corynebacterium, despite its traditional classification as a contaminant.
Quantifying the impact of real-world evidence: the sacubitril/valsartan experience
Authors: Epstein Andrew J , Persky Morgan H , Rathore Saif
Published: September 2024

Background: The impact of RWE publication on use of approved therapies, including the existence of an effect and timing of impact, is unknown. Methods: We assessed the relationship between the cadence of RWE publications and sales of sacubitril/valsartan (Entresto) following launch. Publication data were derived from a PubMed search over 7/01/2015-12/31/2023 for English-language, human subject studies with the drug name (Entresto or sacubitril) and indication (heart failure) in the title or abstract. Quarterly RWE publication data were combined with quarterly information on sacubitril/valsartan sales over the 34-quarter period spanning Q3 2015 through Q4 2023. Quarter-to-quarter change in total sales was modeled with linear regression as a function of counts of previously published RWE-related studies, adjusting for a linear time trend to control for any underlying trends in sales growth; change in total sales from the quarter prior to publication to the quarter of publication to control for recent sales changes; and the cumulative count of RWE publications from Q3 2015 through the previous quarter to control for the contribution of previous RWE publications to future sales. Results: The PubMed search identified 888 studies; of these, 333 (37.5%) were classified as RWE-related. An additional RWE-related publication (in quarter q) was associated with an estimated mean increase in quarterly sales of $1.8M (from quarter q to q+1 following publication), $3.5M (from q+1 to q+2), and $2.7M (from q+2 to q+3). In adjusted models, an additional RWE publication was associated with a mean gain in sales from quarter q+1 to q+2 of $2.6M (95% CI -$0.2M to $5.4M). RWE publications were not associated with an increase in sales in the quarter following publication, and the association was attenuated by third quarter following publication. Conclusion: RWE studies were associated with increased use of sacubitril/valsaratan, providing preliminary evidence of RWE's ability to support therapy adoption.
Parental care modifies the role of early-life size and growth in shaping future physiology
Authors: Laubach Zachary M. , Madden Sage A. , Pardue Aleea , Safran Rebecca J.
Published: September 2024

Size and growth early in life are associated with physiological development and these traits influence fitness. Life history theory predicts that the relationship between traits reflect constraints involving allocation and acquisition of resources. Using longitudinal data from 113 wild nestling barn swallows (Hirundo rustica erythrogaster), we first characterized developmental changes in glucose metabolism, a physiological trait involved in energy mobilization and response to stress. Next, we used these data to test hypotheses from life history theory about allocation and acquisition of resources based on associations of nestling size and growth with glucose physiology and assessed whether these relationships are modified by parental care. We found that larger nestlings had higher baseline blood glucose and larger magnitude of change in glucose in response to a stressor. Further, this relationship was most pronounced among birds in nests that received the lowest amount of parental care. Given that glucose metabolism fuels activity and is critical in the vertebrate stress response, these results suggest that physiological constraints may contribute to the early-life disadvantage of being smaller, especially in the context of lower parental care. While these findings are inconsistent with a trade-off involving differential allocation of resources between life history traits, they align with the differential acquisition hypothesis.
Activation mapping in multi-center rat sensory-evoked functional MRI datasets using a unified pipeline
Authors: Galteau Marie E , Broadwater Margaret , Chen Yi , Desrosiers-Gregoire Gabriel , Gil Rita , Kaesser Johannes , Kim Eugene , Kıryağdı Pervin , Lambers Henriette , Liu Yanyan Y , López-Gil Xavier , MacNicol Eilidh , Mohebkhodaei Parastoo , De Oliveira Ricardo X N. , Pereira Carolina A. , Reimann Henning M , Rivera-Olvera Alejandro , Selingue Erwan , Sirmpilatze Nikoloz , Strobelt Sandra , Sumiyoshi Akira , Tham Channelle , Tudela Raul , Vrooman Roël M. , Wank Isabel , Zhang Yongzhi , van Engelenburg Wessel A , Baudewig Jürgen , Boretius Susann , Cash Diana , Chakravarty M Mallar , Chuang Kai-Hsiang , Ciobanu Luisa , Devenyi Gabriel A , Faber Cornelius , Hess Andreas , Homberg Judith R , Jelescu Ileana O , Justicia Carles , Kawashima Ryuta , Niendorf Thoralf , Scheenen Tom WJ , Shemesh Noam , Soria Guadalupe , Todd Nick , Wachsmuth Lydia , Yu Xin , Zhang Baogui B , Shih Yen-Yu Ian , Lee Sung-Ho , Grandjean Joanes
Published: September 2024

Functional Magnetic Resonance Imaging (fMRI) in rodents is pivotal for understanding the mechanisms underlying Blood Oxygen Level-Dependent (BOLD) signals and phenotyping animal models of disorders, amongst other applications. Despite its growing use, comparing rodent fMRI results across different research sites remains challenging due to variations in experimental protocols. Here, we aggregated and analyzed 22 sensory-evoked rat fMRI datasets from 12 imaging centers, totaling scans from 220 rats, to assess the consistency of results across diverse protocols. We applied a standardized preprocessing pipeline and evaluated the impact of different hemodynamic response function models on group and individual level activity patterns. Our analysis revealed inter-dataset variability attributed to differences in experimental design, anesthesia protocols, and imaging parameters. We identified robust activation clusters in all (22/22) datasets. The comparison between stock human models implemented in software and rat-specific models showed significant variations in the resulting statistical maps. Our findings emphasize the necessity for standardized protocols and collaborative efforts to improve the reproducibility and reliability of rodent fMRI studies. We provide open access to all datasets and analysis code to foster transparency and further research in the field.
Early adipose tissue wasting in a novel preclinical model of human lung cancer cachexia
Authors: Snoke Deena B. , van der Velden Jos L. , Bellafleur Emma R. , Dearborn Jacob S. , Lenahan Sean M. , Heininger Skyler C. J. , Ather Jennifer L. , Sarausky Hailey , Stephenson Daniel , Reisz Julie A. , D’Alessandro Angelo , Majumdar Devdoot , Ahern Thomas P. , Sandler Kim L. , Landman Bennett A. , Janssen-Heininger Yvonne M.W. , Poynter Matthew E. , Seward David J. , Toth Michael J.
Published: September 2024

Cancer cachexia (CC), a syndrome of skeletal muscle and adipose tissue wasting, reduces responsiveness to therapies and increases mortality. There are no approved treatments for CC, which may relate to discordance between pre-clinical models and human CC. To address the need for clinically relevant models, we generated tamoxifen-inducible, epithelial cell specificKrasG12D/+(G12D) mice.G12Dmice develop CC over a protracted time course and phenocopy tissue, cellular, mutational, transcriptomic, and metabolic characteristics of human lung CC. CC inG12Dmice is characterized by early loss of adipose tissue, a phenotype confirmed in a large cohort of patients with lung cancer. Tumor-released factors promote adipocyte lipolysis, a driver of adipose wasting in human CC, and adipose tissue wasting was inversely related to tumor burden. Thus,G12Dmice model key features of human lung CC and suggest a novel role for early adipose tissue wasting in CC.
UPR-induced intracellular C5aR1 promotes adaptation to the hypoxic tumour microenvironment by regulating tumour cell fate
Authors: Suwa Tatsuya , Lee Kelly , Chai Ian , Clark Heather , MacLean David J. , Machado Nicole , Rodriguez Berriguete Gonzalo , Higgins Geoff S , Hammond Ester M , Olcina Monica M
Published: September 2024

Dysregulation of the C5a-C5a receptor 1 (C5aR1) signalling axis underlies inflammation and immune-driven pathology. C5aR1 was traditionally thought to be primarily expressed on the cell membrane, although recent reports indicate the importance of intracellular C5aR1 expression for the inflammatory effector functions of various cell types. However, the mechanisms regulating C5aR1 expression and localisation remain unclear. In tumours with an immunosuppressive microenvironment, we recently found robust C5aR1 expression on malignant epithelial cells, highlighting potential tumour cell–specific functions. Here, we show that hypoxia, a hallmark of immunosuppressive microenvironments, induces C5aR1 expression in an unfolded protein response (UPR)-dependent manner via enhanced endoplasmic reticulum stress. Furthermore, hypoxia drives endocytosis, relocating C5aR1 from the cell membrane to the intracellular compartment. By genetically and pharmacologically targeting the C5a/C5aR1 axis, we show that C5aR1 mediates cellular adaptation to hypoxia by regulating processes associated with cell fate, including autophagy and apoptosis. In line with hypoxia-induced intracellular C5aR1 pools, pharmacological inhibition of C5aR1, particularly with cell-permeable small molecule inhibitors, significantly reduces tumour cell survival. These results suggest that the dysregulated C5a/C5aR1 axis and the hypoxia-induced shift in C5aR1 localisation, support tumour cell survival and provide new insights into therapeutic strategies for targeting the C5a/C5aR1 axis.
Gut colonization ofEnterococcusspecies is associated with COVID-19 disease in Uganda
Authors: Agudelo Carolina , Kateete David Patrick , Nasinghe Emmanuel , Kamulegeya Rogers , Lubega Christopher , Mbabazi Monica M , Baker Noah , Lin Kathryn , Liu Chang C. , Kasambula Arthur Shem , Kigozi Edgar , Komakech Kevin , Mukisa John , Mulumba Kassim , Mwachan Patricia , Nakalanda Brenda Sharon , Nalubega Gloria Patricia , Nsubuga Julius , Sitenda Diana , Ssenfuka Henry , Cirolia Giana , Gustafson Jeshua T. , Wang Ruohong , Nsubuga Moses Luutu , Yiga Fahim , Stanley Sarah A. , Bagaya Bernard Ssentalo , Elliott Alison , Joloba Moses , Wolf Ashley R.
Published: September 2024

Background

Infection with the COVID-19-causing pathogen SARS-CoV-2 is associated with disruption in the human gut microbiome. The gut microbiome enables protection against diverse pathogens and exhibits dysbiosis during infectious and autoimmune disease. Studies based in the United States and China have found that severe COVID-19 cases have altered gut microbiome composition when compared to mild COVID-19 cases. We present the first study to investigate the gut microbiome composition of COVID-19 cases in a population from Sub-Saharan Africa. Given the impact of geography and cultural traditions on microbiome composition, it is important to investigate the microbiome globally and not draw broad conclusions from homogenous populations.

Results

We used stool samples in a Ugandan biobank collected from COVID-19 cases during 2020-2022. We profiled the gut microbiomes of 114 symptomatic individuals who tested positive for SARS-CoV-2 along with 76 household contacts who did not present any symptoms of COVID-19. The inclusion of healthy controls enables us to generate hypotheses about bacterial strains potentially related to susceptibility to COVID-19 disease, which is highly heterogeneous. Comparison of the COVID-19 patients and their household contacts revealed decreased alpha diversity and blooms ofEnterococcusandEggerthellain COVID-19 cases.

Conclusions

Our study finds that the microbiome of COVID-19 individuals is more likely to be disrupted, as indicated by decreased diversity and increased pathobiont levels. This is either a consequence of the disease or may indicate that certain microbiome states increase susceptibility to COVID-19 disease. Our findings enable comparison with cohorts previously published in the Global North, as well as support new hypotheses about the interaction between the gut microbiome and SARS-CoV-2 infection.
Mechanistic Insights into the Stimulation of the Histone H3K9 Methyltransferase Clr4 by Proximal H3K14 Ubiquitination
Authors: Du Yunxiang , Sun Maoshen , Li Zhengqing , Wu Xiangwei , Qu Qian , Ai Huasong , Liu Lei
Published: September 2024

H3K9 methylation is an evolutionarily conserved hallmark of heterochromatin and plays crucial roles in chromosome segregation, genome stability, and gene expression regulation. Clr4 is the sole histone methyltransferase responsible for catalyzing H3K9 methylation inSchizosaccharomyces pombe. Clr4 K455/K472 automethylation and histone H3K14 ubiquitination (H3K14Ub) are vital activators of the catalytic activity of Clr4, ensuring appropriate heterochromatin deposition and preventing deleterious gene silencing. While the mechanism by which automethylation activates Clr4 was recently elucidated, the mechanism of the significantly pronounced stimulatory effect of H3K14Ub on Clr4 remains unclear. Here we determined the crystal structures of Clr4 bound to ubiquitinated and unmodified H3 peptides at resolutions of 2.60 Å and 2.39 Å, respectively. Our structures reveal a synergistic mechanism underlying the stronger stimulatory effect by H3K14Ub compared to automethylation: site-specific ubiquitination constrained by the H3K14 linkage increases substrate affinity through multivalent interactions between ubiquitin and Clr4. Additionally, H3K14Ub facilitates the allosteric transition of Clr4 from an inactive apo conformation to a hyperactive “catalyzing state”, accompanied by conformational changes in the αC-SET-insertion (SI) region, complete release of the autoregulatory loop (ARL), and retraction of the β9/10 loop. Finally, we propose a structural model for the Clr4 catalytic-regulatory cycle, depicting varying levels of conformational regulation mediated by automethylation and ubiquitination. This work provides structural insights into the interplay between different histone modifications and their collective impact on epigenetic regulation.
A Bibliometric Analysis of Research Hotspots and Frontiers in Diabetes and Cardiovascular Disease Comorbidity from 2005 to 2024
Authors: Wang Jingjin , Su Tianyuan , Li Yunlong , Su Yinxia , Li Yukai
Published: September 2024

Nearly two decades ago, diabetes mellitus (DM) and cardiovascular disease (CVD) emerged as major global health threats, with research interest steadily increasing. Despite ongoing in-depth studies in the DM+CVD field, a systematic analysis of overall development trends and future hotspots remains lacking. This study employs bibliometric methods, utilizing CiteSpace and VOSviewer software to analyze and visualize 5,505 DM+CVD-related publications from 2005 to May 2024. The findings reveal a rapid growth trend in the field, with publications peaking at 751 in 2022, and the United States and China as major contributing countries. Keyword analysis identifies research hotspots including oxidative stress, insulin resistance, and heart failure. Highly cited literature analysis shows that the relationship between DM+CVD and obesity, disease mechanisms, treatment strategies, lifestyle interventions, and novel drugs are primary research themes. Analysis of highly cited literature from the past three years indicates that the application of SGLT2 inhibitors and GLP-1 receptor agonists, the association between metabolic abnormalities and DM+CVD, precise management of heart failure and cardiomyopathy, and in-depth epidemiological studies are current and future research priorities. This study not only reveals research hotspots and development trends in the DM+CVD field but also provides important references for optimizing research resource allocation and promoting multidisciplinary collaboration.
The Association Between Estimated Glomerular Filtration Rate and Left Ventricular Function in Children With Chronic Kidney Disease
Authors: Dalpathadu Heshini , Wade Andrew , Greenway Steven
Published: September 2024

Background

Cardiovascular disease is the leading cause of morbidity and mortality in pediatric patients with chronic kidney disease (CKD). However, the kidney-heart relationship in this population remains poorly understood, particularly in the context of dialysis modality and duration. This study aims to investigate the associations between estimated glomerular filtration rate (eGFR), left ventricular ejection fraction (LVEF), left ventricular (LV) mass, and dialysis modality and duration in pediatric CKD patients.

Methods

This retrospective study included 16 pediatric CKD patients (median age 3.6 years; 31.3% female and 68.75% male), stratified by the presence of cardiac dysfunction (LVEF ≤ 50%). Clinical data, including eGFR, LVEF, LV mass, and dialysis history (hemodialysis or peritoneal dialysis), were collected. Independent T-tests, Wilcoxon Two-Sample tests, and Spearman’s correlations were performed to assess renal and cardiac function relationships. Multivariate regression models were employed to evaluate predictors of LVEF over time.

Results

Cardiac dysfunction was observed in 25% of the cohort, with significantly lower LVEF and fractional shortening compared to those without dysfunction. Patients with cardiac dysfunction were younger at CKD diagnosis (p < 0.0001), suggesting an earlier progression of renal and cardiac impairment. Following dialysis, eGFR significantly decreased in patients without cardiac dysfunction (p < 0.0001) but remained unchanged in those with dysfunction. Conversely, LVEF improved post-dialysis in patients with cardiac dysfunction (p = 0.0034) but remained stable in those with normal cardiac function. Prolonged dialysis duration was negatively correlated with eGFR (r = –0.31, p = 0.008) and LV mass (r = –0.26, p = 0.024). Hemodialysis duration was positively correlated with LVEF (r = 0.73, p < 0.001), suggesting potential cardiovascular benefits from prolonged hemodialysis treatment.

Conclusions

Pediatric CKD patients, particularly those with cardiac dysfunction, experience significant alterations in both renal and cardiac parameters, requiring tailored dialysis strategies in this population.
Explainable Artificial Intelligence to Diagnose Early Parkinson’s Disease via Voice Analysis
Authors: Shen Matthew , Mortezaagha Pouria , Rahgozar Arya
Published: September 2024

Abstract

Background

Parkinson’s disease (PD) is a progressive neurodegenerative disorder that affects motor control, leading to symptoms such as tremors or impaired balance. Early diagnosis of PD is crucial for effective treatment, yet traditional diagnostic models are often costly and lengthy. This study explores the use of Artificial Intelligence (AI) and Machine Learning (ML) techniques, particularly voice analysis, to identify early signs of PD and make a precise diagnosis.

Objectives

This paper aims to create an automatic detection and prediction of PD binary classification using vocal biomarkers. We will also use explainability to identify latent and important patterns in the input data in retrospect to the target to inform the definition of Parkinson’s through voice characteristics. Finally, a probability generation will be generated to create a scoring system of a patient’s odds of PD as a spectrum.

Methods

We utilized a dataset comprising 81 voice recordings from both healthy control (HC) and PD patients, applying a hybrid AI model combining Convolutional Neural Networks (CNN), Recurrent Neural Networks (RNN), Multiple Kernel Learning (MKL), and Multilayer Perceptron (MLP). The model’s architecture was designed to extract and analyze acoustic features such as Mel-Frequency Cepstral Coefficients (MFCCs), local jitter, and local shimmer, which are all indicative of PD-related voice impairments. Once features are extracted, the AI model will generate prediction labels for HC or PD files. Then, a scoring system will assign a number ranging from 0-1 to each file, indicating the stage of PD development.

Results

Our champion model yielded the following results: diagnostic accuracy of 91.11%, recall of 92.50%, precision of 89.84%, an F1 score of 0.9113, and an area under curve (AUC) of 0.9125. Furthermore, the use of SHapley Additive exPlanations (SHAP) provided detailed insight into the model’s decision-making process, highlighting the most influential features contributing to a PD diagnosis. The outcomes of the implemented scoring system demonstrate a distinct separation in the probability assessments for PD across the 81 analyzed audio samples, validating our scoring system by confirming that the vocal biomarkers in the audio files accurately correspond with their assigned scores.

Conclusion

This study highlights the efficacy of AI, particularly a hybrid model combining CNN, RNN, MKL, and Deep Learning in diagnosing early PD through voice analysis. The model demonstrated a robust ability to distinguish between HC and PD patients with significant accuracy by leveraging key vocal biomarkers such as MFCCs, jitter, and shimmer.
Concentration-dependent formation of intersegment interactions in viral droplets of influenza A virus infected cells
Authors: Takizawa Naoki , Higashi Koichi , Kawaguchi Risa Karakida , Gotoh Yasuhiro , Hayashi Tetsuya , Kurokawa Ken
Published: September 2024

The influenza A virus genome consists of eight RNA segments, each incorporated into a virion. It has been proposed that intersegment interactions bundle these segments, and viral inclusions, which contain viral ribonucleoproteins (vRNPs) and Rab11, facilitate this process. However, the locations and mechanisms of intersegment interaction formation remain unclear. To investigate this, we identified comprehensive intersegment interactions in infected cells using customized LIGR-seq. Our results revealed that intersegment interactions in infected cells overlapped with those in the virion and were partially formed through direct RNA-RNA interactions. Additionally, we found that the formation of these interactions was delayed in cells expressing a Rab11 dominant-negative. Furthermore, artificially increasing vRNP concentrations in the nucleus, where intersegment interactions typically do not occur, triggered the formation of these interactions, which again overlapped with those in the virion. These results suggest that intersegment interactions are formed in viral inclusions where progeny vRNPs accumulate.
HPL-2/HP1 and MET-2/SETDB1 bind distinct co-factors that promote heterochromatic foci, gene repression and organogenesis independently of H3K9 methylation
Authors: Delaney Colin E. , You Jia Emil , Gasser Susan M. , Padeken Jan , Mango Susan E.
Published: September 2024

Histone post-translational modifications (PTMs) promote genome segregation into heterochromatin and euchromatin by recruiting reader proteins, including HP1 proteins that bind repressive H3 lysine 9 methylation (H3K9me). However, recent studies suggest that H3K9me readers and writers also have PTM-independent activities. Here we examine the PTM-independent roles of the key H3K9 methyltransferase, MET-2/SETDB1, and theC. elegansHP1 orthologue, HPL-2, in organogenesis. The two factors co-localize in sub-nuclear foci independently of each other, and their combined loss additively disrupts gene repression and vulval organogenesis. HPL-2 remains functional in the absence of H3K9me, and HPL-2 lacking its H3K9me-binding chromodomain still localizes to heterochromatin foci, restricting vulva formation and repressing developmental genes. While MET-2 requires the disordered protein LIN-65 to form foci and silence genes, HPL-2 functions together with LIN-13, which is bound through HPL-2’s chromoshadow domain. In conclusion, HPL-2 and MET-2 repress in parallel on largely H3K9me-independent pathways, requiring distinct cofactors; while H3K9me reinforces both.
Unveiling the influence of pedagogical content knowledge in questioning on college students’ conceptual learning of introductory physics
Authors: Wang Jianlan , Wang Yuanhua , Thacker Beth , Wipfli Kyle , Hart Stephanie
Published: September 2024

Learning assistants (LAs) play a pivotal role in transforming traditional physics instruction toward a more inquiry-oriented approach. While empirical evidence supports the effectiveness of LA-involved physics instruction, there is a research gap regarding the specific competencies of LAs that contribute to improved conceptual understanding. One conjectured reason is LAs’ inquiry-oriented pedagogical skills, like questioning, which engender more effective interactions with students at points of instructional needs. This study addresses the gap by constructing a model delineating the contribution of LAs’ competencies of questioning, referred to as pedagogical content knowledge in questioning (PCK-Q), to students’ conceptual learning in introductory classical mechanics and electromagnetism. The participants included an instructional team comprising instructors, graduate teaching assistants, and LAs, and students from two sections over two semesters. PCK-Q was measured using a prevalidated instrument of free-response questions from our previous study, which could predict LAs’ questioning practices. Employing a pre-post design, students’ learning gain in conceptual understanding and critical thinking was assessed, and separate models were constructed to explore the relationship between LAs’ PCK-Q and students’ learning gain. Findings suggest that LAs’ PCK-Q has a significant but slight impact on students’ conceptual learning, with little impact on critical thinking. Furthermore, we developed Likert-scale questions, derived equations to quantify PCK-Q from Likert-scale ratings, verified the feasibility of this streamlined approach in measuring LAs’ PCK-Q, and discussed its limitations. The implications of the research findings are discussed in the context of physics instruction and LA preparation.

Published by the American Physical Society
2024
Gaining confidence on the correct realization of arbitrary quantum computations
Authors: Carrasco Jose , Langer Marc , Neven Antoine , Kraus Barbara
Published: September 2024

We present verification protocols to gain confidence in the correct performance of a device implementing an arbitrary quantum computation. The derivation of the protocols is based on the fact that matchgate computations, which are classically efficiently simulable, become universal if supplemented with additional resources. We combine tools from weak simulation, randomized compiling, and statistics to derive verification circuits that (i) strongly resemble the original circuit and (ii) can be classically efficiently simulated not only in the ideal, i.e., error free scenario, but also in the realistic situation where errors are present. In fact, in one of the protocols we apply exactly the same circuit as in the original computation, however, to a slightly modified input state.

Published by the American Physical Society
2024