bluuebunny/crossref_metadata_2025 huggingface dataset:
A case of early-onset periodontitis with vitamin D deficiency: A case report and literature review
Authors: Li Chen , Zhang Jinmei , Wang Lufei , Yang Jingmei
Published: September 2023

Rationale:

Periodontitis is an inflammatory disease with multifactorial etiology. Vitamin D, a fat-soluble vitamin, has protective effects on inflammatory response in various systemic conditions. The clinical features of vitamin D deficiency include growth failure, hypotonia, pathologic fractures, rachitic rosary, tetany and so on. Here we present a case of 12-year-old girl affected by early-onset periodontitis accompanied with vitamin D deficiency.

Patient concerns:

A 12-year-old girl with gingival redness, bleeding associated with tooth brushing, and mandibular anterior teeth movement, with difficulty in mastication for the past 2 months. There is no relevant family history or special systemic disease history. The serological microelement test showed vitamin D levels were significantly lower than normal range. Immunological test showed abnormal CD4+/CD8+(CD3+CD4+/CD3+CD8+) ratio as well.

Diagnoses:

Based on the clinical and serological findings, this patient was ultimately diagnosed with early-onset periodontitis accompanied with vitamin D deficiency.

Interventions:

The main treatments for this patient were 3-fold: periodontal therapy, vitamin D supplement and oral hygiene instructions.

Outcomes:

Following 1-year therapy, periodontal conditions recovered and became stable. And serological vitamin D levels returned to normal range.

Lessons:

The case of interest serves as an important reminder to clinicians, that the early-onset periodontitis may be associated with micronutrients abnormalities, and early-diagnosis and treatment could avoid the body heathy disorders.
Analysis of abdominal adhesion using the ileostomy model
Authors: Li Guanwei , Zeng Yunfei , Zeng Jie , Lu Shuo , Huang Yu , Huang Yutong , Li Wanglin , Cao Jie
Published: September 2023

Abdominal adhesion occurs commonly in clinical practice, causing unfavorable symptoms and readmission. The ileostomy operation is a common surgical procedure and we utilized this model to evaluate abdominal adhesion. Adhesion grade score was calculated in 35 patients (Cohort 1) and subjected to correlation and receiver operating characteristic analysis. Then 98 consecutive patients (Cohort 2) who underwent ileostomy and ileostomy closure were included into a retrospective study. Logistic regression analysis was performed, and the risk of small bowel obstruction was also assessed. The time of ileostomy closure correlated with adhesion grade score in Cohort 1, justifying its use as an indicator of abdominal adhesion. All patients in Cohort 2 were then divided into the high- and low-adhesion group. A multi-variable logistic regression analysis indicated that type of surgery and peritoneum suture during ileostomy were significant factors affecting the risk of abdominal adhesion. Abdominal adhesion had the trend to prolong the length of stay postoperatively without increasing the risk of bowel obstruction. Nine patients suffered bowel obstruction, and age older than 65 significantly increased the risk. We proposed the ileostomy procedure to be a model of abdominal adhesion, and the operative time of ileostomy closure could be used as an alternative of adhesion score. Type of surgery and peritoneum suture may be risk factors of abdominal adhesion. Older age increased the risk of small bowel obstruction after ileostomy surgery.
Efficacy of scrambler therapy in patients with painful diabetic peripheral neuropathy: A single-arm, prospective, pilot study
Authors: Yoo Seung Hee , Kim Won-joong , Chae Ji Seon , Kang Bo Kyung , Kang Min Jeong , Beak Min Hyouk
Published: September 2023

Background:

A variety of medications are available to manage painful diabetic peripheral neuropathy (DPN), but the proper treatment remains challenging. Accordingly, various neuromodulation modalities have been used. However, no prospective clinical trials have evaluated the use of scrambler therapy (ST) in painful DPN. This study aimed to explore the long-term effects of ST in managing painful DPN.

Methods:

The patients received 10 consecutive STs of 45 minutes every 1 to 2 days. The primary outcome was pain score. We measured the visual analog scale (VAS) pain scores at baseline, during ST, immediately after ST, and at 1, 2, 3, and 6 months after ST. The secondary outcomes were Michigan Neuropathy Screening Instrument (MNSI), Semmes-Weinstein monofilament test, and Leeds Assessment of Neuropathic Symptoms and Signs pain scores, which were measured at baseline, immediately after ST, and at 1, 2, 3, and 6 months after ST.

Results:

VAS scores showed significant improvement at the 8th, 9th, and 10th sessions during ST and 1 month after ST. The MNSI self-report component score was decreased 1 month after the ST. However, all other outcomes did not show significant differences compared to the baseline.

Conclusion:

ST may have short-term effects and limited long-term effects on painful DPN.
The impact of COVID-19 pandemic on the epidemiological characteristics of permanent dental injury in Xi’an of China: A retrospective study
Authors: Yang Yang , Liu Yanli , Wang Ziheng , Li Qiang , Wang Jiang , Zhang Min
Published: September 2023

The coronavirus disease 2019 (COVID-19) has become a major global concern, seriously affecting the lives and health of the population. This retrospective study aimed to investigate changes in permanent tooth injury in the Xi’an area of China influenced by the COVID-19 pandemic. The medical records of 466 dental emergency patients in 2019 and 2020 were retrospectively analyzed. The number of injured teeth in a single patient, the number of injury types, the time from injury to hospital visit and follow-up visits within 1 year before and after the pandemic were analyzed using the chi-squared test and the paired t-test. There was significant difference in the number of emergency patients and trauma types before and during COVID-19 pandemic (P < .05). The time from injury to hospital visit and the interval between the trauma event and visit showed longer during the COVID-19 pandemic (P < .05). The rate of on-time follow-up in the following year was significantly decreased, and the rates of delayed visits and patients lost to follow-up were significantly increased (P < .05). The outbreak of the COVID-19 pandemic brought a certain change in the epidemiological characteristics of dental injury in the Xi’an area of China. Dental emergency departments should provide even more timely and effective treatments. It is also necessary to strengthen public education, with emphasis on the importance of timely medical treatment and regular follow-up for dental trauma.
Efficacy and outcomes of systemic chemotherapy in posttransplant and immunosuppression associated Kaposi sarcoma: Twenty years experience of a tertiary cancer center
Authors: Khanmammadov Nij̇at , Paksoy Nail , Doğan İzzet , Ferhatoğlu Ferhat , Saip Pinar , Aydiner Adnan
Published: September 2023

Kaposi sarcoma is a malignant angioproliferative disease, and human herpesvirus-8 plays a major role in its etiology. Iatrogenic Kaposi sarcoma (IKS) can occur in patients undergoing immunosuppressive therapy. The treatment strategy for patients with IKS is immunosuppressive therapy modification. However, it is unclear which chemotherapy drug is the most effective and safe in the treatment of IKS. Therefore, we investigated the efficacy and safety of systemic treatment in patients with IKS at our tertiary cancer center. This cross-sectional retrospective study analyzed the clinical data of 22 patients diagnosed with IKS between January 2000 and January 2020. The patients were divided into the following 2 groups according to the transplantation status: organ transplant recipient (OTR) group and non-organ transplant recipient (non-OTR) group. Of the 22 patients, 12 were included in the OTR group and 10 were included in the non-OTR group. The median patient age at diagnosis was 52.1 years in the OTR group and 68.1 years in the non-OTR group. The median overall survival (OS) was 65.4 months in the OTR group, while the median OS was not reached in the non-OTR group. There was no statistically significant difference in OS between the 2 groups (P = .45). The 5-year OS rate among all patients was 54%. In the OTR group, the objective response rate and disease control rate were 50% and 83%, respectively, and in the non-OTR group, the objective response rate and disease control rate were 60% and 90%, respectively. Chemotherapy was well tolerated in both groups. Hematological toxicities were the main dose-limiting adverse events. Grade III/IV leucopenia and neutropenia were observed in 5 and 4 patients, respectively; however, no patient experienced febrile neutropenia. No chemotherapy-related death occurred. Systemic chemotherapy is an effective treatment and can be considered for disease control in patients with an aggressive disease course, who do not experience regression with immunosuppressive therapy modification.
Successful perioperative management with damage control surgery following cardiac arrest due to massive postpartum hemorrhage: A case report
Authors: Park Chan Hee , Bae Jin Gon , Lee Jeong Woo
Published: September 2023

Introduction:

Although declining, maternal mortality due to postpartum hemorrhage (PPH) remains significant. Here we report the case of a 31-year-old primipara patient admitted with cardiac arrest due to PPH.

Case presentation:

Labor was induced at gestational week 39, and the infant was delivered rapidly. Cardiac arrest due to PPH occurred during the transfer to our hospital, and the patient underwent cardiopulmonary resuscitation upon arrival to the emergency room. On admission, her hemoglobin level was 0.7 g/dL and she was in hypovolemic shock. Resuscitation and hysterectomy were performed immediately, including damage control surgery and gauze packing, to control the diffuse oozing bleeding due to severe disseminated intravascular coagulation. Relaparotomy for hemostasis was subsequently performed because of a decrease in hemoglobin level and blood pressure, and gauze packing was reinserted with temporary abdominal closure. Two days later, the abdominal wall was closed after confirming the absence of bleeding and the patient recovered well without further intervention.

Conclusion:

A prompt and assertive intensive response through collaborative efforts, utilizing feasible damage control surgery, can elegantly salvage uncontrolled bleeding in PPH patients with disseminated intravascular coagulation.
Sagittal Craniosynostosis: Treatment and Outcomes According to Age at Intervention
Authors: Franco-Mesa Camila , Shah Nikhil R. , Konofaos Petros
Published: September 2023

The purpose of this study is to describe the treatment strategies and outcomes of nonsyndromic single-suture sagittal craniosynostosis based on the patient’s age at intervention. Studies from MEDLINE, Scopus, and Cochrane Central Register of Controlled Trials were systematically searched for patients with nonsyndromic single-suture sagittal craniosynostosis. Inclusion criteria encompassed studies with follow-up of at least 12 months, minimum of 25 patients per cohort, and first-time surgical intervention. The risk of bias in nonrandomized studies of intervention tool [Risk Of Bias In Non-randomized Studies—of Interventions (ROBINS-I)] was applied. A total of 49 manuscripts with 3316 patients met criteria. Articles were categorized based on age at intervention; 0 to 6, older than 6 to 12, and older than 12 months. Fifteen of the manuscripts described interventions in more than 1 age group. From the 49 articles, 39 (n=2141) included patients 0 to 6 months old, 15 (n=669) discussed patients older than 6 to 12 months old, and 9 (n=506) evaluated patients older than 12 months old. Follow-up ranged from 12 to 144 months. Over 8 types of open surgical techniques were identified and 5 different minimally invasive procedures were described. Minimally invasive procedures were exclusively seen in the youngest patient cohort, while open cranial vault reconstructions were often seen in the 2 older cohorts. Endoscopic surgery and open conservative procedures are indicated for younger patients, while complex open cranial vault reconstructions are common in older patients. However, there is no consensus on one approach over the other. Even with the analysis of this review, we cannot factor a strong conclusion on a specific technique.
Haemophagocytic lymphohistiocytosis after intravesical BCG administration for bladder cancer presenting with multiorgan failure
Authors: Liatsos G. D. , Manousopoulou G. , Poulaki A. , Iliaki A. , Mariolis I. , Vassilopoulos D.
Published: September 2023

Bacillus Calmette-Guérin (BCG), is administered intravesically as an adjuvant immunotherapy for the treatment of non-muscle invasive bladder cancer. While mild non-infectious problems can occur in up to 85 % of cases, significant local and systemic complications have been reported in 1–5 % of cases. We report the case of a patient with superficial bladder cancer who developed multiorgan failure after intravesical BCG instillation including the kidney and liver with subsequent haemophagocytic lymphohistiocytosis. Our case illustrates the first reported combination of secondary haemophagocytic lymphohistiocytosis with severe renal and liver failure after BCG immunotherapy for bladder carcinoma. Treatment strategy is discussed.
Cereibacter flavus sp. nov., a novel member of the family Rhodobacteraceae isolated from seawater of the South China Sea and reclassification of Rhodobacter alkalitolerans as Cereibacter alkalitolerans comb. nov.
Authors: Liu Wen-Li , Yang Zi-Wen , Guo Dan-Yuan , Deng Qi-Qi , Li Jia-Ling , Wang Pan-Deng , Chen Sen-Hua , Liu Lan , Nie Guo-Xing , Li Wen-Jun
Published: September 2023

A Gram-stain-negative, aerobic, motile, ovoid-shaped and yellow-coloured strain, designated SYSU M79828T, was isolated from seawater collected from the South China Sea. Growth of this strain was observed at 4–37 °C (optimum, 28 °C), pH 6.0–8.0 (optimum, pH 7.0) and with 0–6% NaCl (optimum, 3.0 %, w/v). The respiratory quinone was found to be Q-10. Major fatty acid constituents were C18 : 1
 ω7c/C18 : 1
 ω6c, C18 : 1
ω7c11-methyl and C18 : 0 (>5 % of total). The major polar lipids were phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, phosphatidylcholine, phosphoglycolipid, two unidentified phospholipid, one unidentified lipid and an unidentified glycolipid. The genomic DNA G+C content was 64.5 mol%. Phylogenetic analyses based on 16S rRNA gene sequences and core genes indicated that strain SYSU M79828T belonged to the genus

Cereibacter

and had the highest sequences similarity to ‘Rhodobacter xinxiangensis’ TJ48T (98.41 %). Based on 16S rRNA gene phylogeny, physiological and chemotaxonomic characterizations, we consider that strain SYSU M79828T represents a novel species of the genus

Cereibacter

, for which the name Cereibacter flavus sp. nov. is proposed. The type strain is SYSU M79828T (=GDMCC 1.3803T=KCTC 92893T). In addition, according to the results of phylogenetic analysis and similar taxonomic characteristics, we propose that

Rhodobacter alkalitolerans

should be reclassified as Cereibacter alkalitolerans comb. nov.
Transcriptomic gene profiles in anex vivomodel of erythropoiesis to unravel molecular pathomechanisms of Sickle Cell Disease
Authors: Tinguely Matthis , Opitz Lennart , Schaer Dominik J. , Vallelian Florence , Schmugge Markus , Franzoso Francesca D.
Published: September 2023

We characterized the transcriptional profiles of erythroid cells differentiated from peripheral blood mononuclear cells (PBMCs) from peripheral blood collected from patients diagnosed with Sickle Cell Disease (SCD), which have been treated with Hydroxyurea (HU) in comparison to untreated SCD patients and healthy controls (HC) using bulk RNAseq. We identified 1398 differentially expressed genes (DEGs) in SCD non-treated-derived erythroid cells and 495 DEGs in SCD HU-treated patient-derived erythroid cells compared to HC. We found biological processes such as oxidative phosphorylation pathway, proteasome, autophagy, natural killer cell (NK) cytotoxicity, adaptive immune response or inflammatory response to be significantly enriched in our patient study groups by using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Our findings collectively suggest different as well as common molecular signatures between our groups. We could validate 12 of our top DEGs in treated patients by qRT-PCR. We found similar regulation patterns when comparing the mRNA levels of mutS homolog 5-Suppressor APC Domain Containing 1 (MSH5-SAPCD1), G protein subunit gamma 4 (GNG4), stabilin 1/ clever-1 (STAB1) and Fas Binding Factor 1 (FBF1) from the bone marrow cells and spleen tissue from the Berkely SCD mouse model to the expressions observed in the transcriptome of our ex-vivo patient-derived erythropoiesis model.
LEOPARD: missing view completion for multi-timepoint omics data via representation disentanglement and temporal knowledge transfer
Authors: Han Siyu , Yu Shixiang , Shi Mengya , Harada Makoto , Ge Jianhong , Lin Jiesheng , Prehn Cornelia , Petrera Agnese , Li Ying , Sam Flora , Matullo Giuseppe , Adamski Jerzy , Suhre Karsten , Gieger Christian , Hauck Stefanie M. , Herder Christian , Roden Michael , Casale Francesco Paolo , Cai Na , Peters Annette , Wang-Sattler Rui
Published: September 2023

Longitudinal multi-view omics data offer unique insights into the temporal dynamics of individual-level physiology, which provides opportunities to advance personalized healthcare. However, the common occurrence of incomplete views makes extrapolation tasks difficult, and there is a lack of tailored methods for this critical issue. Here, we introduce LEOPARD, an innovative approach specifically designed to complete missing views in multi-timepoint omics data. By disentangling longitudinal omics data into content and temporal representations, LEOPARD transfers the temporal knowledge to the omics-specific content, thereby completing missing views. The effectiveness of LEOPARD is validated on three benchmark datasets constructed with data from the MGH COVID study and the KORA cohort, spanning periods from 3 days to 14 years. Compared to conventional imputation methods, such as missForest, PMM, GLMM, and cGAN, LEOPARD yields the most robust results across the benchmark datasets. LEOPARD-imputed data also achieve the highest agreement with observed data in our analyses for age-associated metabolites detection, estimated glomerular filtration rate-associated proteins identification, and chronic kidney disease prediction. Our work takes the first step toward a generalized treatment of missing views in longitudinal omics data, enabling comprehensive exploration of temporal dynamics and providing valuable insights into personalized healthcare.
Intrinsic disorder in flaviviral capsid proteins and their role in pathogenesis
Authors: Sundar Anirudh , Umashankar Pavithra , Sankar Priyanka , Ramasamy Kavitha , Venkataraman Sangita
Published: September 2023

A high level of disorder in many viral proteins is a direct consequence of their small genomes, which makes interaction with multiple binding partners a necessity for infection and pathogenicity. A segment of the flaviviral capsid protein, also known as the molecular recognition feature (MoRF), undergoes a disorder-to-order transition upon binding to several protein partners. In order to understand their role in pathogenesis, the MORFs were identified and their homology was studied. Despite the lack of sequence similarities, the docking studies of Cs with the host proteins indicate conserved interactions involving MORFs across members of the phylogenetic subclades. Additionally, it was observed from the protein-protein networks that some MoRFs preferentially bind proteins that are involved in specialized functions such as ribosome biogenesis. The findings point to the importance of the MoRFs in the flaviviral life cycle, with important consequences for disease progression and suppression of the host immune system. Potentially, they might have impacted the way flaviviruses evolved to infect varied hosts using multiple vectors.
Immune Cells and Inflammatory mediators cause endothelial dysfunction in a vascular microphysiological system
Authors: Rengarajan Aishwarya , Goldblatt Hannah E , Beebe David J. , Virumbrales-Muñoz María , Boeldt Derek S
Published: September 2023

Functional assessment of endothelium serves as an important indicator of vascular health and is compromised in vascular disorders including hypertension, atherosclerosis, and preeclampsia. Endothelial dysfunction in these cases is linked to dysregulation of the immune system involving both changes to immune cells and increased secretion of inflammatory cytokines. Herein, we utilize a well-established microfluidic device to generate a 3-dimensional vascular Microphysiological System (MPS) consisting of a tubular blood vessel lined with Human Umbilical Vein Endothelial Cells (HUVECs) to evaluate endothelial function measured via endothelial permeability and Ca2+signaling. We evaluated the effect of a mixture of factors associated with inflammation and cardiovascular disease (TNFα, VEGF-A, IL-6 at 10ng/ml each) on vascular MPS and inferred that inflammatory mediators contribute to endothelial dysfunction by disrupting the endothelial barrier over a 48-hour treatment and by diminishing coordinated Ca2+activity over a 1-hour treatment.

We also evaluated the effect of peripheral blood mononuclear cells (PBMCs) on endothelial permeability and Ca2+signaling in the HUVEC MPS. HUVECs were co-cultured with PBMCs either directly wherein PBMCs passed through the lumen or embedded in the supporting collagen hydrogel. We revealed that Phytohemagglutinin (PHA)-M activated PBMCs cause endothelial dysfunction in MPS both through increased permeability and decreased coordinated Ca2+activity compared to non-activated PBMCs. Our MPS has potential applications in modeling cardiovascular disorders and screening for potential treatments using measures of endothelial function.
The effects of warming on the stability of consumer-resource interactions
Authors: Synodinos Alexis D. , Sentis Arnaud , Montoya José M. , Haegeman Bart
Published: September 2023

Temperature regulates the physiology and behaviour of organisms. Thus, changing temperatures induce dynamics in species interactions. Considering that consumer-resource interactions underpin ecological communities, the impacts of warming on the stability of consumer-resource interactions have been extensively studied. However, a consensus among empirically determined warming-stability relationships and a clear understanding thereof is lacking. To investigate these systematically, we propose a simplified theoretical framework that can incorporate empirical data in three steps. First, we constrain stability to intrinsic oscillations to avoid comparing disparate stability notions. Second, we reduce complexity by utilising a one-dimensional stability metric. Third, we enable the direct comparison of all data by converting all thermal dependence parameterisations into a single function, with two parameters in the exponent determining its shape. The empirical data generate four different warming-stability relationships: stability increases, decreases, is hump-shaped or U-shaped with temperature. The diversity of warming-stability relationships, though partly attributable to context-dependence, is fundamentally caused by sensitivity to two factors: how the processes within the functional response are defined and the thermal dependence of carrying capacity. Consistency across studies regarding the former and acquiring more data on the latter should help uncover systematic patterns in the thermal dependence of stability in consumer-resource interactions.
Synthetic Hydrogels with Entangled Neutrophil Extracellular Traps Influence Tumor Progression in MDA-MB-231 Cells
Authors: Katz Rachel R. , Shetty Shamitha , West Jennifer L.
Published: September 2023

We incorporated neutrophil extracellular traps (NETs) in a poly(ethylene glycol)-based synthetic extracellular matrix to study their impact on tumorigenesis in triple negative breast carcinoma (TNBC) cells in a highly controlled environment. We observed that NETs helped to increase cell survival, proliferation, and pro-metastatic morphological phenotype. We also showed that the presence of NETs influenced the secretion of IL-8, a pro-NETosis factor, and that conditioned media from cells cultured in these gels influenced NETosis in an IL-8 dependent manner. The results observed in this system correlate with murine models and clinical studies in the literature and help to provide additional insight of the individual factors at play in the NET-mediated promotion of TNBC progression and metastasis.
The Integration of Proteogenomics and Ribosome Profiling Circumvents Key Limitations to Increase the Coverage and Confidence of Novel Microproteins
Authors: de Souza Eduardo V. , Bookout Angie L. , Barnes Christopher A. , Miller Brendan , Machado Pablo , Basso Luiz A. , Bizarro Cristiano V. , Saghatelian Alan
Published: September 2023

There has been a dramatic increase in the identification of non-conical translation and a significant expansion of the protein-coding genome and proteome. Among the strategies used to identify novel small ORFs (smORFs), Ribosome profiling (Ribo-Seq) is the gold standard for the annotation of novel coding sequences by reporting on smORF translation. In Ribo-Seq, ribosome-protected footprints (RPFs) that map to multiple sites in the genome are computationally removed since they cannot unambiguously be assigned to a specific genomic location, or to a specific transcript in the case of multiple isoforms. Furthermore, RPFs necessarily result in short (25-34 nucleotides) reads, increasing the chance of ambiguous and multi-mapping alignments, such that smORFs that reside in these regions cannot be identified by Ribo-Seq. Here, we show that the inclusion of proteogenomics to create a Ribosome Profiling and Proteogenomics Pipeline (RP3) bypasses this limitation to identify a group of microprotein-encoding smORFs that are missed by current Ribo-Seq pipelines. Moreover, we show that the microproteins identified by RP3 have different sequence compositions from the ones identified by Ribo-Seq-only pipelines, which can affect proteomics identification. In aggregate, the development of RP3 maximizes the detection and confidence of protein-encoding smORFs and microproteins.
Probing sustained attention and fatigue across the lifespan
Authors: Hanzal S. , Learmonth G. , Thut G , Harvey M
Published: September 2023

Trait fatigues reflects tiredness that persists throughout a prolonged period, whereas state fatigue is defined to be short term after “intense and/or prolonged effort”. We investigated the impact of prolonged sustained attention (using the SART task) on both trait and state fatigue levels in the general population. A JsPsych online version of the SART task was undertaken by 115 participants, stratified across the whole adult lifespan. While pre-task trait fatigue was a strong indicator of the initial state fatigue levels, undergoing the task itself induced an increase in reported subjective state fatigue, as well as reduced energy. Consistent with this finding, greater subjective state fatigue levels were associated with reduced accuracy. In addition, age was the best predictor of inter-participant accuracy (the older the participants, the greater the accuracy), and learning (i.e., task duration reducing reaction times). Moreover, a ceiling effect occurred where participants with higher trait fatigue did not experience greater state fatigue changes relative to those with low trait scores. In summary, we found improved accuracy in older adults, as well as a tight coupling between state fatigue and SART performance decline (in an online environment). The findings warrant further investigation into fatigue as a dynamic, task-dependent state and into SART task performance as an objective measure and inducer of fatigue.
ATF2 phosphorylation is essential for neuronal apoptosis, linking the DLK/LZK kinase cascade to JUN upregulation
Authors: Gomez-Deza Jorge , Nebiyou Matthew , Alkaslasi Mor R. , El Touny Lara H. , Slavutsky Anastasia L. , Ashby Nathan , Cheng Ken , Le Pichon Claire E.
Published: September 2023

Apoptotic neuron death is a common feature of many neurodegenerative diseases. Perhaps surprisingly, the exact mechanisms by which neurons undergo apoptosis have yet to be elucidated. We conducted an unbiased whole genome screen in human neurons to discover genes required for apoptotic neuron death, and found ATF2, MAP3K12 and JUN among top hits. We demonstrate that ATF2 is a previously unappreciated master regulator of neuron death. ATF2 is phosphorylated downstream of MAP3K12 (dual leucine zipper kinase) and MAP3K13 (leucine zipper kinase) and its phosphorylation is essential for transcriptional upregulation of JUN. We show that JUN upregulation is essential for apoptosis – but not its phosphorylation. Contrary to previous assumptions, cJun phosphorylation is therefore simply a correlate of JUN upregulation. In this study, we identify phosphorylation of ATF2 as a key event in the mechanism of neuronal apoptosis, linking the MAP3K12/13 kinase cascade to transcriptional upregulation of JUN. Since targeting members of this signaling pathway to block neuronal death has proved difficult, ATF2 offers a novel and promising alternative.
Bidirectional interaction between Protocadherin 8 and transcription factor Dbx1 regulates cerebral cortex development
Authors: Cwetsch Andrzej W , Gilabert-Juan Javier , Ferreira Sofia , Moreau Matthieu X. , Saillour Yoann , Delberghe Elodie , González Martínez Jose , Borello Ugo , Causeret Frédéric , Pierani Alessandra
Published: September 2023

Brain development requires correct tissue patterning and production of appropriate cell types. Transcription factors (TFs) play essential roles in these processes, regulating the expression of target genes responsible for neuronal subtypes specific features. Cell adhesion molecules are key components of neuronal identities that control cell sorting, migration, neurite outgrowth/guidance and synaptogenesis. To date, the link between TFs and cell adhesion molecules is considered to be unidirectional. Here, we demonstrate that ectopic expression of Dbx1 leads to spatio-temporally restricted increased expression ofPcdh8and cell aggregation, together with changes in neuronal identity. Surprisingly, Pcdh8 overexpression also induces Dbx1 expression as well as a complete reorganisation of apico-basal polarity and dorso-ventral patterningviaNotch signalling. Altogether, our work therefore points to cell adhesion molecules as unexpected, yet important, players in the regulation of cell identity and, in particular, Pcdh8 through its bidirectional interaction with the Dbx1 transcription factor.
Cadherins orchestrate specific patterns of perisomatic inhibition onto distinct pyramidal cell populations
Authors: Jézéquel Julie , Condomitti Giuseppe , Kroon Tim , Hamid Fursham , Sanalidou Stella , Garces Teresa , Maeso Patricia , Balia Maddalena , Rico Beatriz
Published: September 2023

In the mammalian neocortex, excitatory pyramidal cells are assembled into distinct subnetworks, which project to different brain areas. GABAergic interneurons were long thought to connect promiscuously and extensively to pyramidal neurons, but recent evidence supports the existence of a cell type-specific inhibitory connectome. How and when interneurons establish such a precise connectivity pattern among intermingled populations of excitatory neurons remains enigmatic. Here, we investigated the molecular rules shaping cell type- and input-specific inhibitory connectivity in different Layer 5 (L5) pyramidal cell populations. We found that neighboring L5 intra- (L5 IT) and extra-telencephalic (L5 ET) neurons receive different combinations of inhibitory perisomatic inputs from Parvalbumin- (PV+) and Cholecystokynine-positive (CCK+) basket cells. We also identifiedCdh12andCdh13, two cadherin superfamily members, as critical mediators of L5 pyramidal cell type-specific inhibitory connectivity. Our data revealed a minimal overlap between L5 IT and L5 ET presynaptic inhibitory networks, and suggests that different populations PV+ basket cells innervate distinct L5 pyramidal cell types. Altogether, our work unravels the contribution of cadherins in shaping cortical interneuron wiring and provides new insights into the development of inhibitory microcircuits.
Patterns of Cerebellar-Cortical Structural Covariance Mirror Anatomical Connectivity of Sensorimotor and Cognitive Networks
Authors: Alasmar Zaki , Chakravarty M. Mallar , Penhune Virginia , Steele Christopher J.
Published: September 2023

The cortex and cerebellum are densely connected through reciprocal input/output projections that form segregated loop circuits. Anatomical studies in primates and imaging studies in humans show that anterior lobules of the cerebellum exhibit denser connections to sensorimotor and parietal cortical regions, while lobules Crus I and II are more heavily connected to prefrontal regions. The cerebellum and cortex develop in tandem in childhood, leading to the hypothesis that individual differences in structure should be related, especially for connected regions. To test this hypothesis we examined covariation between the volumes of anterior sensorimotor and lateral cognitive lobules of the cerebellum and measures of cortical thickness (CT) and surface surface area (SA) across the whole brain in a sample of 270 young, healthy adults drawn from the HCP dataset. We found that patterns of cerebellar-cortical covariance differed between sensorimotor and cognitive networks such that anterior motor lobules of the cerebellum showed greater covariance with sensorimotor regions of the cortex, while lobules Crus I and Crus II showed greater covariance with frontal and temporal regions. Interestingly, cerebellar volume showed predominantly negative relationships with CT and predominantly positive relationships with SA. Individual differences in SA are thought to be largely under genetic control while CT is thought to be more malleable by experience. This suggests that cerebellar-cortical covariation for SA may be a more stable feature, whereas covariation for CT may be more affected by development. Additionally, dissimilarity metrics revealed that the pattern of covariance showed a gradual transition between sensorimotor and cognitive lobules, consistent with evidence of functional gradients within the cerebellum. Taken together, these findings are consistent with known patterns of structural and functional connectivity between the cerebellum and cortex. They also shed new light on possibly differing relationships between cerebellar volume and cortical thickness and surface area. Finally, our findings are consistent with the interactive specialization framework which proposes that structurally and functionally connected brain regions develop in concert.
Neural Representations of Beat and Rhythm in Motor and Association Regions
Authors: Hoddinott Joshua D. , Grahn Jessica A.
Published: September 2023

Humans perceive a pulse, or beat, underlying musical rhythm. Beat strength correlates with activity in the basal ganglia and SMA, suggesting these regions support beat perception. However, the basal ganglia and SMA make up a general timing network active during rhythm and timing perception, regardless of beat. Therefore, activity in these regions may represent basic rhythmic features, in addition to beat. Using RSA, we characterized the neural representation of rhythm in the basal ganglia, SMA, and across the whole brain. During fMRI, participants heard 12 rhythms – 4 strong-beat, 4 weak-beat, and 4 non-beat. Multi-voxel activity patterns for each rhythm, and for the mean of each condition, were tested for uniqueness. Activity patterns in beat-sensitive regions should alter as a function of beat strength, eliciting greater dissimilarities between rhythms with different beat strength than between rhythms with similar beat strength. Indeed, mean activity patterns in the putamen and SMA were significantly dissimilar for strong-beat and non-beat conditions, and dissimilarity between activity patterns across all 12 rhythms correlated with beat strength models, not basic rhythmic features. Whole-brain analyses also identified beat-sensitivity in the IFG, and inferior parietal cortex. These findings build upon univariate work suggesting that motor and association regions are beat-sensitive.
4R-Tau seeding activity unravels molecular subtypes in patients with Progressive Supranuclear Palsy
Authors: Martinez-Valbuena Ivan , Lee Seojin , Santamaria Enrique , Irigoyen Joaquin Fernandez , Forrest Shelley L. , Li Jun , Tanaka Hidetomo , Couto Blas , Reyes Nikolai Gil , Qamar Hania , Karakani Ali M. , Kim Ain , Senkevich Konstantin , Rogaeva Ekaterina , Fox Susan H. , Tartaglia M. Carmela , Visanji Naomi P. , Andrews Tallulah , Lang Anthony E. , Kovacs Gabor G.
Published: September 2023

Progressive Supranuclear palsy (PSP) is a 4-repeat (4-R) tauopathy. We hypothesized that the molecular diversity of tau could explain the heterogeneity seen in PSP disease progression. To test this hypothesis, we performed an extensive biochemical characterisation of the high molecular weight tau species (HMW-Tau) in 20 different brain regions of 25 PSP patients. We found a correlation between the HMW-Tau species and tau seeding capacity in the primary motor cortex, where we confirmed that an elevated 4R-Tau seeding activity correlates with a shorter disease duration. To identify factors that contribute to these differences, we performed proteomic and spatial transcriptomic analysis that revealed key mechanistic pathways, in particular those involving the immune system, that defined patients demonstrating high and low tau seeding capacity. These observations suggest that differences in the tau seeding activity may contribute to the considerable heterogeneity seen in disease progression of patients suffering from PSP.
Mapping the molecular motions of 5-HT3serotonin-gated channel by Voltage-Clamp Fluorometry
Authors: Peverini Laurie , Shi Sophie , Medjebeur Karima , Corringer Pierre-Jean
Published: September 2023

The serotonin-gated ion channel (5-HT3R) mediates excitatory neuronal communication in the gut and the brain. It is the target for setrons, a class of competitive antagonists widely used as antiemetics, and is involved in several neurological diseases. Cryo-electron microscopy of the 5-HT3R in complex with serotonin or setrons revealed that the protein has access to a wide conformational landscape. However, assigning known high-resolution structures to actual states contributing to the physiological response remains a challenge.

In the present study, we used voltage-clamp fluorometry (VCF) to measure simultaneously, for 5-HT3R expressed at a cell membrane, conformational changes by fluorescence and channel opening by electrophysiology. Four positions identified by mutational screening report motions around and outside the serotonin-binding site through incorporation of cysteine-tethered rhodamine dyes with or without a nearby quenching tryptophan. VCF recordings show that the 5-HT3R has access to four families of conformations endowed with distinct fluorescence signatures: “resting-like” without ligand, “inhibited-like” with setrons, “pre-active-like” with partial agonists and “active-like” (open channel) with partial and strong agonists. Data are remarkably consistent with cryo-EM structures, the fluorescence partners matching respectively Apo, setron-bound, 5-HT bound-closed and 5-HT-bound-open conformations. Data show that strong agonists promote a concerted motion of all fluorescently labelled sensors during activation, while partial agonists, especially when loss-of-function mutations are engineered, stabilize both active and pre-active conformations.

In conclusion, VCF, though the monitoring of electrophysiologically silent conformational changes, illuminates allosteric mechanisms contributing to signal transduction and their differential regulation by important classes of physiological and clinical effectors.

Significance Statement

High-resolution structures of serotonin-gated receptors (5-HT3AR) have evidenced a wide range of conformations that are challenging to annotate to physiologically relevant states. Voltage-clamp fluorometry allows to investigate the activation of 5-HT3AR by simultaneously following molecular motions and electrophysiological states at the plasma membrane. Here, we developed four fluorescent sensors reporting conformational changes at the serotonin binding site and at the extracellular domain and transmembrane domain interface. Investigation of a series of agonists, partial agonists and antagonists show that strong agonists promote a concerted motion of the whole protein during activation, while antagonists and partial agonists stabilize distinct closed-channel conformations. Data offer insights into allosteric mechanisms, unravelling the conformational dynamics of the receptors and helping to annotate high-resolution static structures.
An amphipathic helix drives interaction of Fibrillins with plastoglobule lipid droplets
Authors: Shivaiah Kiran-Kumar , Boren Duncan M. , Tequia-Herrera Andres , Vermaas Josh , Lundquist Peter Knut
Published: September 2023

Plastoglobule lipid droplets of chloroplasts serve complex roles affecting plant development, stress tolerance and photosynthesis. They harbor a set of approximately 42 proteins that collectively dictate plastoglobule functions. Due to the monolayer structure of plastoglobules which encompass a neutral lipid core, these proteins must associate monotopically on the plastoglobule surface. However, targeting determinants have not been identified for plastoglobule proteins, and the protein-membrane interaction mechanisms that establish the plastoglobule proteome remain unclear. Here, we demonstrate that plastoglobule-localized Fibrillins harbor an amphipathic helix at the lip of their β-barrel that is necessary for proper plastoglobule association. Molecular dynamics simulations support the specific interaction of the amphipathic helix of AtFBN1a with membranes rich in lipid packing defects which are expected to be especially prevalent on the tightly curved surface of plastoglobules. Introduction of one of the amphipathic helices into stromal-or thylakoid-localized FBNs was ineffective at redirecting the proteins to plastoglobules, likely due to endogenous protein-protein interactions that override the influence of the amphipathic helix. Proteomic analyses indicate AtFBN1a influences the plastoglobule proteome through outcompeting and recruiting specific proteins. We also demonstrate that the plastoglobule-localized FBNs, AtFBN1a and AtFBN7a, bind unsaturated fatty acids, particularly C18:1, and that elimination of the amphipathic helix suppresses fatty acid binding in AtFBN1a, but promotes fatty acid binding in AtFBN7a. Predicted amphipathic helices can be identified on two-thirds of plastoglobule proteins, indicating the use of amphipathic helices may be a general mechanism by which proteins selectively associate with plastoglobules.
Potentiating NaV1.1 in Dravet syndrome patient iPSC-derived GABAergic neurons increases neuronal firing frequency and decreases network synchrony
Authors: Kelley Matt R. , Chipman Laura B. , Asano Shoh , Knott Matthew , Howard Samantha T. , Berg Allison P.
Published: September 2023

Dravet syndrome is a developmental and epileptic encephalopathy characterized by seizures, behavioral abnormalities, developmental deficits, and elevated risk of sudden unexpected death in epilepsy (SUDEP). Most patient cases are caused byde novoloss-of-function mutations in the geneSCN1A, causing a haploinsufficiency of the alpha subunit of the voltage-gated sodium channel NaV1.1. Within the brain, NaV1.1 is primarily localized to the axons of inhibitory neurons, and decreased NaV1.1 function is hypothesized to reduce GABAergic inhibitory neurotransmission within the brain, driving neuronal network hyperexcitability and subsequent pathology. We have developed a humanin vitromodel of Dravet syndrome using differentiated neurons derived from patient iPSC and enriched for GABA expressing neurons. Neurons were plated on high definition multielectrode arrays (HD-MEAs), permitting recordings from the same cultures over the 7-weeks duration of study at the network, single cell, and subcellular resolution. Using this capability, we characterized the features of axonal morphology and physiology. Neurons developed increased spiking activity and synchronous network bursting. Recordings were processed through a spike sorting pipeline for curation of single unit activity and to assess the effects of pharmacological treatments. At 7-weeks, the application of the GABAAR receptor agonist muscimol eliminated network bursting, indicating the presence of GABAergic neurotransmission. To identify the role of NaV1.1 on neuronal and network activity, cultures were treated with a dose-response of the NaV1.1 potentiator δ-theraphotoxin-Hm1a. This resulted in a strong increase in firing rates of putative GABAergic neurons, an increase in the intraburst firing rate, and eliminated network bursting. These results validate that potentiation of NaV1.1 in Dravet patient iPSC-derived neurons results in decreased firing synchrony in neuronal networks through increased GABAergic neuron activity and support the use of human neurons and HD-MEAs as viable high-throughput electrophysiological platform to enable therapeutic discovery.
Technology assisted research assessment: algorithmic bias and transparency issues
Authors: Thelwall Mike , Kousha Kayvan
Published: September 2023

Purpose

Technology is sometimes used to support assessments of academic research in the form of automatically generated bibliometrics for reviewers to consult during their evaluations or by replacing some or all human judgements. With artificial intelligence (AI), there is increasing scope to use technology to assist research assessment processes in new ways. Since transparency and fairness are widely considered important for research assessment and AI introduces new issues, this review investigates their implications.

Design/methodology/approach

This article reviews and briefly summarises transparency and fairness concerns in general terms and through the issues that they raise for various types of Technology Assisted Research Assessment (TARA).

Findings

Whilst TARA can have varying levels of problems with both transparency and bias, in most contexts it is unclear whether it worsens the transparency and bias problems that are inherent in peer review.

Originality/value

This is the first analysis that focuses on algorithmic bias and transparency issues for technology assisted research assessment.