bluuebunny/crossref_metadata_2025 huggingface dataset:
Pediatric retroperitoneal non-organ-originated malignancies: An analysis based on SEER database
Authors: Shen Wei , Geng Hongqiong , Zhou Yin , Yang Xinghai
Published: October 2023

Retroperitoneal non-organ-originated malignancies are rare pediatric tumors with challenging diagnosis and treatment. The present study aimed to analyze the clinicopathological characteristics, treatment, and prognosis of retroperitoneal non-organ-originated malignancies. In the study, we included the pathological diagnosis of pediatric retroperitoneal non-organ-originated malignant tumors between 2000 to 2019 through the updated Surveillance, Epidemiology, and End Results database. We use the Kaplan–Meier survival curve to calculate the overall survival (OS) and cancer-specific survival (CSS). The risk of all-cause death and disease-specific death were analyzed using Cox proportional hazard regression model and Fine-and-Grey competitive hazard model, respectively. In the study, a total of 443 pediatric retroperitoneal non-organ-originated malignancies were included. Of them, only 22.3% of patients had no metastatic disease, 42.9% had distant metastasis and 34.8% had locally advanced diseases. The primary pathological tumor was neuroblastoma followed by germ cell tumor. The overall 10-year OS and CSS were 70.7% and 73.1%, respectively, and the 10-year OS and CSS of metastatic diseases were 54.4% and 56.6%, respectively. Older children, worse tumor stage at diagnosis, incomplete resection, and prolonged time from diagnosis to treatment were significantly associated with worse survival outcomes. Radiotherapy and chemotherapy did not significantly improve the prognosis of patients without complete tumor resection. The study indicated that most pediatric retroperitoneal non-organ-originated malignancies diagnosed with metastatic diseases have plagued treatment. Radiotherapy and chemotherapy are the main treatment methods for children unable to undergo complete surgical treatment. However, these treatments do not reach the same therapeutic effect as complete tumor resection after early diagnosis. Hence, early diagnosis and surgery for complete tumor resection are of utmost importance.
Gastric cancer metastasis-related NT5DC2 indicates unfavorable prognosis of patients
Authors: Sha Rula , Zhang Jiaming , Meng Fanjie , Zhaori Getu
Published: October 2023

Purpose:

Approximately 80 to 90% of patients with gastric cancer (GC) eventually develop into metastatic GC nowadays,because GC is difficult to be diagnosed at an early stage. GC patients with metastases typically have a poor prognosis. It is necessary to explore a potential prognostic marker in metastatic GC.

Methods:

All GC data were obtained from The Cancer Genome Atlas and Gene Expression Omnibus databases. The metastasis-related candidate gene and its role in GC were analyzed by comprehensive analysis.

Results:

Totally 1049 metastasis-related genes were identified in GC. Univariate Cox regression analysis screened the top 10 genes (PDHX, SLC43A1, CSAG2, NT5DC2, CSAG1, FMN1, MED1, HIVEP2, FNDC3A, and PPP1R2) that were closely correlated with prognosis of GC patients. Among which, NT5DC2 was screened as the target gene for subsequent study. The NT5DC2 expression were increased in primary GC and metastatic GC samples. Moreover, GC patients with high NT5DC2 expression exhibited shorter overall survival and post progression survival, and the NT5DC2 was metastatic GC patients’ independent prognostic factor. Totally 29 pathways were activated in metastatic GC samples with high NT5DC2 expression. Four immune cells’ infiltration were significantly different between NT5DC2 high and low expressed metastatic GC patients. NT5DC2 showed significantly negative correlations with 6 types of immune cells’ critical marker genes and 5 types of immune cell infiltration. The 10 immune checkpoint expressions were decreased in high NTDC2 expression metastatic GC patients.

Conclusions:

NT5DC2 plays a prognostic role in metastatic GC. GC patients with high NT5DC2 expression indicates unfavorable prognosis.
Adult patients with tetanus in Anhui Province of China from 2013 to 2022: A retrospective study
Authors: Cheng Dai , Liang Li , Miaomiao Hu , Guolei Han , Wei Sun
Published: October 2023

Tetanus is a highly fatal infectious disease with an incubation period of 7 to 8 days. The aim of this study was to identify risk factors for death in tetanus patients, develop a nomogram model for predicting mortality risk. This retrospective study included tetanus patients who were admitted to the intensive care unit department between January 2013 and December 2022. The patients were divided into 2 groups based on their final outcome, namely death group and survival group. Risk factors associated with mortality were analyzed using univariate and multivariate logistic regression analysis. Finally, a nomogram model was developed using the rms package. A total of 91 patients were enrolled in this study, including 54 males and 37 females. The average age of the tetanus patients was 52.88 ± 16.56 years, with a mean incubation period of 8.51 ± 3.97 days. The foot was the most common injury site (42.86%), and metal product stabbing was the leading cause of injury (48.78%). Ventilator-associated pneumonia was the most frequent complication (21.98%). Univariate and multivariate logistic regression analyses revealed that Ablett classification (odds ratio [OR], 21.999; 95% confidence interval [CI], 4.124–117.352), white blood cell count (OR, 6.033; 95%CI, 1.275–28.552), and autonomic nervous dysfunction (OR, 22.663; 95%CI, 4.363–117.728) as independent risk factors for tetanus patients. The C-index of the nomogram model was 0.942, with an area under the curve of the receiver operating characteristic curve at 0.942 (95%CI, 0.871–0.905). Ablett classification, white blood cell count, autonomic nervous dysfunctions were associated with the prognosis of patients with tetanus. The nomogram model developed based on risk factors has high accuracy.
Comparing diagnostic accuracy of biomarkers for acute kidney injury after major surgery: A PRISMA systematic review and network meta-analysis
Authors: Lan Hui , Liu Xia , Yang Dongmei , Zhang De , Wang Li , Hu Liping
Published: October 2023

Background:

The timely identification of patients at risk of acute kidney injury (AKI), along with early prevention, real-time monitoring, and prompt intervention, plays a crucial role in enhancing patient prognosis after major surgery.

Methods:

We conducted a comprehensive search across multiple databases, including Web of Science, EMBASE, MEDLINE, China National Knowledge Infrastructure, and Cochrane Library. Each study’s risk of bias was independently evaluated as low, moderate, or high, utilizing criteria adapted from Quality Assessment of Diagnostic Accuracy Studies 2. The analysis was performed using STATA V.17.0 and R software V.3.4.1. Diagnostic tests were ranked based on the dominance index. We performed meta-analyses to calculate odds ratios (ORs) and 95% confidence intervals (CIs) individually. We then carried out a network meta-analysis to compare the performances of these biomarkers.

Results:

Fifteen studies were included in this analysis. The meta-analysis findings revealed that among all the biomarkers assessed, serum cystatin C (s-CysC) (hierarchical summary receiver operating characteristic curve [HSROC] 82%, 95% CI 0.78–0.85) exhibited the highest HSROC value. The network meta-analysis demonstrated that urinary kidney injury molecule-1 (u-KIM-1) and s-CysC displayed relatively higher sensitivity and specificity, respectively. In subgroup analyses, u-KIM-1 in the urine output (OU) group (OR 303.75, 95% CI 3.39–1844.88), s-CysC in the non-OU group (OR 10.31, 95% CI 3.09–26.2), interleukin-18 in the noncardiac surgery group (OR 46.20, 95% CI 0.48–307.68), s-CysC in the cardiac group (OR 12.42, 95% CI 2.9–35.86), u-KIM-1 in the retrospective group (OR 243.00, 95% CI 1.73–1582.11), and s-CysC in the prospective group (OR 8.35, 95% CI 2.34–21.15) had the best diagnostic accuracy. However, it is important to note that existing publication bias may reduce the reliability of the above-mentioned results.

Conclusion:

The biomarker of s-CysC has the highest HSROC value to predicting acute kidney injury after major surgery in meta-analysis and relatively higher specificity in network meta-analyses. u-KIM-1 exhibited relatively higher sensitivity, with best diagnostic accuracy in the OU and retrospective group in the subgroup analysis.
Long-term outcomes of highly experienced people with HIV undergoing salvage therapy with raltegravir
Authors: Patiño Escarcina Jesús Enrique , Netto Eduardo Martins , Brites Carlos
Published: October 2023

Raltegravir and other third-line drugs have shown promise in improving outcomes in treatment-experienced patients. However, the efficacy and tolerability of these agents vary. This study assessed real-life virologic success, long-term survival, and adverse events in patients receiving raltegravir or other third-line drugs as salvage regimens. This retrospective cohort study included adults who experienced treatment failure (human immunodeficiency syndrome-1 RNA plasma viral load >1000 copies/mL) and subsequently initiated raltegravir or other third-line drugs (darunavir/ritonavir, maraviroc, or etravirine). Propensity score matching methods were employed to account for differences at the time of switching from failing antiretroviral therapy regimens. The matched subset was analyzed using the Kaplan–Meier method and Generalized Wilcoxon tests to evaluate the probability of achieving virologic suppression (plasma viral load <50 copies/mL). Mortality rates, toxicity, treatment interruption, virologic failure, and loss to follow-up were determined using Poisson regression. One hundred and sixty-eight patients initiating salvage regimens were included, with 123 receiving raltegravir and 45 other third-line drugs. Propensity score matching resulted in a subset of 90 patients, 45 in each group. During the follow-up period, there were no significant differences observed between the groups in terms of virologic suppression (77.8% vs 82.2%, P = .73), mortality rates (4.04 vs 6.18 persons per 100 person-years [p-y]; P = .67), drug toxicity (0.00 vs 2.06 persons per 100 p-y; P = .49), treatment interruption (8.07 vs 0.00 persons per 100 p-y; P = .06), virologic failure (2.02 vs 4.12 persons per 100 p-y; P = .61), and loss of follow-up (6.05 vs 4.12 persons per 100 p-y; P = .70). Our findings indicate comparable survival and virological success rates between raltegravir and other drugs used in salvage regimens. Similar rates of drug toxicity, treatment interruption, virologic failure, and loss of follow-up were also observed. These results suggest that raltegravir may be a viable option for salvage therapy, demonstrating outcomes comparable to other third-line drugs in real life.
Impact of anastomotic leakage on survival after surgery for gastric carcinoma: A PRISMA systematic review and meta-analysis
Authors: Zhang Lei , Wang Beibei , Huang Yi
Published: October 2023

Background:

The long-term survival of postoperative anastomotic leakage (AL) following gastric cancer (GC) surgery is still debating. Our aim was to investigate the association between AL and survival of the patients following GC.

Methods:

We searched articles in databases from inception to July 2023 to retrieve literature related to postoperative AL and survival of GC patients. We evaluated the association of postoperative AL and survival of GC patients using the software STAT10.0.

Results:

Seven articles with 6209 GC patients were included. Our results showed that the postoperative AL were associated with pooled 1-year patient overall survival (OS) result in an odds ratio (OR) of 0.504 (95% confidence interval (CI): 0.372–0.682; I
2 = 84.1%; P = .000), pooled 3-year patient OS (OR = 0.467, 95% CI: 0.356–0.614; I
2 = 85.3%; P = .000) and pooled 5-year patient OS (OR = 0.370, 95% CI: 0.171–0.805; I
2 = 82.5%; P = .012). The P value of Egger test were 0.759, 0.187, 0.175. The postoperative AL were associated with pooled 1-year patient disease-free survival (DFS) result in an OR of 0.538 (95% CI: 0.171–1.691; I
2 = 89.0%; P = .289), the pooled 3-year patient DFS (OR = 0.143, 95% CI: 0.119–1.431; I
2 = 91.7%; P = .163), and the pooled 5-year patient DFS (OR = 0.344, 95% CI: 0.088–1.338; I
2 = 91.0%; P = .124), and the P value of Egger test of pooled 1-, 3-, and 5-year DFS were 0.759, 0.247, 0.07.

Conclusion:

Postoperative AL was correlated with a worse OS in GC patients, but not correlated with DFS in GC patients, but more studies are required to confirm this conclusion.
Clinical efficacy of minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) in the treatment of II° lumbar isthmic spondylolisthesis: A retrospective cohort study
Authors: Zhang Bin , Ma Jun-Song , Feng Pin , Hu Yuan , Liu Jun-Lin , Kong Qing-Quan
Published: October 2023

Minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) is not suitable for high-grade isthmic spondylolisthesis, whether MIS-TLIF can treat II° lumbar isthmic spondylolisthesis (IS) is still controversial. This retrospective cohort study compared the clinical efficacy of MIS-TLIF and open transforaminal lumbar interbody fusion (OPEN-TLIF) in the treatment of II° lumbar IS. From January 2017 to January 2023, 101 patients with II° lumbar IS were diagnosed in our hospital and underwent surgical treatment, of which 53 received MIS-TLIF surgery and 48 received OPEN-TLIF surgery. The operation time, blood loss and surgical complications were compared between the 2 groups. The pain, function, reduction rate and fusion rate of the patients were evaluated during follow-up. The amount of intraoperative blood loss, postoperative drainage, and postoperative hospital stay in the MIS-TLIF group were significantly lower than those in the OPEN-TLIF group were (P < .01). In the MIS-TLIF group, there were 1 case of dural sac injury and 3 cases of lower limb paralysis. The complication rate of MIS-TLIF was lower than the OPEN-TLIF group (P = .032). In the visual analog scale score of low back pain, the MIS-TLIF group was lower than the OPEN-TLIF group after operation and at the last follow-up. There were no significant differences in postoperative leg pain score, slippage rate, and fusion rate between the 2 groups. Compared with OPEN-TLIF, MIS-TLIF has the advantages of better low back pain relief, less trauma, less bleeding and faster recovery, and is worthy of clinical promotion.
IgG level of the third booster dose for mRNA of SARS-CoV-2 vaccines among Iraqi healthcare workers
Authors: Rasheed Waleed S. , Sarkees Alaa Noori
Published: October 2023

Mass vaccination is an effective method for controlling the outbreak of coronavirus disease 2019 (COVID-19) and limiting the consequent mortality due to severe COVID-19. After the second dose, immunity can decline in certain cases over time; therefore, a third booster dose should be administered. Therefore, the present study aimed to assess the immunogenicity of the third dose of the messenger ribonucleic acid BioNTech COVID-19 vaccine and determine the effect of the third booster dose of messenger ribonucleic acid COVID-19 vaccines, specifically (Oxford/AstraZeneca COVID-19 vaccine/AZD1222), BioNTech COVID-19 vaccine, and Sinopharm among healthcare workers. This longitudinal panel design was conducted with 256 healthcare workers in Duhok Province, Iraq, from June to October 2022. Most participants had a normal body mass index (44% and 41% in the first and second phase, respectively). In the first phase, significant associations were observed between COVID-19 vaccines and positivity (P value ≤ .001), and between age groups and positivity (P value = .001). The mean severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) anti-spike receptor-binding domain immunoglobulin G antibody level in the ninth month was the highest among those who had received the Pfizer vaccine (6.7930), followed by AstraZeneca (2.8492), and Sinopharm (0.3060). In the 12th month, all 82 participants received Pfizer as a booster dose, and the highest mean SARS-CoV-2 anti-spike receptor-binding domain immunoglobulin G antibody in the 12th month belonged to those whose second dose was Pfizer (46.8835), followed by AstraZeneca (36.4635), and Sinopharm (21.7815). The Pfizer vaccine is highly effective in restoring SARS-CoV-2-specific immune responses and is well-tolerated. However, further investigation is required to determine the duration of disease protection of the third dose of the COVID-19 vaccine.
Treatment of multiple myeloma based on autologous stem cell transplant: An overview of systematic reviews
Authors: Liang Juan , Yang Ying , He Peijie , Mandizadza Oscar Onayi , Zhang Wanjun , Lin Shengyun , Ji Conghua
Published: October 2023

Background:

Multiple myeloma (MM) is a malignant plasma cell disease. In recent years, several systematic reviews, and meta-analyses have been published on treatment protocols, including autologous stem cell transplantation for MM.

Methods:

Web of Science, PubMed, Embase, and Cochrane Library were searched to systematically summarize the quality of the methodology and evidence of meta-analyses regarding treatment of MM including autologous stem cell transplantation.

Results:

Total 11 meta-analyses were included. The preferred reporting items for systematic reviews and meta-analyses evaluation revealed that the quality of included reviews was affected by possible unevaluated bias between studies and the lack of protocol and registration. The AMSTAR2 scale indicated that the quality of the methodology of included reviews ranged from very low to moderate. The grading, assessment, development, and evaluation of recommendations evaluation showed that among the included outcome indicators, most of them are of low quality.

Conclusion:

This overview suggested that the combination of drugs has improved patient survival rates, efficacy and safety compared with the standard regimen. However, the strength of the evidence is uneven and due to methodological errors, the results should be interpreted with caution in order to provide a reference for further improvement of the study design. The methodological quality of the relevant meta-analysis needs to be further improved.
Efficacy and safety of Xiao-ai-ping injection add-on therapy to chemotherapy in patients with non-small cell lung cancer: A systematic review and meta-analysis
Authors: Li Andong , Liu Shilin , Zhang Hui , Lin Minghao , Guo Lijiao , Yuan Chengbo , Li Zhenyu , Xu Jianan , Wang Tan
Published: October 2023

Background:

Xiao-ai-ping injection (XAPI) combined with chemotherapy has potential efficacy and less side effects in the treatment of non-small cell lung cancer (NSCLC). At present, there are many clinical studies on XAPI combined with chemotherapy in the treatment of NSCLC, but the results are different. The purpose of this study was to evaluate the efficacy and safety of XAPI combined with chemotherapy in the treatment of NSCLC by meta-analysis system.

Methods:

The databases to be searched include PubMed, Cochrane Library, Web of Science, Chinese National Knowledge Infrastructure, Chinese Biomedical Literature Database, Wanfang database, Chinese Scientific Journal Database, and so on. In addition, relevant journals and magazines will manually search in various fields as supplements. The search date is set from the establishment of the database until July 8, 2023. The 2 researchers will use Endnote X9 software for literature screening and data extraction and independently evaluate the quality. We then assessed the quality and risk of inclusion in the study and observed outcome indicators.

Results:

A total of 28 trials were included in this study, 1947 patients with NSCLC (974 receiving XAPI combined chemotherapy and 973 receiving chemotherapy alone). The results of meta-analysis showed that: Objective tumor response rate of NSCLC (P < .00001). Improvement in Karnofsky performance score of NSCLC (P < .00001). Quality of life score of NSCLC (P < .00001). The result of CD3 + (P < .00001). The result of CD4 + (P < .00001). The result of CD8 + (P < .00001). The result of CD4+/CD8 + (P = .0001). Leukopenia (P < .00001). Thrombocytopenia (P < .00001). Hemoglobin decrease (P < .00001). Liver function (P = .04). Nausea and vomiting (P < .00001).

Conclusion:

Our meta-analyses demonstrated that XAPI adjunct with chemotherapy can improve the patient quality of life, reduce adverse reactions, and enhanced immune function, the treatment is effective and high safety. Which suggests that it might be used for NSCLC. However, a large sample of randomized controlled trials are needed to further study the long-term efficacy of XAPI.
Acute management of childhood stroke
Authors: Chung Melissa G. , Pabst Lisa
Published: October 2023

Purpose of review

The purpose of this paper is to review recent updates in the acute management of childhood arterial ischemic stroke, including reperfusion therapies and neuroprotective measures.

Recent findings

With the emergence of pediatric stroke centers in recent years, processes facilitating rapid diagnosis and treatment have resulted in improved implementation of early targeted neuroprotective measures as well as the increased use of reperfusion therapies in childhood arterial ischemic stroke. Retrospective data has demonstrated that alteplase is safe in carefully selected children with arterial ischemic stroke in the first 4.5 h from symptom onset, though data regarding its efficacy in children are still lacking. There is also increasing data that suggests that thrombectomy in children with large vessel occlusion improves functional outcomes. Recent adult studies, including the use of Tenecteplase as an alteplase alternative and expansion of late thrombectomy to include patients with large ischemic cores, also are reviewed along with limitations to application of the adult data to pediatric care.

There have been significant advances in the hyperacute care of children with ischemic stroke and early diagnosis and targeted management are of the upmost importance in improving long-term outcomes.
Validation of the Xpert Breast Cancer STRAT 4 Assay on the GeneXpert instrument to Assess Hormone Receptor, Ki67, and HER2 Gene Expression Status in Breast Cancer Tissue Samples
Authors: Sewanywa Lina , Hale Martin , Michelow Pamela , Mayne Elizabeth , Wiggill Tracey
Published: October 2023

Breast cancer is the commonest cause of cancer-related mortality in African females where patients often present later and with advanced disease. Causes for delayed diagnosis include restricted diagnostic access and international controversy on interpretation of ancillary tests like immunohistochemistry (IHC). Fine needle aspirates (FNAC) are an attractive alternative although may have reduced sensitivity. The Xpert Breast Cancer STRAT4 (STRAT4) (CE-IVD*) assay (Cepheid, Sunnyvale) is a semi-quantitative reverse-transcription polymerase chain reaction assay which detects messenger RNA (mRNA) expression in breast samples for estrogen receptor (ESR1), progesterone receptor (PGR1), human epidermal growth factor receptor/Erb-B2 receptor tyrosine kinase 2 (HER2/ERBB2) and the proliferation marker, MKi67. We assessed the performance of this assay on both formalin-fixed paraffin-embedded (FFPE, n=31) and matched FNAC (n=20) samples from patients presenting with breast cancer to the Johannesburg academic hospitals. IHC and Fluorescent in situ hybridization analysis (performed on HER2-indeterminate samples) was compared with the mRNA expression of the corresponding target genes in FFPE samples, and mRNA expression on FNAC samples was compared with the FFPE results for both mRNA expression and IHC. Concordance between IHC/FISH and Xpert Breast Cancer STRAT4 in FFPE and FNAC samples using the Quick lysis (Q) method (a research-use-only modification of the validated FFPE-lysis method), showed an overall percentage agreement for ESR1 expression of 90.3% and 81.3%, and for PGR1 expression at 86.7% and 81.3% respectively in FFPE and FNAC samples. Concordance was lowest for Ki67 expression, using a binary IHC cutoff for Ki67 positivity at ≥20% staining) at 83.9% and 62.5%, for FFPE and FNAC samples, respectively. This suggests that the STRAT4 assay may be a useful ancillary test in determining HR and Ki67 status in FFPE samples and that use on FNAC samples may be feasible. Future studies should expand the sample numbers and establish locally relevant cutoffs.
Validation of an antigenic site targeted by monoclonal antibodies against Puumala virus
Authors: Plyusnin Alexander , Kedari Ashwini , Rissanen Ilona , Iheozor-Ejiofor Rommel Paneth , Lundkvist Åke , Vapalahti Olli , Levanov Lev
Published: October 2023

Identification of B-cell epitopes facilitates the development of vaccines, therapeutic antibodies and diagnostic tools. Previously, the binding site of the bank vole monoclonal antibody (mAb) 4G2 against Puumala virus (PUUV, an orthohantavirus in the Hantaviridae family of the Bunyavirales order) was predicted using a combination of methods, including pepscan, phage-display, and site-directed mutagenesis of vesicular stomatitis virus (VSV) particles pseudotyped with Gn and Gc glycoproteins from PUUV. These techniques led to the identification of the neutralization escape mutation F915A. To our surprise, a recent crystal structure of PUUV Gc in complex with Fab 4G2 revealed that residue F915 is distal from epitope of mAb 4G2. To clarify this issue and explore potential explanations for the inconsistency, we designed a mutagenesis experiment to probe the 4G2 epitope, with three PUUV pseudoviruses carrying amino acid changes E725A, S944F, and S946F, located within the structure-based 4G2 epitope on the Gc. These amino acid changes were able to convey neutralization escape from 4G2, and S944F and S946F also conveyed escape from neutralization by human mAb 1C9. Furthermore, our mapping of all the known neutralization evasion sites from hantaviral Gcs onto PUUV Gc revealed that over 60 % of these sites reside within or close to the epitope of mAb 4G2, indicating that this region may represent a crucial area targeted by neutralizing antibodies against PUUV, and to a lesser extent, other hantaviruses. The identification of this site of vulnerability could guide the creation of subunit vaccines against PUUV and other hantaviruses in the future.
Method for Spatially Confined Stimulation by Retinal Scanning Displays: Are Blind Spots Really Blind?
Authors: Tavakoli Amir-Vala , Omata Takanobu , Imamura Teppei , Ogawa Ryo , Iwasaki Masanori , del Rio Salgado Jesus , Rossi Iyla , Hung Shao-Min , Wu Daw-An , Shimojo Shinsuke
Published: October 2023

Conventional displays, such as CRTs and LCDs, are commonly used to present and manipulate visual stimuli in many vision science studies. However, such displays pose difficulties when the goal is to constrain stimulation to specific retinal locations, so as to isolate their contribution to downstream effects. Scattered and refracted light can stimulate unintended areas, contaminating the outcomes. In this investigation, we evaluate a laser-based retinal scanning display for its ability to map and exclusively stimulate the retinal blind spot. This application stimulates melanopsin receptors inside the blind spot, separately from rod and cone photoreceptors, which lie outside the blind spot. This paper covers three experiments: 1. The initial exploratory observations; 2. the examination of pupillary responses, and; 3. the inference of implicit visual perception arising from the blind spot. We aimed to simultaneously validate our technical methods, while increasing our understanding of the role of melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) in vision and implicit visual perception.
Inflammatory Profiles Induced following Intranasal Vaccination with Ricin Toxin-Immune Complexes
Authors: Tolman Lindsey E. , Mantis Nicholas J.
Published: October 2023

Ricin toxin (RT), a ribosome-inactivating protein derived from castor beans (Ricinus communis), is lethal in extremely small doses via inhalation, due in part to pulmonary inflammation triggeredby the toxin. While no licensed countermeasures for RT exists, a myriad of toxin-neutralizing monoclonal antibodies (mAbs) against RT’s enzymatic (RTA) and binding (RTB) subunits have been described, including PB10 (anti-RTA) and SylH3 (anti-RTB). We recently demonstrated that a single administration of PB10 and SylH3 as an RT immune complex (RIC) to mice by the intranasal route functions as a potent immunogen, stimulating the rapid onset of high titer toxin-neutralizing antibodies that persist for months. In this report, we demonstrate that the de novo antibody response following RICs exposure is wholly dependent on CD4+T cell help, as treatment of mice with an anti-CD4 monoclonal antibody abrogated the onset of RT-specific antibodies. To investigate other immunological factors associated with RICs, we examined the early local and systemic inflammatory cytokine and chemokine responses associated with intranasal RT and RIC administration. We report that RICs stimulate an inflammatory profile in the bronchoalveolar lavage fluids (BALF) and serum similar to that elicited by RT itself, but markedly reduced in magnitude. Of the 32 analytes examined, the most pronounced were IL-6, KC (CXCL1), G-CSF, and GM-CSF. To evaluate the role of IL-6 in driving the de novo onset of RT antibodies, groups of mice were treated (or not) with an IL-6 neutralizing monoclonal antibody prior to intranasal RICs challenge. While the monoclonal antibody treatment successfully depleted circulating IL-6 to levels below detection, it had no impact on the kinetics or magnitude of RICs-induced RT-specific antibody response. Thus, our results suggest that other cytokines/chemokines triggered by RICs are involved in influencing long lasting durable antibody responses to RT.
Darwin’s Overlooked Radiation: genomic evidence points to the early stages of a radiation in the Galápagos prickly pear cactus (Opuntia,Cactaceae)
Authors: Zapata Felipe , Cerca José , McCarney Dana , Henriquez Claudia L. , Tiamiyu Bashir B. , McCormack John E. , Reckling Kelsey R. , Chaves Jaime A. , Rivas-Torres Gonzalo
Published: October 2023

The Galápagos Islands are a prime example of a natural laboratory for the study of evolutionary radiations. While much attention has been devoted to iconic species like Darwin’s finches1–4, the islands offer an equally unique but often overlooked opportunity for plant radiations5. Yet, compared to their animal counterparts, our understanding of the patterns and processes underpinning Galápagos plant radiations remains relatively limited6,7. We present evidence of the early stages of a radiation in prickly-pear cactus (Opuntia, Cactaceae), a plant lineage widespread across the archipelago. Phylogenomic and population genomic analyses show that notwithstanding overall low genetic differentiation across populations, there is marked geographic structure that is broadly consistent with current taxonomy and the dynamic paleogeography of the Galápagos. Because such low genetic differentiation stands in stark contrast to the exceptional eco-phenotypic diversity displayed by cacti across islands, it is plausible that phenotypic plasticity precedes genetic divergence and is the source of adaptive evolution, or that introgression between populations facilitates local adaptation. Models of population relationships including admixture indicate that gene flow is common between certain islands, likely facilitated by dispersal via animals known to feed onOpuntiaflowers, fruits, and seeds across the archipelago. Scans of genetic differentiation between populations reveal candidate loci associated with seed traits and environmental stressors, suggesting that a combination of biotic interactions and abiotic pressures due to the harsh conditions characterizing island life in a volcanic, equatorial archipelago may underlie the diversification of prickly-pear cacti. Considered in concert, these results are relevant to both the mechanisms of plant eco-phenotypic differentiation and the evolutionary history and conservation of the Galápagos biota.
FedGMMAT: Federated Generalized Linear Mixed Model Association Tests
Authors: Li Wentao , Chen Han , Jiang Xiaoqian , Harmanci Arif
Published: October 2023

Increasing genetic and phenotypic data size is critical for understanding the genetic determinants of diseases. Evidently, establishing practical means for collaboration and data sharing among institutions is a fundamental methodological barrier for performing high-powered studies. As the sample sizes become more heterogeneous, complex statistical approaches, such as generalized linear mixed effects models, must be used to correct for confounders that may bias results. On another front, due to the privacy concerns around Protected Health Information (PHI), genetic information is restrictively protected by sharing according to regulations such as Health Insurance Portability and Accountability Act (HIPAA). This limits data sharing among institutions and hampers efforts around executing high-powered collaborative studies. Federated approaches are promising to alleviate the issues around privacy and performance, since sensitive data never leaves the local sites.

Motivated by these, we developed FedGMMAT, a federated genetic association testing tool that utilizes a federated statistical testing approach for efficient association tests that can correct for arbitrary fixed and random effects among different collaborating sites. Genetic data is never shared among collaborating sites, and the intermediate statistics are protected by homomorphic encryption. Using simulated and real datasets, we demonstrate FedGMMAT can achieve the virtually same results as pooled analysis under a privacy-preserving framework with practical resource requirements.
Accurate prediction of protein tertiary structural changes induced by single-site mutations with equivariant graph neural networks
Authors: Mahmud Sajid , Morehead Alex , Cheng Jianlin
Published: October 2023

Predicting the change of protein tertiary structure caused by singlesite mutations is important for studying protein structure, function, and interaction. Even though computational protein structure prediction methods such as AlphaFold can predict the overall tertiary structures of most proteins rather accurately, they are not sensitive enough to accurately predict the structural changes induced by single-site amino acid mutations on proteins. Specialized mutation prediction methods mostly focus on predicting the overall stability or function changes caused by mutations without attempting to predict the exact mutation-induced structural changes, limiting their use in protein mutation study. In this work, we develop the first deep learning method based on equivariant graph neural networks (EGNN) to directly predict the tertiary structural changes caused by single-site mutations and the tertiary structure of any protein mutant from the structure of its wild-type counterpart. The results show that it performs substantially better in predicting the tertiary structures of protein mutants than the widely used protein structure prediction method AlphaFold.
Laminar architecture of visual responses in supplementary eye field of macaques
Authors: Thirunavukkarasu Pranavan , Errington Steven P. , Sajad Amirsaman , Schall Jeffrey D.
Published: October 2023

Previously, we have described the laminar organization of neurons in the supplementary eye field (SEF) that signal error, reward gain and loss, conflict, event timing, and goal maintenance. Here we describe the laminar organization of visually responsive neurons that were active during performance of a saccade stop-signal task. Nearly 40% of isolated neurons exhibited enhanced or suppressed responses to a visual target for a potential saccade, with the majority exhibiting enhanced activity and three-quarters with broad spikes. Visually responsive neurons were observed in all layers but were less common in layers 5 and 6. Response latencies were comparable to those reported previously, which are significantly later than those measured in occipital and temporal visual areas but overlapping those measured in cingulate cortex. Task-related visual response latency varied across cortical layers. Response latency was significantly earlier for neurons with narrow spikes. Neurons with task-related visual responses discharged until after saccade production. Around three-fifths of visually responsive neurons were most sensitive to the visual target appearing in one hemifield. Many neurons in layer 2 had ipsilateral receptive fields. Laminar current-source density aligned on visual target presentation revealed the earliest sink in layers 3 followed by a prolonged strong sink more superficially coupled with a weaker prolonged sink in layer 5 and a transient sink in layer 6. The current sink in layers 2 and 3 was stronger for ipsilateral stimuli. These findings reveal new details about visual processing in medial frontal cortex and complete the first catalogue of laminar organization of functional signals in a frontal lobe area.
Identifying key underlying regulatory networks and predicting targets of orphan C/D boxSNORD116snoRNAs in Prader-Willi syndrome
Authors: Gilmore Rachel B. , Liu Yaling , Stoddard Christopher E. , Chung Michael S. , Carmichael Gordon G. , Cotney Justin
Published: October 2023

Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder characterized principally by initial symptoms of neonatal hypotonia and failure-to-thrive in infancy, followed by hyperphagia and obesity. It is well established that PWS is caused by loss of paternal expression of the imprinted region on chromosome 15q11-q13. While most PWS cases exhibit megabase-scale deletions of the paternal chromosome 15q11-q13 allele, several PWS patients have been identified harboring a much smaller deletion encompassing primarilySNORD116. This finding suggestsSNORD116is a direct driver of PWS phenotypes. TheSNORD116gene cluster is composed of 30 copies of individualSNORD116C/D box small nucleolar RNAs (snoRNAs). Many C/D box snoRNAs have been shown to guide chemical modifications of other RNA molecules, often ribosomal RNA (rRNA). However,SNORD116snoRNAs are termed ‘orphans’ because no verified targets have been identified and their sequences show no significant complementarity to rRNA. It is crucial to identify the targets and functions ofSNORD116snoRNAs because all reported PWS cases lack their expression. To address this, we engineered two different deletions modelling PWS in two distinct human embryonic stem cell (hESC) lines to control for effects of genetic background. Utilizing an inducible expression system enabled quick, reproducible differentiation of these lines into neurons. Systematic comparisons of neuronal gene expression across deletion types and genetic backgrounds revealed a novel list of 42 consistently dysregulated genes. Employing the recently described computational tool snoGloBe, we discovered these dysregulated genes are significantly enriched for predictedSNORD116targeting versus multiple control analyses. Importantly, our results showed it is critical to use multiple isogenic cell line pairs, as this eliminated many spuriously differentially expressed genes. Our results indicate a novel gene regulatory network controlled bySNORD116is likely perturbed in PWS patients.
Rummagene: Mining Gene Sets from Supporting Materials of PMC Publications
Authors: Clarke Daniel J. B. , Marino Giacomo B. , Deng Eden Z. , Xie Zhuorui , Evangelista John Erol , Ma’ayan Avi
Published: October 2023

Every week thousands of biomedical research papers are published with a portion of them containing supporting tables with data about genes, transcripts, variants, and proteins. For example, supporting tables may contain differentially expressed genes and proteins from transcriptomics and proteomics assays, targets of transcription factors from ChIP-seq experiments, hits from genome-wide CRISPR screens, or genes identified to harbor mutations from GWAS studies. Because these gene sets are commonly buried in the supplemental tables of research publications, they are not widely available for search and reuse. Rummagene, available fromhttps://rummagene.com, is a web server application that provides access to hundreds of thousands human and mouse gene sets extracted from supporting materials of publications listed on PubMed Central (PMC). To create Rummagene, we first developed a softbot that extracts human and mouse gene sets from supporting tables of PMC publications. So far, the softbot has scanned 5,448,589 PMC articles to find 121,237 articles that contain 642,389 gene sets. These gene sets are served for enrichment analysis, free text, and table title search. Users of Rummagene can submit their own gene sets to find matching gene sets ranked by their overlap with the input gene set. In addition to providing the extracted gene sets for search, we investigated the massive corpus of these gene sets for statistical patterns. We show that the number of gene sets reported in publications is rapidly increasing, containing both short sets that are highly enriched in highly studied genes, and long sets from omics profiling. We also demonstrate that the gene sets in Rummagene can be used for transcription factor and kinase enrichment analyses, and for gene function predictions. By combining gene set similarity with abstract similarity, Rummagene can be used to find surprising relationships between unexpected biological processes, concepts, and named entities. Finally, by overlaying the Rummagene gene set space with the Enrichr gene set space we can discover areas of biological and biomedical knowledge unique to each resource.
Systematic Investigation of Machine Learning on Limited Data: A Study on Predicting Protein-Protein Binding Strength
Authors: Zheng Feifan , Jiang Xin , Wen Yuhao , Yang Yan , Li Minghui
Published: October 2023

The application of machine learning techniques in biological research, especially when dealing with limited data availability, poses significant challenges. In this study, we leveraged advancements in method development for predicting protein-protein binding strength to conduct a systematic investigation into the application of machine learning on limited data. The binding strength, quantitatively measured as binding affinity, is vital for understanding the processes of recognition, association, and dysfunction that occur within protein complexes. By incorporating transfer learning, integrating domain knowledge, and employing both deep learning and traditional machine learning algorithms, we mitigate the impact of data limitations and make significant advancements in predicting protein-protein binding affinity. In particular, we developed over 20 models, ultimately selecting three representative best-performing ones that belong to distinct categories. The first model is structure-based, consisting of a random forest regression and thirteen handcrafted features. The second model is sequence-based, employing an architecture that combines transferred embedding features with a multilayer perceptron. Finally, we created an ensemble model by averaging the predictions of the two aforementioned models. The comparison with other predictors on three independent datasets confirmed the significant improvements achieved by our models in predicting protein-protein binding affinity. The source codes for these three models are available athttps://github.com/minghuilab/BindPPI.
Automated evaluation of multiple sequence alignment methods to handle third generation sequencing errors
Authors: Rohmer Coralie , Touzet Hélène , Limasset Antoine
Published: October 2023

Most third-generation sequencing (TGS) processing tools rely on multiple sequence alignment (MSA) methods to manage sequencing errors. Despite the broad range of MSA approaches available, a limited selection of implementations are commonly used in practice for this type of application, and no comprehensive comparative assessment of existing tools has been under-taken to date. In this context, we have developed an automatic pipeline, named MSA_Limit, designed to facilitate the execution and evaluation of diverse MSA methods across a spectrum of conditions representative of TGS reads. MSA_Limit offers insights into alignment accuracy, time efficiency, and memory utilization. It serves as a valuable resource for both users and developers, aiding in the assessment of algorithmic performance and assisting users in selecting the most appropriate tool for their specific experimental settings. Through a series of experiments using real and simulated data, we demonstrate the value of such exploration. Our findings reveal that in certain scenarios, popular methods may not consistently exhibit optimal efficiency and that the choice of the most effective method varies depending on factors such as sequencing depth, genome characteristics, and read error patterns. MSA_Limit is open source is freely available atgitlab.cristal.univ-lille.fr/crohmer/msa-limitand all presented results and necessary information to reproduce the experiments are available atgitlab.cristal.univ-lille.fr/crohmer/msa-limit
Visual selectivity and motor role of action observation/execution neurons in macaque ventral premotor cortex
Authors: Sofie De Schrijver , Thomas Decramer , Peter Janssen
Published: October 2023

Neurons responding during action execution and action observation were discovered in the ventral premotor cortex three decades ago. However, neither the minimum visual features nor the motor involvement of Action Observation/Execution Neurons (AOENs) have been revealed at present. We investigated the minimal visual stimulus for activation and the involvement in motor behavior of AOENs in ventral premotor area F5c of four macaques. The large majority of AOENs showed highly phasic responses during the action videos, and also responded to an abstract shape moving towards but not interacting with an object, even when the shape moved on a scrambled background, implying that most AOENs in F5c do not require the perception of causality or a meaningful action. Additionally, electrical microstimulation of AOEN sites invariably elicited motor responses and frequently interfered with visually guided object grasping. Our findings suggest that an important role of F5c AOENs in visuomotor control during object grasping.