bluuebunny/crossref_metadata_2025 huggingface dataset:
STMO-12 Efforts for safe malignant brain tumor surgery at our hospital
Authors: Kobayashi Yusuke , Satou Yosuke , Kon Takashi , Tanioka Daisuke , Shimizu Katsuyoshi , Mizutani Tohru
Published: December 2021

Although maximal safe resection is the current standard for glioblastoma surgery, its safety and removal rate conflict with each other. Electrophysiological monitoring, such as motor evoked potential monitoring and awake craniotomy, can be utilized as safety measures; not all facilities can perform them. Herein, we present a representative case report on our efforts for a safe malignant brain tumor surgery.

Case: A 77-year-old woman with glioblastoma in the premotor cortex presented with seizure of the upper left lower limb. Her pyramidal tract ran from the medial bottom to the posterior of the tumor. We performed excision from the site using the lowest gamma entropy. We then removed all parts of the tumor, with the exception of the pyramidal tract infiltration, and no paralysis was observed. She was definitively diagnosed with glioblastoma and is currently on maintenance chemotherapy.

As a preoperative examination, we performed cerebrovascular angiography. We then performed various other tests to ascertain the patient’s condition. Considering lesions that affect language, Wada tests were performed regardless of laterality. For all patients with epilepsy onset, preoperative 256-channel electroencephalogram measurement and intraoperative the gamma entropy analysis were performed to confirm epileptogenicity. Considering lesions that affect eloquence, subdural electrodes were placed and brain function mapping was performed the next day. Based on the results, the safest cortical incision site and excision range were determined, and excision was performed on the following day.

Of the 14 operated glioblastoma cases after November 2018, more than 85% of the contrast-enhanced lesions were completely removed in 7 cases, partially removed in 5 cases, and underwent biopsy in 2 cases. Postoperative Karnofsky performance status scores remained unchanged in 11 cases, improved in 1 case, and deteriorated in 2 cases.

Our efforts have resulted in safe and sufficient removal of malignant brain tumors during surgery.
NI-12 The ratio of T1-Weighted to T2-Weighted Signal Intensity and IDH mutation in glioma
Authors: Sanada Takahiro , Yamamoto Shota , Sato Hirotaka , Sakai Mio , Saito Masato , Mitsui Nobuyuki , Hiroshima Satoru , Anei Ryogo , Kanemura Yonehiro , Nakanishi Katsuyuki , Kishima Haruhiko , Kinoshita Manabu
Published: December 2021

Introduction: Prediction of IDH mutation status for Lower-grade glioma (LrGG) is clinically significant. The purpose of this study is to test the hypothesis that the T1-weighted image/T2-weighted image ratio (rT1/T2), an imaging surrogate developed for myelin integrity, is a useful MRI biomarker for predicting the IDH mutation status of LrGG.

Methods: Twenty-five LrGG patients (IDHwt: 8, IDHmt: 17) at Asahikawa Medical University Hospital (AMUH) were used as an exploratory cohort. Twenty-nine LrGG patients (IDHwt: 13, IDHmt: 16) from Osaka International Cancer Institute (OICI) and 103 patients from the Cancer Imaging Archive (TCIA) / Cancer Genome Atlas (TCGA) dataset (IDHwt: 19, IDHmt: 84) were used as validation cohorts. rT1/T2 images were calculated from T1- and T2-weighted images using a recommended signal correction. The region-of-interest was defined on T2-weighted images, and the relationship between the mean rT1/T2 (mrT1/T2) and the IDH mutation status was investigated.

Results: The mrT1/T2 was able to significantly predict the IDH mutation status for the AMUH exploratory cohort (AUC = 0.75, p = 0.048). The ideal cut-off for detecting mutant IDH was mrT1/T2 < 0.666 ~ 0.677, with a sensitivity of 58.8% and a specificity of 87.5%. This result was further validated by the OICI validation cohort (AUC = 0.75, p = 0.023) with a sensitivity of 56.3% and a specificity of 69.2%. On the other hand, the sensitivity was 42.9% and the specificity was 68.4 % for the TCIA validation cohort (AUC = 0.63, p = 0.068).

Conclusion: Our results supported the hypothesis that mrT1/T2 could be a useful image surrogate to predict the IDH mutation status of LrGG using two domestic cohorts. The decline of the accuracy for the TCIA cohort should be further investigated.
NI-14 estimation of property of MRI non-contrast enhanced lesion of Glioblastoma using T1/T2 ratio
Authors: Yamamoto Shota , Sanada Takahiro , Sakai Mio , Arisawa Atsuko , Shimosegawa Eku , Nakanishi Katsuyuki , Kanemura Yonehiro , Kagawa Naoki , Kishima Haruhiko , Kinoshita Manabu
Published: December 2021

Background: Tumor mass of glioblastoma is considered to exist beyond gadolinium-enhancing lesion into T2/FLAIR-high intensity lesions (T2/FL-HIL) on MRI. However, it is challenging to differentiate non-enhancing tumor region (NET) from pure brain edema for T2/FL-HIL. The T1/T2 ratio (rT1/T2) is an MRI metric considered to semi-quantify the tissue relaxation time on MRI. This research tested the hypothesis that rT1/T2 is useful for identifying NET within T2/FL-HIL by comparing it with 11C-methionine positron emission tomography (MET-PET). Method: Forty-six glioblastoma (GBM) patients at Osaka International Cancer Institute and Osaka University Hospital where T1-, T2- and contrast-enhanced T1-weighted MRI and MET-PET were available were included in this study. rT1/T2 maps were obtained after signal corrections were performed, as reported previously. Region-of-interests (ROIs) were defined within T2/FL-HILs beyond the gadolinium-enhanced lesion. MET-PET and rT1/T2 maps were co-registered to the same coordinate system, and the relationship between methionine uptake and rT1/T2 values was examined in a voxel-wise manner.ResultApproximately three million voxels were included for analysis. Lesions with methionine uptake higher than 5.0 on T/N showed 0.7 < rT1/T2 < 0.98. For those with methionine uptake higher than 3.0, rT1/T2 was between 0.70 and 1.04.DiscussionThis report suggested that rT1/T2 represents histological characteristics of the glioblastoma within T2/FL-HIL. It also indicated that rT1/T2 could be a useful biomarker for detecting NET within T2/FL-HIL for glioblastoma.
NI-19 A case of Leber’s hereditary optic neuropathy with diffuse white matter changes mimicking gliomatosis cerebri
Authors: Saruta Wakiko , Shibahara Ichiyo , Inukai Madoka , Kanayama Shunsuke , Akiyama Hisanao , Ishikawa Hitoshi , Sato Sumito , Hide Takuichiro , Kumabe Toshihiro
Published: December 2021

BACKGROUND: Leber’s hereditary optic neuropathy (LHON) is a mitochondrial disease characterized by bilateral severe subacute central vision loss and a mutation in the mitochondrial DNA (mtDNA). The cranial magnetic resonance imaging (MRI) of LHON patients varies from subtle to multiple white matter changes. However, they rarely present with diffuse infiltrative white matter changes. CASE REPORT: We report a case with diffuse white matter changes mimicking gliomatosis cerebri (GC). The histological findings included only mild glial hyperplasia without immunohistochemical positivity supporting the diagnosis of glial tumors. Analysis of mtDNA obtained from the blood and brain tissue revealed mutation of m.11778G>A in the NADH dehydrogenase 4 gene, which confirmed the case as LHON. Immunohistochemistry of the brain tissue revealed 8-hydroxy-2’-deoxyguanosine positivity, suggesting the presence of oxidative stress. CONCLUSION: LHON is extremely difficult to diagnose unless we suspect or know the disease. The present case brings attention not only to LHON but other mtDNA mutated diseases that need to be considered with diffuse white matter changes or GC.
ML-3 A Case of Primary Central Nervous System Anaplastic Lymphoma Kinase Positive Anaplastic Large cell Lymphoma at Neurohypophysis and Pineal Gland
Authors: Kohno Shohei , Omae Ryo , Shinko Aiko , Takahashi Kazuya
Published: December 2021

The majority of primary central nerve system (CNS) lymphomas (PCNSL) are diffuse large B-cell lymphomas. Anaplastic large cell lymphoma (ALCL) that is a type of T-cell tumor is very rare in the PCNSL. ALCLs are divided into two entities: anaplastic lymphoma kinase (ALK)-positive and ALK-negative. We report a case of a 26-year-old woman who presented with a one month historyof headache and nausea. Magnetic resonance imaging (MRI) of the brain revealed pituitary and pineal gland mass diagnosed as ALK-positive ALCL by endoscopic brain biopsy. She underwent chemotherapy following methotrexate (MTX) and cyclophosphamide + doxorubicin + vincristine + prednisolone (CHOP). The follow-up contrast-enhanced brain MRI showed no recurrent lesion after chemotherapy. In previous reports, most of the lesions were in cerebral hemisphere, dura mater and spinal cord. Many of these patients were given primary diagnoses of meningitis. To our knowledge, there is no case report of initial diagnosis of germinoma due to lesions in Neurohypophysis and pineal gland as in this case.
ML-16 First clinical experience of administration of Tirabrutinib for the patients with newly diagnosed primary central nervous system lymphoma
Authors: Onodera Sho , Akimoto Jiro
Published: December 2021

Tirabrutinib (TIR), a Burton’s tyrosine kinase inhibitory drug, has been approved in Japan for treating relapsed/refractory primary central nervous system lymphoma (PCNSL). The authors recently encountered three patients with newly diagnosed refractory PCNSL using TIR.

Three patients, 48, 78 and 88 years-old males, diagnosed with PCNSL by histologically verification were firstly treated with high dose Methotrexate based chemotherapy (HD-MTX) and/or radiotherapy, however these cases were refractory for these standard treatments, demonstrated early cerebrospinal fluid dissemination or accompanied with severe adverse event. The authors decided to administrate TIR to these patients with a full informed consent. TIR demonstrated dramatic reduction of the volume of tumor on MRI within one month after administration of TIR, and improved the patient’s performance status. However, one case demonstrated liver dysfunction and multiple brain abscess due to aspergillus infection, and one case demonstrated early progression of the tumor 49 days after starting TIR.

Administration of TIR for the patients with newly diagnosed refractory PCNSL demonstrated a rapid and dramatic clinical response, and presented with several clinical implications for this complicated condition.
CS-6 A case of poorly differentiated chordoma with systemic metastasis
Authors: Shinojima Naoki , Harada Keisuke , Dekita Yuji , Yamamoto Haruaki , Itouyama Mai , Mikami Yoshiki , Mukasa Akitake
Published: December 2021

A case report: The patient was a 32-year-old man with diplopia. He was diagnosed as sphenoid sinusitis on MRI by a local doctor and visited an otolaryngologist. MRI showed extensive extension of neoplastic lesions from the clivus to the sphenoid sinus to the anterior ethmoid sinuses, bilateral cavernous sinuses, and the right medial and lateral pterygoid muscles. The right Lebiere’s lymph node was enlarged and thought to be a metastatic site. Based on the rapid growth and extension of the tumor, the patient was referred to the Department of Otolaryngology at our hospital on suspicion of sinonasal carcinoma. The possibility of chordoma could not be denied, so the patient was referred to our department. The patient underwent a joint endoscopic extended transsphenoidal tumor resection. The pathological diagnosis showed mitotic and necrotic features, and the majority of the cells showed highly atypical components without mucous substrate. However, brachyury, a marker for chordoma, was diffusely positive, and there was loss of INI1 (SMARCB1) expression. The final diagnosis was poorly differentiated chordoma. Postoperatively, the tumor in the right cavernous sinus grew rapidly, and the right eye became blind due to obstruction of the superior ophthalmic vein. The patient was treated with Gamma Knife as soon as possible in the hope of local control by high-dose irradiation, and after a total of three irradiations, the residual tumor shrank markedly and symptoms improved, but systemic metastasis occurred in a short period of time and the patient died. The number of cases of poorly differentiated chordoma has been reported rarely (more than 50), and it is more common in children and even rarer in adults. We report this case with a review of the literature.
COT-9 Prognostic impact of hypercoagulation in glioblastoma and molecular mechanism thereof
Authors: Negoto Tetsuya , Komaki Satoru , Moritsubo Mayuko , Furuta Takuya , Nakamura Hideo , Morioka Motohiro
Published: December 2021

Introduction: Pathological features of glioblastoma include intravascular thrombosis, suggesting that the thrombus formation in tumor microenvironment contributes to progression of gliomas. Meanwhile, glioblastoma has been known to be high risk malignant tumor for venous thromboembolism, however, it remains unclear how the coagulation-fibrinolysis system is disrupted, which essentially grow within the cranium in a localized manner, and how the disruption contributes to the malignant transformation.

Methods: Total 64 patients with glioblastoma between January 2014 and April 2021 who underwent a D-dimer test before the therapeutic intervention were divided into two groups: the high D-dimer group (D-dimer level >3.0μg/ml) and the low D-dimer group (D-dimer level <3.0μg/ml). We compared the two groups in the maximum gadolinium-enhanced MRI lesions, MIB-1 index, and gene abnormalities (IDH mutation, TERT promoter mutation, and MGMT promotor methylation). The progression-free survival (PFS) and overall survival were analyzed using the Kaplan-Meier method. Furthermore, in 23 patients who underwent a D-dimer test at recurrence, the time to death after recurrence was analyzed.

Results: The PFS in high D-dimer group was significantly shorter than that in the low D-dimer group (log-rank p = 0.0075). The D-dimer increase at the time of recurrence significantly correlated with the decrease in post-recurrence survival duration (log-rank p = 0.0226). Moreover, the gadolinium-enhanced lesions in the high D-dimer group were significantly larger.

Conclusion: The Pre-intervention D-dimer levels and PFS suggest that glioblastoma-induced systemic enhancement of the coagulation-fibrinolysis system plays a role in the malignant transformation. The D-dimer increase during the treatment was found to be a predictor of poor prognosis after recurrence. Furthermore, the MRI findings revealed a correlation between the D-dimer increase and the size of intratumoral necrosis. Meanwhile, no correlation with the MIB-1 index was found, suggesting that the mechanism of malignant transformation by hypercoagulation differ from enhanced cell proliferation.
Qurliqnoria (Mammalia: Bovidae) fossils from Qaidam Basin, Tibetan Plateau and deep-time endemism of the Tibetan antelope lineage
Authors: Tseng Z Jack , Wang Xiaoming , Li Qiang , Xie Guangpu
Published: December 2021

The Tibetan antelope (Pantholops hodgsonii) is an endemic bovid of the Tibetan Plateau, which was, until recently, considered an endangered species. Researchers have long speculated on the evolutionary origin of Pantholops, suggesting a connection to the rare fossil bovid Qurliqnoria. However, the lack of adequate fossil samples has prevented the testing of this deep-time endemism hypothesis for eight decades. Here, we report new fossils of Qurliqnoria cheni from the northern Tibetan Plateau, substantially increasing the amount of morphological data that can be brought to bear on the question of Tibetan antelope evolution. Phylogenetic analysis supports a Pantholops–Qurliqnoria clade and suggests that this lineage has been endemic to the Plateau for 11 Myr. Recent morphological and molecular studies that support the outgroup position of Pantholops relative to caprins (goats and relatives) and the fossil record of stem bovids from Europe together suggest that the Qurliqnoria–Pantholops lineage is likely to have dispersed to the Tibetan Plateau 15–11 Mya. Furthermore, the harsh environmental conditions to which Pantholops has adapted are likely to extend back to the time of its evolutionary origin. These findings provide an important new context for conservation management and research into the near-threatened Tibetan antelope, as the longest-living endemic member of the Tibetan Plateau fauna.
Genome-scale molecular and phylogenetic characterization of Middle Point orbiviruses from Australia
Authors: Agnihotri Kalpana , Oakey Jane , Smith Craig , Weir Richard , Pyke Alyssa , Melville Lorna
Published: December 2021

Middle Point orbivirus (MPOV) is an Australian arbovirus, belongs to the Yunnan orbivirus species found in China. First detected and reported from Beatrice Hill, Northern Territory (NT), MPOV has to date, only been exclusively reported from the NT, Australia. Whilst genetic characterization of MPOV has been previously described, only restricted to sequence information for segments 2 and 3 coding core protein VP2 and outer capsid protein VP3, respectively. This study presents for the first time nearly full-length genome sequences of MPOV, which represent 24 isolates collected over a span of more than 20 years from 1997 to 2018. Whilst the majority of isolates were sampled at Beatrice Hill, NT where MPOV is most frequently isolated, this report also describes the first two isolations of MPOV from Queensland (QLD), Australia. One of which is the first non-bovine isolate obtained from the mosquito vector Aedes vittiger. We further compared these MPOV sequences with known sequences of the Yunnan orbivirus and other known orbivirus sequences of mosquito origin found in Australia. The phylogenetic analyses indicate the Australian MPOV sequences are more closely related to each other than other known sequences of Yunnan orbivirus. Furthermore, MPOV sequences are closely related to sequences from the Indonesian isolate JKT-8650. The clustering of Australian sequences in the phylogenetic tree suggests the monophyletic lineage of MPOV circulating in Australia. Further, ongoing surveillance is required to assess the existence and prevalence of this or other yet undetected lineages of MPOV and other orbiviruses in Australia.
Prevalence of genotypic antimicrobial resistance in clinical Shiga toxin-producing Escherichia coli in Norway, 2018 to 2020
Authors: Ramstad Silje N. , Brandal Lin T. , Taxt Arne M. , Wasteson Yngvild , Bjørnholt Jørgen V. , Naseer Umaer
Published: December 2021

Introduction. Shiga toxin-producing

Escherichia coli

(STEC) can cause severe to fatal disease in humans. Antimicrobial treatment is sometimes necessary, but contraindicated due to undesirable clinical outcome. However, recent studies have shown promising outcomes following antimicrobial treatment. Before the establishment of a possible antimicrobial treatment strategy for STEC infections, the prevalence of antimicrobial resistance in STEC needs to be determined.

Gap Statement. The resistance status of Norwegian clinical STEC is not known and should be assessed.

Aim. We aim to characterize genotypic antimicrobial resistance determinants in clinical STEC in Norway, and determine the prevalence of genotypic resistance in order to inform possible antimicrobial treatment options for STEC infections.

Methodology. We included all clinical STEC submitted to the Norwegian Reference Laboratory from March 2018 to April 2020. All samples were whole-genome sequenced and screened for genotypic antimicrobial resistance,virulence determinants and plasmid incompatibility groups. We performed phylogenetic clustering of STEC by core-genome multi-locus sequence typing, and statistical association analyses between isolate characteristics and genotypic resistance.

Results. A total of 459 STEC were analysed. For 385 (83.9 %) STEC we did not identify any antimicrobial resistance determinants. Seventy-four STEC (16.1 %) harboured antimicrobial resistance determinants against one or more antimicrobial classes. The most frequent genotypic resistance was identified against aminoglycosides (10.5 %). Thirty-nine STEC (8.5 %) had a multi-drug resistance (MDR) genotype. Genotypic resistance was more prevalent in non-O157 than O157 STEC (P=0.02). A positive association was seen between genotypic resistance and the low-virulent STEC O117:H7 phylogenetic cluster (no. 14) (P<0.001). Genotypic resistance was not significantly associated to high-virulent STEC. STEC O146:H28 and isolates harbouring the plasmid replicon type IncQ1 were positively associated with MDR.

Conclusion. The overall prevalence of genotypic resistance in clinical STEC in Norway is low (16.1 %). Genotypic resistance is more prevalent in non-O157 strains compared to O157 strains, and not significantly associated to high-virulent STEC. Resistance to antimicrobials suggested for treatment, especially azithromycin is low and may present an empiric treatment alternative for severe STEC infections.
Cerebrovascular insulin receptors are defective in Alzheimerˈs disease
Authors: Leclerc M. , Bourassa P. , Tremblay C. , Caron V. , Sugère C. , Emond V. , Bennett D.A. , Calon F.
Published: December 2021

Central response to insulin is suspected to be defective in Alzheimer’s disease (AD), but its localization in the brain remains unknown. While most insulin is secreted in the bloodstream by the pancreas, how it interacts with the blood-brain barrier (BBB) to alter brain function remains poorly defined.

Here, we show that human and murine cerebral insulin receptors (INSR), particularly the long isoform INSRα-B, are concentrated in microvessels rather than in the parenchyma. Vascular concentrations of INSRα-B were lower in the parietal cortex of subjects diagnosed with AD, positively correlating with cognitive scores, leading to a shift toward a higher INSRα-A/B ratio, consistent with cerebrovascular insulin resistance in the AD brain. Vascular INSRα was inversely correlated with β-amyloid (Aβ) plaques and β-site APP cleaving enzyme 1 (BACE1), but positively correlated with insulin-degrading enzyme (IDE), neprilysin and ABCB1. Using brain cerebral intracarotid perfusion, we found that the transport rate of insulin across the BBB remained very low (<0.03 µl.g-1.s-1) and was not inhibited by an INSR antagonist. However, intracarotid perfusion of insulin induced the phosphorylation of INSRβ which was restricted to microvessels. Such an activation of vascular INSR was blunted in 3xTg-AD mice, suggesting that AD neuropathology induces insulin resistance at the level of the BBB.

Overall, the present data in postmortem AD brains and an animal model of AD indicate that defects in the INSR localized at the BBB strongly contribute to brain insulin resistance in AD, in association with Aβ pathology.

Highlights

Circulating insulin activates brain insulin receptors in microvessels.

BBB INSR contribute to cerebral insulin resistance in AD.

Cognitive impairment in AD is associated with a loss of cerebrovascular INSRα-B.

Loss of isoform INSRα-B is associated with increased BACE1 activity.

Leclerc et al. show that circulating insulin activates cerebral insulin receptor localized on the blood-brain-barrier level (BBB), not in the parenchyma. Experiments with human brain samples and animal models provide evidence that INSR at the BBB are impaired in Alzheimer’s disease, thereby contributing to brain insulin resistance.
Tadr Is an Axonal Histidine Transporter Required for Visual Neurotransmission in Drosophila
Authors: Han Yongchao , Peng Lei , Wang Tao
Published: December 2021

Neurotransmitters are generated by de novo synthesis and are essential for sustained, high-frequency synaptic transmission. Histamine, a monoamine neurotransmitter, is synthesized through decarboxylation of histidine by Histidine decarboxylase (Hdc). However, little is known about how histidine is presented to Hdc as a precursor. Here, we identified a specific histidine transporter, TADR (Torn And Diminished Rhabdomeres), that is required for visual transmission in Drosophila. TADR and Hdc co-localized to neuronal terminals, and mutations in tadr reduced levels of histamine, thus disrupting visual synaptic transmission and phototaxis behavior. These results demonstrate that a specific amino acid transporter provides precursors for monoamine neurotransmitters, providing the first genetic evidence that a histidine amino acid transporter plays a critical role in synaptic transmission. These results suggest that TADR-dependent local de novo synthesis of histamine is required for synaptic transmission.
Tibial nerve stimulation increases vaginal blood perfusion and bone mineral density and yield load in ovariectomized rat menopause model
Authors: Xu Jiajie Jessica , Zimmerman Lauren L. , Soriano Vanessa , Mentzelopoulos Georgios , Kennedy Eric , Bottorff Elizabeth C. , Stephan Chris , Kozloff Kenneth , Devlin Maureen J. , Bruns Tim M.
Published: December 2021

Introduction and Hypothesis

Human menopause transition and post-menopausal syndrome, driven by reduced ovarian activity and estrogen levels, are associated with an increased risk for symptoms including but not limited to sexual dysfunction, metabolic disease, and osteoporosis. Current treatments are limited in efficacy and may have adverse consequences, so investigation for additional treatment options is necessary. Previous studies have demonstrated that tibial nerve stimulation (TNS) or electro-acupuncture near the tibial nerve are minimally invasive treatments that increase vaginal blood perfusion or serum estrogen in the rat model. We hypothesized that TNS would protect against harmful reproductive and systemic changes associated with menopause.

Methods

We examined the effects of twice weekly TNS (0.2 ms pulse width, 20 Hz, 2x motor threshold) under ketamine-xylazine anesthesia in ovariectomized (OVX) female Sprague Dawley rats on menopause-associated physiological parameters including serum estradiol, body weight, blood glucose, bone health, and vaginal blood flow. Rats were split into three groups (n = 10 per group): 1) intact control (no stimulation), 2) OVX control (no stimulation), and 3) OVX stimulation (treatment group).

Results

TNS did not affect serum estradiol levels, body weight, or blood glucose. TNS transiently increased vaginal blood perfusion during stimulation for up to 5 weeks after OVX and increased areal bone mineral density and yield load of the right femur (side of stimulation) compared to the unstimulated OVX control.

Conclusion

TNS may ameliorate some symptoms associated with menopause. Additional studies to elucidate the full potential of TNS on menopause-associated symptoms under different experimental conditions are warranted.

Percutaneous tibial nerve stimulation increases vaginal blood perfusion, areal bone mineral density, and femur yield load in an ovariectomized rat model of menopause.
A Computational Model of Stereoscopic Prey Capture in Praying Mantises”
Authors: O’Keeffe James , Nityananda Vivek , Read Jenny
Published: December 2021

We present a simple model which can account for the stereoscopic sensitivity of praying mantis predatory strikes. The model consists of a single “disparity sensor”: a binocular neuron sensitive to stereoscopic disparity and thus to distance from the animal. The model is based closely on the known behavioural and neurophysiological properties of mantis stereopsis. The monocular inputs to the neuron reflect temporal change and are insensitive to contrast sign, making the sensor insensitive to interocular correlation. The monocular receptive fields have a excitatory centre and inhibitory surround, making them tuned to size. The disparity sensor combines inputs from the two eyes linearly, applies a threshold and then an exponent output nonlinearity. The activity of the sensor represents the model mantis’s instantaneous probability of striking. We integrate this over the stimulus duration to obtain the expected number of strikes in response to moving targets with different stereoscopic distance, size and vertical disparity. We optimised the parameters of the model so as to bring its predictions into agreement with our empirical data on mean strike rate as a function of stimulus size and distance. The model proves capable of reproducing the relatively broad tuning to size and narrow tuning to stereoscopic distance seen in mantis striking behaviour. The model also displays realistic responses to vertical disparity. Most surprisingly, although the model has only a single centre-surround receptive field in each eye, it displays qualitatively the same interaction between size and distance as we observed in real mantids: the preferred size increases as prey distance increases beyond the preferred distance. We show that this occurs because of a stereoscopic “false match” between the leading edge of the stimulus in one eye and its trailing edge in the other; further work will be required to find whether such false matches occur in real mantises. This is the first image-computable model of insect stereopsis, and reproduces key features of both neurophysiology and striking behaviour.
Treatment of Recurrent Glioblastoma by Chronic Convection-Enhanced Delivery of Topotecan
Authors: Spinazzi Eleonora F. , Argenziano Michael G. , Upadhyayula Pavan S. , Banu Matei A. , Neira Justin A. , Higgins Dominique M.O. , Wu Peter B. , Pereira Brianna , Mahajan Aayushi , Humala Nelson , Al-Dalahmah Osama , Zhao Wenting , Save Akshay V. , Boyett Deborah M. , Marie Tamara , Furnari Julia L , Sudhakar Tejaswi D. , Stopka Sylwia A. , Regan Michael S. , Catania Vanessa , Good Laura , Behl Meenu , Jambawalikar Sachin , Mintz Akiva , Lignelli Angela , Agar Nathalie Y.R. , Sims Peter A. , Welch Mary , Lassman Andrew , Iwamoto Fabio , D’Amico Randy S. , Grinband Jack , Canoll Peter , Bruce Jeffrey N.
Published: December 2021

Glioblastoma, the most common primary brain malignancy, is invariably fatal. Systemic chemotherapy is ineffective mostly because of drug delivery limitations. To overcome this, we devised an internalized pump-catheter system for direct chronic convection-enhanced delivery (CED) into peritumoral brain tissue. Topotecan (TPT) by chronic CED in 5 patients with refractory glioblastoma selectively eliminated tumor cells without toxicity to normal brain. Large, stable drug distribution volumes were non-invasively monitored with MRI of co-infused gadolinium. Analysis of multiple radiographically localized biopsies taken before and after treatment showed a decreased proliferative tumor signature resulting in a shift to a slow-cycling mesenchymal/astrocytic-like population. Tumor microenvironment analysis showed an inflammatory response and preservation of neurons. This novel drug delivery strategy and innovative clinical trial paradigm overcomes current limitations in delivery and treatment response assessment as shown here for glioblastoma and is potentially applicable for other anti-glioma agents as well as other CNS diseases.
The p53 transactivation domain 1-dependent response to acute DNA damage in endothelial cells protects against radiation-induced cardiac injury
Authors: Kuo Hsuan-Cheng , Luo Lixia , Ma Yan , Williams Nerissa T. , da Silva Campos Lorraine , Attardi Laura D. , Lee Chang-Lung , Kirsch David G.
Published: December 2021

Thoracic radiation therapy can cause endothelial injury in the heart, leading to cardiac dysfunction and heart failure. Although it has been demonstrated that the tumor suppressor p53 functions in endothelial cells to prevent the development of radiation-induced myocardial injury, the key mechanism(s) by which p53 regulates the radiosensitivity of cardiac endothelial cells is not completely understood. Here, we utilized genetically engineered mice that express mutations in p53 transactivation domain 1 (TAD1) (p5325,26) or mutations in p53 TAD1 and TAD2 (p5325,26,53,54) specifically in endothelial cells to study the p53 transcriptional program that protects cardiac endothelial cells from ionizing radiation in vivo. p5325,26,53,54 loses the ability to drive transactivation of p53 target genes after irradiation while p5325,26 can induce transcription of a group of non-canonical p53 target genes, but not the majority of classic radiation-induced p53 targets critical for p53-mediated cell cycle arrest and apoptosis. After 12 Gy whole-heart irradiation, we found that both p5325,26 and p5325,26,53,54 sensitized mice to radiation-induced cardiac injury, in contrast to wild-type p53. Histopathological examination suggested that mutation of TAD1 contributes to myocardial necrosis after whole-heart irradiation, while mutation of both TAD1 and TAD2 abolishes the ability of p53 to prevent radiation-induced heart disease. Taken together, our results show that the transcriptional program downstream of p53 TAD1, which activates the acute DNA damage response after irradiation, is necessary to protect cardiac endothelial cells from radiation injury in vivo.
HLAncPred: A method for predicting promiscuous non-classical HLA binding sites
Authors: Dhall Anjali , Patiyal Sumeet , Raghava Gajendra P. S.
Published: December 2021

In the last two decades, ample of methods have been developed to predict the classical HLA binders in an antigen. In contrast, limited attempts have been made to develop methods for predicting binders for non-classical HLA; due to the scarcity of sufficient experimental data and lack of community interest. Of Note, non-classical HLA plays a crucial immunomodulatory role and regulates various immune responses. Recent studies revealed that non-classical HLA (HLA-E & HLA-G) based immunotherapies have many advantages over classical HLA based-immunotherapy, particularly against COVID-19. In order to facilitate the scientific community, we have developed an artificial intelligence-based method for predicting binders of non-classical HLA alleles (HLA-G and HLA-E). All the models were trained and tested on experimentally validated data obtained from the recent release of IEDB. The machine learning based-models achieved more than 0.98 AUC for HLA-G alleles on validation or independent dataset. Similarly, our models achieved the highest AUC of 0.96 and 0.88 on the validation dataset for HLA-E*01:01, HLA-E*01:03, respectively. We have summarized the models developed in the past for non-classical HLA binders and compared with the models developed in this study. Moreover, we have also predicted the non-classical HLA binders in the spike protein of different variants of virus causing COVID-19 including omicron (B.1.1.529) to facilitate the community. One of the major challenges in the field of immunotherapy is to identify the promiscuous binders or antigenic regions that can bind to a large number of HLA alleles. In order to predict the promiscuous binders for the non-classical HLA alleles, we developed a web server HLAncPred (https://webs.iiitd.edu.in/raghava/hlancpred), and a standalone package.

Key Points

Non-classical HLAs play immunomodulatory roles in the immune system.

HLA-E restricted T-cell therapy may reduce COVID-19 associated cytokine storm.

In silico models developed for predicting binders for HLA-G and HLA-E.

Identification of non-classical HLA binders in strains of coronavirus

A webserver for predicting promiscuous binders for non-classical HLA alleles

Author’s Biography

Anjali Dhall is currently working as Ph.D. in Bioinformatics from Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi, India.

Sumeet Patiyal is currently working as Ph.D. in Bioinformatics from Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi, India.

Gajendra P. S. Raghava is currently working as Professor and Head of Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi, India.
Effects of stimulus pulse rate on somatosensory adaptation in the human cortex
Authors: Hughes Christopher L , Flesher Sharlene N , Gaunt Robert A
Published: December 2021

Background

Intracortical microstimulation (ICMS) of the somatosensory cortex can restore sensation to people with neurological diseases. However, many aspects of ICMS are poorly understood, including the effect of continuous stimulation on percept intensity over time.

Objective

Here, we evaluate how tactile percepts, evoked by ICMS in the somatosensory cortex of a human participant adapt over time.

Methods

We delivered continuous and intermittent ICMS to the somatosensory cortex and assessed the reported intensity of tactile percepts over time in a human participant. Experiments were conducted across approximately one year and linear mixed effects models were used to assess significance.

Results

Continuous stimulation at high frequencies led to rapid decreases in intensity, while low frequency stimulation maintained percept intensity for longer periods. Burst-modulated stimulation extended the time before the intensity began to decrease, but all protocols ultimately resulted in complete sensation loss within one minute. Intermittent stimulation paradigms with several seconds between stimulus trains also led to decreases in intensity on many electrodes, but never resulted in extinction of sensation after over three minutes of stimulation. Additionally, longer breaks between each pulse train resulted in some recovery of the stimulus-evoked percepts. For several electrodes, intermittent stimulation had almost no effect on the perceived intensity.

Conclusions

Intermittent ICMS paradigms were more effective at maintaining percepts, and given that transient activity in the somatosensory cortex dominates the response to object contact, this stimulation method may mimic natural cortical activity and improve the perception of stimulation over time.
Axial Stress Provides a Lower Bound on Shear Wave Velocity in Active and Passive Muscle
Authors: Bernabei Michel , Lee Sabrina S. M. , Perreault Eric J. , Sandercock Thomas G.
Published: December 2021

Ultrasound shear wave elastography can be used to characterize mechanical properties of unstressed tissue by measuring shear wave velocity (SWV), which increases with increasing tissue stiffness. Measurements of SWV have often been assumed to be directly related to the stiffness of muscle. Some have also used measures of SWV to estimate stress, since muscle stiffness and stress covary during active contractions. However, few have considered the direct influence of muscle stress on SWV, independent of the stress-dependent changes in muscle stiffness, even though it is well known that stress alters shear wave propagation. The objective of this study was to determine how well the theoretical dependency of SWV on stress can account for measured changes of SWV in passive and active muscle. Data were collected from six isoflurane-anesthetized cats; three soleus muscles and three medial gastrocnemius muscles. Muscle stress and stiffness were measured directly along with SWV. Measurements were made across a range of passively and actively generated stresses, obtained by varying muscle length and activation, which was controlled by stimulating the sciatic nerve. Our results show that SWV depends primarily on the stress in a passively stretched muscle. In contrast, the SWV in active muscle is higher than would be predicted by considering only stress, presumably due to activation-dependent changes in muscle stiffness. Our results demonstrate that while SWV is sensitive to changes in muscle stress and activation, there is not a unique relationship between SWV and either of these quantities when considered in isolation.
Evaluating the role of coevolution in a horizontally transmitted mutualism
Authors: Stoy Kayla , Chavez Joselyne , De Las Casas Valeria , Talla Venkat , Berasategui Aileen , Morran Levi , Gerardo Nicole
Published: December 2021

Mutualism depends on the alignment of host and symbiont fitness. Horizontal transmission can readily decouple fitness interests, yet horizontally transmitted mutualisms are common in nature. We hypothesized that pairwise coevolution and specialization in host-symbiont interactions underlies the maintenance of cooperation in a horizontally transmitted mutualism. Alternatively, we predicted selection by multiple host species may select for cooperative traits in a generalist symbiont through diffuse coevolution. We tested for signatures of pairwise coevolutionary change between the squash bug Anasa tristis and its horizontally acquired bacterial symbiont Caballeronia spp. by measuring local adaptation. We found no evidence for local adaptation between sympatric combinations of A. tristis squash bugs and Caballeronia spp. across their native geographic range. To test for diffuse coevolution, we performed reciprocal inoculations to test for specialization between three Anasa host species and Caballeronia spp. symbionts isolated from conspecific hosts. We observed no evidence of specialization across host species. Our results demonstrate generalist dynamics underlie the interaction between Anasa insect hosts and their Caballeronia spp. symbionts. Specifically, diffuse coevolution between multiple host species with a shared generalist symbiont may maintain cooperative traits despite horizontal transmission.
Deep-learning microscopy image reconstruction with quality control reveals second-scale rearrangements in RNA polymerase II clusters
Authors: Hajiabadi Hamideh , Mamontova Irina , Prizak Roshan , Pancholi Agnieszka , Koziolek Anne , Hilbert Lennart
Published: December 2021

Fluorescence microscopy, a central tool of biological research, is subject to inherent trade-offs in experiment design. For instance, image acquisition speed can only be increased in exchange for a lowered signal quality, or for an increased rate of photo-damage to the specimen. Computational denoising can recover some loss of signal, extending the trade-off margin for high-speed imaging. Recently proposed denoising on the basis of neural networks shows exceptional performance but raises concerns of errors typical of neural networks. Here, we present a work-flow that supports an empirically optimized reduction of exposure times, as well as per-image quality control to exclude images with reconstruction errors. We implement this work-flow on the basis of the denoising tool Noise2Void and assess the molecular state and three-dimensional shape of RNA Polymerase II (Pol II) clusters in live zebrafish embryos. Image acquisition speed could be tripled, achieving 2-second time resolution and 350-nanometer lateral image resolution. The obtained data reveal stereotyped events of approximately 10 seconds duration: initially, the molecular mark for initiated Pol II increases, then the mark for active Pol II increases, and finally Pol II clusters take on a stretched and unfolded shape. An independent analysis based on fixed sample images reproduces this sequence of events, and suggests that they are related to the transient association of genes with Pol II clusters. Our work-flow consists of procedures that can be implemented on commercial fluorescence microscopes without any hardware or software modification, and should therefore be transferable to many other applications.
Profiling of the drug resistance of thousands of Src tyrosine kinase mutants uncovers a regulatory network that couples autoinhibition to catalytic domain dynamics
Authors: Chakraborty Sujata , Ahler Ethan , Simon Jessica J. , Fang Linglan , Potter Zachary E. , Sitko Katherine A. , Stephany Jason J. , Guttman Miklos , Fowler Douglas M. , Maly Dustin J.
Published: December 2021

Kinase inhibitors are effective cancer therapies but resistance often limits clinical efficacy. Despite the cataloguing of numerous resistance mutations, our understanding of kinase inhibitor resistance is still incomplete. Here, we comprehensively profiled the resistance of ∼3500 Src tyrosine kinase mutants to four different ATP-competitive inhibitors. We found that ATP-competitive inhibitor resistance mutations are distributed throughout Src’s catalytic domain. In addition to inhibitor contact residues, residues that participate in regulating Src’s phosphotransferase activity were prone to the development of resistance. Unexpectedly, we found that a resistance-prone cluster of residues located on the top face of the N-terminal lobe of Src’s catalytic domain contributes to autoinhibition by reducing catalytic domain dynamics, and mutations in this cluster led to resistance by lowering inhibitor affinity and promoting kinase hyperactivation. Together, our studies demonstrate how drug resistance profiling can be used to define potential resistance pathways and uncover new mechanisms of kinase regulation.
Standard setting in times of technological change: accounting for cryptocurrency holdings
Authors: Ramassa Paola , Leoni Giulia
Published: December 2021

Purpose

This paper explores how the International Accounting Standards Board (IASB) has dealt with the emerging issue of accounting for cryptocurrencies by investigating its constituents' expectations and the motivations underlying its regulatory response.

Design/methodology/approach

The theoretical lens of regulatory space is used to analyse the four-year debate around cryptocurrency holdings and informs the extensive thematic analysis of public documents, meetings recordings and comment letters on the topic.

Findings

Facing national standard setters' initiatives to regulate accounting for cryptocurrency, the IASB defended its position in the regulatory space through an agenda decision based on ewct 2xisting standards, which was finalised by the International Financial Reporting Standards Interpretation Committee (IFRS IC) despite criticism from constituents and Board members.

Research limitations/implications

The paper provides insights into the IASB approach to a regulatory vacuum regarding a new class of items, which derive from a new and rapidly-evolving technology. Disruptive technology impacts the contested arena of accounting regulation, in which the constituents ask for new solutions and the IASB tries to resist such pressures, while defending its position.

Practical implications

The paper sheds light on the growing importance of agenda decisions in the IFRS environment and on the limits of the IASB long regulatory process in the circumstance of emerging accounting issues deriving from rapidly-evolving technology.

Originality/value

This investigation is timely and relevant as it considers the regulatory issues arising from disruptive technological innovations (i.e. cryptocurrency), shedding light on the limits of regulatory processes in times of technological change.
A modified genetic algorithm for system optimization
Authors: Zemliak Alexander
Published: December 2021

Purpose

In this paper, the previously developed idea of generalized optimization of circuits for deterministic methods has been extended to genetic algorithm (GA) to demonstrate new possibilities for solving an optimization problem that enhance accuracy and significantly reduce computing time.

Design/methodology/approach

The disadvantages of GAs are premature convergence to local minima and an increase in the computer operation time when setting a sufficiently high accuracy for obtaining the minimum. The idea of generalized optimization of circuits, previously developed for the methods of deterministic optimization, is built into the GA and allows one to implement various optimization strategies based on GA. The shape of the fitness function, as well as the length and structure of the chromosomes, is determined by a control vector artificially introduced within the framework of generalized optimization. This study found that changing the control vector that determines the method for calculating the fitness function makes it possible to bypass local minima and find the global minimum with high accuracy and a significant reduction in central processing unit (CPU) time.

Findings

The structure of the control vector is found, which makes it possible to reduce the CPU time by several orders of magnitude and increase the accuracy of the optimization process compared with the traditional approach for GAs.

Originality/value

It was demonstrated that incorporating the idea of generalized optimization into the body of a stochastic optimization method leads to qualitatively new properties of the optimization process, increasing the accuracy and minimizing the CPU time.