bluuebunny/crossref_metadata_2025 huggingface dataset:
Normalization of impaired emotion inhibition in bipolar disorder mediated by cholinergic neurotransmission in the cingulate cortex
Authors: Nabulsi Leila , Farrell Jennifer , McPhilemy Genevieve , Kilmartin Liam , Dauvermann Maria R. , Akudjedu Theophilus N. , Najt Pablo , Ambati Srinath , Martyn Fiona M. , McLoughlin James , Gill Michael , Meaney James , Morris Derek , Frodl Thomas , McDonald Colm , Hallahan Brian , Cannon Dara M.
Published: January 2022

The muscarinic-cholinergic system is involved in the pathophysiology of bipolar disorder (BD), and contributes to attention and the top-down and bottom-up cognitive and affective mechanisms of emotional processing, functionally altered in BD. Emotion processing can be assessed by the ability to inhibit a response when the content of the image is emotional. Impaired regulatory capacity of cholinergic neurotransmission conferred by reduced M2-autoreceptor availability is hypothesized to play a role in elevated salience of negative emotional distractors in euthymic BD relative to individuals with no history of mood instability. Thirty-three euthymic BD type-I (DSM-V-TR) and 50 psychiatrically-healthy controls underwent functional magnetic resonance imaging (fMRI) and an emotion-inhibition paradigm before and after intravenous cholinergic challenge using the acetylcholinesterase inhibitor, physostigmine (1 mg), or placebo. Mood, accuracy, and reaction time on either recognizing or inhibiting a response associated with an image involving emotion and regional functional activation were examined for effects of cholinergic challenge physostigmine relative to placebo, prioritizing any interaction with the diagnostic group. Analyses revealed that (1) at baseline, impaired behavioral performance was associated with lower activation in the anterior cingulate cortex in BD relative to controls during emotion processing; (2) physostigmine (vs. placebo) affected behavioral performance during the inhibition of negative emotions, without altering mood, and increased activation in the posterior cingulate cortex in BD (vs. controls); (3) In BD, lower accuracy observed during emotion inhibition of negative emotions was remediated by physostigmine and was associated with cingulate cortex overactivation. Our findings implicate abnormal regulation of cholinergic neurotransmission in the cingulate cortices in BD, which may mediate exaggerated emotional salience processing, a core feature of BD.
No infectious SARS-CoV-2 in breast milk from a cohort of 110 lactating women
Authors: Krogstad Paul , Contreras Deisy , Ng Hwee , Tobin Nicole , Chambers Christina D. , Bertrand Kerri , Bode Lars , Aldrovandi Grace M.
Published: January 2022

Background

Genomic RNA of severe acute respiratory syndrome-associated coronavirus type 2 (SARS-CoV-2) has been detected in the breast milk of lactating women, but its pathological significance has remained uncertain due to the small size of prior studies.

Methods

Breast milk from 110 lactating women was analyzed by reverse transcription-polymerase chain reaction (285 samples) and viral culture (160 samples). Those containing SARS-CoV-2 viral RNA (vRNA) were examined for the presence of subgenomic RNA (sgRNA), a putative marker of infectivity.

Results

Sixty-five women had a positive SARS-CoV-2 diagnostic test, 9 had symptoms but negative diagnostic tests, and 36 symptomatic women were not tested. SARS-CoV-2 vRNA was detected in the milk of 7 (6%) women with either a confirmed infection or symptomatic illness, including 6 of 65 (9%) women with a positive SARS-CoV-2 diagnostic test. Infectious virus was not detected in any culture and none had detectable sgRNA. In control experiments, infectious SARS-CoV-2 could be cultured after addition to breastmilk despite several freeze–thaw cycles, as it occurs in the storage and usage of human milk.

Conclusions

SARS-CoV-2 RNA can be found infrequently in the breastmilk after recent infection, but we found no evidence that breastmilk contains an infectious virus or that breastfeeding represents a risk factor for transmission of infection to infants.

Impact

This article goes beyond prior small studies to provide evidence that infectious SARS-CoV-2 is not present in the milk of lactating women with recent infection, even when SARS-CoV-2 RNA is detected.

Recent SARS-CoV-2 infection or detection of its RNA in human milk is not a contraindication to breastfeeding.
JMJD2C-mediated long non-coding RNA MALAT1/microRNA-503-5p/SEPT2 axis worsens non-small cell lung cancer
Authors: Zhang Jun , Wang Mingliang , Wang Jiashun , Wang Wendong
Published: January 2022

Jumonji domain containing protein 2C (JMJD2C) could epigenetically regulate cancer cells. We specifically explored the downstream mechanism of JMJD2C in non-small cell lung cancer (NSCLC) from the long non-coding RNA metastasis associated with lung adenocarcinoma transcript 1/microRNA-503-5p/septin 2 (MALAT1/miR-503-5p/SEPT2) axis. NSCLC clinical tissues were utilized to assess JMJD2C, MALAT1, miR-503-5p and SEPT2 levels. NSCLC cell lines (A549 and H1299) were applied for loss-of-function and gain-of-function tests to identify the functional roles of JMJD2C, MALAT1, miR-503-5p, and SEPT2. The interactions among JMJD2C, MALAT1, miR-503-5p, and SEPT2 were assessed. Augmented JMJD2C, MALAT1, and SEPT2 and reduced miR-503-5p levels were found in NSCLC. Depleting JMJD2C or MALAT1, or restoring miR-503-5p exerted anti-tumor effects on NSCLC cells in vitro and in vivo. JMJD2C is bound to the promoter of MALAT1. MALAT1 bound to miR-503-5p and miR-503-5p targeted SEPT2. Knocking down MALAT1 or SEPT2, or elevating miR-503-5p mitigated the pro-tumor effects of upregulated JMJD2C on NSCLC. It is evident that the JMJD2C-mediated MALAT1/miR-503-5p/SEPT2 axis takes part in the process of NSCLC and even worsens NSCLC.
STAT6 contributes to renal fibrosis by modulating PPARα-mediated tubular fatty acid oxidation
Authors: Li Jianzhong , Yang Youjing , Li Qianmin , Wei Shuhui , Zhou Yujia , Yu Wangjianfei , Xue Lian , Zhou Ling , Shen Lei , Lu Guoyuan , Chen Ling , Tao Shasha
Published: January 2022

Lipid metabolism, especially fatty acid oxidation (FAO) dysfunction, is a major driver of renal fibrosis; however, the detailed regulatory mechanisms involved remain unclear. In this study, we showed that there existed an association between the signal transducer and activator of transcription 6 (STAT6) and tubular lipid metabolism in fibrotic kidneys. Specifically, STAT6 was activated along with the accumulation of lipids via the downregulation of FAO-related genes when mice were subjected to unilateral ureteral obstruction (UUO) or high-fat diet challenge. Tubular-specific depletion, or pharmacologic inhibitor of Stat6 in mice, and Stat6 knockdown in cultured tubular cells attenuated lipid accumulation and renal fibrosis by enhancing FAO. Mechanistically, STAT6 transcriptionally inhibited the expression of PPARα and its FAO-related target genes through a sis-inducible element located in the promoter region of the protein. In conclusion, our study demonstrates the mechanistic details of STAT6-mediated FAO dysregulation in the progression of renal fibrosis and provides a preclinical rationale for efforts to improve the management of renal fibrosis brought about by FAO dysregulation.
Charge-neutral fermions and magnetic field-driven instability in insulating YbIr3Si7
Authors: Sato Y. , Suetsugu S. , Tominaga T. , Kasahara Y. , Kasahara S. , Kobayashi T. , Kitagawa S. , Ishida K. , Peters R. , Shibauchi T. , Nevidomskyy A. H. , Qian L. , Morosan E. , Matsuda Y.
Published: January 2022

Kondo lattice materials, where localized magnetic moments couple to itinerant electrons, provide a very rich backdrop for strong electron correlations. They are known to realize many exotic phenomena, with a dramatic example being recent observations of quantum oscillations and metallic thermal conduction in insulators, implying the emergence of enigmatic charge-neutral fermions. Here, we show that thermal conductivity and specific heat measurements in insulating YbIr3Si7 reveal emergent neutral excitations, whose properties are sensitively changed by a field-driven transition between two antiferromagnetic phases. In the low-field phase, a significant violation of the Wiedemann-Franz law demonstrates that YbIr3Si7 is a charge insulator but a thermal metal. In the high-field phase, thermal conductivity exhibits a sharp drop below 300 mK, indicating a transition from a thermal metal into an insulator/semimetal driven by the magnetic transition. These results suggest that spin degrees of freedom directly couple to the neutral fermions, whose emergent Fermi surface undergoes a field-driven instability at low temperatures.
Crystal structure of the α1B-adrenergic receptor reveals molecular determinants of selective ligand recognition
Authors: Deluigi Mattia , Morstein Lena , Schuster Matthias , Klenk Christoph , Merklinger Lisa , Cridge Riley R. , de Zhang Lazarus A. , Klipp Alexander , Vacca Santiago , Vaid Tasneem M. , Mittl Peer R. E. , Egloff Pascal , Eberle Stefanie A. , Zerbe Oliver , Chalmers David K. , Scott Daniel J. , Plückthun Andreas
Published: January 2022

α-adrenergic receptors (αARs) are G protein-coupled receptors that regulate vital functions of the cardiovascular and nervous systems. The therapeutic potential of αARs, however, is largely unexploited and hampered by the scarcity of subtype-selective ligands. Moreover, several aminergic drugs either show off-target binding to αARs or fail to interact with the desired subtype. Here, we report the crystal structure of human α1BAR bound to the inverse agonist (+)-cyclazosin, enabled by the fusion to a DARPin crystallization chaperone. The α1BAR structure allows the identification of two unique secondary binding pockets. By structural comparison of α1BAR with α2ARs, and by constructing α1BAR-α2CAR chimeras, we identify residues 3.29 and 6.55 as key determinants of ligand selectivity. Our findings provide a basis for discovery of α1BAR-selective ligands and may guide the optimization of aminergic drugs to prevent off-target binding to αARs, or to elicit a selective interaction with the desired subtype.
Experimental identification of aminomethanol (NH2CH2OH)—the key intermediate in the Strecker Synthesis
Authors: Singh Santosh K. , Zhu Cheng , La Jeunesse Jesse , Fortenberry Ryan C. , Kaiser Ralf I.
Published: January 2022

The Strecker Synthesis of (a)chiral α-amino acids from simple organic compounds, such as ammonia (NH3), aldehydes (RCHO), and hydrogen cyanide (HCN) has been recognized as a viable route to amino acids on primordial earth. However, preparation and isolation of the simplest hemiaminal intermediate – the aminomethanol (NH2CH2OH)– formed in the Strecker Synthesis to even the simplest amino acid glycine (H2NCH2COOH) has been elusive. Here, we report the identification of aminomethanol prepared in low-temperature methylamine (CH3NH2) – oxygen (O2) ices upon exposure to energetic electrons. Isomer-selective photoionization time-of-flight mass spectrometry (PI-ReTOF-MS) facilitated the gas phase detection of aminomethanol during the temperature program desorption (TPD) phase of the reaction products. The preparation and observation of the key transient aminomethanol changes our perception of the synthetic pathways to amino acids and the unexpected kinetic stability in extreme environments.
Advances in mixed cell deconvolution enable quantification of cell types in spatial transcriptomic data
Authors: Danaher Patrick , Kim Youngmi , Nelson Brenn , Griswold Maddy , Yang Zhi , Piazza Erin , Beechem Joseph M.
Published: January 2022

Mapping cell types across a tissue is a central concern of spatial biology, but cell type abundance is difficult to extract from spatial gene expression data. We introduce SpatialDecon, an algorithm for quantifying cell populations defined by single cell sequencing within the regions of spatial gene expression studies. SpatialDecon incorporates several advancements in gene expression deconvolution. We propose an algorithm harnessing log-normal regression and modelling background, outperforming classical least-squares methods. We compile cell profile matrices for 75 tissue types. We identify genes whose minimal expression by cancer cells makes them suitable for immune deconvolution in tumors. Using lung tumors, we create a dataset for benchmarking deconvolution methods against marker proteins. SpatialDecon is a simple and flexible tool for mapping cell types in spatial gene expression studies. It obtains cell abundance estimates that are spatially resolved, granular, and paired with highly multiplexed gene expression data.
A case of antiferrochirality in a liquid crystal phase of counter-rotating staircases
Authors: Li Ya-xin , Gao Hong-fei , Zhang Rui-bin , Gabana Kutlwano , Chang Qing , Gehring Gillian A. , Cheng Xiao-hong , Zeng Xiang-bing , Ungar Goran
Published: January 2022

Helical structures continue to inspire, prompted by examples such as DNA double-helix and alpha-helix in proteins. Most synthetic polymers also crystallize as helices, which relieves steric clashes by twisting, while keeping the molecules straight for their ordered packing. In columnar liquid crystals, which often display useful optoelectronic properties, overall helical chirality can be induced by inclusion of chiral chemical groups or dopants; these bias molecular twist to either left or right, analogous to a magnetic field aligning the spins in a paramagnet. In this work, however, we show that liquid-crystalline columns with long-range helical order can form by spontaneous self-assembly of straight- or bent-rod molecules without inclusion of any chiral moiety. A complex lattice with Fddd symmetry and 8 columns per unit cell (4 right-, 4 left-handed) characterizes this “antiferrochiral” structure. In selected compounds it allows close packing of their fluorescent groups reducing their bandgap and giving them promising light-emitting properties.
Spontaneous dewetting transitions of droplets during icing & melting cycle
Authors: Wang Lizhong , Tian Ze , Jiang Guochen , Luo Xiao , Chen Changhao , Hu Xinyu , Zhang Hongjun , Zhong Minlin
Published: January 2022

Anti-icing superhydrophobic surfaces have been a key research topic due to their potential application value in aviation, telecommunication, energy, etc. However, superhydrophobicity is easily lost during icing & melting cycles, where the water-repellent Cassie-Baxter state turns to the sticky Wenzel state. The reversible transition during icing & melting cycle without external assistance is challenging but vital for reliable anti-icing superhydrophobic performance, such a topic has rarely been reported. Here we demonstrate a spontaneous Wenzel to Cassie-Baxter dewetting transition during icing & melting cycle on well-designed superhydrophobic surfaces. Bubbles in ice droplets rapidly impact the micro-nano valleys under Marangoni force, prompting the continuous recovery of air pockets during melting processes. We establish models to confirm the bubbles movement broadens the dewetting conditions greatly and present three criteria for the dewetting transitions. This research deepens the understanding of wettability theory and extends the design of anti-icing superhydrophobic surfaces.
A phase 2 single center open label randomised control trial for convalescent plasma therapy in patients with severe COVID-19
Authors: Ray Yogiraj , Paul Shekhar Ranjan , Bandopadhyay Purbita , D’Rozario Ranit , Sarif Jafar , Raychaudhuri Deblina , Bhowmik Debaleena , Lahiri Abhishake , Vasudevan Janani Srinivasa , Maurya Ranjeet , Kanakan Akshay , Sharma Sachin , Kumar Manish , Singh Praveen , Roy Rammohan , Chaudhury Kausik , Maiti Rajsekhar , Bagchi Saugata , Maiti Ayan , Perwez Md. Masoom , Mondal Abhinandan , Tewari Avinash , Mandal Samik , Roy Arpan , Saha Moumita , Biswas Durba , Maiti Chikam , Bhaduri Ritwik , Chakraborty Sayantan , Sarkar Biswanath Sharma , Haldar Anima , Saha Bibhuti , Sengupta Shantanu , Pandey Rajesh , Chatterjee Shilpak , Bhattacharya Prasun , Paul Sandip , Ganguly Dipyaman
Published: January 2022

A single center open label phase 2 randomised control trial (Clinical Trial Registry of India No. CTRI/2020/05/025209) was done to assess clinical and immunological benefits of passive immunization using convalescent plasma therapy. At the Infectious Diseases and Beleghata General Hospital in Kolkata, India, 80 patients hospitalized with severe COVID-19 disease and fulfilling the inclusion criteria (aged more than 18 years, with either mild ARDS having PaO2/FiO2 200–300 or moderate ARDS having PaO2/FiO2 100–200, not on mechanical ventilation) were recruited and randomized into either standard of care (SOC) arm (N = 40) or the convalescent plasma therapy (CPT) arm (N = 40). Primary outcomes were all-cause mortality by day 30 of enrolment and immunological correlates of response to therapy if any, for which plasma abundance of a large panel of cytokines was quantitated before and after intervention to assess the effect of CPT on the systemic hyper-inflammation encountered in these patients. The secondary outcomes were recovery from ARDS and time taken to negative viral RNA PCR as well as to report any adverse reaction to plasma therapy. Transfused convalescent plasma was characterized in terms of its neutralizing antibody content as well as proteome. The trial was completed and it was found that primary outcome of all-cause mortality was not significantly different among severe COVID-19 patients with ARDS randomized to two treatment arms (Mantel-Haenszel Hazard Ratio 0.6731, 95% confidence interval 0.3010-1.505, with a P value of 0.3424 on Mantel-Cox Log-rank test). No adverse effect was reported with CPT. In severe COVID-19 patients with mild or moderate ARDS no significant clinical benefit was registered in this clinical trial with convalescent plasma therapy in terms of prespecified outcomes.
Developing and enforcing fracking regulations to protect groundwater resources
Authors: Esterhuyse S. , Vermeulen D. , Glazewski J.
Published: January 2022

Unconventional oil and gas (UOG) extraction can augment energy supplies in countries with viable gas resources, but it risks damaging water resources. Water supply problems for fracking can also limit UOG extraction, especially in water-stressed regions. Regulations are one of the main tools used to minimize UOG extraction impacts on water resources. Many states in the US and Canada have extensive regulations to protect water resources during UOG extraction but they are often ineffective, either because they were poorly drafted or because they are not properly enforced. South Africa is a water-scarce, groundwater-dependent country that is considering UOG extraction in the future. South African groundwater experts were surveyed on what regulations are needed to protect groundwater resources and how to enforce them. This study recommends specific UOG extraction regulations to protect groundwater resources, which are not only relevant to South Africa, but also to other countries that extract UOG resources.
Abnormal whole-body energy metabolism in iron-deficient humans despite preserved skeletal muscle oxidative phosphorylation
Authors: Frise Matthew C. , Holdsworth David A. , Johnson Andrew W. , Chung Yu Jin , Curtis M. Kate , Cox Pete J. , Clarke Kieran , Tyler Damian J. , Roberts David J. , Ratcliffe Peter J. , Dorrington Keith L. , Robbins Peter A.
Published: January 2022

Iron deficiency impairs skeletal muscle metabolism. The underlying mechanisms are incompletely characterised, but animal and human experiments suggest the involvement of signalling pathways co-dependent upon oxygen and iron availability, including the pathway associated with hypoxia-inducible factor (HIF). We performed a prospective, case–control, clinical physiology study to explore the effects of iron deficiency on human metabolism, using exercise as a stressor. Thirteen iron-deficient (ID) individuals and thirteen iron-replete (IR) control participants each underwent31P-magnetic resonance spectroscopy of exercising calf muscle to investigate differences in oxidative phosphorylation, followed by whole-body cardiopulmonary exercise testing. Thereafter, individuals were given an intravenous (IV) infusion, randomised to either iron or saline, and the assessments repeated ~ 1 week later. Neither baseline iron status nor IV iron significantly influenced high-energy phosphate metabolism. During submaximal cardiopulmonary exercise, the rate of decline in blood lactate concentration was diminished in the ID group (P = 0.005). Intravenous iron corrected this abnormality. Furthermore, IV iron increased lactate threshold during maximal cardiopulmonary exercise by ~ 10%, regardless of baseline iron status. These findings demonstrate abnormal whole-body energy metabolism in iron-deficient but otherwise healthy humans. Iron deficiency promotes a more glycolytic phenotype without having a detectable effect on mitochondrial bioenergetics.
Ge/Si multilayer epitaxy and removal of dislocations from Ge-nanosheet-channel MOSFETs
Authors: Chu Chun-Lin , Chang Jen-Yi , Chen Po-Yen , Wang Po-Yu , Hsu Shu-Han , Chou Dean
Published: January 2022

Horizontally stacked pure-Ge-nanosheet gate-all-around field-effect transistors (GAA FETs) were developed in this study. Large lattice mismatch Ge/Si multilayers were intentionally grown as the starting material rather than Ge/GeSi multilayers to acquire the benefits of the considerable difference in material properties of Ge and Si for realising selective etching. Flat Ge/Si multilayers were grown at a low temperature to preclude island growth. The shape of Ge nanosheets was almost retained after etching owing to the excellent selectivity. Additionally, dislocations were observed in suspended Ge nanosheets because of the absence of a Ge/Si interface and the disappearance of the dislocation-line tension force owing to the elongation of misfit dislocation at the interface. Forming gas annealing of the suspended Ge nanosheets resulted in a significant increase in the glide force compared to the dislocation-line tension force; the dislocations were easily removed because of this condition and the small size of the nanosheets. Based on this structure, a new mechanism of dislocation removal from suspended Ge nanosheet structures by annealing was described, which resulted in the structures exhibiting excellent gate control and electrical properties.
The clinical outcomes of combination chemotherapy in elderly patients with advanced biliary tract cancer: an exploratory analysis of JCOG1113
Authors: Yamada Ikuhiro , Morizane Chigusa , Okusaka Takuji , Mizusawa Junki , Kataoka Tomoko , Ueno Makoto , Ikeda Masafumi , Okano Naohiro , Todaka Akiko , Shimizu Satoshi , Mizuno Nobumasa , Sekimoto Mitsugu , Tobimatsu Kazutoshi , Yamaguchi Hironori , Nishina Tomohiro , Shirakawa Hirofumi , Kojima Yasushi , Oono Takamasa , Kawamoto Yasuyuki , Furukawa Masayuki , Iwai Tomohisa , Sudo Kentaro , Okamura Keiya , Yamashita Tatsuya , Kato Naoya , Shioji Kazuhiko , Shimizu Kyouko , Nakagohri Toshio , Kamata Ken , Ishii Hiroshi , Furuse Junji ,   JCOG-HBPOG, Yamada Ikuhiro , Morizane Chigusa , Okusaka Takuji , Mizusawa Junki , Kataoka Tomoko , Ueno Makoto , Ikeda Masafumi , Ozaka Masato , Okano Naohiro , Sugimori Kazuya , Todaka Akiko , Shimizu Satoshi , Mizuno Nobumasa , Sekimoto Mitsugu , Sano Keiji , Tobimatsu Kazutoshi , Katanuma Akio , Sakai Kenji , Yamaguchi Hironori , Nishina Tomohiro , Shirakawa Hirofumi , Kojima Yasushi , Oono Takamasa , Kawamoto Yasuyuki , Furukawa Masayuki , Iwai Tomohisa , Sudo Kentaro , Okamura Keiya , Yamashita Tatsuya , Yasuda Ichirou , Takahashi Hidenori , Kato Naoya , Shioji Kazuhiko , Shimizu Kyouko , Nakagohri Toshio , Kamata Ken , Ishii Hiroshi , Furuse Junji
Published: January 2022

In the FUGA-BT trial (JCOG1113), gemcitabine plus S-1 (GS) showed non-inferiority to gemcitabine plus cisplatin (GC) in overall survival (OS) with good tolerance for patients with advanced biliary tract cancer (BTC). We performed a subgroup analysis focused on the elderly cohort of this trial. All 354 enrolled patients in JCOG1113 were classify into two groups; < 75 (non-elderly) and ≥ 75 years (elderly) group. We investigated the influence of age on the safety analysis, including the incidence of chemotherapeutic adverse events and the efficacy analysis, including OS. There were no remarkable differences in OS between the elderly (n = 60) and the non-elderly groups (n = 294). In the elderly group, median OS was 12.7 and 17.7 months for those who received GC (n = 20) and GS (n = 40), respectively. The prevalence of all-grade adverse events was similar between the elderly and the non-elderly groups. However, among the elderly group, Grade ≥ 3 hematological adverse events were more frequently observed in the GC arm than in the GS arm. The clinical outcomes of combination chemotherapy in elderly patients with advanced BTC were comparable to non-elderly patients. GS may be the more favorable treatment for elderly patients with advanced BTC.
Pre-clinical activity of the oral DNA-PK inhibitor, peposertib (M3814), combined with radiation in xenograft models of cervical cancer
Authors: Gordhandas Sushmita B. , Manning-Geist Beryl , Henson Christina , Iyer Gopa , Gardner Ginger J. , Sonoda Yukio , Moore Kathleen N. , Aghajanian Carol , Chui M. Herman , Grisham Rachel N.
Published: January 2022

DNA-dependent protein kinase (DNA-PK) plays a crucial role in repair of DNA double-strand breaks by facilitating non-homologous end-joining. Inhibitors of DNA-PK have the potential to block DNA repair and enhance DNA-damaging agents. Peposertib (M3814) is a DNA-PK inhibitor that has shown preclinical activity in combination with DNA-damaging agents, including ionizing radiation (IR) and topoisomerase II inhibitors. Here we evaluated the activity of peposertib (M3814) in combination with radiation in a mouse xenograft model of HPV-associated cervical cancer. Athymic nude female mice with established tumors derived from HeLa cells injected into the flank were treated with vehicle alone (n = 3), IR alone (n = 4), and peposertib (M38814) in combination with IR (M3814 + IR; n = 4). While IR alone was associated with a trend towards decreased tumor volume compared with untreated, only the M3814 + IR treatment arm was associated with consistent and significant reduction in tumor burden, which correlated with higher levels of γ-H2AX in tumor cells, a marker of double-strand DNA breaks. Our data support further clinical evaluation of the combination of peposertib (M38814) and IR in cervical cancer.
Plasma membrane effects of sphingolipid-synthesis inhibition by myriocin in CHO cells: a biophysical and lipidomic study
Authors: Monasterio Bingen G. , Jiménez-Rojo Noemi , García-Arribas Aritz B. , Riezman Howard , Goñi Félix M. , Alonso Alicia
Published: January 2022

Suppression of a specific gene effect can be achieved by genetic as well as chemical methods. Each approach may hide unexpected drawbacks, usually in the form of side effects. In the present study, the specific inhibitor myriocin was used to block serine palmitoyltransferase (SPT), the first enzyme in the sphingolipid synthetic pathway, in CHO cells. The subsequent biophysical changes in plasma membranes were measured and compared with results obtained with a genetically modified CHO cell line containing a defective SPT (the LY-B cell line). Similar effects were observed with both approaches: sphingomyelin values were markedly decreased in myriocin-treated CHO cells and, in consequence, their membrane molecular order (measured as laurdan general polarization) and mechanical resistance (AFM-measured breakthrough force values) became lower than in the native, non-treated cells. Cells treated with myriocin reacted homeostatically to maintain membrane order, synthesizing more fully saturated and less polyunsaturated GPL than the non-treated ones, although they achieved it only partially, their plasma membranes remaining slightly more fluid and more penetrable than those from the control cells. The good agreement between results obtained with very different tools, such as genetically modified and chemically treated cells, reinforces the use of both methods and demonstrates that both are adequate for their intended use, i.e. the complete and specific inhibition of sphingolipid synthesis in CHO cells, without apparent unexpected effects.
Effect of nano h-BN particles on growth regularity and tribological behavior of PEO composite ceramic coating of ZL109 alloy
Authors: Zhu Xinhe , Fu Jingguo , Ma Dengqing , Ma Chunsheng , Fu Yunyang , Zhang Zhuokai
Published: January 2022

A composite ceramic coating containing h-BN particles was prepared on the ZL109 alloy via plasma electrolytic oxidation. The h-BN particles were modified by Polyethylene glycol to improve the dispersibility. The results revealed that the h-BN particles in the electrolyte were inertly incorporated into the coating. Meanwhile, the incorporation of h-BN particles can reduce the porosity and slightly increase the roughness of the composite ceramic coating. Furthermore, the growth rate of the coating and the conversion of γ-Al2O3 and α-Al2O3 were promoted by the incorporation of h-BN particles via the change of the current. In addition, due to the presence of h-BN particles, the composite ceramic coating had a lower friction coefficient and a lower wear rate under dry sliding condition.
Blood cancer prediction using leukemia microarray gene data and hybrid logistic vector trees model
Authors: Rupapara Vaibhav , Rustam Furqan , Aljedaani Wajdi , Shahzad Hina Fatima , Lee Ernesto , Ashraf Imran
Published: January 2022

Blood cancer has been a growing concern during the last decade and requires early diagnosis to start proper treatment. The diagnosis process is costly and time-consuming involving medical experts and several tests. Thus, an automatic diagnosis system for its accurate prediction is of significant importance. Diagnosis of blood cancer using leukemia microarray gene data and machine learning approach has become an important medical research today. Despite research efforts, desired accuracy and efficiency necessitate further enhancements. This study proposes an approach for blood cancer disease prediction using the supervised machine learning approach. For the current study, the leukemia microarray gene dataset containing 22,283 genes, is used. ADASYN resampling and Chi-squared (Chi2) features selection techniques are used to resolve imbalanced and high-dimensional dataset problems. ADASYN generates artificial data to make the dataset balanced for each target class, and Chi2 selects the best features out of 22,283 to train learning models. For classification, a hybrid logistics vector trees classifier (LVTrees) is proposed which utilizes logistic regression, support vector classifier, and extra tree classifier. Besides extensive experiments on the datasets, performance comparison with the state-of-the-art methods has been made for determining the significance of the proposed approach. LVTrees outperform all other models with ADASYN and Chi2 techniques with a significant 100% accuracy. Further, a statistical significance T-test is also performed to show the efficacy of the proposed approach. Results using k-fold cross-validation prove the supremacy of the proposed model.
Mothers adapt their voice during children’s adolescent development
Authors: Leipold Simon , Abrams Daniel A. , Menon Vinod
Published: January 2022

Mothers alter their speech in a stereotypical manner when addressing infants using high pitch, a wide pitch range, and distinct timbral features. Mothers reduce their vocal pitch after early childhood; however, it is not known whether mother’s voice changes through adolescence as children become increasingly independent from their parents. Here we investigate the vocal acoustics of 50 mothers of older children (ages 7–16) to determine: (1) whether pitch changes associated with child-directed speech decrease with age; (2) whether other acoustical features associated with child-directed speech change with age; and, (3) the relative contribution of acoustical features in predicting child’s age. Results reveal that mothers of older children used lower pitched voices than mothers of younger children, and mother’s voice pitch height predicted their child’s age. Crucially, these effects were present after controlling for mother’s age, accounting for aging-related pitch reductions. Brightness, a timbral feature correlated with pitch height, also showed an inverse relation with child’s age but did not improve prediction of child’s age beyond that accounted for by pitch height. Other acoustic features did not predict child age. Findings suggest that mother’s voice adapts to match their child’s developmental progression into adolescence and this adaptation is independent of mother’s age.
Analysis of soil bacterial communities and physicochemical properties associated with Fusarium wilt disease of banana in Malaysia
Authors: Jamil Fatin Nadiah , Hashim Amalia Mohd , Yusof Mohd Termizi , Saidi Noor Baity
Published: January 2022

Fusarium wilt (FW) caused by Fusarium oxysporum f. sp. cubense Tropical Race 4 (TR4) is a soil-borne disease that infects bananas, causing severe economic losses worldwide. To reveal the relationship between bacterial populations and FW, the bacterial communities of healthy and TR4-infected rhizosphere and bulk soils were compared using 16S rRNA gene sequencing. Soil physicochemical properties associated with FW were also analyzed. We found the community structure of bacteria in the healthy and TR4 infected rhizosphere was significantly different compared to bulk soil within the same farm. The rhizosphere soils of infected plants exhibited higher richness and diversity than healthy plant with significant abundance of Proteobacteria. In the healthy rhizosphere soil, beneficial bacteria such as Burkholderia and Streptomyces spp. were more abundant. Compared to the infected rhizosphere soil, healthy rhizosphere soil was associated with RNA metabolism and transporters pathways and a high level of magnesium and cation exchange capacity. Overall, we reported changes in the key taxa of rhizospheric bacterial communities and soil physicochemical properties of healthy and FW-infected plants, suggesting their potential role as indicators for plant health.
Unveiling the mystery of scale dependence of surface roughness of natural rock joints
Authors: Li Yingchun , Yang Hongwei , Sun Shengyue
Published: January 2022

Scale dependence of surface roughness of natural rock joints has long been an outstanding issue in rock mechanics. Controversial results were reported by various studies; however, the nature of scale dependency and the underlying mechanism for the conflicting observations remain unclear. Rock joints at different scales characterise two-order asperities, namely, waviness and unevenness; thus understanding how the individual roughness of waviness and unevenness vary as the joint size increases from the laboratory-scale to the large-scale is crucial for revealing the scale effect mystery. Here we digitise three natural granite joint surfaces with the same dimension of 1000 mm × 1000 mm through a high-resolution, three-dimensional scanner. Waviness and unevenness of each rock joint surface are quantitatively separated by selecting an appropriate sampling interval. The respective fractal dimensions of waviness and unevenness of joint surfaces sized from 100 mm × 100 mm to 1000 mm × 1000 mm are estimated through an improved roughness-length method. We find that the fractal dimensions of two-order roughness are scale-dependent but without generalised trends. The stationarity threshold beyond which the scale-dependency of roughness vanishes is absent for all the three joint samples, suggesting that the roughness of natural rock joints be assessed at the specific scale of the rock mass in-situ. We reveal that previous controversial results regarding scale effect are likely due to the composition of the roughness scaling of waviness and unevenness. Thus, accurate stability analysis of rock-engineering projects should consider separate contributions of multi-order asperities across scales to the strength and deformation of jointed rock masses.
A decade of travel-associated malaria at King Fahad Hospital of the University in the Eastern Province of Saudi Arabia
Authors: Alanazi Ashwaq , Almusailhi Bayan Ahmad Hasan , Bamousa Gheed K. , Alhawashim Nabaa H. , Alotaibi Nourah M. , AlShamekh Sumiyah , Hunasemarada Basavaraja Channabasappa , Al Jindan Reem Y. , El-Badry Ayman A.
Published: January 2022

Travel-associated malaria is a health hazard, even in non-malaria endemic regions. This is a hospital-based retrospective study of 12,931 febrile patients who presented at King Fahad Hospital of the University (KFHU) from January 2009 to December 2019. Patients either returning from malaria endemic countries and/or for whom malaria was suspected, had blood films microscopically screened for malaria parasites. Malaria prevalence was very low in febrile patients attending KFHU. Out of the 12,931 febrile patients, 0.63% (n = 81) were malaria positive, all travel-related, except for one case of transfusion malaria. Indian nationals were the most infected (29.6%, n = 24), followed by Sudanese nationals (24.7%, n = 20). P. falciparum (47%, n = 38) and P. vivax (42%, n = 24) were the predominant species. The majority of P. falciparum (64.5%, n = 20) cases were from African nationals and the majority of P. vivax (72.7%, n = 24) cases were from Asia. The highest percentage of malaria patients were adult (90%, n = 73), males (85.2%, n = 69), ages ranged from 6 to 65, with a mean of 34.6 years. Most of the malaria cases presented at the emergency room (ER), only 3 required critical care. Only sex, hospitalized in-patient (IP) and attendance at ER were statistically associated with malaria. In the presence of a potential vector, travel-associated malaria in non-malaria endemic areas should be monitored to guide control strategies.

Author summary: Malaria is a neglected potentially fatal tropical mosquito-born disease. Travel-associated malaria is a health hazard, even in non-malaria endemic regions. In spite of previous efforts to estimate malaria prevalence, morbidity and mortality in Saudi Arabia in the last decade, there have been no studies that determine the prevalence of malaria in Al-Khobar, Eastern Province of Saudi Arabia. Malaria prevalence was very low in febrile patients (81/12,931) attending King Fahad Hospital of the University over a decade. Cases were all travel-related, except for one case of transfusion malaria. Indian nationals were the most infected (29.6%), followed by Sudanese nationals (24.7%). P. falciparum (47%) and P. vivax (42%) were the predominant species. The majority of P. falciparum (64.5%) cases were from Africa and the majority of P. vivax (72.7%) cases were from Asia. No patient factors predicted malaria in febrile travelers. In non-malaria endemic areas, in the presence of a potential vector, patients with acute fever coming from endemic areas or having received blood transfusion, should be screened for travel-associated malaria to guide control strategies.
A potential target gene CD63 for different degrees of intervertebral disc degeneration
Authors: Gao Sheng , Jia Shu , Fan Xutao , Gao Chengcan , Li Qingwei , Wu Yuxue , Meng Chunyang
Published: January 2022

Understanding molecular mechanisms of intervertebral disc degeneration (IDD) and providing a novel target for the treatment of IDD have important implications. We sought to explore a new promising gene target for the treatment of IDD. This study integrated 19,678 genes of 38 IDD patients from two gene datasets. Differentially Expressed Genes (DEGs) of annulus fibrosus were analyzed in groups with mild disc degeneration (MDD) and severe disc degeneration (SDD). We screened the hub gene through biological information technology (bioinformatic) methods. Then, we further validated the hub gene using annulus fibrosus and nucleus pulposus tissues from 12 patients with qRT-PCR. In addition, we explored its underlying molecular mechanism with GO, KEGG and GSEA. Through multiple screening bioinformatics methods, the hub gene CD63 was identified. The qRT-PCR explored that CD63 decreased significantly in SDD group compared to that in MDD group (P < 0.001). The GO, KEGG and GSEA of CD63 explored significant enrichment of the molecular features (P < 0.001), including the cellular component (Extracellular matrix, P < 0.001), the molecular function (collagen binding, P < 0.001), the biological processes (protein targeting, collagen fibril organization and platelet degranulation, P < 0.001) and the signaling pathways. Our research explored and validated a new regulatory gene, CD63 for different degrees of IDD. A new novel form of therapeutic target for IDD may be developed.
Wear-adaptive optimization of in-process conditioning parameters during face plunge grinding of PcBN
Authors: Denkena Berend , Krödel-Worbes Alexander , Müller-Cramm Dominik
Published: January 2022

Polycrystalline cubic boron nitride is a very hard material. Machining of this material is performed by grinding with diamond tools. Due to its high hardness, grinding tools are subjected to severe microscopic and macroscopic tool wear. This wear leads to short tool life and results in high effort in conditioning the abrasive layer. Contrary to the usual conditioning of diamond grinding wheels with diamond dressing tools, this study investigates a conditioning process based entirely on the use of white corundum cup rolls. These conditioning tools allow the in-process face plunge conditioning of vitrified bond diamond grinding tools. The circumferential speed of the conditioning tool and the average grain diameter of the corundum are identified as the main factors influencing the topography of the generated grinding layer. To describe the performance of the conditioning process, a specific conditioning removal rate $$Q_{sd}^{\prime }$$

Q

sd

′

is derived. This parameter represents a cumulated variable that allows a comparison of different conditioning strategies. It is shown that an increase in $$Q_{sd}^{\prime }$$

Q

sd

′

significantly counteracts microscopic wear on the abrasive layer. Therefore, optimized process parameters enable the process of in-process conditioning to significantly reduce wear on the grinding tool without increasing the process time or the non-productive time.
Contrasting maternal and paternal genetic histories among five ethnic groups from Khyber Pakhtunkhwa, Pakistan
Authors: Tariq Muhammad , Ahmad Habib , Hemphill Brian E. , Farooq Umar , Schurr Theodore G.
Published: January 2022

Northwest Pakistan has served as a point of entry to South Asia for different populations since ancient times. However, relatively little is known about the population genetic history of the people residing within this region. To better understand human dispersal in the region within the broader history of the subcontinent, we analyzed mtDNA diversity in 659 and Y-chromosome diversity in 678 individuals, respectively, from five ethnic groups (Gujars, Jadoons, Syeds, Tanolis and Yousafzais), from Swabi and Buner Districts, Khyber Pakhtunkhwa Province, Pakistan. The mtDNAs of all individuals were subject to control region sequencing and SNP genotyping, while Y-chromosomes were analyzed using 54 SNPs and 19 STR loci. The majority of the mtDNAs belonged to West Eurasian haplogroups, with the rest belonging to either South or East Asian lineages. Four of the five Pakistani populations (Gujars, Jadoons, Syeds, Yousafzais) possessed strong maternal genetic affinities with other Pakistani and Central Asian populations, whereas one (Tanolis) did not. Four haplogroups (R1a, R1b, O3, L) among the 11 Y-chromosome lineages observed among these five ethnic groups contributed substantially to their paternal genetic makeup. Gujars, Syeds and Yousafzais showed strong paternal genetic affinities with other Pakistani and Central Asian populations, whereas Jadoons and Tanolis had close affinities with Turkmen populations from Central Asia and ethnic groups from northeast India. We evaluate these genetic data in the context of historical and archeological evidence to test different hypotheses concerning their origins and biological relationships.
Machine learning in vascular surgery: a systematic review and critical appraisal
Authors: Li Ben , Feridooni Tiam , Cuen-Ojeda Cesar , Kishibe Teruko , de Mestral Charles , Mamdani Muhammad , Al-Omran Mohammed
Published: January 2022

Machine learning (ML) is a rapidly advancing field with increasing utility in health care. We conducted a systematic review and critical appraisal of ML applications in vascular surgery. MEDLINE, Embase, and Cochrane CENTRAL were searched from inception to March 1, 2021. Study screening, data extraction, and quality assessment were performed by two independent reviewers, with a third author resolving discrepancies. All original studies reporting ML applications in vascular surgery were included. Publication trends, disease conditions, methodologies, and outcomes were summarized. Critical appraisal was conducted using the PROBAST risk-of-bias and TRIPOD reporting adherence tools. We included 212 studies from a pool of 2235 unique articles. ML techniques were used for diagnosis, prognosis, and image segmentation in carotid stenosis, aortic aneurysm/dissection, peripheral artery disease, diabetic foot ulcer, venous disease, and renal artery stenosis. The number of publications on ML in vascular surgery increased from 1 (1991–1996) to 118 (2016–2021). Most studies were retrospective and single center, with no randomized controlled trials. The median area under the receiver operating characteristic curve (AUROC) was 0.88 (range 0.61–1.00), with 79.5% [62/78] studies reporting AUROC ≥ 0.80. Out of 22 studies comparing ML techniques to existing prediction tools, clinicians, or traditional regression models, 20 performed better and 2 performed similarly. Overall, 94.8% (201/212) studies had high risk-of-bias and adherence to reporting standards was poor with a rate of 41.4%. Despite improvements over time, study quality and reporting remain inadequate. Future studies should consider standardized tools such as PROBAST and TRIPOD to improve study quality and clinical applicability.
Genome-wide identification of bacterial colonization and fitness determinants on the floating macrophyte, duckweed
Authors: Ishizawa Hidehiro , Kuroda Masashi , Inoue Daisuke , Ike Michihiko
Published: January 2022

Bacterial communities associated with aquatic macrophytes largely influence host primary production and nutrient cycling in freshwater environments; however, little is known about how specific bacteria migrate to and proliferate at this unique habitat. Here, we separately identified bacterial genes involved in the initial colonization and overall fitness on plant surface, using the genome-wide transposon sequencing (Tn-seq) of Aquitalea magnusonii H3, a plant growth-promoting bacterium of the floating macrophyte, duckweed. Functional annotation of identified genes indicated that initial colonization efficiency might be simply explained by motility and cell surface structure, while overall fitness was associated with diverse metabolic and regulatory functions. Genes involved in lipopolysaccharides and type-IV pili biosynthesis showed different contributions to colonization and fitness, reflecting their metabolic cost and profound roles in host association. These results provide a comprehensive genetic perspective on aquatic-plant-bacterial interactions, and highlight the potential trade-off between bacterial colonization and proliferation abilities on plant surface.
An activatable and tumor-targeting NIR fluorescent probe for imaging of histone deacetylase 6 in cancer cells and in vivo
Authors: Li Min , Liu Jin , Chen Xuefei , Dang Yijing , Shao Yong , Xu Zhiai , Zhang Wen
Published: January 2022

We designed an activatable NIR fluorescent probe for imaging of histone deacetylase 6 in cancer cells and in vivo.
Rapid preparation of water-soluble Ag@Au nanoclusters with bright deep-red emission
Authors: Yin Miao-Miao , Chen Wen-Qi , Hu Yan-Jun , Liu Yi , Jiang Feng-Lei
Published: January 2022

Deep-red (λem ∼710 nm) thiolated Ag@Au nanoclusters with a quantum yield of ∼18% were rapidly (∼12 min) prepared in aqueous solutions.