bluuebunny/crossref_metadata_2025 huggingface dataset:
The Informal Economy in Masande Ntshanga’sThe Reactive
Authors: Jewell Josh
Published: December 2022

The idea that (semi-)peripheral societies might follow developmental pathways distinct from those prescribed by globalization has been explored at length in the last twenty years by scholars such as G. G. Alcock, Rem Koolhaus, Jane Guyer, AbdouMaliq Simone, Achille Mbembe, and Sarah Nuttall. For scholars who have celebrated these kinds of sociality, the informal economy—as Keith Hart has called it—represents Gordimer’s “space that lies between camps”: an alternative social velocity to both the corrupt or “can’t do” state and global capitalist modernization. But more and more South African writers are using their work to interrogate the idea that living in the interstices of institutions such as the state, traditional community, and capital is in fact liberatory or counter-hegemonic. In this article I argue that Masande Ntshanga’s 2014 novelThe Reactiveis the paradigm of the “disaffection” of present fiction—as Ivan Vladislavić describes it—with contemporary South Africa.
A preliminary study of the rare earth element-enriched Twyfelskupje carbonatite complex, southern Namibia
Authors: Marlow Alan G. , Palmer Martin R.
Published: December 2022

The Twyfelskupje carbonatite complex, Southern Namibia, exhibits the typical igneous emplacement structures of carbonatites, including plugs, cone sheets and dyke stockworks. The excellent exposure allows for detailed studies of the high-level geochemical and structural evolution of the carbonatite, and the nature of the concomitant rare earth element mineralization. Radiogenic isotope analyses (Sr, Nd, Pb) reveal that, in common with many other carbonatites, the Twyfelskupje carbonatite complex appears to be predominantly derived from mixing between HIMU and EM1 mantle end-members. Following partial melting of these mantle sources, the geochemical and structural evolution of the Twyfelskupje carbonatite complex proceeded by a staged process involving separate magma pulses, a series of emplacement structures, sub-solidus crystallization, fractionation and low-temperature hydrothermal alteration. The dominant rare earth element minerals in the Twyfelskupje carbonatite complex are fluorcarbonates and monazite, and are characterized by variable Ca, high F and light rare earth elements in the order Ce>La>Nd. Comparison between the rare earth element concentrations of the whole rocks, dominant rare earth element minerals and carbonates suggests that ∼95 % of the total rare earth element abundance of the Twyfelskupje carbonatite complex is contained within fluorcarbonates and monazite. Overall, the early calcio-carbonatite plugs are rare earth element enriched (mean 4.47 wt % rare earth oxides) relative to the magnesio-carbonatite cone sheets (mean 2.51 wt % rare earth oxides).
Effect of mother bonded rearing on growth, health and physiological state of Murrah buffalo calves
Authors: Jamwal Shwetambri , Singh Pawan , Choudhary Sanjay , Kamboj Madan Lal , Thakur Rajneesh
Published: December 2022

We investigated the effect of different types of mother-young contacts (fenceline, restricted and no contact) on the health, growth performance, behaviour and physiological state of Murrah buffalo calves. A total of 24 calves were allocated to three groups of 8: NCM (no calf–mother contact), RCM (restricted calf–mother contact) and FCM (fenceline calf–mother contact). At three months of age, the FCM calves had a higher average body weight (58.6 ± 1.5 kg) than the RCM (52.8 ± 1.3 kg) and NCM (53.6 ± 1.3 kg) calves (P <0.05). The average daily gain (ADG) at three months of age was greater in FCM (0.6 ± 0.1 kg/d) than RCM (0.5 ± 0.1 kg/d) and NCM (0.5 ± 0.1 kg/d) calves (P <0.05). The mean immunoglobulin G (IgG) concentrations were significantly greater on d 7, 28, 42 and d 56 of sampling (P <0.05 for all comparisons) in FCM than RCM and NCM calves. The mean cortisol levels were highest in the NCM calves followed by RCM and the lowest values were observed in FCM calves on d 0, d 7, d 28, d 42 and d 56, respectively (P <0.05, for all recorded days). The diarrhoea score and eggs per gram of faeces (EPG) were significantly greater in the NCM group compared to the RCM and FCM groups. The time spent in cross sucking, licking inanimate objects and self-licking was greatest (P <0.05) in NCM calves, followed by RCM calves, and was almost non-existent in the FCM group on all the recorded weeks. Time spent in backward ear position was greater (P <0.05) in FCM than RCM and NCM calves. The average time spent in forward ear position was greatest (P <0.05) in the RCM calves followed by NCM with the lowest time observed in FCM calves. The mean duration of time spent by calves in the asymmetrical and axial ear position differed significantly (P <0.05) among NCM, RCM and FCM calves,P <0.05. The full and fenceline buffalo calf–mother contact system showed higher growth rates, lower levels of stress responses, oral stereotypies and eggs per gram of faeces. In addition, ear postures may be used as a dependable, and reliable measure of positive, low arousal emotional states.
Evidence for strain-specific virulence ofTrichomonas gallinaein African columbiformes
Authors: Dunn Jenny C. , Thomas Rebecca C. , Hipperson Helen , Sheehan Danaë J. , Orsman Chris , Mallord John , Goodman Simon J.
Published: December 2022

Infection by parasites or pathogens can have marked physiological impacts on individuals. In birds, infection may affect moult and feather growth, which is an energetically demanding time in the annual cycle. Previous work has suggested a potential link between clinically visibleTrichomonas gallinaeinfection and wing length in turtle dovesStreptopelia turturarriving on breeding grounds. First,T. gallinaeinfection was characterized in 149 columbids from 5 species, sampled on turtle dove wintering grounds in Senegal during the moulting period, testing whether infection byT. gallinaeis linked to moult.Trichomonas gallinaeprevalence was 100%, so rather than testing for differences between infected and uninfected birds, we tested for differences in moult progression between birds infected by differentT. gallinaestrains. Twelve strains ofT. gallinaewere characterized at the internal transcribed spacer 1 (ITS1)/5.8S/ITS2 region, of which 6 were newly identified within this study. In turtle doves only, evidence for differences in wing length by strain was found, with birds infected by strain Tcl-1 having wings nearly 6 mm longer than those infected with strain GEO. No evidence was found for an effect of strain identity within species on moult progression, but comparisons between infected and uninfected birds should be further investigated in species where prevalence is lower.
Phenomenology, quality of life, and predictors of reversibility in patients with drug-induced movement disorders: a prospective study
Authors: Anand Rohit , Pandey Shweta , Garg Ravindra Kumar , Singh Malhotra Hardeep , Shrivastava Shrikant , Kar Sujita Kumar , Rungta Sumit , Verma Rajesh , Kumar Sharma Praveen , Kumar Neeraj , Uniyal Ravi , Rizvi Imran
Published: December 2022

Background

Drug-induced movement disorders (DIMDs) form an important subgroup of secondary movement disorders, which despite conferring a significant iatrogenic burden, tend to be under-recognized and inappropriately managed.

Objective

We aimed to look into phenomenology, predictors of reversibility, and its impact on the quality of life of DIMD patients.

Methods

We conducted the study in the Department of Neurology at a tertiary-care centre in India. The institutional ethics-committee approved the study. We assessed 55-consecutive DIMD patients at presentation to our movement disorder clinic. Subsequently, they followed up to evaluate improvement in severity-scales (UPDRS, UDRS, BARS, AIMS) and quality of life (EuroQol-5D-5L). Wilcoxan-signed-rank test compared the scales at presentation and follow-up. Binary-logistic-regrerssion revealed the independent predictors of reversibility.

Results

Fourteen patients (25.45%) had acute-subacute DIMD and 41 (74.55%) had tardive DIMD. Tardive-DIMD occurred more commonly in the elderly (age 50.73±16.92 years, p<0.001). Drug-induced-Parkinsonism (DIP) was the most common MD, followed by tardivedyskinesia. Risperidone and levosulpiride were the commonest culprit drugs. Patients in both the groups showed a statistically significant response to drug-dose reduction /withdrawal based on follow-up assessment on clinical-rating-scales and quality of life scores (EQ-5D-5L). DIMD was reversible in 71.42% of acute-subacute DIMD and 24.40% of patients with chronic DIMD (p=0.001). Binary-logistic-regression analysis showed acute-subacute DIMDs and DIP as independent predictors of reversibility.

Conclusion

DIP is the commonest and often reversible drug-induced movement disorder. Levosulpiride is notorious for causing DIMD in the elderly, requiring strict pharmacovigilance.
Positive relation between dietary inflammatory index and osteoporosis in postmenopausal women
Authors: Mohammadisima Neda , Farshbaf-Khalili Azizeh , Ostadrahimi Alireza , Pourmoradian Samira
Published: December 2022

Abstract: Background: Previous studies have shown that some dietary components may be implicated in the aetiology of postmenopausal osteoporosis. Objective: We examined the relationship between Dietary Inﬂammatory Index (DII®) and osteoporosis in postmenopausal women. Study design: Eight hundred and fifty postmenopausal women aged 50–65 years were randomly selected from 87 health care centers. Bone mineral density (BMD) was measured using the anterior-posterior lumbar spine (L1-L4) and proximal femur neck through Hologic QDR 4500W (S/N 50266) dual-energy X-ray absorptiometry device. After checking inclusion and exclusion criteria and diagnosis of osteoporosis, 124 women with normal bone mineral density (normal-BMD) and 108 women with osteoporosis were selected. Demographic, anthropometric, physical activity, midwifery, and dietary intake questionnaires were completed. DII was calculated based on a valid and reliable 168-item semi-quantitative food frequency questionnaire using 37 (out of 45) food parameters. A Logistic regression model adjusted for confounders was applied to estimate osteoporosis’s odds ratio (OR) based on modeling DII as a continuous and dichotomous variable. Results: In this study, DII scores ranged from −3.71 (the most anti-inﬂammatory score) to +4.16 (the most pro-inﬂammatory score). The median DII value among the osteoporosis group was 0.97, among the normal group it was −0.31, indicating a more pro-inflammatory diet for osteoporosis. There were positive associations between osteoporosis and DII based on both continuous (Adjusted OR=3.467, 95% confidence interval (CI): 2.280–5.272, P-value<0.001) and dichotomous (Adjusted OR: DII ≤−0.31 / >−0.31=0.248, 95% CI: 0.110–0.561, P-value=0.001) measures in modeling adjusted for age, BMI, post-menopausal years, parity, education, total energy intake, and physical activity. Conclusions: These data suggest a pro-inflammatory diet, as indicated by increasing the DII score, may be a risk factor for osteoporosis in postmenopausal Iranian women.
Causes for Atlantic Freshwater Content Variability in the GECCO3 Ocean Synthesis
Authors: Liu Xin , Köhl Armin , Stammer Detlef
Published: December 2022

Regional freshwater content (FWC) changes are studied over the period 1961–2018 using the GECCO3 ocean synthesis. In four dynamically distinct regions of the Atlantic, the study identifies causes for FWC variability with a focus on interannual and decadal time‐scale changes. Results show that in each region, it is a combination of the surface freshwater flux and the net freshwater transport across the region's boundaries that act jointly in changing the respective FWC. Surface flux mainly contributes to the FWC variability on multi‐decadal time scales. The impact of surface flux also increases toward the tropics. On shorter time scales, it is especially horizontal transport fluctuations, leading to FWC changes in mid and high latitudes. Going from north to the south, the transport across a single meridional boundary becomes less correlated with the FWC changes but the net transport across both boundaries plays an increasingly important role. Moreover, the subpolar box is mainly gyre driven, which differs from the other two, essentially overturning driven, North Atlantic boxes. In the tropical Atlantic, the shallow overturning cell and the deep overturning contribute about equal amounts to the freshwater variations.
Neuronal haemoglobin induces loss of dopaminergic neurons in mouse Substantia nigra, cognitive deficits and cleavage of endogenous α-synuclein
Authors: Santulli Chiara , Bon Carlotta , De Cecco Elena , Codrich Marta , Narkiewicz Joanna , Parisse Pietro , Perissinotto Fabio , Santoro Claudio , Persichetti Francesca , Legname Giuseppe , Espinoza Stefano , Gustincich Stefano
Published: December 2022

Parkinson’s disease (PD) presents the selective loss of A9 dopaminergic (DA) neurons of Substantia Nigra pars compacta (SNpc) and the presence of intracellular aggregates called Lewy bodies. α-synuclein (α-syn) species truncated at the carboxy-terminal (C-terminal) accumulate in pathological inclusions and promote α-syn aggregation and toxicity. Haemoglobin (Hb) is the major oxygen carrier protein in erythrocytes. In addition, Hb is expressed in A9 DA neurons where it influences mitochondrial activity. Hb overexpression increases cells’ vulnerability in a neurochemical model of PD in vitro and forms cytoplasmic and nucleolar aggregates upon short-term overexpression in mouse SNpc. In this study, α and β-globin chains were co-expressed in DA cells of SNpc in vivo upon stereotaxic injections of an Adeno-Associated Virus isotype 9 (AAV9) and in DA iMN9D cells in vitro. Long-term Hb over-expression in SNpc induced the loss of about 50% of DA neurons, mild motor impairments, and deficits in recognition and spatial working memory. Hb triggered the formation of endogenous α-syn C-terminal truncated species. Similar α-syn fragments were found in vitro in DA iMN9D cells over-expressing α and β- globins when treated with pre-formed α-syn fibrils. Our study positions Hb as a relevant player in PD pathogenesis for its ability to trigger DA cells’ loss in vivo and the formation of C-terminal α-syn fragments.
BAF53A drives colorectal cancer development by regulating DUSP5-mediated ERK phosphorylation
Authors: Yang Ziqing , Huang Dandan , Meng Manqi , Wang Wencong , Feng Junyan , Fang Lekun , Chen Honglei , Zou Shaomin
Published: December 2022

BAF53A, an important subunit of the SWI/SNF epigenetic chromatin regulatory complex, has been implicated as the driver of diverse cancers. However, the role of BAF53A in colorectal cancer (CRC) remains poorly understood. Here, we examined the expression of BAF53A in CRC samples and observed that BAF53A was significantly upregulated in CRC tissues compared with paired adjacent normal tissues. In vitro and in vivo studies suggested that ectopic expression of BAF53A promoted colorectal cancer cell proliferation, colony formation, and tumorigenesis, whereas knockdown of BAF53A hindered these cellular functions. DUSP5 (dual-specificity phosphatase 5), an ERK1/2-specific endogenous phosphatase, was expressed at low levels in CRC. We found a negative correlation between BAF53A and DUSP5 expression in a set of CRC samples. Mechanistic studies revealed that P63 was a potential transcription repressor of DUSP5. BAF53A could interact with P63, decreasing the DUSP5 expression level and subsequently promoting ERK1/2 phosphorylation. Thus, our study provides insights into the applicability of the BAF53A-DUSP5-ERK1/2 axis as a potential therapeutic target in CRC.
Unconventional self-similar Hofstadter superconductivity from repulsive interactions
Authors: Shaffer Daniel , Wang Jian , Santos Luiz H.
Published: December 2022

Fractal Hofstadter bands have become widely accessible with the advent of moiré superlattices, opening the door to studies of the effect of interactions in these systems. In this work we employ a renormalization group (RG) analysis to demonstrate that the combination of repulsive interactions with the presence of a tunable manifold of Van Hove singularities provides a new mechanism for driving unconventional superconductivity in Hofstadter bands. Specifically, the number of Van Hove singularities at the Fermi energy can be controlled by varying the flux per unit cell and the electronic filling, leading to instabilities toward nodal superconductivity and chiral topological superconductivity with Chern number $${{{{{{{\mathcal{C}}}}}}}}=\pm 6$$
C
=
±
6
. The latter is characterized by a self-similar fixed trajectory of the RG flow and an emerging self-similarity symmetry of the order parameter. Our results establish Hofstadter quantum materials such as moiré heterostructures as promising platforms for realizing novel reentrant Hofstadter superconductors.
Perpendicular electric field drives Chern transitions and layer polarization changes in Hofstadter bands
Authors: Adak Pratap Chandra , Sinha Subhajit , Giri Debasmita , Mukherjee Dibya Kanti , Chandan  , Sangani L. D. Varma , Layek Surat , Mukherjee Ayshi , Watanabe Kenji , Taniguchi Takashi , Fertig H. A. , Kundu Arijit , Deshmukh Mandar M.
Published: December 2022

Moiré superlattices engineer band properties and enable observation of fractal energy spectra of Hofstadter butterfly. Recently, correlated-electron physics hosted by flat bands in small-angle moiré systems has been at the foreground. However, the implications of moiré band topology within the single-particle framework are little explored experimentally. An outstanding problem is understanding the effect of band topology on Hofstadter physics, which does not require electron correlations. Our work experimentally studies Chern state switching in the Hofstadter regime using twisted double bilayer graphene (TDBG), which offers electric field tunable topological bands, unlike twisted bilayer graphene. Here we show that the nontrivial topology reflects in the Hofstadter spectra, in particular, by displaying a cascade of Hofstadter gaps that switch their Chern numbers sequentially while varying the perpendicular electric field. Our experiments together with theoretical calculations suggest a crucial role of charge polarization changing concomitantly with topological transitions in this system. Layer polarization is likely to play an important role in the topological states in few-layer twisted systems. Moreover, our work establishes TDBG as a novel Hofstadter platform with nontrivial magnetoelectric coupling.
Detecting and quantifying liquid–liquid phase separation in living cells by model-free calibrated half-bleaching
Authors: Muzzopappa Fernando , Hummert Johan , Anfossi Michela , Tashev Stanimir Asenov , Herten Dirk-Peter , Erdel Fabian
Published: December 2022

Cells contain numerous substructures that have been proposed to form via liquid–liquid phase separation (LLPS). It is currently debated how to reliably distinguish LLPS from other mechanisms. Here, we benchmark different methods using well-controlled model systems in vitro and in living cells. We find that 1,6-hexanediol treatment and classical FRAP fail to distinguish LLPS from the alternative scenario of molecules binding to spatially clustered binding sites without phase-separating. In contrast, the preferential internal mixing seen in half-bleach experiments robustly distinguishes both mechanisms. We introduce a workflow termed model-free calibrated half-FRAP (MOCHA-FRAP) to probe the barrier at the condensate interface that is responsible for preferential internal mixing. We use it to study components of heterochromatin foci, nucleoli, stress granules and nuage granules, and show that the strength of the interfacial barrier increases in this order. We anticipate that MOCHA-FRAP will help uncover the mechanistic basis of biomolecular condensates in living cells.
Hepatic neddylation deficiency triggers fatal liver injury via inducing NF-κB-inducing kinase in mice
Authors: Xu Cheng , Zhou Hongyi , Jin Yulan , Sahay Khushboo , Robicsek Anna , Liu Yisong , Dong Kunzhe , Zhou Jiliang , Barrett Amanda , Su Huabo , Chen Weiqin
Published: December 2022

The conjugation of neural precursor cell expressed, developmentally downregulated 8 (NEDD8) to target proteins, termed neddylation, participates in many cellular processes and is aberrant in various pathological diseases. Its relevance to liver function and failure remains poorly understood. Herein, we show dysregulated expression of NAE1, a regulatory subunit of the only NEDD8 E1 enzyme, in human acute liver failure. Embryonic- and adult-onset deletion of NAE1 in hepatocytes causes hepatocyte death, inflammation, and fibrosis, culminating in fatal liver injury in mice. Hepatic neddylation deficiency triggers oxidative stress, mitochondrial dysfunction, and hepatocyte reprogramming, potentiating liver injury. Importantly, NF-κB-inducing kinase (NIK), a serine/Thr kinase, is a neddylation substrate. Neddylation of NIK promotes its ubiquitination and degradation. Inhibition of neddylation conversely causes aberrant NIK activation, accentuating hepatocyte damage and inflammation. Administration of N-acetylcysteine, a glutathione surrogate and antioxidant, mitigates liver failure caused by hepatic NAE1 deletion in adult male mice. Therefore, hepatic neddylation is important in maintaining postnatal and adult liver homeostasis, and the identified neddylation targets/pathways provide insights into therapeutically intervening acute liver failure.
Multiple pathways promote microtubule stabilization in senescent intestinal epithelial cells
Authors: Chu Siwei , Moujaber Ossama , Lemay Serge , Stochaj Ursula
Published: December 2022

Intestinal epithelial cells are critical for gastrointestinal homeostasis. However, their function declines during aging. The aging-related loss of organ performance is largely driven by the increase in senescent cells. To date, the hallmarks and molecular mechanisms related to cellular senescence are not fully understood. Microtubules control epithelial functions, and we identified microtubule stabilization as a phenotypic marker of senescent intestinal epithelial cells. The senescence inducer determined the pathway to microtubule stabilization. Specifically, enhanced microtubule stability was associated with α-tubulin hyperacetylation or increased abundance of the microtubule-binding protein tau. We show further that overexpression of MAPT, which encodes tau, augmented microtubule stability in intestinal epithelial cells. Notably, pharmacological microtubule stabilization was sufficient to induce cellular senescence. Taken together, this study provides new insights into the molecular mechanisms that control epithelial cell homeostasis. Our results support the concept that microtubule stability serves as a critical cue to trigger intestinal epithelial cell senescence.
The Wsp chemosensory system modulates c-di-GMP-dependent biofilm formation by integrating DSF quorum sensing through the WspR-RpfG complex in Lysobacter
Authors: Xu Kangwen , Wang Limin , Xiong Dan , Chen Hongjun , Tong Xinru , Shao Xiaolong , Li Tao , Qian Guoliang
Published: December 2022

The ubiquitous Wsp (wrinkly spreader phenotype) chemosensory system and DSF (diffusible signal factor) quorum sensing are two important chemically associated signaling systems that mediate bacterial communications between the host and environment. Although these two systems individually control biofilm formation in pathogenic bacteria via the ubiquitous second messenger c-di-GMP, their crosstalk mechanisms remain elusive. Here we present a scenario from the plant-beneficial and antifungal bacterium Lysobacter enzymogenes OH11, where biofilm formation favors the colonization of this bacterium in fungal hyphae. We found that the Wsp system regulated biofilm formation via WspR-mediated c-di-GMP signaling, whereas DSF system did not depend on the enzymatic activity of RpfG to regulate biofilm formation. We further found that WspR, a diguanylate cyclase (DGC) responsible for c-di-GMP synthesis, could directly bind to one of the DSF signaling components, RpfG, an active phosphodiesterase (PDE) responsible for c-di-GMP degradation. Thus, the WspR-RpfG complex represents a previously undiscovered molecular linker connecting the Wsp and DSF systems. Mechanistically, RpfG could function as an adaptor protein to bind and inhibit the DGC activity of unphosphorylated WspR independent of its PDE activity. Phosphorylation of WspR impaired its binding affinity to RpfG and also blocked the ability of RpfG to act as an adaptor protein, which enabled the Wsp system to regulate biofilm formation in a c-di-GMP-dependent manner by dynamically integrating the DSF system. Our findings demonstrated a previously uncharacterized mechanism of crosstalk between Wsp and DSF systems in plant-beneficial and antifungal bacteria.
Bone metabolism during strict head-down tilt bed rest and exposure to elevated levels of ambient CO2
Authors: McGrath Emily R. , Frings-Meuthen Petra , Sibonga Jean , Heer Martina , Clement Gilles R. , Mulder Edwin , Smith Scott M. , Zwart Sara R.
Published: December 2022

Astronauts on the International Space Station are exposed to levels of atmospheric carbon dioxide (CO2) above typical terrestrial levels. We explored the possibility that increased levels of ambient CO2 further stimulate bone resorption during bed rest. We report here data from 2 ground-based spaceflight analog studies in which 12 male and 7 female subjects were placed in a strict 6° head-down tilt (HDT) position for either 30 days at 0.5% ambient CO2 or 60 days with nominal environmental exposure to CO2. Bone mineral density (BMD) and bone mineral content (BMC) were determined using dual-energy X-ray absorptiometry (DXA). Blood and urine were collected before and after HDT for biochemical analysis. No change was detected in either BMD or BMC, as expected given the study duration. Bone resorption markers increased after bed rest as expected; however, elevated CO2 had no additive effect. Elevated CO2 did not affect concentrations of minerals in serum and urine. Serum parathyroid hormone and 1,25-dihydroxyvitamin D were both reduced after bed rest, likely secondary to calcium efflux from bone. In summary, exposure to 0.5% CO2 for 30 days did not exacerbate the typical bone resorption response observed after HDT bed rest. Furthermore, results from these strict HDT studies were similar to data from previous bed rest studies, confirming that strict 30–60 days of HDT can be used to evaluate changes in bone metabolism. This is valuable in the continuing effort to develop and refine efficacious countermeasure protocols to mitigate bone loss during spaceflight in low-Earth orbit and beyond.
Identification and prediction of Parkinson’s disease subtypes and progression using machine learning in two cohorts
Authors: Dadu Anant , Satone Vipul , Kaur Rachneet , Hashemi Sayed Hadi , Leonard Hampton , Iwaki Hirotaka , Makarious Mary B. , Billingsley Kimberley J. , Bandres‐Ciga Sara , Sargent Lana J. , Noyce Alastair J. , Daneshmand Ali , Blauwendraat Cornelis , Marek Ken , Scholz Sonja W. , Singleton Andrew B. , Nalls Mike A. , Campbell Roy H. , Faghri Faraz
Published: December 2022

The clinical manifestations of Parkinson’s disease (PD) are characterized by heterogeneity in age at onset, disease duration, rate of progression, and the constellation of motor versus non-motor features. There is an unmet need for the characterization of distinct disease subtypes as well as improved, individualized predictions of the disease course. We used unsupervised and supervised machine learning methods on comprehensive, longitudinal clinical data from the Parkinson’s Disease Progression Marker Initiative (n = 294 cases) to identify patient subtypes and to predict disease progression. The resulting models were validated in an independent, clinically well-characterized cohort from the Parkinson’s Disease Biomarker Program (n = 263 cases). Our analysis distinguished three distinct disease subtypes with highly predictable progression rates, corresponding to slow, moderate, and fast disease progression. We achieved highly accurate projections of disease progression 5 years after initial diagnosis with an average area under the curve (AUC) of 0.92 (95% CI: 0.95 ± 0.01) for the slower progressing group (PDvec1), 0.87 ± 0.03 for moderate progressors, and 0.95 ± 0.02 for the fast-progressing group (PDvec3). We identified serum neurofilament light as a significant indicator of fast disease progression among other key biomarkers of interest. We replicated these findings in an independent cohort, released the analytical code, and developed models in an open science manner. Our data-driven study provides insights to deconstruct PD heterogeneity. This approach could have immediate implications for clinical trials by improving the detection of significant clinical outcomes. We anticipate that machine learning models will improve patient counseling, clinical trial design, and ultimately individualized patient care.
Muscle stem cells and fibro-adipogenic progenitors in female pelvic floor muscle regeneration following birth injury
Authors: Sesillo Francesca Boscolo , Rajesh Varsha , Wong Michelle , Duran Pamela , Rudell John B. , Rundio Courtney P. , Baynes Brittni B. , Laurent Louise C. , Sacco Alessandra , Christman Karen L. , Alperin Marianna
Published: December 2022

Pelvic floor muscle (PFM) injury during childbirth is a key risk factor for pelvic floor disorders that affect millions of women worldwide. Muscle stem cells (MuSCs), supported by the fibro-adipogenic progenitors (FAPs) and immune cells, are indispensable for the regeneration of injured appendicular skeletal muscles. However, almost nothing is known about their role in PFM regeneration following birth injury. To elucidate the role of MuSCs, FAPs, and immune infiltrate in this context, we used radiation to perturb cell function and followed PFM recovery in a validated simulated birth injury (SBI) rat model. Non-irradiated and irradiated rats were euthanized at 3,7,10, and 28 days post-SBI (dpi). Twenty-eight dpi, PFM fiber cross-sectional area (CSA) was significantly lower and the extracellular space occupied by immune infiltrate was larger in irradiated relative to nonirradiated injured animals. Following SBI in non-irradiated animals, MuSCs and FAPs expanded significantly at 7 and 3 dpi, respectively; this expansion did not occur in irradiated animals at the same time points. At 7 and 10 dpi, we observed persistent immune response in PFMs subjected to irradiation compared to non-irradiated injured PFMs. CSA of newly regenerated fibers was also significantly smaller following SBI in irradiated compared to non-irradiated injured PFMs. Our results demonstrate that the loss of function and decreased expansion of MuSCs and FAPs after birth injury lead to impaired PFM recovery. These findings form the basis for further studies focused on the identification of novel therapeutic targets to counteract postpartum PFM dysfunction and the associated pelvic floor disorders.
Polydactyly-derived allogeneic chondrocyte cell-sheet transplantation with high tibial osteotomy as regenerative therapy for knee osteoarthritis
Authors: Hamahashi Kosuke , Toyoda Eriko , Ishihara Miya , Mitani Genya , Takagaki Tomonori , Kaneshiro Nagatoshi , Maehara Miki , Takahashi Takumi , Okada Eri , Watanabe Ayako , Nakamura Yoshihiko , Kato Reiko , Matoba Ryo , Takagi Takehiko , Akutsu Hidenori , Umezawa Akihiro , Kobayashi Hiroyuki , Akamatsu Tadashi , Yamato Masayuki , Okano Teruo , Watanabe Masahiko , Sato Masato
Published: December 2022

Allogeneic cell therapies are not fully effective in treating osteoarthritis of the knee (OAK). We recently reported that transplantation of autologous chondrocyte cell-sheets along with open-wedge high tibial osteotomy promoted hyaline cartilage repair in humans. Here we describe our regenerative therapy for OAK using polydactyly-derived allogeneic chondrocyte cell-sheets (PD sheets) and temperature-responsive culture inserts. Ten patients with OAK and cartilage defects categorized arthroscopically as Outerbridge grade III or IV received the therapy. Cartilage viscoelasticity and thickness were assessed before and after transplantation. Arthroscopic biopsies obtained 12 months after transplantation were analyzed histologically. Gene expression was analyzed to evaluate the PD sheets. In this small initial longitudinal series, PD sheet transplantation was effective in treating OAK, as indicated by changes in cartilage properties. Gene marker sets in PD sheets may predict outcomes after therapy and provide markers for the selection of donor cells. This combined surgery may be an ideal regenerative therapy with disease-modifying effects in OAK patients.
Serum antibody profiling identifies vaccine-induced correlates of protection against aerosolized ricin toxin in rhesus macaques
Authors: Roy Chad J. , Ehrbar Dylan , Van Slyke Greta , Doering Jennifer , Didier Peter J. , Doyle-Meyers Lara , Donini Oreola , Vitetta Ellen S. , Mantis Nicholas J.
Published: December 2022

Inhalation of the biothreat agent, ricin toxin (RT), provokes a localized inflammatory response associated with pulmonary congestion, edema, neutrophil infiltration, and severe acute respiratory distress. The extreme toxicity of RT is the result of the toxin’s B chain (RTB) promoting rapid uptake into alveolar macrophages and lung epithelial cells, coupled with the A chain’s (RTA) potent ribosome-inactivating properties. We previously reported that intramuscular vaccination of rhesus macaques with a lyophilized, alum-adsorbed recombinant RTA subunit vaccine (RiVax®) was sufficient to confer protection against a lethal dose of aerosolized RT. That study implicated RT-specific serum IgG, toxin-neutralizing activity (TNA), and epitope-specific responses as being associated with immunity. However, it was not possible to define actual correlates of protection (COP) because all vaccinated animals survived the RT challenge. We addressed the issue of COP in the current study, by vaccinating groups of rhesus macaques with RiVax® following the previously determined protective regimen (100 µg on study days 0, 30 and 60) or one of two anticipated suboptimal regimens (100 µg on study days 30 and 60; 35 µg on study days 0, 30, and 60). Two unvaccinated animals served as controls. The animals were challenged with ~5 × LD50s of aerosolized RT on study day 110. We report that all vaccinated animals seroconverted prior to RT challenge, with the majority also having measurable TNA, although neither antibody levels nor TNA reached statistical significance with regard to a correlation with protection. By contrast, survival correlated with pre-challenge, epitope-specific serum IgG levels, derived from a competitive sandwich ELISA using a panel of toxin-neutralizing monoclonal antibodies directed against distinct epitopes on RiVax®. The identification of a species-neutral, competitive ELISA that correlates with vaccine-induced protection against RT in nonhuman represents an important advance in the development of medical countermeasures (MCM) against a persistent biothreat.
A genetically modified Plasmodium berghei parasite as a surrogate for whole-sporozoite vaccination against P. vivax malaria
Authors: Moita Diana , Maia Teresa G. , Duarte Miguel , Andrade Carolina M. , Albuquerque Inês S. , Dwivedi Ankit , Silva Joana C. , González-Céron Lilia , Janse Chris J. , Mendes António M. , Prudêncio Miguel
Published: December 2022

Two malaria parasite species, Plasmodium falciparum (Pf) and P. vivax (Pv) are responsible for most of the disease burden caused by malaria. Vaccine development against this disease has focused mainly on Pf. Whole-sporozoite (WSp) vaccination, targeting pre-erythrocytic (PE) parasite stages, is a promising strategy for immunization against malaria and several PfWSp-based vaccine candidates are currently undergoing clinical evaluation. In contrast, no WSp candidates have been developed for Pv, mainly due to constraints in the production of Pv sporozoites in the laboratory. Recently, we developed a novel approach for WSp vaccination against Pf based on the use of transgenic rodent P. berghei (Pb) sporozoites expressing immunogens of this human-infective parasite. We showed that this platform can be used to deliver PE Pf antigens, eliciting both targeted humoral responses and cross-species cellular immune responses against Pf. Here we explored this WSp platform for the delivery of Pv antigens. As the Pv circumsporozoite protein (CSP) is a leading vaccine candidate antigen, we generated a transgenic Pb parasite, PbviVac, that, in addition to its endogenous PbCSP, expresses PvCSP under the control of a strictly PE promoter. Immunofluorescence microscopy analyses confirmed that both the PbCSP and the PvCSP antigens are expressed in PbviVac sporozoites and liver stages and that PbviVac sporozoite infectivity of hepatic cells is similar to that of its wild-type Pb counterpart. Immunization of mice with PbviVac sporozoites elicits the production of anti-PvCSP antibodies that efficiently recognize and bind to Pv sporozoites. Our results warrant further development and evaluation of PbviVac as a surrogate for WSp vaccination against Pv malaria.
Less invasive surfactant administration via infant feeding tube versus InSurE method in preterm infants: a randomized control trial
Authors: Anand Rohit , Nangia Sushma , Kumar Gunjana , Mohan M. Vishnu , Dudeja Ajay
Published: December 2022

There is growing evidence that less invasive surfactant administration (LISA) is a better alternative to the standard Intubate-surfactant-extubate (InSurE) procedure in spontaneously breathing preterm infants with RDS. The infant feeding tube is easily available and cost-effective in comparison to special catheters used for surfactant administration in various studies on LISA and cost-effective health care is the need of the hour for countries like ours which are Low and middle-income countries(LMICs).The present study was planned to compare the total duration of respiratory support in preterm babies between 26 to 34 weeks of gestation with RDS requiring surfactant therapy administered by LISA technique using an infant feeding tube or InSurE method. In this unblinded randomised controlled trial, 150 infants were allocated to LISA (n = 74) or InSurE group (n = 76). An 8F feeding tube was used for surfactant delivery in the LISA group. The primary outcome was the total duration of respiratory support required and secondary outcomes included the proportion of babies developing BPD, IVH, PDA, NEC, ROP, air leaks, CPAP failure, and those requiring a repeat dose of surfactant along with the duration of hospitalization, time to regain birth weight and Death. The baseline variables including birth weight and gestation age were similar in the two groups. Nearly 27% of the mothers did not receive any dose of antenatal steroids (ANS) while around 37% of the mothers received complete course of ANS. A high proportion of babies (57%) were delivered by cesarean section. Intrapharyngeal reflux was significantly more in babies who received surfactant with the LISA method in comparison to InSurE technique (32% v/s 3%, p < 0.001). There was no statistically significant difference in the primary outcome of the total duration of respiratory support in both groups with a median duration of 120 h, 95% CI (69–235), and p = 0.618. The need for invasive mechanical ventilation was significantly lower in the LISA group (p = 0.017) with RR (95% CI) 0.498 (0.259–0.958). The rate of CPAP failure was significantly lower in the LISA group (p = 0.005) with RR (95% CI) 0.55 (0.34–0.89). In this study, the total duration of hospital stay was reduced in the LISA group (19 days) compared to InSurE group (26 days), although the same was not statistically significant. LISA with an 8F feeding tube is feasible and an effective strategy for surfactant administration which resulted in a significant reduction in CPAP failure and the need for invasive mechanical ventilation.

Trial registration: www.ctri.nic.in id CTRI/2020/05/025360. Trial was registered at CTRI on 26/05/2020. First case of trial was enrolled on 28/05/2020.
Enhancing photon generation rate with broadband room-temperature quantum memory
Authors: Zhang Chao-Ni , Pang Xiao-Ling , Dou Jian-Peng , Li Hang , Yang Tian-Huai , Jin Xian-Min
Published: December 2022

Photons with high generation rate is one of the essential resources for quantum communication, quantum computing and quantum metrology. Due to the naturally memory-built-in feature, the memory-based photon source is a promising route towards large-scale quantum information processing. However, such photon sources are mostly implemented in extremely low-temperature ensembles or isolated systems, limiting its physical scalability. Here we realize a single-photon source based on a far off-resonance Duan-Lukin-Cirac-Zoller quantum memory at broadband and room-temperature regime. By harnessing high-speed feedback control and repeat-until-success write process, the photon generation rate obtains considerable enhancement up to tenfold. Such a memory-enhanced single-photon source, based on the broadband room-temperature quantum memory, suggests a promising way for establishing large-scale quantum memory-enabled network at ambient condition.
Functional evaluation of a novel kisspeptin analogue on the reproduction of female goldfish
Authors: Rabouti Hanieh , Asghari S. Mohsen , Sariri Reihaneh , Balalaie Saeed , Valipour AbdolMajid , Omidian Navid , Heidari Behrooz
Published: December 2022

Kisspeptin (kp) is a key regulator of reproduction, which stimulates sexual maturation and gametogenesis in mammals, amphibians, and teleosts. In the present study, to enhance the biological activity of kp10, a novel analog (referred to as M-kp10) was designed based on the endogenous goldfish variant, in which phenylalanine 6 was substituted by tryptophan and the N-terminus was acetylated. Compared with the native kp-10 and salmon gonadotropin-releasing hormone (GnRH3), the effect of M-kp10 on sexual hormones and reproductive indices as well as the expression ofkiss1,cyp19a1, andkiss1ragenes in goldfish (Carassius auratus) was investigated. In practice, peptides were synthesized based on the standard Fmoc-solid-phase peptide synthesis and purified by employing RP-HPLC, followed by approving their structure using ESI-MS. The results showed that M-kp10 increased significantly 17,20β-DHP, LH, FSH and E2 as well as fecundity, hatching and fertilization percentages than the other peptides. Histological studies revealed that M-kp10 led to the faster growth of ovarian follicles compared to the kp-10 and GnRH3. The genes ofcyp19a1,kiss1ra, andkiss1were remarkably more expressed after treatment with M-kp10. In conclusion, the results indicated the superiority of M-kp10 over kp-10 in inducing sexual maturation and accelerating the percentage of fecundity, suggesting that M-kp10 could be a promising candidate for application in the artificial breeding of fish.
Simultaneous loading of PCR-based multiple fragments on mouse artificial chromosome vectors in DT40 cell for gene delivery
Authors: Yamazaki Kyotaro , Matsuo Kyosuke , Okada Akane , Uno Narumi , Suzuki Teruhiko , Abe Satoshi , Hamamichi Shusei , Kishima Nanami , Togai Shota , Tomizuka Kazuma , Kazuki Yasuhiro
Published: December 2022

Homology-directed repair-mediated knock-in (HDR-KI) in combination with CRISPR-Cas9-mediated double strand break (DSB) leads to high frequency of site-specific HDR-KI. While this characteristic is advantageous for generating genetically modified cellular and animal models, HDR-KI efficiency in mammalian cells remains low. Since avian DT40 cells offer distinct advantage of high HDR-KI efficiency, we expanded this practicality to adapt to mammalian research through sequential insertion of target sequences into mouse/human artificial chromosome vector (MAC/HAC). Here, we developed the simultaneous insertion of multiple fragments by HDR method termed the simHDR wherein a target sequence and selection markers could be loaded onto MAC simultaneously. Additionally, preparing each HDR donor containing homology arm by PCR could bypass the cloning steps of target sequence and selection markers. To confirm the functionality of the loaded HDR donors, we constructed a MAC with human leukocyte antigen A (HLA-A) gene in the DT40 cells, and verified the expression of this genomic region by reverse transcription PCR (RT-PCR) and western blotting. Collectively, the simHDR offers a rapid and convenient approach to generate genetically modified models for investigating gene functions, as well as understanding disease mechanisms and therapeutic interventions.
The fate of visual long term memories for images across weeks in adults and children
Authors: Goujon Annabelle , Mathy Fabien , Thorpe Simon
Published: December 2022

What is the content and the format of visual memories in Long Term Memory (LTM)? Is it similar in adults and children? To address these issues, we investigated, in both adults and 9-year-old children, how visual LTM is affected over time and whether visual vs semantic features are affected differentially. In a learning phase, participants were exposed to hundreds of meaningless and meaningful images presented once or twice for either 120 ms or 1920 ms. Memory was assessed using a recognition task either immediately after learning or after a delay of three or six weeks. The results suggest that multiple and extended exposures are crucial for retaining an image for several weeks. Although a benefit was observed in the meaningful condition when memory was assessed immediately after learning, this benefit tended to disappear over weeks, especially when the images were presented twice for 1920 ms. This pattern was observed for both adults and children. Together, the results call into question the dominant models of LTM for images: although semantic information enhances the encoding & maintaining of images in LTM when assessed immediately, this seems not critical for LTM over weeks.
Attenuation law of concentrated stress under coal pillar of close coal seams and its application
Authors: Kang Qingtao , He Fulian , Yin Shuaifeng , Yang Yang
Published: December 2022

When mining the multiple coal seams in close proximity, the coal pillar left in the goaf causes stress concentration in the floor. The layout of mining roadway in lower short distance coal seam is affected by the propagation of concentrated stress caused by the upper coal pillar. To determine the reasonable distance of the roadway in the lower coal seam outside the coal pillar, the attenuation law of concentrated stress outside the coal pillar boundary has been studied through simulation model, theoretical analysis, and example analysis. The results show that the concentrated stress of coal pillar decreases with the distance from the coal pillar. At the coal pillar boundary position, the stress change rate reaches the maximum in the floor with different depths, and the stress decreases rapidly in the floor strata outside the coal pillar. Under the same stress condition, the roadway layout in strata at different depths is different. The joint formula of stress and stress change rate was deduced to determine the reasonable horizontal distance of roadway outside coal pillar. The results obtained by the numerical simulation fitting formula and the theoretical calculation formula are close to each other when calculating an engineering example. The roadway pressure appearance is not obvious in the experiment and physical simulation, which indicates that the theoretical formula can satisfy the requirement of engineering calculation. The method provides a reference for roadway location selection under similar conditions.