bluuebunny/crossref_metadata_2025 huggingface dataset:
Derivation of a Kalman-type filter for linear systems with pointwise delay in signal noise
Authors: Abuasbeh Kinda , Bashirov Agamirza E.
Published: September 2022

Recently, it was demonstrated that a modification of the Kalman-filtering model with a pointwise delay of the signal noise could improve communication with considerably distanced spacecraft. However, a complete and correct derivation of the equations of the Kalman-type filter for this case has not yet been provided. In this paper, we close this gap. The method of derivation is based on a passage from the distributed delay to pointwise by means of a delta function. The derived equations constitute a system of first-order partial differential equations with the initial and boundary conditions.
Phraseological competence in IELTS academic writing task 2: phraseological units and test-takers’ perceptions and use
Authors: Estaji Masoomeh , Hashemi Mina
Published: September 2022

This study intended to explore the different types of phraseological units in IELTS academic writing task 2 and probe into the IELTS candidates’ perceptions of phraseological competence. To this end, a corpus entailing 100 essays (26,423 words) written for IELTS writing task 2 was scrutinized, through which phraseological units were extracted and their types were identified based on Moon’s (Phraseology: Theory, analysis, and application, 1998) typology. In addition, semi-structured interviews were conducted with nine IELTS candidates. The results indicated that simple formulae were the most commonly used phraseological units in IELTS writing task 2. The interview data, using inductive thematic and summative content analyses, also demonstrated that IELTS candidates have had varying perceptions of phraseological competence, wherein higher band score candidates appeared to have a deeper and more accurate understanding of the concept. As for the candidates’ perceived phraseological competence, they were found to under- or overestimate their own competence at using phraseology. The findings of the study can be employed in making learner dictionaries based on the phraseologies used in IELTS.
Assessment and language improvement: the effect of peer assessment (PA) on reading comprehension, reading motivation, and vocabulary learning among EFL learners
Authors: Ritonga Mahyudin , Tazik Khalil , Omar Abdulfattah , Saberi Dehkordi Elham
Published: September 2022

Assessment is an inseparable part of teaching and learning, and it helps teachers and students to modify their teaching and learning processes. One type of assessment is peer assessment (PA), and its effects were examined on developing Iranian EFL learners’ reading comprehension (RC), reading motivation (RM) and vocabulary learning (VL) in this research. To achieve this goal, 60 Iranian EFL students at the intermediate level and with the age range of 18 to 26 years were selected based on a convenience sampling method and divided into two groups: the control group (CG) and experimental group (EG). After that, the groups took the pre-tests of RC, RM, and VL. The EG then was divided into six sub-groups of five, and PA was applied to evaluate their reading and vocabulary performances. The learners in the EG checked their classmates’ performances in peers with the teacher’s help. In the CG class, the participants themselves assessed their own performances after each test with the help of the teacher. After a 15-session treatment, the post-tests of vocabulary, RM, and RC were carried out on both groups. The outcomes of the one-way ANCOVA tests demonstrated that the EG outflanked the CG on the three post-tests of RC, RM, and VL. In fact, the results indicated that using PA generated positive effects on Iranian EFL learners’ RC, RM, and VL. It can be claimed that the PA is a practical technique to improve EFL learners’ language learning. The implications of this research can reduce students’ dependency on teachers and increase their independence in the evaluation process.
Development and validation of a potential assessment inventory for assessing EFL teachers’ ecological agency
Authors: Ghamoushi Masoumeh , Zenouzagh Zohre Mohammadi , Hashamdar Mohammad
Published: September 2022

Teacher agency as an influential factor in teacher professionalism has recently gained global inquiry in the EFL context. However, no valid instrument has ever been designed to evaluate EFL teachers’ ecological agency. This gap prompted the researchers of the current study to develop and validate a questionnaire to assess EFL teachers’ ecological agency. In the first phase, a comprehensive review of the literature and semi-structured interviews were conducted to determine the underlying components of the teacher ecological (TEA) questionnaire based on Priestley et al.’s (Flip the System134–148, 2015) ecological agency model. In the second phase, the newly developed TEA questionnaire including 40 items was subjected to reliability and validity issues. Therefore, it was piloted with 222 Iranian EFL teachers selected through non-probability convenience sampling. The Cronbach alpha results confirmed an acceptable reliability index (.858). The results of factor analysis revealed that the number of items was reduced to 37 and indicated that the data on teacher ecological agency loaded on 3 components: iterational (9 items), practical-evaluative (14 items), and projective (10 items). In addition, the structural equation modeling (SEM) results confirmed that the model enjoyed sound psychometric properties. The upshots of the current study have undoubtedly significant implications for teacher educators and teaching practitioners.
Mitochondrial dysfunction is a key pathological driver of early stage Parkinson’s
Authors: Toomey Christina E. , Heywood Wendy E. , Evans James R. , Lachica Joanne , Pressey Sarah N. , Foti Sandrine C. , Al Shahrani Mesfer , D’Sa Karishma , Hargreaves Iain P. , Heales Simon , Orford Michael , Troakes Claire , Attems Johannes , Gelpi Ellen , Palkovits Miklos , Lashley Tammaryn , Gentleman Steve M. , Revesz Tamas , Mills Kevin , Gandhi Sonia
Published: September 2022

Background

The molecular drivers of early sporadic Parkinson’s disease (PD) remain unclear, and the presence of widespread end stage pathology in late disease masks the distinction between primary or causal disease-specific events and late secondary consequences in stressed or dying cells. However, early and mid-stage Parkinson’s brains (Braak stages 3 and 4) exhibit alpha-synuclein inclusions and neuronal loss along a regional gradient of severity, from unaffected-mild-moderate-severe. Here, we exploited this spatial pathological gradient to investigate the molecular drivers of sporadic PD.

Methods

We combined high precision tissue sampling with unbiased large-scale profiling of protein expression across 9 brain regions in Braak stage 3 and 4 PD brains, and controls, and verified these results using targeted proteomic and functional analyses.

Results

We demonstrate that the spatio-temporal pathology gradient in early-mid PD brains is mirrored by a biochemical gradient of a changing proteome. Importantly, we identify two key events that occur early in the disease, prior to the occurrence of alpha-synuclein inclusions and neuronal loss: (i) a metabolic switch in the utilisation of energy substrates and energy production in the brain, and (ii) perturbation of the mitochondrial redox state. These changes may contribute to the regional vulnerability of developing alpha-synuclein pathology. Later in the disease, mitochondrial function is affected more severely, whilst mitochondrial metabolism, fatty acid oxidation, and mitochondrial respiration are affected across all brain regions.

Conclusions

Our study provides an in-depth regional profile of the proteome at different stages of PD, and highlights that mitochondrial dysfunction is detectable prior to neuronal loss, and alpha-synuclein fibril deposition, suggesting that mitochondrial dysfunction is one of the key drivers of early disease.
Regulating microglial miR-155 transcriptional phenotype alleviates Alzheimer’s-induced retinal vasculopathy by limiting Clec7a/Galectin-3+ neurodegenerative microglia
Authors: Shi Haoshen , Yin Zhuoran , Koronyo Yosef , Fuchs Dieu-Trang , Sheyn Julia , Davis Miyah R. , Wilson Jered W. , Margeta Milica A. , Pitts Kristen M. , Herron Shawn , Ikezu Seiko , Ikezu Tsuneya , Graham Stuart L. , Gupta Vivek K. , Black Keith L. , Mirzaei Mehdi , Butovsky Oleg , Koronyo-Hamaoui Maya
Published: September 2022

Single cell RNA sequencing studies identified novel neurodegeneration-associated microglial (MGnD/DAM) subtypes activated around cerebral amyloid plaques. Micro-RNA (miR)-155 of the TREM2-APOE pathway was shown to be a key transcriptional regulator of MGnD microglial phenotype. Despite growing interest in studying manifestations of Alzheimer’s disease (AD) in the retina, a CNS organ accessible to noninvasive high-resolution imaging, to date MGnD microglia have not been studied in the AD retina. Here, we discovered the presence and increased populations of Clec7a+ and Galectin-3+ MGnD microglia in retinas of transgenic APPSWE/PS1L166P AD-model mice. Conditionally targeting MGnD microglia by miR-155 ablation via the tamoxifen-inducible CreERT2 system in APPSWE/PS1L166P mice diminished retinal Clec7a+ and Galectin-3+ microglial populations while increasing homeostatic P2ry12+ microglia. Retinal MGnD microglia were often adhering to microvessels; their depletion protected the inner blood-retina barrier and reduced vascular amyloidosis. Microglial miR-155 depletion further limits retinal inflammation. Mass spectrometry analysis revealed enhanced retinal PI3K-Akt signaling and predicted IL-8 and Spp1 decreases in mice with microglia-specific miR-155 knockout. Overall, this study identified MGnD microglia in APPSWE/PS1L166P mouse retina. Transcriptional regulation of these dysfunctional microglia mitigated retinal inflammation and vasculopathy. The protective effects of microglial miR-155 ablation should shed light on potential treatments for retinal inflammation and vascular damage during AD and other ocular diseases.
Clinical validation of a population-based input function for 20-min dynamic whole-body 18F-FDG multiparametric PET imaging
Authors: Dias André H. , Smith Anne M. , Shah Vijay , Pigg David , Gormsen Lars C. , Munk Ole L.
Published: September 2022

Purpose

Contemporary PET/CT scanners can use 70-min dynamic whole-body (D-WB) PET to generate more quantitative information about FDG uptake than just the SUV by generating parametric images of FDG metabolic rate (MRFDG). The analysis requires the late (50–70 min) D-WB tissue data combined with the full (0–70 min) arterial input function (AIF). Our aim was to assess whether the use of a scaled population-based input function (sPBIF) obviates the need for the early D-WB PET acquisition and allows for a clinically feasible 20-min D-WB PET examination.

Methods

A PBIF was calculated based on AIFs from 20 patients that were D-WB PET scanned for 120 min with simultaneous arterial blood sampling. MRFDG imaging using PBIF requires that the area under the curve (AUC) of the sPBIF is equal to the AUC of the individual patient’s input function because sPBIF AUC bias translates into MRFDG bias. Special patient characteristics could affect the shape of their AIF. Thus, we validated the use of PBIF in 171 patients that were divided into 12 subgroups according to the following characteristics: diabetes, cardiac ejection fraction, blood pressure, weight, eGFR and age. For each patient, the PBIF was scaled to the aorta image-derived input function (IDIF) to calculate a sPBIF, and the AUC bias was calculated.

Results

We found excellent agreement between the AIF and IDIF at all times. For the clinical validation, the use of sPBIF led to an acceptable AUC bias of 1–5% in most subgroups except for patients with diabetes or patients with low eGFR, where the biases were marginally higher at 7%. Multiparametric MRFDG images based on a short 20-min D-WB PET and sPBIF were visually indistinguishable from images produced by the full 70-min D-WB PET and individual IDIF.

Conclusions

A short 20-min D-WB PET examination using PBIF can be used for multiparametric imaging without compromising the image quality or precision of MRFDG. The D-WB PET examination may therefore be used in clinical routine for a wide range of patients, potentially allowing for more precise quantification in e.g. treatment response imaging.
Solar farm cable layout optimization as a graph problem
Authors: Gritzbach Sascha , Stampa Dominik , Wolf Matthias
Published: September 2022

We introduce the Solar Farm Cable Layout Problem (SoFaCLaP), a novel graph-theoretic optimization problem. SoFaCLaP formalizes the task of finding a cost-optimal cable layout in a solar farm where PV string positions are already determined but the positions of other components such as transformers can be picked from a set of candidate positions. The problem statement incorporates a network flow model in which the flow value of a connection represents the number of strings that are (indirectly) connected to a transformer via this connection. A mixed-integer linear program (MILP) formulation is proposed that uses binary variables to indicate which of several available cable types is chosen for each connection. We propose a framework to randomly generate benchmark instances to evaluate any algorithmic approach to SoFaCLaP. In particular, we generate a set of instances based on real-world solar farm characteristics. With an extensive evaluation of the MILP formulation on those instances we establish mixed-integer linear programming as a baseline for future algorithmic approaches to finding solar farm cable layouts.
Qualitative evaluation of the Systems Analysis and Improvement Approach as a strategy to increase HIV testing in family planning clinics using the Consolidated Framework for Implementation Research and the Implementation Outcomes Framework
Authors: Eastment McKenna C. , Long Jessica E. , Wanje George , Richardson Barbra A. , Mwaringa Emily , Sherr Kenneth , Barnabas Ruanne V. , Mandaliya Kishorchandra , Jaoko Walter , McClelland R. Scott
Published: September 2022

Background

Significant gaps remain in HIV testing and counseling (HTC) in family planning (FP) clinics. To address these gaps, our group tested an implementation strategy called the Systems Analysis and Improvement Approach (SAIA), an evidenced-based multi-component implementation strategy focused on improving entire care cascades. In a cluster randomized trial of 24 FP clinics in Mombasa County, Kenya, SAIA led to a significant increase in HTC in intervention clinics compared to control clinics. The objective of this manuscript was to evaluate SAIA using the Consolidated Framework for Implementation Research (CFIR) and assess the Implementation Outcomes Framework outcomes of acceptability, appropriateness, and feasibility.

Methods

This qualitative assessment was nested within the cluster-randomized trial. Data collection included questionnaires to assess modifiable and non-modifiable health system factors related to HTC and in-depth interviews to query clinic norms, priorities, communication strategies, and readiness for change. The primary outcomes of interest were feasibility, appropriateness, and acceptability of SAIA. Data on inner setting and structural characteristics of FP clinics were collected to inform how context may impact outcomes. All interviews were recorded and analyzed using a rapid assessment approach.

Results

Of the 12 intervention clinics, 6 (50%) were public facilities. Availability of resources varied by clinic. Most clinics had a positive implementation climate, engaged leadership, and access to resources and information. While not all clinics identified HTC as a clinic priority, most reported a strong culture of embracing change and recognition of the importance of HIV testing within FP clinics. Interviews highlighted very high acceptability, appropriateness, and feasibility of SAIA. The implementation strategy was not complicated and fit well into existing clinic processes. In particular, staff appreciated that SAIA allowed clinic staff to generate contextually relevant solutions that they implemented.

Conclusions

SAIA was implemented in FP clinics of varying sizes, capacity, and management support and was found to be acceptable, appropriate, and feasible. The agency that clinic staff felt in proposing and implementing their own solutions was likely part of SAIA’s success. We anticipate this will continue to be a mechanism of SAIA’s success when it is scaled up to more clinics in future trials.

Trial registration

ClinicalTrials.gov (NCT02994355) registered 16 December 2016.
Islet Autoantibody Level Distribution in Type 1 Diabetes and Their Association With Genetic and Clinical Characteristics
Authors: Grace Sian Louise , Bowden Jack , Walkey Helen C , Kaur Akaal , Misra Shivani , Shields Beverley M , McKinley Trevelyan J , Oliver Nick S , McDonald Timothy J , Johnston Desmond G , Jones Angus G , Patel Kashyap A
Published: September 2022

Context

The importance of the autoantibody level at diagnosis of type 1 diabetes (T1D) is not clear.

Objective

We aimed to assess the association of glutamate decarboxylase (GADA), islet antigen-2 (IA-2A), and zinc transporter 8 (ZnT8A) autoantibody levels with clinical and genetic characteristics at diagnosis of T1D.

Methods

We conducted a prospective, cross-sectional study. GADA, IA-2A, and ZnT8A were measured in 1644 individuals with T1D at diagnosis using radiobinding assays. Associations between autoantibody levels and the clinical and genetic characteristics for individuals were assessed in those positive for these autoantibodies. We performed replication in an independent cohort of 449 people with T1D.

Results

GADA and IA-2A levels exhibited a bimodal distribution at diagnosis. High GADA level was associated with older age at diagnosis (median 27 years vs 19 years, P = 9 × 10−17), female sex (52% vs 37%, P = 1 × 10−8), other autoimmune diseases (13% vs 6%, P = 3 × 10−6), and HLA-DR3-DQ2 (58% vs 51%, P = .006). High IA-2A level was associated with younger age of diagnosis (median 17 years vs 23 years, P = 3 × 10−7), HLA-DR4-DQ8 (66% vs 50%, P = 1 × 10−6), and ZnT8A positivity (77% vs 52%, P = 1 × 10−15). We replicated our findings in an independent cohort of 449 people with T1D where autoantibodies were measured using enzyme-linked immunosorbent assays.

Conclusion

Islet autoantibody levels provide additional information over positivity in T1D at diagnosis. Bimodality of GADA and IA-2A autoantibody levels highlights the novel aspect of heterogeneity of T1D. This may have implications for T1D prediction, treatment, and pathogenesis.
Familial Male-limited Precocious Puberty (FMPP) and Testicular Germ Cell Tumors
Authors: Kooij Cezanne D , Mavinkurve-Groothuis Annelies M C , Kremer Hovinga Idske C L , Looijenga Leendert H J , Rinne Tuula , Giltay Jacques C , de Kort Laetitia M O , Klijn Aart J , de Krijger Ronald R , Verrijn Stuart Annemarie A
Published: September 2022

Objective

The purpose of this study is to report development of a malignant testicular germ cell tumor (GCT) in 2 young adult males with familial male-limited precocious puberty (FMPP) because of LHCGR pathogenic variants in 2 families. Secondarily, to study the possible relation between FMPP and testicular tumors and to investigate whether FMPP might predispose to development of malignant testicular tumors in adulthood a literature review is conducted.

Methods

Data on 6 cases in 2 families are obtained from the available medical records. In addition, a database search is performed in Cochrane, PubMed, and Embase for studies that report on a possible link between FMPP and testicular tumors.

Results

The characteristics of 6 males with FMPP based on activating LH receptor (LHCGR) germline pathogenic variants are described, as are details of the testicular GCTs. Furthermore, a literature review identified 4 more patients with signs of FMPP and a (precursor of) testicular GCT in adolescence or adulthood (age 15-35 years). Additionally, 12 patients with signs of precocious puberty and, simultaneously, occurrence of a Leydig cell adenoma or Leydig cell hyperplasia are reported.

Conclusion

There is a strong suggestion that FMPP might increase the risk of development of testicular GCTs in early adulthood compared with the risk in the general population. Therefore, prolonged patient monitoring from mid-pubertal age onward including instruction for self-examination and periodic testicular ultrasound investigation in patients with a germline LHCGR pathogenic variant might contribute to early detection and thus early treatment of testicular GCT.
Long-term Burosumab Administration Is Safe and Effective in Adults With X-linked Hypophosphatemia
Authors: Weber Thomas J , Imel Erik A , Carpenter Thomas O , Peacock Munro , Portale Anthony A , Hetzer Joel , Merritt J Lawrence , Insogna Karl
Published: September 2022

Context

Burosumab was developed as a treatment option for patients with the rare, lifelong, chronically debilitating, genetic bone disease X-linked hypophosphatemia (XLH).

Objective

Collect additional information on the safety, immunogenicity, and clinical response to long-term administration of burosumab.

Methods

UX023-CL203 (NCT02312687) was a Phase 2b, open-label, single-arm, long-term extension study of adult subjects with XLH who participated in KRN23-INT-001 or KRN23-INT-002 studies. The long-term UX023-CL203 study (January 5, 2015 through November 30, 2018) provided data up to 184 weeks. Participants in UX023-CL203 received burosumab based on the last dose in the prior KRN23-INT-001 or KRN23-INT-002 studies (0.3, 0.6, or 1.0 mg/kg given by subcutaneous injection every 4 weeks). At Week 12, burosumab could be titrated upward/downward to achieve fasting serum phosphate levels within the normal range. Primary objectives included long-term safety, the proportion of subjects achieving fasting serum phosphate in the normal range, changes in bone turnover markers, patient-reported outcomes for pain and stiffness, and measures of mobility.

Results

Fasting serum phosphate levels at the midpoint of the dosing interval (2 weeks postdose, the time of peak effect) were within the normal range in 85% to 100% of subjects. Measures of phosphate metabolism and bone biomarkers generally improved with burosumab therapy, approaching or reaching their respective normal ranges by study end. Improvements in patient-reported outcomes and mobility were sustained throughout the observation period. No new safety findings emerged with longer-term burosumab treatment.

Conclusion

These data support the conclusion that burosumab therapy may be a safe and effective long-term treatment option for adult patients with XLH.
Reproductive Markers of Testicular Function and Size During Puberty in Boys With and Without a History of Cryptorchidism
Authors: Rodprasert Wiwat , Koskenniemi Jaakko J , Virtanen Helena E , Sadov Sergey , Perheentupa Antti , Ollila Helena , Albrethsen Jakob , Andersson Anna-Maria , Juul Anders , Skakkebaek Niels E , Main Katharina M , Toppari Jorma
Published: September 2022

Context

Longitudinal data on levels of hypothalamic-pituitary-gonadal axis hormones and insulin-like growth factor I (IGF-I) during puberty in boys with a history of cryptorchidism are largely missing.

Objective

We aimed to compare pubertal hormone levels between boys with a history of congenital cryptorchidism who experienced spontaneous testicular descent or underwent orchiopexy and boys without a history of cryptorchidism.

Methods

This was a nested case-control study within a population-based birth cohort, with a prospective, longitudinal pubertal follow-up every 6 months (2005 to 2019). Participants were 109 Finnish boys, including boys with a history of unilateral cryptorchidism who underwent orchiopexy (n = 15), unilateral cryptorchidism who had spontaneous testicular descent (n = 15), bilateral cryptorchidism who underwent orchiopexy (n = 9), bilateral cryptorchidism who had spontaneous testicular descent (n = 7), and controls (n = 63). Serum reproductive hormone levels and testicular volumes were measured.

Results

From around onset of puberty, boys with bilateral cryptorchidism who underwent orchiopexy had significantly higher follicle-stimulating hormone (FSH) and lower inhibin B levels than controls. Boys with unilateral cryptorchidism who underwent orchiopexy had significantly higher FSH than controls, whereas inhibin B levels were similar. Testosterone, luteinizing hormone, insulin-like factor 3, and IGF-I were generally similar between groups. Testicular volume of boys with unilateral or bilateral cryptorchidism who underwent orchiopexy was smaller than that of the controls from 1 year after pubertal onset (P < 0.05).

Conclusion

Cryptorchid boys, particularly those with bilateral cryptorchidism who underwent orchiopexy, had altered levels of serum biomarkers of Sertoli cells and germ cells and smaller testicular volumes compared with controls.
Premature Ovarian Insufficiency in CLPB Deficiency: Transcriptomic, Proteomic and Phenotypic Insights
Authors: Tucker Elena J , Baker Megan J , Hock Daniella H , Warren Julia T , Jaillard Sylvie , Bell Katrina M , Sreenivasan Rajini , Bakhshalizadeh Shabnam , Hanna Chloe A , Caruana Nikeisha J , Wortmann Saskia B , Rahman Shamima , Pitceathly Robert D S , Donadieu Jean , Alimi Aurelia , Launay Vincent , Coppo Paul , Christin-Maitre Sophie , Robevska Gorjana , van den Bergen Jocelyn , Kline Brianna L , Ayers Katie L , Stewart Phoebe N , Stroud David A , Stojanovski Diana , Sinclair Andrew H
Published: September 2022

Context

Premature ovarian insufficiency (POI) is a common form of female infertility that usually presents as an isolated condition but can be part of various genetic syndromes. Early diagnosis and treatment of POI can minimize comorbidity and improve health outcomes.

Objective

We aimed to determine the genetic cause of syndromic POI, intellectual disability, neutropenia, and cataracts.

Methods

We performed whole-exome sequencing (WES) followed by functional validation via RT-PCR, RNAseq, and quantitative proteomics, as well as clinical update of previously reported patients with variants in the caseinolytic peptidase B (CLPB) gene.

Results

We identified causative variants in CLPB, encoding a mitochondrial disaggregase. Variants in this gene are known to cause an autosomal recessive syndrome involving 3-methylglutaconic aciduria, neurological dysfunction, cataracts, and neutropenia that is often fatal in childhood; however, there is likely a reporting bias toward severe cases. Using RNAseq and quantitative proteomics we validated causation and gained insight into genotype:phenotype correlation. Clinical follow-up of patients with CLPB deficiency who survived to adulthood identified POI and infertility as a common postpubertal ailment.

Conclusion

A novel splicing variant is associated with CLPB deficiency in an individual who survived to adulthood. POI is a common feature of postpubertal female individuals with CLPB deficiency. Patients with CLPB deficiency should be referred to pediatric gynecologists/endocrinologists for prompt POI diagnosis and hormone replacement therapy to minimize associated comorbidities.
Aldosterone-Producing Adenomas of Increased Size Are Associated With Higher Steroidogenic Activity
Authors: Nakai Kazuki , Manaka Katsunori , Sato Junichiro , Takeuchi Maki , Yamazaki Yuto , Sasano Hironobu , Tsurutani Yuya , Saito Jun , Nishikawa Tetsuo , Iiri Taroh , Nangaku Masaomi , Makita Noriko
Published: September 2022

Context

There are inconsistent results and insufficient evidence as to whether an association exists between the size and aldosterone-producing ability of aldosterone-producing adenomas.

Objective

We further investigated this possible association retrospectively.

Methods

A total of 142 cases of primary aldosteronism diagnosed as unilateral by adrenal venous sampling at 2 referral centers between 2009 and 2019 were included. We classified these individuals into small and large tumor groups using a diameter of 14 mm as a cutoff. This size was the median diameter of the tumor on the affected side of the adrenal gland. We compared plasma aldosterone concentration (PAC), plasma renin activity (PRA), PAC to PRA ratio, PAC from a saline infusion test (SIT), urinary aldosterone secretion (uAld), and serum potassium as indices of aldosterone-producing ability between the 2 groups. In some cases, we conducted histopathological evaluations and detection of the KCNJ5 mutation.

Results

PAC, PAC to PRA ratio, PAC from SIT, and uAld were higher and serum potassium was lower in the large tumor group. PAC, PAC from SIT, uAld, and serum potassium significantly correlated with tumor diameter. PRA was not associated with tumor diameter. Clear cell–dominant cases were more common in the large tumor group, while cases showing a strong expression of CYP11B2 were not significantly different between the groups. KCNJ5 mutations tended to be more common in the large tumor group.

Conclusion

The higher aldosterone-producing ability in larger adenomas can be used to infer the responsible lesion and disease type.
Cilia proteins getting to work – how do they commute from the cytoplasm to the base of cilia?
Authors: Hibbard Jaime V. K. , Vázquez Neftalí , Wallingford John B.
Published: September 2022

Cilia are multifunctional organelles that originated with the last eukaryotic common ancestor and play central roles in the life cycles of diverse organisms. The motile flagella that move single cells like sperm or unicellular organisms, the motile cilia on animal multiciliated cells that generate fluid flow in organs, and the immotile primary cilia that decorate nearly all cells in animals share many protein components in common, yet each also requires specialized proteins to perform their specialized functions. Despite a now-advanced understanding of how such proteins are transported within cilia, we still know very little about how they are transported from their sites of synthesis through the cytoplasm to the ciliary base. Here, we review the literature concerning this underappreciated topic in ciliary cell biology. We discuss both general mechanisms, as well as specific examples of motor-driven active transport and passive transport via diffusion-and-capture. We then provide deeper discussion of specific, illustrative examples, such as the diverse array of protein subunits that together comprise the intraflagellar transport (IFT) system and the multi-protein axonemal dynein motors that drive beating of motile cilia. We hope this Review will spur further work, shedding light not only on ciliogenesis and ciliary signaling, but also on intracellular transport in general.
Achieving sustainable transformation in science – green grassroots groups need nurturing from the top
Authors: Dobbelaere Jeroen , Heidelberger Jan B. , Borgermann Nikoline
Published: September 2022

Climate change is the greatest challenge of our time, and drastic climate action is needed urgently across industries and sectors to prevent the worst in terms of consequences. Although academic research brings great benefits to society, it leaves behind a considerable environmental footprint at the same time. This is particularly true for lab research within the life sciences. To reduce the climate impact of academic research, both bottom-up and top-down strategies are necessary. On the bottom-up side, ‘green’ grassroots groups are emerging in academia, but most institutions fail to nurture and harness their potential for driving change. We report findings from a survey of 63 such grassroots groups operating in academic environments, highlighting that their main challenges in making research more sustainable include lack of time, budget, involvement in management decisions and support from management. For the first time, we map the inception, goals and structure of green grassroots groups in academia and outline concrete steps in overcoming barriers to harvest their full potential, thus making academic research fit for the future.
Defects in division plane positioning in the root meristematic zone affect cell organization in the differentiation zone
Authors: Mills Alison M. , Rasmussen Carolyn G.
Published: September 2022

Cell-division-plane orientation is critical for plant and animal development and growth. TANGLED1 (TAN1) and AUXIN-INDUCED IN ROOT CULTURES 9 (AIR9) are division-site-localized microtubule-binding proteins required for division-plane positioning. The single mutants tan1 and air9 of Arabidopsis thaliana have minor or no noticeable phenotypes, but the tan1 air9 double mutant has synthetic phenotypes including stunted growth, misoriented divisions and aberrant cell-file rotation in the root differentiation zone. These data suggest that TAN1 plays a role in non-dividing cells. To determine whether TAN1 is required in elongating and differentiating cells in the tan1 air9 double mutant, we limited its expression to actively dividing cells using the G2/M-specific promoter of the syntaxin KNOLLE (pKN:TAN1–YFP). Unexpectedly, in addition to rescuing division-plane defects, expression of pKN:TAN1–YFP rescued root growth and cell file rotation defects in the root-differentiation zone in tan1 air9 double mutants. This suggests that defects that occur in the meristematic zone later affect the organization of elongating and differentiating cells.
Estimation of microtubule-generated forces using a DNA origami nanospring
Authors: Nick Maleki Ali , Huis in 't Veld Pim J. , Akhmanova Anna , Dogterom Marileen , Volkov Vladimir A.
Published: September 2022

Microtubules are dynamic cytoskeletal filaments that can generate forces when polymerizing and depolymerizing. Proteins that follow growing or shortening microtubule ends and couple forces to cargo movement are important for a wide range of cellular processes. Quantifying these forces and the composition of protein complexes at dynamic microtubule ends is challenging and requires sophisticated instrumentation. Here, we present an experimental approach to estimate microtubule-generated forces through the extension of a fluorescent spring-shaped DNA origami molecule. Optical readout of the spring extension enables recording of force production simultaneously with single-molecule fluorescence of proteins getting recruited to the site of force generation. DNA nanosprings enable multiplexing of force measurements and only require a fluorescence microscope and basic laboratory equipment. We validate the performance of DNA nanosprings against results obtained using optical trapping. Finally, we demonstrate the use of the nanospring to study proteins that couple microtubule growth and shortening to force generation.
Foxc1 and Foxc2 are indispensable for the maintenance of nephron and stromal progenitors in the developing kidney
Authors: Motojima Masaru , Tanaka Masayuki , Kume Tsutomu
Published: September 2022

Nephron development proceeds with reciprocal interactions among three layers: nephron progenitors (NPs), ureteric buds and stromal progenitors (SPs). We found that Foxc1 and Foxc2 (Foxc1/2) are expressed in NPs and SPs. Systemic deletion of Foxc1/2 2 days after the onset of metanephros development (embryonic day 13.5) resulted in the epithelialization of NPs and ectopic formation of renal vesicles. NP-specific deletion did not cause these phenotypes, indicating that Foxc1/2 in other cells (likely in SPs) contributed to the maintenance of NPs. Single-cell RNA-sequencing analysis revealed the existence of NP and SP subpopulations, the border between committed NPs and renewing NPs, and similarity between the cortical interstitium and vascular smooth muscle type cells. Integrated analysis of the control and Foxc1/2 knockout data indicated transformation of some NPs to strange cells expressing markers of the vascular endothelium, reduced numbers of self-renewing NP and SP populations, and downregulation of crucial genes for kidney development, such as Fgf20 and Frem1 in NPs, and Foxd1 and Sall1 in SPs. It also revealed upregulation of genes that were not usually expressed in NPs and SPs. Thus, Foxc1/2 maintain NPs and SPs by regulating the expression of multiple genes.
Release of HIV-1 particles from macrophages is promoted by an anchored cytoskeleton and driven by mechanical constraints
Authors: Rodrigues Vasco , Taheraly Sarah , Maurin Mathieu , San-Roman Mabel , Granier Emma , Hanouna Anaël , Benaroch Philippe
Published: September 2022

A feature of HIV-1 replication in macrophages is that viral assembly occurs at the limiting membrane of a compartment often named the virus-containing compartment (VCC). Assembled virions accumulate in the lumen of the VCC, from where they can be released into the extracellular medium via mechanisms that remain poorly described. Here, we show that the actin cytoskeleton contributes to this process by performing experiments combining pharmacological and mechanical perturbations with imaging and biochemical analysis. We found that jasplakinolide inhibited HIV-1 release from macrophages and led to scattering of the compartment. Concomitantly, both the integrin CD18 (β2-integrin) and the phosphorylated form of PYK2 (also known as PTK2B) were displaced away from the VCC. Inhibition of PYK2 activity promoted retention of viral particles in VCCs that lost their connections to the surface. Finally, in infected macrophages undergoing frustrated phagocytosis, VCCs rapidly trafficked to the basal membrane and released their viral content, in a manner dependent on their association with the actin cytoskeleton. These results highlight that the trafficking of VCCs and virus release are intimately linked to a reorganization of the macrophage actin cytoskeleton that can be modulated by external physical cues.
Sea turtle hatchlings can distinguish between coastal and oceanic seawaters
Authors: Soeiro Gabriel , Mendes da Silva Eduardo , Leduc Antoine O. H. C.
Published: September 2022

Following their emergence on land, sea turtle hatchlings need to travel through the open ocean. Whether hatchlings can detect ecologically and functionally relevant chemical cues released in the marine habitat is unknown. We collected seawater at 6 and 27 km off the Brazilian coast, i.e. within and beyond the continental shelf. In a two-choice flume, we exposed post-emergent (<24 h old) loggerhead (Caretta caretta) turtles to these seawaters. Based on their life history, we posited that if hatchlings could distinguish between the seawater from these regions, they should prefer the oceanic seawater and/or avoid the coastal seawater. Hatchlings were tested singly and could access any parts of the flume. We recorded the seawater plume first visited and the time spent in each plume. Of all the first choices and time spent in a plume, nearly 70% involved the oceanic seawater. The ability of hatchlings to distinguish between seawaters could provide goal-recognition information.
Liquidity Provision with Adverse Selection and Inventory Costs
Authors: Herdegen Martin , Muhle-Karbe Johannes , Stebegg Florian
Published: September 2022

We study one-shot Nash competition between an arbitrary number of identical dealers that compete for the order flow of a client. The client trades either because of proprietary information, exposure to idiosyncratic risk, or a mix of both trading motives. When quoting their price schedules, the dealers do not know the client’s type but only its distribution, and in turn choose their price quotes to mitigate between adverse selection and inventory costs. Under essentially minimal conditions, we show that a unique symmetric Nash equilibrium exists and can be characterized by the solution of a nonlinear ordinary differential equation.
The Impact of Committing to Customer Orders in Online Retail
Authors: Figueira Gonçalo , van Jaarsveld Willem , Amorim Pedro , Fransoo Jan C.
Published: September 2022

Problem definition: Online retailers are on a consistent drive to increase on-time delivery and reduce customer lead time. However, in reality, an increasing share of consumers places orders early. Academic/practical relevance: Such advance demand information can be deployed strategically to reduce costs and improve the customer service experience. This requires inventory and allocation policies that make optimal use of this information and that induce consumers to place their orders early. An increasing number of online retailers not only offer customers a choice of lead time but also, actively back-order missing items from a consumer basket. Methodology: We develop new allocation policies that commit to a customer order upon arrival of the order rather than at the moment the order is due. We provide analytical results for the performance of these allocation policies and evaluate their behavior with real data from a large food retailer. Results: Our policy leads to a higher fill rate at the expense of a slight increase in average delay. The analysis based on real-life data suggests a sizeable impact that should impact current best practices in online retail. Managerial implications: With the changing landscape in online retail, customers increasingly place baskets of orders that they would like to receive at a planned and confirmed moment in time. Especially in grocery, this has grown fast. This fundamentally changes the strategic management of inventory. We demonstrate that online retailers should commit early to customer orders to enhance the customer service experience and eventually, to also create opportunities for reducing the cost of operations.

Supplemental Material: The online appendix is available at https://doi.org/10.1287/msom.2022.1124 .
The Promise of mHealth for Chronic Disease Management Under Different Payment Systems
Authors: Rajan Balaraman , Sainathan Arvind , Agnihothri Saligrama , Cui Leon
Published: September 2022

Problem definition: Rapid innovations in technology have created opportunities for different modes of healthcare delivery including digital services provided via mobile applications (mHealth). mHealth technology has the potential to provide efficient, effective, and patient-centered healthcare to manage chronic conditions. However, the economics associated with the adoption and integration of mHealth into the care delivery process is not well understood. In a chronic care clinical practice setting, we investigate fee-for-service (FFS) and capitation payment systems, and explore their performance in a traditional office-visit mode and in a mHealth-adopted mode. We identify conditions under which it is preferable to switch to an mHealth-based practice from an office visit-based practice. Methodology/results: We use an analytical model to track the progression of a chronic disease and formulate an optimization problem in which the clinic decides the time between scheduled visits and patient panel size. We consider many patient-doctor interaction factors including the risk-index of patients, the cost of being sick, and the effectiveness of treatment. We measure the performance based on four different criteria: physician net revenue, physician panel size, total patient utility, and payor net revenue. Although patients may find mHealth mode to be very beneficial, physicians under an FFS system may only adopt mHealth for moderately risky patients but for neither low-risk nor high-risk patients. Capitation clinics are likely to adopt mHealth (higher net revenue) even if the technology is moderately effective. Importantly, mHealth is preferred by patients (higher total utility) and policy makers (greater coverage) when the clinic serves moderate-risk or high-risk patients. Managerial implications: Chronic conditions need continuous care management and use of mHealth has been very promising. However, adoption of mHealth by healthcare providers has been very slow. Our research explores payment systems, physician incentives, and optimal conditions for mHealth to achieve its full potential.

Supplemental Material: The e-companion is available at https://doi.org/10.1287/msom.2022.1143 .
Identifying Merger Opportunities: The Case of Air Traffic Control
Authors: Adler Nicole , Olesen Ole Bent , Volta Nicola
Published: September 2022

In “Identifying Merger Opportunities: The Case of Air Traffic Control,” N. Adler, O. Olesen, and N. Volta propose a model to identify an optimal horizontal merger configuration at the level of an industry or firm with multiple branches. Assuming that each firm operates within a catchment area or owns part of a network, we extend the model to consider feasible mergers that cover a contiguous area, should network effects be a consideration. An application to the European air traffic control system suggests that four contiguous air navigation service providers should replace the current 29 providers and the nine functional airspace blocks proposed in the Single European Skies initiative. The technological developments in air traffic management in which regulators on both sides of the Atlantic have invested heavily, namely SESAR and NextGen, are unlikely to be used without a concomitant reduction in operating costs through economies of scale. We find that the politically oriented solution may save around one third of current costs, but an optimal solution will save closer to 46%.
A Meta-Analysis of Instructional Management Models Affecting Creative Thinking Development
Authors: Ayutthaya Tanapat Itsarangkul Na , Damrongpanit Suntonrapot
Published: September 2022

The main objective of this research was to study the effects of instructional management models and nominal variables on the development of students’ creative thinking. The researchers used the research synthesis of 400 studies on the development of students' creative thinking by a meta-analysis of research according to Cohen. The meta-analysis results revealed that the average effect size of the instructional management model (d = 3.43; [3.10, 3.17]) was positive and had a very high effect size with statistical significance. The most significant influence on the creative thinking development model was creative development theory (d = 4.217; [3.32, 5.11]). In addition, effect sizes varied with the attribute variables of the research, particularly the attribute variable of the research on instruction with the highest effect consisted of research with the focus on language, at the primary level, applied Torrance's creativity theory, designed between one to six lesson plans. Moreover, there was less than one hour per plan, the instructional period including the experiment conducted more than 31 hours and there were four weeks of instruction. In addition, there were six steps for instruction, there had quiz as an assessment tool, number of exams varied between 30 and 39 questions, and knowledge sheets were used as instructional materials. In the context of the meta-analysis, the findings indicated that the teachers should apply creative development theory in developing the students’ creative thinking for more effective instructional management.
MORAL INJURIES, PSYCHOLOGICAL RESILIENCE AND POST-TRAUMATIC GROWTH AS A POSSIBLE CONSEQUENCE OF SOLDIERS' AND CIVILIANS' PARTICIPATION IN TRAUMATIC SITUATIONS
Authors:   Institute of Psychology, Cardinal Stefan Wyszynski University in Warsaw, Truszczyński Olaf
Published: September 2022

This paper addresses the psychological consequences associated with experiencing traumatic events during warfare. The negative aspect of these experiences is discussed, which should be associated with post-traumatic stress syndrome, but also with the possibility of “moral injury” that may occur as a result of transgression of ethical and cultural norms. The positive aspect of traumatic events is also presented, which is connected with the possibility of increased psychological resilience, as well as experience of “post-traumatic growth” understood as experiencing positive psychological change as a result of coping with very difficult life circumstances.