bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of LRRK2 kinase activity promotes anterograde axonal transport and presynaptic targeting of α-synuclein
Authors: Brzozowski Charlotte F. , Hijaz Baraa A. , Singh Vijay , Gcwensa Nolwazi Z. , Kelly Kaela , Boyden Edward S. , West Andrew B. , Sarkar Deblina , Volpicelli-Daley Laura A. 
Published: November 2021

AbstractPathologic inclusions composed of α-synuclein called Lewy pathology are hallmarks of Parkinson’s Disease (PD). Dominant inherited mutations in leucine rich repeat kinase 2 (LRRK2) are the most common genetic cause of PD. Lewy pathology is found in the majority of individuals with LRRK2-PD, particularly those with the G2019S-LRRK2 mutation. Lewy pathology in LRRK2-PD associates with increased non-motor symptoms such as cognitive deficits, anxiety, and orthostatic hypotension. Thus, understanding the relationship between LRRK2 and α-synuclein could be important for determining the mechanisms of non-motor symptoms. In PD models, expression of mutant LRRK2 reduces membrane localization of α-synuclein, and enhances formation of pathologic α-synuclein, particularly when synaptic activity is increased. α-Synuclein and LRRK2 both localize to the presynaptic terminal. LRRK2 plays a role in membrane traffic, including axonal transport, and therefore may influence α-synuclein synaptic localization. This study shows that LRRK2 kinase activity influences α-synuclein targeting to the presynaptic terminal. We used the selective LRRK2 kinase inhibitors, MLi-2 and PF-06685360 (PF-360) to determine the impact of reduced LRRK2 kinase activity on presynaptic localization of α-synuclein. Expansion microscopy (ExM) in primary hippocampal cultures and the mouse striatum, in vivo, was used to more precisely resolve the presynaptic localization of α-synuclein. Live imaging of axonal transport of α-synuclein-GFP was used to investigate the impact of LRRK2 kinase inhibition on α-synuclein axonal transport towards the presynaptic terminal. Reduced LRRK2 kinase activity increases α-synuclein overlap with presynaptic markers in primary neurons, and increases anterograde axonal transport of α-synuclein-GFP. In vivo, LRRK2 inhibition increases α-synuclein overlap with glutamatergic, cortico-striatal terminals, and dopaminergic nigral-striatal presynaptic terminals. The findings suggest that LRRK2 kinase activity plays a role in axonal transport, and presynaptic targeting of α-synuclein. These data provide potential mechanisms by which LRRK2-mediated perturbations of α-synuclein localization could cause pathology in both LRRK2-PD, and idiopathic PD.
Effect of biochemical and biomechanical factors on vascularization of kidney organoid-on-a-chip
Authors: Lee Han Na , Choi Yoon Young , Kim Jin Won , Lee Young Seo , Choi Ji Wook , Kang Taewook , Kim Yong Kyun , Chung Bong Guen 
Published: November 2021

AbstractKidney organoids derived from the human pluripotent stem cells (hPSCs) recapitulating human kidney are the attractive tool for kidney regeneration, disease modeling, and drug screening. However, the kidney organoids cultured by static conditions have the limited vascular networks and immature nephron-like structures unlike human kidney. Here, we developed a kidney organoid-on-a-chip system providing fluidic flow mimicking shear stress with optimized extracellular matrix (ECM) conditions. We demonstrated that the kidney organoids cultured in our microfluidic system showed more matured podocytes and vascular structures as compared to the static culture condition. Additionally, the kidney organoids cultured in microfluidic systems showed higher sensitivity to nephrotoxic drugs as compared with those cultured in static conditions. We also demonstrated that the physiological flow played an important role in maintaining a number of physiological functions of kidney organoids. Therefore, our kidney organoid-on-a-chip system could provide an organoid culture platform for in vitro vascularization in formation of functional three-dimensional (3D) tissues.
Non-cancer to anti-cancer: investigation of human ether-a-go-go-related gene potassium channel inhibitors as potential therapeutics
Authors: Patil Vaishali M. , Gaurav Anand , Garg Priyanka , Masand Neeraj 
Published: November 2021

Abstract
Background
The expression of hERG K+ channels is observed in various cancer cells including epithelial, neuronal, leukemic, and connective tissue. The role of hERG potassium channels in regulating the growth and death of cancer cells include cell proliferation, survival, secretion of proangiogenic factors, invasiveness, and metastasis.

Methods
In the reported study, an attempt has been made to investigate some non-cancer hERG blockers as potential cancer therapeutics using a computational drug repurposing strategy. Preliminary investigation for hERG blockers/non-blockers has identified 26 potential clinically approved compounds for further studies using molecular modeling.

Results
The interactions at the binding pockets have been investigated along with the prioritization based on the binding score. Some of the identified potential hERG inhibitors, i.e., Bromocriptine, Darglitazone, and Troglitazone, have been investigated to derive the mechanism of cancer inhibition.

Conclusions
The proposed mechanism for anti-cancer properties via hERG blocking for some of the potential compounds is required to be explored using other experimental methodologies. The drug repurposing approach applied to investigate anti-cancer therapeutics may direct to provide a therapeutic solution to late-stage cancer and benefit a significant population of patients.
Patient social functioning in acute mental health inpatient wards: the role of emotional regulation, attachment styles and nurse–patient relationships
Authors: Wainwright Laura D , Berry Katherine , Dunster-Page Charlotte , Haddock Gillian 
Published: November 2021

Background/aims Improvement in social functioning is an important aspect of recovery from severe mental health problems. Nurses on acute mental health wards play an important role in facilitating this recovery. Therefore, it is important to explore potential predictors of social functioning and the quality of nurse–patient relationships. The aim of this study was to explore associations between patient social functioning, nurse–patient therapeutic alliances, emotional regulation, attachment style and nurse distress in acute mental health settings. Methods: A questionnaire-based, cross-sectional approach with correlational and regression analyses was used for this study. A total of 50 nurse–patient dyads in acute mental health inpatient wards across four NHS trusts in the north-west of England took part. Patients and nurses completed questionnaires regarding demographic information, emotional regulation, attachment style and alliance. Nurses also rated patient social functioning and their own distress. Results The patient anxious attachment style was associated with difficulties in regulating emotions. Patient emotional regulation, patient insecure attachment and the patient-rated alliance predicted nurse-rated patient social functioning. Nurse emotion regulation, nurse insecure attachment style and nurse-rated alliance did not significantly predict nurse-rated patient social functioning and correlations were non-significant. Nurse distress was associated with nurse emotion regulation, nurse anxious attachment and nurse-rated alliance. These factors significantly predicted nurse distress. Conclusions: Patient social functioning is predicted by emotion regulation, attachment and alliance. Similarly, nurse distress is predicted by nurse emotion regulation, attachment style and alliance. Interventions targeting emotion regulation or attachment-informed wards would be beneficial.
Hydroxynonenal causes Langerhans cell degeneration in the pancreas of Japanese macaque monkeys
Authors: Boontem Piyakarn , Yamashima Tetsumori 
Published: November 2021

Background
For their functions of insulin biosynthesis and glucose- and fatty acid- mediated insulin secretion, Langerhans β-cells require an intracellular milieu rich in oxygen. This requirement makes β-cells, with their constitutively low antioxidative defense, susceptible to the oxidative stress. Although much progress has been made in identifying its molecular basis in experimental systems, whether the oxidative stress due to excessive fatty acids plays a crucial role in the Langerhans cell degeneration in primates is still debated.

Methods
Focusing on Hsp70.1, which has dual functions as molecular chaperone and lysosomal stabilizer, the mechanism of lipotoxicity to Langerhans cells was studied using macaque monkeys after the consecutive injections of the lipid peroxidation product ‘hydroxynonenal’. Based on the ‘calpain-cathepsin hypothesis’ formulated in 1998, calpain activation, Hsp70.1 cleavage, and lysosomal integrity were studied by immunofluorescence histochemistry, electron microscopy, and Western blotting.

Results
Light microscopy showed more abundant vacuole formation in the hydroxynonenal-treated islet cells than the control cells. Electron microscopy showed that vacuolar changes, which were identified as enlarged rough ER, occurred mainly in β-cells followed by δ-cells. Intriguingly, both cell types showed a marked decrease in insulin and somatostatin granules. Furthermore, they exhibited marked increases in peroxisomes, autophagosomes/autolysosomes, lysosomal and peroxisomal membrane rupture/permeabilization, and mitochondrial degeneration. Disrupted peroxisomes were often localized in the close vicinity of degenerating mitochondria or autolysosomes. Immunofluorescence histochemical analysis showed an increased co-localization of activated μ-calpain and Hsp70.1 with the extralysosomal release of cathepsin B. Western blotting showed increases in μ-calpain activation, Hsp70.1 cleavage, and expression of the hydroxynonenal receptor GPR109A.

Conclusions
Taken together, these data implicate hydroxynonenal in both oxidation of Hsp70.1 and activation of μ-calpain. The calpain-mediated cleavage of the carbonylated Hsp70.1, may cause lysosomal membrane rupture/permeabilization. The low defense of primate Langerhans cells against hydroxynonenal and peroxisomally-generated hydrogen peroxide, was presumably overwhelmed to facilitate cell degeneration.
Contribution of “complete response to treatment” to survival in patients with unresectable metastatic colorectal cancer: A retrospective analysis
Authors: Bulut Gulcan , Guner Oytun Merve , Almuradova Elvina , Harman Mustafa , Uslu Ruchan , Karabulut Bulent 
Published: November 2021

Background
The aim of the study is to reveal the contribution of complete response (CR) to treatment to overall survival (OS) in patients with unresectable metastatic colorectal cancer. In addition, to evaluate progression-free survival (PFS) in patients who attained CR to treatment and to examine the clinicopathologic features of the patient group with CR.

Methods
This article is a retrospective chart review. Patients diagnosed with metastatic colorectal cancer were divided into two groups. The systemic treatment was compared with the patients who received a full response according to the Response Evaluation Criteria in Solid Tumors (RECIST1.1) and those who did not attain CR (progression partial response and stable response) in terms of both PFS and OS data, and the effect of attaining CR to treatment on prognosis was evaluated.

Results
A total of 222 patients were included in the study. 202 of 222 patients could be evaluated in terms of complete response. All data from their files were tabulated and analyzed retrospectively. The mean age of diagnosis of the study group was 60.13 ± 12.52 years. The total number of patients who attained CR to treatment was 31 (15.3%); 171 (84.6%) patients did not attain CR. Patients who had a CR had longer median PFS times than patients who did not have a CR (15.2 vs. 7.4 months, P<0.001). Patients who had CR had longer median survival times than patients who did not have a CR (39.2 vs. 16.9 months, P<0.001). In subgroup patients who underwent primary surgery, the number of patients who attained CR was statistically higher compared with the number of patients who did not attain CR (p<0.001). Complete response was less common in the presence of liver metastasis and bone metastasis (p = 0.041 and p = 0.046, respectively), had a negative prognostic effect. In other words, 89.1% of patients with liver metastasis, 100.0% of patients with bone metastasis, and 88.7% of those who died did not have a CR to the treatment. According to multivariate analysis, CR to treatment, primary surgery, first-line chemotherapy (combination compared with fluoropyrimidine), and no bone metastasis were found to be predictors for OS.

Conclusion
Providing CR with systemic treatment in patients with unresectable metastatic colorectal cancer (mCRC) contributes to prognosis. The primary resection in our secondary acquisitions from the study, the number of metastatic regions and the combination therapy regimens also contributed to the prognosis.
Sharing Happy Stories Increases Interpersonal Closeness: Interpersonal Brain Synchronization as a Neural Indicator
Authors: Xie Enhui , Yin Qing , Li Keshuang , Nastase Samuel A. , Zhang Ruqian , Wang Ning , Li Xianchun 
Published: November 2021

AbstractOur lives revolve around sharing emotional stories (i.e., happy and sad stories) with other people. Such emotional communication enhances the similarity of story comprehension and neural across speaker-listener pairs. The theory of Emotions as Social Information Model (EASI) suggests that such emotional communication may influence interpersonal closeness. However, few studies have examined speaker-listener interpersonal brain synchronization (IBS) during emotional communication and whether it is associated with meaningful aspects of the speaker-listener interpersonal relationship. Here, one speaker watched emotional videos and communicated the content of the videos to 32 people as listeners (happy/sad/neutral group). Both speaker and listeners’ neural activities were recorded using EEG. After listening, we assessed the interpersonal closeness between the speaker and listeners. Compared with the sad group, sharing happy stories showed a better recall quality and a higher rating of interpersonal closeness. The happy group showed higher IBS in the frontal cortex and left temporoparietal cortex than the sad group. The relationship between frontal IBS and interpersonal closeness was moderated by sharing happy/sad stories. Exploratory analysis using support vector regression (SVR) showed that the IBS could also predict the ratings of interpersonal closeness. These results suggest that frontal IBS could serve as an indicator of whether sharing emotional stories facilitate interpersonal closeness. These findings improve our understanding of emotional communication among individuals that guides behaviors during interpersonal interactions.
Basal Forebrain Cholinergic Neurons Selectively Drive Coordinated Motor Learning in Mice
Authors: Li Yue , Hollis Edmund 
Published: November 2021

Motor control requires precise temporal and spatial encoding across distinct motor centers that is refined through the repetition of learning. The recruitment of motor regions requires modulatory input to shape circuit activity. Here, we identify a role for the baso-cortical cholinergic pathway in the acquisition of a coordinated motor skill in mice. Targeted depletion of basal forebrain cholinergic neurons results in significant impairments in training on the rotarod task of coordinated movement. Cholinergic neuromodulation is required during training sessions as chemogenetic inactivation of cholinergic neurons also impairs task acquisition. Rotarod learning is known to drive refinement of corticostriatal neurons arising in both medial prefrontal cortex (mPFC) and motor cortex, and we have found that cholinergic input to both motor regions is required for task acquisition. Critically, the effects of cholinergic neuromodulation are restricted to the acquisition stage, as depletion of basal forebrain cholinergic neurons after learning does not affect task execution. Our results indicate a critical role for cholinergic neuromodulation of distant cortical motor centers during coordinated motor learning.SIGNIFICANCE STATEMENTAcetylcholine release from basal forebrain cholinergic neuron terminals rapidly modulates neuronal excitability, circuit dynamics, and cortical coding; all processes required for processing complex sensory information, cognition, and attention. We found that depletion or transient silencing of cholinergic inputs to anatomically isolated motor areas, medial prefrontal cortex (mPFC) and motor cortex, selectively led to significant impairments on coordinated motor learning; disrupting this baso-cortical network after acquisition elicited no effect on task execution. Our results indicate a pivotal role for cholinergic neuromodulation of distant cortical motor centers during coordinated motor learning. These findings support the concept that cognitive components (such as attention) are indispensable in the adjustment of motor output and training-induced improvements in motor performance.
Coping Strategies and Irritable Bowel Syndrome: A Systematic Review
Authors: David Liliana , Fadgyas Stanculete Mihaela , Bolba Andreea Ramona , Chiaroni Giuseppe , Barsan Maria , Popa Stefan L 
Published: November 2021

Background and Aims: Irritable bowel syndrome (IBS) is associated with a high prevalence of psychiatric comorbidities. While psychosocial determinants were intently studied, coping strategies with stress used by IBS patients were never comprehensively reviewed. Therefore, this systematic review aimed to summarize the coping strategies used by IBS patients and to identify which tools are frequently used to measure coping strategies.
Methods: According to PRISMA guidelines, we searched for articles indexed in PubMed, EBSCOhost, EMBASE and Cochrane Library. The search terms included: (coping OR coping strategies OR coping mechanism) AND (irritable bowel syndrome OR IBS). The initial search identified 756 articles. After applying all filters (human filters, excluding conference abstracts and conference papers), 96 studies remained. Finally, a total of 21 articles were included in this systematic review.
Results: Twenty-one articles using fifteen coping instruments and six measures of quality of life were found. One was interventional, one longitudinal, and the rest were cross-sectional studies. One study was qualitative, while the rest used quantitative measures. Emotion-focused coping was associated with worse psychological outcomes, while the effect of problem-focused coping was not regularly associated with better psychological outcomes. Catastrophizing was negatively associated with health-related quality of life. Psychological distress (anxiety, depression) was significantly related to the impairment of health-related quality of life.
Conclusion: Patients with IBS cope in different ways when confronted with health and daily-life stressors. The maladaptive strategy of coping is associated with poor health-related quality of life and psychiatric comorbidities but methodological problems limit conclusions regarding the strength and nature of this association. Future research needs to focus on which strategies are most effective at reducing psychological distress in IBS patients.
Model Child Care Health Policies
Authors:   Pennsylvania Chapter American Academy of Pediatrics
Published: November 2021

Significantly revised and updated, the new Model Child Care Health Policies, 5th Edition is a must-have tool to foster adoption and implemenation of best practices for health and safety in group care settings for young children. These settings include early care and education as well as before and after school child care programs. These model policies are intended to ease the burden of writing site-specific health and safety policies from scratch. They cover a wide range of aspects of operation of early education and child care programs.
Child care programs of any type can use Model Child Care Health Policies by selecting relevant issues for their operation and modifying the wording to make selected policies appropriate to the specific settings. These settings include early education and child care centers, small and large family child care homes, part day-programs for ill children, facilities that serve children with special needs, school-age child care facilities, and drop-in facilities. The model policies can be adapted for public, private, Head Start, and tuition-funded facilities.
All of the most commonly covered health and safety topics the National Association of Child Care Resource and Referral Agencies found in state regulations are included in this guide.
Procedural Sedation for Infants, Children, and Adolescents
Authors:   American Academy of Pediatrics Section on Anesthesiology and Pain Medicine
Published: November 2021

New! Invasive and noninvasive procedures are a common and necessary component in the management of infants and children with acute and chronic diseases. As technology continues to expand, there are an increasing number of techniques that require procedural sedation outside of the operating room.
Authored by experts in a variety of specialties, Procedural Sedation for Infants, Children, and Adolescents is a comprehensive guide for the initial design and implementation of a procedural sedation program and a tool to educate pediatric health professionals on medications used for sedation, associated adverse events, and the treatment of these adverse effects.
Contents include:
Pre-sedation evaluation
Documentation and parental instructions
Monitoring for procedural sedation
Medications
Specific clinical scenarios
Non-pharmacologic interventions
Topical and local anesthetic agents
Quality improvement and assurance
and more
AM:STARs: Sports Medicine and Sports Injuries, Vol. 26, No. 1
Authors:   American Academy of Pediatrics Section on Adolescent Health
Published: November 2021

With more than 30 million US children and teenagers participating in both recreational and team sports, the adolescent physician is faced with many medical, parental and community questions and concerns regarding diagnosis, treatment and prevention of youth sports injuries.
This issue provides the adolescent physician with comprehensive, practical and up-to-date information regarding diagnosis and treatment of acute and chronic sports injuries, sports concussion, the pre-participation physical evaluation (PPE), mental health concerns, the female athlete, bone health, nutrition, travel, performance enhancing substances, injury rehabilitation, the role of the team physician and injury prevention in youth sports.
Contents in Sports Medicine and Sports Injuries include
Being a Team Doctor
Preparticipation Physical Evaluation
Concussion in Teenage Athletes
Musculoskeletal Injuries Not to Miss in Teens
Overuse and Overtraining Injuries in Teenage Athletes
Rehabilitation of Musculoskeletal Injuries in Young Athletes
The Female Athlete Triad: Energy Deficiency, Physiologic Consequences, and Treatment
The Adolescent Dancer: Common Medical Concerns and Relevant Anticipatory Guidance
Mental Health and Pressures in Teen Sports
Performance-Enhancing Substances
Extreme Sports and the Adolescent Athlete