bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association Between a National Behavioral Weight Management Program and Veterans Affairs Health Expenditures
Authors: Smith Valerie A. , Stechuchak Karen M. , Wong Edwin S. , Hung Anna , Dennis Paul A. , Hoerster Katherine D. , Blalock Dan V. , Raffa Susan D. , Maciejewski Matthew L. 
Published: March 2024

Objective:
The association between participation in a behavioral weight intervention and health expenditures has not been well characterized. We compared Veterans Affairs (VA) expenditures of individuals participating in MOVE!, a VA behavioral weight loss program, and matched comparators 2 years before and 2 years after MOVE! initiation.

Methods:
Retrospective cohort study of Veterans who had one or more MOVE! visits in 2008–2017 who were matched contemporaneously to up to 3 comparators with overweight or obesity through sequential stratification on an array of patient characteristics, including sex. Baseline patient characteristics were compared between the two cohorts through standardized mean differences. VA expenditures in the 2 years before MOVE! initiation and 2 years after initiation were modeled using generalized estimating equations with a log link and distribution with variance proportional to the standard deviation (gamma).

Results:
MOVE! participants (n=499,696) and comparators (n=1,336,172) were well-matched, with an average age of 56, average body mass index of 35, and similar total VA expenditures in the fiscal year before MOVE! initiation ($9662 for MOVE! participants and $10,072 for comparators, standardized mean difference=−0.019). MOVE! participants had total expenditures that were statistically lower than matched comparators in the 6 months after initiation but modestly higher in the 6 months to 2 years after initiation, though differences were small in magnitude (1.0%–1.6% differences).

Conclusions:
The VA’s system-wide behavioral weight intervention did not realize meaningful short-term health care cost savings for participants.
Ambulatory Care Fragmentation and Total Health Care Costs
Authors: Kern Lisa M. , Ringel Joanna B. , Rajan Mangala , Casalino Lawrence P. , Pesko Michael F. , Pinheiro Laura C. , Colantonio Lisandro D. , Safford Monika M. 
Published: March 2024

Background:
The magnitude of the relationship between ambulatory care fragmentation and subsequent total health care costs is unclear.

Objective:
To determine the association between ambulatory care fragmentation and total health care costs.

Research Design:
Longitudinal analysis of 15 years of data (2004–2018) from the national Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, linked to Medicare fee-for-service claims.

Subjects:
A total of 13,680 Medicare beneficiaries who are 65 years and older.

Measures:
We measured ambulatory care fragmentation in each calendar year, defining high fragmentation as a reversed Bice-Boxerman Index ≥0.85 and low as <0.85. We used generalized linear models to determine the association between ambulatory care fragmentation in 1 year and total Medicare expenditures (costs) in the following year, adjusting for baseline demographic and clinical characteristics, a time-varying comorbidity index, and accounting for geographic variation in reimbursement and inflation.

Results:
The average participant was 70.9 years old; approximately half (53%) were women. One-fourth (26%) of participants had high fragmentation in the first year of observation. Those participants had a median of 9 visits to 6 providers, with the most frequently seen provider accounting for 29% of visits. By contrast, participants with low fragmentation had a median of 8 visits to 3 providers, with the most frequently seen provider accounting for 50% of visits. High fragmentation was associated with $1085 more in total adjusted costs per person per year (95% CI $713 to $1457) than low fragmentation.

Conclusions:
Highly fragmented ambulatory care in 1 year is independently associated with higher total costs the following year.
Locomotion Efficiency in Children With Cerebral Palsy Experiencing Limited Gross Motor Function: Walking Versus Cycling
Authors: Dussault-Picard Cloé , Pouliot-Laforte Annie , Cherriere Claire , Houle Eloïse , Ballaz Laurent 
Published: March 2024

Purpose:
This study compares cycling and walking efficiency, and energy expenditure in children with bilateral spastic cerebral palsy (CP). In children with CP, locomotion with body weight support aids such as a tricycle is a potential alternative for less exhausting movements.

Methods:
Nine children with CP traveled at comfortable speed for 6 minutes by cycling and walking. The energy expenditure index (EEI) and the percentage of the reserve heart rate (%HRR) were calculated.

Results:
The EEI was lower while cycling than walking, the traveled distance was higher while cycling than walking, and %HRR remained similar between cycling and walking.

Conclusion:
Cycling appears an efficient alternative to walking for children with CP for adapted school environments and in the community.
Mechanisms mediating arylidene-indolinones induced degradation: thoughts on “Discovery of a Drug-like, Natural Product-Inspired, DCAF11 Ligand Chemotype”
Authors: Zhong Chao , Wang Ziying , Li Zhaoyang , Li Haofeng , Xu Qianhui , Wu Wanli , Liu Cong , Fei Yiyan , Ding Yu , Lu Boxun 
Published: March 2024

AbstractIn the recent issue of Nature Communications (2023 Nov 30;14(1):7908), Xue et. al. reported a very interesting and significant discovery of a possible DCAF11 ligand chemotype that could be used as the “warhead” to design bifunctional compounds for targeted degradation via engaging the E3 ligase DCAF111(annotated as ref 1 hereafter). The discovery is of importance to the targeted protein degradation field and was inspired by previous reports suggesting that similar compounds may also engage the autophagosome protein LC3 for degradation and function as autophagy-tethering compounds (ATTECs)2, 3, 4, 5, 6, 7, which seem to be inconsistent with ref 1. We think that the conclusions based on these data are not necessarily mutually exclusive. After performing additional experiments and analyses, we would like to discuss some possibilities explaining such discrepancies and make a few points of clarification.
Using site-directed mutagenesis to further the understanding of insulin receptor-insulin like growth factor-1 receptor heterodimer structure
Authors: Turvey Samuel , Muench Stephen P , Issad Tarik , Fishwick Colin WG , Kearney Mark T , Simmons Katie J 
Published: March 2024

AbstractType 2 diabetes is characterised by the disruption of insulin and insulin-like growth factor (IGF) signalling. The key hubs of these signalling cascades - the Insulin receptor (IR) and Insulin-like growth factor 1 receptor (IGF1R) – are known to form functional IR-IGF1R hybrid receptors which are insulin resistant. However, the mechanisms underpinning IR-IGF1R hybrid formation are not fully understood, hindering the ability to modulate this for future therapies targeting this receptor. To pinpoint suitable sites for intervention, computational hotspot prediction was utilised to identify promising epitopes for targeting with point mutagenesis. Specific IGF1R point mutations F450A, R391A and D555A show reduced affinity of the hybrid receptor in a BRET based donor-saturation assay, confirming hybrid formation could be modulated at this interface. These data provide the basis for rational design of more effective hybrid receptor modulators, supporting the prospect of identifying a small molecule that specifically interacts with this target.
Striatal Dopamine Modulates Temporal Surprise P3a
Authors: Whitaker Grace A. , Schwartze Michael , Martin Sarah , Astudillo Aland , Silverdale Monty , El-Deredy Wael , Kotz Sonja A. 
Published: March 2024

AbstractDopamine is vital in forming mental models of “what” and “when” sensory events occur that essentially guide goal-directed behaviour. However, it remains largely unknown how variations in temporal predictability are incorporated into such mental models. A better understanding of the underlying mechanisms is important, considering dopaminergic depletion in diseases such as Parkinson’s Disease and Schizophrenia, where abnormal temporal processing is observed. Some electroencephalographic (EEG) studies indicate that noradrenergic mechanisms, as reflected in the P3b event-related potential, are modulated by temporal predictability, whereas others indicate that dopaminergic mechanisms as reflected in the P3a, underlie surprise. In this study, resting-state and task-dependent EEG was recorded from 24 healthy participants who were administered a selective D2 agonist or antagonist before they performed a pure tone auditory “oddball” task. Two oddball sequences included either partially predictable, with inter-stimulus intervals (ISIs) of 400ms/1200ms; or fully temporally predictable tones, with a consistent ISI of 600ms. Tones following 400ms ISIs were perceived as surprising, or “early”, as shown in an enhanced P3a response; tones following a 1200ms ISIs showed a much reduced P3a response (“late”). The agonist accentuated the “late” effect, demonstrating that drugs targeting D2 receptors modulate temporal prediction. These findings differentiate the role of the dopaminergic system in temporal processing and model-based auditory predictions.
Engulfment of viable neurons by reactive microglia in prion diseases
Authors: Makarava Natallia , Safadi Tarek , Mychko Olga , Pandit Narayan P. , Molesworth Kara , Baiardi Simone , Zhang Li , Parchi Piero , Baskakov Ilia V. 
Published: March 2024

AbstractMicroglia are recognized as the main cells in the central nervous system responsible for phagocytosis. During brain development, microglia eliminate excessive synapses and neurons, whereas in normal aging and neurodegenerative diseases, microglia are responsible for clearing protein aggregates and cell debris. The current study demonstrates that in prion disease, microglia effectively phagocytose prions or PrPScduring early preclinical stages. However, during the late preclinical stage, a critical shift occurs in microglial activity from PrPScuptake to the engulfment of neurons. This change occurs before the manifestation of clinical symptoms and is followed by a rapid accumulation of total PrPSc, suggesting a potential link to neuronal dysfunction and behavioral deficits. Surprisingly, the engulfed neurons do not show apoptotic markers, indicating that microglia are targeting viable neurons. Despite up to 40% of neurons being partially engulfed at the clinical stage, there is no significant neuronal loss, suggesting that many engulfment events are incomplete, terminated or protracted. This phenomenon of partial engulfment by reactive microglia is independent of the CD11b pathway, previously associated with phagocytosis of newborn neurons during neurodevelopment. The study establishes partial engulfment as a consistent occurrence across multiple prion-affected brain regions, various mouse-adapted strains, and different subtypes of sporadic Creutzfeldt-Jakob disease (sCJD) in humans. The current work describes a new phenomenon of partial engulfment of neurons by reactive microglia, shedding light on a novel aspect of neuronal-microglia interactions.
Repeated Binge Alcohol Drinking Leads to Reductions in Corticostriatal Theta Coherence in Female but not Male Mice
Authors: Ardinger Cherish E. , Lapish Christopher C. , Linsenbardt David N. 
Published: March 2024

AbstractDecreased functional connectivity between the striatum and frontal cortex is observed in individuals with alcohol use disorder (AUD), and predicts the probability of relapse in abstinent individuals with AUD. To further our understanding of how repeated alcohol (ethanol; EtOH) consumption impacts the corticostriatal circuit, extracellular electrophysiological recordings (local field potentials; LFPs) were gathered from the nucleus accumbens (NAc) and prefrontal cortex (PFC) of C57BL/6J mice voluntarily consuming EtOH or water using a ‘drinking-in-the-dark’ (DID) procedure. Following a three-day acclimation period wherein only water access was provided during DID, mice were given 15 consecutive days of access to EtOH. Each session consisted of a 30-minute baseline period where water was available and was followed immediately by a 2-hour period where sippers containing water were replaced with new sippers containing either unsweetened 20% (v/v) EtOH (days 4-18; DID) or water (days 1-3; acclimation). Our analyses focused primarily on theta coherence during bouts of drinking, as differences in this band are associated with several behavioral markers of AUD. Both sexes displayed decreases in theta coherence during the first day of binge EtOH consumption. However, only females displayed further decreases in theta coherence on the 14thday of EtOH access. No differences in theta coherence were observed between the first and final bout on any EtOH drinking days. These results provide additional support for decreases in the functional coupling of corticostriatal circuits as a consequence of alcohol consumption and suggests that female mice are uniquely vulnerable to these effects following repeated EtOH drinking.
PPFlow: Target-Aware Peptide Design with Torsional Flow Matching
Authors: Lin Haitao , Zhang Odin , Zhao Huifeng , Jiang Dejun , Wu Lirong , Liu Zicheng , Huang Yufei , Li Stan Z. 
Published: March 2024

AbstractTherapeutic peptides have proven to have great pharmaceutical value and potential in recent decades. However, methods of AI-assisted peptide drug discovery are not fully explored. To fill the gap, we propose a target-aware peptide design method called PPFlow, based on conditional flow matching on torus manifolds, to model the internal geometries of torsion angles for the peptide structure design. Besides, we establish a protein-peptide binding dataset namedPPBench2024to fill the void of massive data for the task of structure-based peptide drug design and to allow the training of deep learning methods. Extensive experiments show that PPFlowreaches state-of-the-art performance in tasks of peptide drug generation and optimization in comparison with baseline models, and can be generalized to other tasks including docking and side-chain packing.
Coronavirus Spike-RBD Variants Differentially Bind to the Human ACE2 Receptor
Authors: Feinstein Paul 
Published: March 2024

AbstractThe SARS-CoV-2 betacoronavirus infects people through binding the human Angiotensin Receptor 2 (ACE2), followed by import into a cell utilizing the Transmembrane Protease, Serine 2 (TMPRSS2) and Furin cofactors. Analysis of the SARS-CoV-2 extracellular spike protein has suggested critical amino acids necessary for binding within a 197-residue portion, the receptor binding domain (RBD). A cell-based assay between a membrane tethered RBD-GFP fusion protein and the membrane bound ACE2-Cherry fusion protein allowed for mutational intersection of both RBD and ACE2 proteins. Data shows Omicron BA.1 and BA.2 variants have altered dependency on the amino terminus of ACE2 protein and suggests multiple epitopes on both proteins stabilize their interactions at the Nt and internal region of ACE2. In contrast, the H-CoV-NL63 RBD is only dependent on the ACE2 internal region for binding. A peptide inhibitor approach to this internal region thus far have failed to block binding of RBDs to ACE2, suggesting that several binding regions on ACE2 are sufficient to allow functional interactions. In sum, the RBD binding surface of ACE2 appears relatively fluid and amenable to bind a range of novel variants.
The role of metals in hypothiocyanite resistance inEscherichia coli
Authors: Gray Michael J. 
Published: March 2024

ABSTRACTThe innate immune system employs a variety of antimicrobial oxidants to control and kill host-associated bacteria. Hypothiocyanite/hypothiocyanous acid (-OSCN/HOSCN) is one such antimicrobial oxidant that is synthesized by lactoperoxidase, myeloperoxidase, and eosinophil peroxidase at sites throughout the human body. HOSCN has potent antibacterial activity while being largely non-toxic towards human cells. The molecular mechanisms by which bacteria sense and defend themselves against HOSCN have only recently begun to be elaborated, notably by the discovery of bacterial HOSCN reductase (RclA), an HOSCN-degrading enzyme widely conserved among bacteria that live on epithelial surfaces. In this paper, I show that Ni2+sensitizesEscherichia colito HOSCN by inhibiting glutathione reductase, and that inorganic polyphosphate protectsE. coliagainst this effect, probably by chelating Ni2+ions. I also found that RclA is very sensitive to inhibition by Cu2+and Zn2+, metals that are accumulated to high levels by innate immune cells, and that, surprisingly, thioredoxin and thioredoxin reductase are not involved in HOSCN stress resistance inE. coli. These results advance our understanding of the contribution of different oxidative stress response and redox buffering pathways to HOSCN resistance inE. coliand illustrate important interactions between metal ions and the enzymes bacteria use to defend themselves against oxidative stress.IMPORTANCEHypothiocyanite (HOSCN) is an antimicrobial oxidant produced by the innate immune system. The molecular mechanisms by which host-associated bacteria defend themselves against HOSCN have only recently begun to be understood. The results in this paper are significant because they show that the redox buffer glutathione and enzyme glutathione reductase are critical components of theEscherichia coliHOSCN response, working by a mechanism distinct from that of the HOSCN-specific defenses provided by the RclA, RclB, and RclC proteins, and that metal ions (including nickel, copper, and zinc) may impact the ability of bacteria to resist HOSCN by inhibiting specific defensive enzymes (e.g.glutathione reductase or RclA).
Released Bacterial ATP Shapes Local and Systemic Inflammation during Abdominal Sepsis
Authors: Spari Daniel , Schmid Annina , Sánchez-Taltavull Daniel , Murugan Shaira , Keller Keely , Ennaciri Nadia , Salm Lilian , Stroka Deborah , Beldi Guido 
Published: March 2024

AbstractSepsis causes millions of deaths per year worldwide and is a current global health priority declared by the WHO. Sepsis-related deaths are a result of dysregulated inflammatory immune responses indicating the need to develop strategies to target inflammation. An important mediator of inflammation is extracellular adenosine triphosphate (ATP) that is secreted by inflamed host cells and tissues, and also by bacteria in a strain-specific and growth phase-dependent manner. Here, we investigated the mechanisms by which bacteria release ATP. Using genetic mutant strains ofEscherichia coli(E. coli), we demonstrate that ATP release is dependent on ATP synthase within the inner bacterial membrane. In addition, impaired integrity of the outer bacterial membrane and bacterial death notably contribute to ATP release. In a mouse model of abdominal sepsis, local effects of bacterial ATP were analysed using a transformedE. colibearing an arabinose-inducible periplasmic apyrase hydrolyzing ATP to be released. Abrogating bacterial ATP release shows that bacterial ATP suppresses local immune responses, resulting in reduced neutrophil counts and impaired survival. In addition, bacterial ATP has systemic effects via its transport in outer membrane vesicles (OMV). ATP-loaded OMV are quickly distributed throughout the body and upregulated expression of genes activating degranulation in neutrophils, potentially contributing to the exacerbation of sepsis severity. This study reveals mechanisms of bacterial ATP release and its local and systemic roles in sepsis pathogenesis.
Monitoring myelin lipid composition and structure of myelinated fibers reveals a maturation delay in CMT1A
Authors: Capodivento Giovanna , Camera Mattia , Liessi Nara , Trada Anna , Debellis Doriana , Schenone Angelo , Armirotti Andrea , Visigalli Davide , Nobbio Lucilla 
Published: March 2024

1.AbstractFindings accumulated over time show that neurophysiological, neuropathological, and molecular alterations are present in CMT1A and support the dysmyelinating rather than demyelinating nature of this neuropathy. Moreover, uniform slowing of nerve conduction velocity is already manifest in CMT1A children and does not improve throughout their life. This evidence and our previous studies displaying aberrant myelin composition and structure in adult CMT1A rats prompt us to hypothesize a myelin and axon developmental defect in the CMT1A peripheral nervous system. Peripheral myelination begins during the early stages of development in mammals and, during this process, chemical and structural features of myelinated fibers (MFs) evolve towards a mature phenotype; deficiencies within this self-modulating circuit can cause its blockage. Therefore, to shed light on pathophysiological mechanisms that occur during development, and to investigate the relationship among axonal, myelin, and lipidome deficiencies in CMT1A, we extensively analyzed the evolution of both myelin lipid profile and MF structure in WT and CMT1A rats. Lipidomic analysis revealed a delayed maturation of CMT1A myelin already detectable at P10 characterized by deprivation of sphingolipid species such as hexosylceramides and long-chain sphingomyelins, whose concentration physiologically increases in WT, and an increase in lipids typical of unspecialized plasma membranes, including phosphatidylcholines and phosphatidylethanolamines. Consistently, advanced morphometric analysis on more than 130.000 MFs revealed a delay in the evolution of CMT1A axon and myelin geometric parameters, appearing concomitantly with lipid impairment. We here demonstrate that, during normal development, MFs undergo a continuous maturation process in both chemical composition and physical structure, but these processes are delayed in CMT1A.
PROTEOME DATA BASED IDENTIFICATION OF POTENTIAL RNAi TARGETS FOR COTTON MEALYBUG (Phenacoccus solenopsisTinsley) POPULATION MANAGEMENT
Authors: Singh Sanchita , Rahangdale Somnath , Pandita Shivali , Singh Manisha , Saxena Gauri , Jain Gaurav , Verma Praveen C. 
Published: March 2024

ABSTRACTBackgroundof the studyPhenacoccus solenopsisTinsley (Hemiptera: Pseudococcidae), commonly known as cotton mealybug, regarded as an invasive pest worldwide, particularly in the tropics and subtropics. It is one of the major pests of cotton and other commercially important crops. Despite the significant economic losses caused by cotton mealybug the molecular aspects of this insect are under-studied.MethodsIn the present study, proteome data of four different developmental stages of cotton mealybug is generated. Differential expression of proteins (DEPs) was studied among six different groups of which, maximum DEPs (550 up-regulated and 1118 down-regulated) were obtained when the quantifiable proteins of Egg+first nymphal were compared with second nymphal instar (FC ≥ 2, P < 0.05). From this proteomics data fifteen potential target genes were predicted for insect pest management. Further, these fifteen genes were explored and evaluated the for RNAi based pest control and optimisation of dsRNA delivery system in cotton mealybug. The analysis of transient expression of target genes was performed.ResultsThe results signified that dsRNA ofFerritincaused ∼69% mortality hence, could be exploited as a promising candidate gene to design a sustainable method for cotton mealybug management.ConclusionThis study provides an urgently required, alternate green control strategy based on proteomics to identify potential RNAi targets for pest management.