Evaluating a Speech-Specific and a Computerized Step-Training-Specific Rhythmic Intervention in Parkinson's Disease: A Cross-Over, Multi-Arms Parallel Study

Background:Recent studies suggest movements of speech and gait in patients with Parkinson's Disease (PD) are impaired by a common underlying rhythmic dysfunction. If this being the case, motor deficits in speech and gait should equally benefit from rhythmic interventions regardless of whether it is a speech-specific or step-training-specific approach.Objective:In this intervention trial, we studied the effects of two rhythmic interventions on speech and gait. These rhythmic intervention programs are similar in terms of intensity and frequency (i.e., 3x per week, 45 min-long sessions for 4 weeks in total), but differ regarding therapeutic approach (rhythmic speech vs. rhythmic balance-mobility training).Methods:This study is a cross-over, parallel multi-arms, single blind intervention trial, in which PD patients treated with rhythmic speech-language therapy (rSLT; N = 16), rhythmic balance-mobility training (rBMT; N = 10), or no therapy (NT; N = 18) were compared to healthy controls (HC; N = 17; matched by age, sex, and education: p > 0.82). Velocity and cadence in speech and gait were evaluated at baseline (BL), 4 weeks (4W-T1), and 6 months (6M-T2) and correlated.Results:Parameters in speech and gait (i.e., speaking and walking velocity, as well as speech rhythm with gait cadence) were positively correlated across groups (p < 0.01). Statistical analyses involved repeated measures ANOVA across groups and time, as well as independent and one-samples t-tests for within groups analyses. Statistical analyses were amplified using Reliable Change (RC) and Reliable Change Indexes (RCI) to calculate true clinically significant changes due to the treatment on a patient individual level. Rhythmic intervention groups improved across variables and time (total Mean Difference: 3.07 [SD 1.8]; 95% CI 0.2–11.36]) compared to the NT group, whose performance declined significantly at 6 months (p < 0.01). HC outperformed rBMT and NT groups across variables and time (p < 0.001); the rSLT performed similarly to HC at 4 weeks and 6 months in speech rhythm and respiration.Conclusions:Speech and gait deficits in PD may share a common mechanism in the underlying cortical circuits. Further, rSLT was more beneficial to dysrhythmic PD patients than rBMT, likely because of the nature of the rhythmic cue.

Octogenarian Motor Vehicle Collisions: Injury Patterns Matter

Introduction. Motor vehicle collision (MVC) is the second most common mechanism of injury among octogenarians and is on the rise. These “oldest old” trauma patients have much higher mortality rates than expected. This study examined potential factors influencing this increased mortality including comorbidities, medications, injury patterns, and hospital interventions. Methods. A 10-year retrospective review was conducted of patients aged 80 and over who were injured in a MVC. Data collected included patient demographics, comorbidities, medication use prior to injury, collision details, injury severity and patterns, hospitalization details, outcomes, and discharge disposition. Results. We identified 239 octogenarian patients involved in a MVC. Overall mortality was 18.8%. We recognized an increased mortality for specific injury patterns, patients injured in a rural setting, and those who were transfused, intubated, or admitted to the ICU. We found no correlation between mortality and medications or comorbidities. Conclusions. The high mortality rate for octogenarian patients involved in a MVC is related to injury severity, type of injury, and in-hospital complications, and not due to comorbidities and prior medications.

The identification of type I MADS box genes as the upstream activators of an endosperm-specific invertase inhibitor in Arabidopsis

Background Nuclear endosperm development is a common mechanism among Angiosperms, including Arabidopsis. During nuclear development, the endosperm nuclei divide rapidly after fertilization without cytokinesis to enter the syncytial phase, which is then followed by the cellularized phase. The endosperm can be divided into three spatial domains with distinct functions: the micropylar, peripheral, and chalazal domains. Previously, we identified two putative small invertase inhibitors, InvINH1 and InvINH2, that are specifically expressed in the micropylar region of the syncytial endosperm. In addition, ectopically expressing InvINH1 in the cellularized endosperm led to a reduction in embryo growth rate. However, it is not clear what are the upstream regulators responsible for the specific expression of InvINHs in the syncytial endosperm. Results Using protoplast transient expression system, we discovered that a group of type I MADS box transcription factors can form dimers to activate InvINH1 promoter. Promoter deletion assays carried out in the protoplast system revealed the presence of an enhancer region in InvINH1 promoter, which contains several consensus cis-elements for the MADS box proteins. Using promoter deletion assay in planta, we further demonstrated that this enhancer region is required for InvINH1 expression in the syncytial endosperm. One of the MADS box genes, AGL62, is a key transcription factor required for syncytial endosperm development. Using promoter-GFP reporter assay, we demonstrated that InvINH1 and InvINH2 are not expressed in agl62 mutant seeds. Collectively, our data supports the role of AGL62 and other type I MADS box genes as the upstream activators of InvINHs expression in the syncytial endosperm. Conclusions Our findings revealed several type I MADS box genes that are responsible for activating InvINH1 in the syncytial endosperm, which in turn regulates embryo growth rate during early stage of seed development.

To New Beginnings: Riboproteogenomics Discovery of N-Terminal Proteoforms in Arabidopsis Thaliana

Alternative translation initiation is a widespread event in biology that can shape multiple protein forms or proteoforms from a single gene. However, the respective contribution of alternative translation to protein complexity remains largely enigmatic. By complementary ribosome profiling and N-terminal proteomics (i.e., riboproteogenomics), we provide clear-cut evidence for ~90 N-terminal proteoform pairs shaped by (alternative) translation initiation in Arabidopsis thaliana. Next to several cases additionally confirmed by directed mutagenesis, identified alternative protein N-termini follow the enzymatic rules of co-translational N-terminal protein acetylation and initiator methionine removal. In contrast to other eukaryotic models, N-terminal acetylation in plants cannot generally be considered as a proxy of translation initiation because of its posttranslational occurrence on mature proteolytic neo-termini (N-termini) localized in the chloroplast stroma. Quantification of N-terminal acetylation revealed differing co- vs. posttranslational N-terminal acetylation patterns. Intriguingly, our data additionally hints to alternative translation initiation serving as a common mechanism to supply protein copies in multiple cellular compartments, as alternative translation sites are often in close proximity to cleavage sites of N-terminal transit sequences of nuclear-encoded chloroplastic and mitochondrial proteins. Overall, riboproteogenomics screening enables the identification of (differential localized) N-terminal proteoforms raised upon alternative translation.

Does choice of athletic footwear affect musculoskeletal injury risk in US Coast Guard recruits? A retrospective cohort study.

Context: Musculoskeletal injuries (MSKIs) are ubiquitous during initial entry military training, with overuse injuries in the lower extremities the most frequent. A common mechanism for overuse injuries is running, an activity that is an integral part of United States Coast Guard (USCG) training and a requirement for graduation. Objective: Assess the effects of athletic footwear choice on lower quarter MSKI risk in USCG recruits. Design: Descriptive Epidemiological Study Setting: USCG Training Center, Cape May, NJ Participants: A retrospective cohort study was performed in which 1229 recruits (1038 males, 191 females) were allowed to self-select athletic footwear during training. A group of 2876 recruits (2260 males, 616 females) who trained under a policy that required obligatory wear of prescribed athletic shoes served as a control. Main Outcome Measures: Demographic data and physical performance were derived from administrative records. Injury data were abstracted from a medical tracking database. Multivariable logistic regression was used to assess group, age, sex, height, body mass, and run times on MSKI outcomes. Results: Ankle-foot, leg, knee and lumbopelvic-hip complex diagnoses were ubiquitous in both groups (experimental: 20.37 to 29.34 per 1000 recruits; control: 18.08 to 25.59 per 1000 recruits). Group was not a significant factor for any of the injuries assessed. Sex was a significant factor in all injury types, with female recruits demonstrating ~2.00 greater odds of experiencing running-related injuries (RRIs), overuse injuries, or any MSKI in general. When considering ankle-foot or bone stress injuries, the risk in female recruits was 3.73 to 4.11 greater odds than their male counterparts. Run time was a significant predictor in RRI, all overuse injuries, and for any MSKI in general. Conclusion: While footwear choice did not influence MSKI risk in USCG recruits, female sex was a primary, nonmodifiable intrinsic risk factor.

Receptor-Ribosome Coupling: A Link Between Extrinsic Signals and mRNA Translation in Neuronal Compartments

Axons receive extracellular signals that help to guide growth and synapse formation during development and to maintain neuronal function and survival during maturity. These signals relay information via cell surface receptors that can initiate local intracellular signaling at the site of binding, including local messenger RNA (mRNA) translation. Direct coupling of translational machinery to receptors provides an attractive way to activate this local mRNA translation and change the local proteome with high spatiotemporal resolution. Here, we first discuss the increasing evidence that different external stimuli trigger translation of specific subsets of mRNAs in axons via receptors and thus play a prominent role in various processes in both developing and mature neurons. We then discuss the receptor-mediated molecular mechanisms that regulate local mRNA translational with a focus on direct receptor-ribosome coupling. We advance the idea that receptor-ribosome coupling provides several advantages over other translational regulation mechanisms and is a common mechanism in cell communication. Expected final online publication date for the Annual Review of Neuroscience, Volume 45 is July 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

The entrepreneurial advantages of experiencing foreignness: leveraging shocks for capability clusters

Purpose Drawing on the “shocks to the system” concept in image theory, a mid-range theoretical model is developed to illuminate understanding on why cross-cultural experience is so conducive to stimulating entrepreneurship yet has remained largely unexplained at the individual level.Design/methodology/approach The novel idea is put forth that experience of foreignness, in itself, can be harnessed as a powerful cognitive resource for entrepreneurship – particularly the nascent stages of new venture development. Providing cross-cultural exposures arouse “self-image shocks”, they manifest over time as skill clusters that reflect the sensing, seizing and transforming capabilities at the heart of entrepreneurship. This paper's pivot helps delineate a common mechanism to explain how a diverse range of seemingly disparate cross-cultural experiences can be processed in a way that enhances entrepreneurial pursuits.Findings The insights of this paper reinforce the need for educators and policymakers to encourage and provide opportunities for aspiring entrepreneurs to engage in cross-cultural and overseas exposures as they are influential for stimulating each of the core sets of entrepreneurial capabilities. The model and synthesis table also help to practically unpack how to design and plan such cultural experiences to optimize the enduring entrepreneurial advantages.Originality/value The author turns a long-standing assumption surrounding cultural differences in entrepreneurship on its head. The shocks and tensions arising from intercultural interactions are not always inevitable liabilities to be “managed away” or attenuated. Rather, cross-cultural experience can be explicitly leveraged as an asset for nascent venturing as the juxtapositions they evoke provide both proximal and distal enhancements to ways in which entrepreneurs think and develop skills at the core of venturing.

Structural Basis of Antibody Conformation and Stability Modulation by Framework Somatic Hypermutation

Accumulation of somatic hypermutation (SHM) is the primary mechanism to enhance the binding affinity of antibodies to antigens in vivo. However, the structural basis of the effects of many SHMs remains elusive. Here, we integrated atomistic molecular dynamics (MD) simulation and data mining to build a high-throughput structural bioinformatics pipeline to study the effects of individual and combination SHMs on antibody conformation, flexibility, stability, and affinity. By applying this pipeline, we characterized a common mechanism of modulation of heavy-light pairing orientation by frequent SHMs at framework positions 39H, 91H, 38L, and 87L through disruption of a conserved hydrogen-bond network. Q39LH alone and in combination with light chain framework 4 (FWR4L) insertions further modulated the elbow angle between variable and constant domains of many antibodies, resulting in improved binding affinity for a subset of anti-HIV-1 antibodies. Q39LH also alleviated aggregation induced by FWR4L insertion, suggesting remote epistasis between these SHMs. Altogether, this study provides tools and insights for understanding antibody affinity maturation and for engineering functionally improved antibodies.

Refining the Pediatric Multiple Organ Dysfunction Syndrome

Since its introduction into the medical literature in the 1970s, the term multiple organ dysfunction syndrome (or some variant) has been applied broadly to any patient with >1 concurrent organ dysfunction. However, the epidemiology, mechanisms, time course, and outcomes among children with multiple organ dysfunction vary substantially. We posit that the term pediatric multiple organ dysfunction syndrome (or MODS) should be reserved for patients with a systemic pathologic state resulting from a common mechanism (or mechanisms) that affects numerous organ systems simultaneously. In contrast, children in whom organ injuries are attributable to distinct mechanisms should be considered to have additive organ system dysfunctions but not the syndrome of MODS. Although such differentiation may not always be possible with current scientific knowledge, we make the case for how attempts to differentiate multiple organ dysfunction from other states of additive organ dysfunctions can help to evolve clinical and research priorities in diagnosis, monitoring, and therapy from largely organ-specific to more holistic strategies.

Transmembrane 29 (Tmem29), a Newly Identified Molecule Showed Downregulation in Hypoxic-Ischemic Brain Damage

Transmembrane 29 (Tmem29) gene with unknown function is a gene located on the X chromosome of the mouse genome. The gene showed differential expression in the Vannucci neonatal hypoxic-ischemic mouse brain model. We found the gene expresses with different molecular forms, including a group of long non-coding RNA forming a family of transcripts. It was predominantly expressed in the testes, brain, and kidney of mouse. In vitro identification and functional characterization were carried out in Neuro2a cells. Using fluorescence microscopy, Tmem29 protein was found to be constitutively expressed in mouse cell lines of different origins. Oxygen glucose deprivation (OGD) induced apoptotic cell death in Neuro2a cells and was confirmed by activations of caspase 3. Tmem29 protein was found to be associated with cell death especially at the time points of caspase 3 activations. A similar response was obtained in glucose deprivation (GD) cultures suggesting Tmem29 response to a common mechanism induced by OGD and GD. Downregulation of Tmem29 was induced by OGD and GD, further validating its response to hypoxia-ischemia (HI) insults. Our findings contributed to further understanding of molecular events after hypoxic-ischemic insults and opens new avenues for developing protective and therapeutic strategies for hypoxic-ischemic encephalopathy or even pathological programmed cell death.