Consensus Paper: Language and the Cerebellum: an Ongoing Enigma

In less than three decades, the concept “cerebellar neurocognition” has evolved from a mere afterthought to an entirely new and multifaceted area of neuroscientific research. A close interplay between three main strands of contemporary neuroscience induced a substantial modification of the traditional view of the cerebellum as a mere coordinator of autonomic and somatic motor functions. Indeed, the wealth of current evidence derived from detailed neuroanatomical investigations, functional neuroimaging studies with healthy subjects and patients and in-depth neuropsychological assessment of patients with cerebellar disorders shows that the cerebellum has a cardinal role to play in affective regulation, cognitive processing, and linguistic function. Although considerable progress has been made in models of cerebellar function, controversy remains regarding the exact role of the “linguistic cerebellum” in a broad variety of nonmotor language processes. This consensus paper brings together a range of different viewpoints and opinions regarding the contribution of the cerebellum to language function. Recent developments and insights in the nonmotor modulatory role of the cerebellum in language and some related disorders will be discussed. The role of the cerebellum in speech and language perception, in motor speech planning including apraxia of speech, in verbal working memory, in phonological and semantic verbal fluency, in syntax processing, in the dynamics of language production, in reading and in writing will be addressed. In addition, the functional topography of the linguistic cerebellum and the contribution of the deep nuclei to linguistic function will be briefly discussed. As such, a framework for debate and discussion will be offered in this consensus paper.     

Developing the “120 by 20” Goal for the Global FP2020 Initiative

This report describes the purpose for developing a quantitative goal for the London Summit on Family Planning held in July 2012, the methodology behind its formulation, and the lessons learned in the process. The London Summit has evolved into the global initiative known as FP2020, and the goal has become “120 by 20,” or reaching 120 million additional users of modern contraceptive methods by 2020 in the world's poorest countries. The success of FP2020 will first be evaluated on the basis of quantitative verification to determine that the “120 by 20” goal was reached. More important, however, is the extent to which the goal today serves as a global rallying cry to mobilize resources and leadership around current family planning programs, with a focus on voluntary family planning and quality of care, and with an emphasis on meeting girls' and women's unmet needs and their right to practice contraception. We hope this article provides greater transparency and understanding of the FP2020 goal, and that the global goal spurs annual monitoring of progress toward national goals in the world's poorest countries.     

Preparation,Optimization and Characterization of Bovine Lactoferrin‐loaded Liposomes and Solid Lipid Particles Modified by Hydrophilic Polymers Using Factorial Design

Bioadhesive liposomes and solid lipid particles (SLPs) modified by pectin and chitosan for oral administration of bovine lactoferrin (bLf) were prepared using a 2⁴ full‐factorial design to identify the key formulation variables influencing particle size and drug entrapment efficiency (EE). Netlike structures of the polymer–particle mixture consisting of a polymeric network in which multiple particles were imbedded were observed by scanning electron microscopy (SEM). Chemical stability of bLf after encapsulation into pectin‐ and chitosan‐modified liposomes and SLPs was confirmed by Fourier transform infrared spectra (FTIR). Bovine lactoferrin was located within phospholipid bilayer, whereas in SLPs bLf was within the matrix. The crystalline nature of bLf after encapsulation was investigated by differential scanning calorimetry (DSC) of drug‐loaded particles, indicating amorphous dispersion of bLf in the polymer–lipid matrix of pectin‐ and chitosan‐modified liposomes and SLPs. In vivo pharmacokinetic investigation of bLf in pectin‐ and chitosan‐modified liposomes and SLPs showed prolonged mean residence time (MRT) of bLf in rat blood and increased the relative bioavailability (F_bio%) by 1.95‐ to 2.69‐fold compared with free bLf. The developed carrier systems are considered to be promising vehicles for oral delivery.     

International Tuberculosis Laboratory Consulting

Improving tuberculosis (TB) laboratory test capacity internationally is essential to combat the increasing prevalence of drug-resistant TB in many countries throughout the world, which poses a direct public health threat to the United States. Microbiologists from the U.S. who plan to serve as consultants to assist in improving TB laboratories in resource-challenged countries should prepare for such work using available resources that are readily available from the Centers for Disease Control and Prevention, as well as the Global Laboratory Initiative of the World Health Organization (WHO). Identifying and networking with potential collaborators in various countries can help ensure success. Consultants should also become familiar with WHO-recommended TB laboratory test methods, available training programs, and tools for laboratory accreditation.     

Genome-wide nucleosome map and cytosine methylation levels of an ancient human genome

Epigenetic information is available from contemporary organisms, but is difficult to track back in evolutionary time. Here, we show that genome-wide epigenetic information can be gathered directly from next-generation sequence reads of DNA isolated from ancient remains. Using the genome sequence data generated from hair shafts of a 4000-yr-old Paleo-Eskimo belonging to the Saqqaq culture, we generate the first ancient nucleosome map coupled with a genome-wide survey of cytosine methylation levels. The validity of both nucleosome map and methylation levels were confirmed by the recovery of the expected signals at promoter regions, exon/intron boundaries, and CTCF sites. The top-scoring nucleosome calls revealed distinct DNA positioning biases, attesting to nucleotide-level accuracy. The ancient methylation levels exhibited high conservation over time, clustering closely with modern hair tissues. Using ancient methylation information, we estimated the age at death of the Saqqaq individual and illustrate how epigenetic information can be used to infer ancient gene expression. Similar epigenetic signatures were found in other fossil material, such as 110,000- to 130,000-yr-old bones, supporting the contention that ancient epigenomic information can be reconstructed from a deep past. Our findings lay the foundation for extracting epigenomic information from ancient samples, allowing shifts in epialleles to be tracked through evolutionary time, as well as providing an original window into modern epigenomics.Ancient DNA research started in the mid-1980s with the successful cloning and sequencing of a short mitochondrial DNA fragment from the quagga zebra, a species that became extinct in the early 20th century (Higuchi et al. 1984). Soon after, the invention of PCR unlocked access to this fragmented and degraded DNA material (Pääbo 1989), making it possible to amplify short gene markers of interest and compare their sequence to that from extant organisms. This illuminated a range of topics ranging from the reconstruction of the evolutionary origins of several now-extinct iconic mammals (Orlando et al. 2003; Krause et al. 2006), the evaluation of the possible role played by major past climatic changes in driving mega-fauna extinctions (Shapiro et al. 2004; Campos et al. 2010; Lorenzen et al. 2011), to the identification of the pathogens responsible for massive historical outbreaks (Taubenberger et al. 1997).However, before the advent of next-generation sequencing (NGS) platforms, the amount of ancient sequence information one had access to was limited to several tens of thousands of nucleotides at best (Noonan et al. 2005, 2006), and until very recently, sequencing whole ancient mitochondrial genomes was considered a major achievement (Cooper et al. 2001; Krause et al. 2006). Parallel sequencing of millions to billions of short DNA fragments has revolutionized ancient DNA research, and today a series of ancient genomes has been reconstructed from humans (Rasmussen et al. 2010, 2011; Keller et al. 2012; Raghavan et al. 2013), archaic hominins (Green et al. 2010; Reich et al. 2010; Meyer et al. 2012), the woolly mammoth (Miller et al. 2008), and several microbial pathogens (Bos et al. 2011; Martin et al. 2013; Schuenemann et al. 2013; Yoshida et al. 2013). Those mainly date back to recent historical periods or the Late Pleistocene, but most recently, the characterization of a 560,000- to 780,000-yr-old horse draft genome revealed that genomic information could be retrieved over much longer evolutionary time scales, probably up until the last million years (Orlando et al. 2013).Ancient genomes have provided important new insights into human evolution and dispersals (Rasmussen et al. 2010, 2011; Keller et al. 2012; Raghavan et al. 2013), revealing an admixture between contemporary human ancestors and archaic hominins (Green et al. 2010; Reich et al. 2010; Meyer et al. 2012) and multiple early human expansions into both Asia and North America (Rasmussen et al. 2010, 2011). The information gained from these samples has largely been limited to nucleotide polymorphisms. Unlike mutations, epigenetic modifications do not alter the underlying DNA sequence, but can be inherited across cell divisions and from parents to offspring and can control gene expression by reshaping cytosine methylation landscapes, nucleosome organization, and histone modification patterns. The range of biological processes that depend on some level of epigenetic regulation is diverse and includes imprinting (Bird 2002), transposition (Hollister and Gaut 2009), cell differentiation (Meissner et al. 2008), and cancer (Teschendorff et al. 2011). In this study, we use the Saqqaq genome that was retrieved from an ∼4000-yr-old tuft of hair of a Paleo-Eskimo from Greenland and sequenced to an average depth of 20× (Rasmussen et al. 2010). We demonstrate that NGS data can be used in the absence of bisulfite or further experimental treatment to directly infer genome-wide nucleosome organization and regional methylation levels, thereby providing the first survey of an ancient epigenome.     

Singapore Neonatal Resuscitation Guidelines 2021

Neonatal resuscitation is a coordinated, team-based series of timed sequential steps that focuses on a transitional physiology to improve perinatal and neonatal outcomes. The practice of neonatal resuscitation has evolved over time and continues to be shaped by emerging evidence as well as key opinions. We present the revised Neonatal Resuscitation Guidelines for Singapore 2021. The recommendations from the International Liaison Committee on Resuscitation Neonatal Task Force Consensus on Science and Treatment Recommendations (2020) and guidelines from the American Heart Association and European Resuscitation Council were compared with existing guidelines. The recommendations of the Neonatal Subgroup of the Singapore Resuscitation and First Aid Council were derived after the work group discussed and appraised the current available evidence and their applicability to local clinical practice.     

Proof of concept study to develop a novel connectivity-based electric-field modelling approach for individualized targeting of transcranial magnetic stimulation treatment

Resting state functional connectivity (rsFC) offers promise for individualizing stimulation targets for transcranial magnetic stimulation (TMS) treatments. However, current targeting approaches do not account for non-focal TMS effects or large-scale connectivity patterns. To overcome these limitations, we propose a novel targeting optimization approach that combines whole-brain rsFC and electric-field (e-field) modelling to identify single-subject, symptom-specific TMS targets. In this proof of concept study, we recruited 91 anxious misery (AM) patients and 25 controls. We measured depression symptoms (MADRS/HAMD) and recorded rsFC. We used a PCA regression to predict symptoms from rsFC and estimate the parameter vector, for input into our e-field augmented model. We modeled 17 left dlPFC and 7 M1 sites using 24 equally spaced coil orientations. We computed single-subject predicted ΔMADRS/HAMD scores for each site/orientation using the e-field augmented model, which comprises a linear combination of the following elementwise products (1) the estimated connectivity/symptom coefficients, (2) a vectorized e-field model for site/orientation, (3) rsFC matrix, scaled by a proportionality constant. In AM patients, our connectivity-based model predicted a significant decrease depression for sites near BA9, but not M1 for coil orientations perpendicular to the cortical gyrus. In control subjects, no site/orientation combination showed a significant predicted change. These results corroborate previous work suggesting the efficacy of left dlPFC stimulation for depression treatment, and predict better outcomes with individualized targeting. They also suggest that our novel connectivity-based e-field modelling approach may effectively identify potential TMS treatment responders and individualize TMS targeting to maximize the therapeutic impact.Subject terms: Cognitive control, Depression